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World Journal of Clinical CasesWorld J Clin Cases 2018 September 6; 6(9): 233-307

ISSN 2307-8960 (online)

World Journal ofClinical CasesW J C C

Contents Semimonthly Volume 6 Number 9 September 6, 2018

IWJCC|www.wjgnet.com September 6, 2018|Volume 6|Issue 9|

MINIREVIEWS233 HepatitisBvirus-persistentinfectionandinnateimmunitydefect:Cell-relatedorvirus-related?

Tang J, Wu ZY, Dai RJ, Ma J, Gong GZ

242 Diagnosticvalueofimagingexaminationsinpatientswithprimaryhepatocellularcarcinoma

Li XH, Liang Q, Chen TW, Wang J, Zhang XM

ORIGINAL ARTICLE

Basic Study249 Impactofsorafenibonepiduralfibrosis:Animmunohistochemicalstudy

Tanriverdi O, Erdogan U, Tanik C, Yilmaz I, Gunaldi O, Adilay HU, Arslanhan A, Eseoglu M

SYSTEMATIC REVIEWS259 Conversiontherapyandsuitabletimingforsubsequentsalvagesurgeryforinitiallyunresectable

hepatocellularcarcinoma:Whatisnew?

Zhang ZF, Luo YJ, Lu Q, Dai SX, Sha WH

CASE REPORT274 Unexpectedcomplicationduringextracorporealmembraneoxygenationsupport:Ventilatorassociated

systemicairembolism

Ryu SM, Park SM

279 Chroniccarpaltunnelsyndromecausedbycoverttophaceousgout:Acasereport

Luo PB, Zhang CQ

284 Casereportandreviewoftheliteratureofprimarygastrointestinalamyloidosisdiagnosedwith

enteroscopyandendoscopicultrasonography

Liu YP, Jiang WW, Chen GX, Li YQ

291 Acetaminophen-inducedacutepancreatitis:Acasereportandliteraturereview

He YH, Lu L, Wang YF, Huang JS, Zhu WQ, Guo Y, Li CX, Li HM

296 Polycystickidneyandhepaticdisease1genemutationsinvonMeyenburgcomplexes:Casereport

Lin S, Shang TY, Wang MF, Lin J, Ye XJ, Zeng DW, Huang JF, Zhang NW, Wu YL, Zhu YY


Contents Semimonthly Volume 6 Number 9 September 6, 2018

IIWJCC|www.wjgnet.com September 6, 2018|Volume 6|Issue 9|

301 Clivalmetastasisofrenalclearcellcarcinoma:Casereportandliteraturereview

Zhang WQ, Bao Y, Qiu B, Wang Y, Li ZP, Wang YB

ContentsWorld Journal of Clinical Cases

Volume 6 Number 9 September 6, 2018

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Xiang Li Responsible Science Editor: Fang-Fang Ji Responsible Electronic Editor: Wen-Wen Tan Proofing Editorial Office Director: Jin-Lei WangProofing Editor-in-Chief: Lian-Sheng Ma

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IIIWJCC|www.wjgnet.com

ABOUT COVER

AIM AND SCOPE

INDExING/ABSTRACTING

September 6, 2018|Volume 6|Issue 9|

NAMEOFJOURNALWorld Journal of Clinical Cases

ISSNISSN 2307-8960 (online)

LAUNCHDATEApril 16, 2013

FREQUENCYSemimonthly

EDITORS-IN-CHIEFSandro Vento, MD, Department of Internal Medicine, University of Botswana, Private Bag 00713, Gaborone, Botswana

EDITORIALBOARDMEMBERSAll editorial board members resources online at http://www.wjgnet.com/2307-8960/editorialboard.htm

EDITORIALOFFICEJin-Lei Wang, Director

EditorialBoardMemberofWorldJournalofClinicalCases ,StevenMSchwarz,

MD,Professor,DepartmentofPediatrics,Children'sHospitalatDownstate,SUNY-

DownstateMedicalCenter,Brooklyn,NY11203,UnitedStates

World Journal of Clinical Cases (World J Clin Cases, WJCC, online ISSN 2307-8960, DOI: 10.12998) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians.

The primary task of WJCC is to rapidly publish high-quality Autobiography, Case Re-port, Clinical Case Conference (Clinicopathological Conference), Clinical Management, Diagnostic Advances, Editorial, Field of Vision, Frontier, Medical Ethics, Original Ar-ticles, Clinical Practice, Meta-Analysis, Minireviews, Review, Therapeutics Advances, and Topic Highlight, in the fields of allergy, anesthesiology, cardiac medicine, clinical genetics, clinical neurology, critical care, dentistry, dermatology, emergency medicine, endocrinol-ogy, family medicine, gastroenterology and hepatology, geriatrics and gerontology, he-matology, immunology, infectious diseases, internal medicine, obstetrics and gynecology, oncology, ophthalmology, orthopedics, otolaryngology, pathology, pediatrics, peripheral vascular disease, psychiatry, radiology, rehabilitation, respiratory medicine, rheumatology, surgery, toxicology, transplantation, and urology and nephrology.

World Journal of Clinical Cases (WJCC)is now indexed in PubMed, PubMed Central, Science Citation Index Expanded (also known as SciSearch®), and Journal Citation Reports/Science Edition. The 2018 Edition of Journal Citation Reports cites the 2017 impact factor for WJCC as 1.931 (5-year impact factor: N/A), ranking WJCC as 60 among 154 journals in Medicine, General and Internal (quartile in category Q2).

Received: April 3, 2018Peer-review started: April 3, 2018First decision: May 29, 2018Revised: July 31, 2018Accepted: August 6, 2018Article in press: August 7, 2018Published online: September 6, 2018

AbstractThe outcomes of hepatitis B virus (HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be self-limited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Further-more, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Key words: Hepatitis B virus; Innate immunity; Immune evasion; Pattern recognition receptor; Toll-like receptor;

Jian Tang, Zhen-Yu Wu, Rong-Juan Dai, Jing Ma, Guo-Zhong Gong

MINIREVIEWS

233 September 6, 2018|Volume 6|Issue 9|WJCC|www.wjgnet.com

Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

Jian Tang, Zhen-Yu Wu, Jing Ma, Guo-Zhong Gong, Department of Infectious Disease, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China

Rong-Juan Dai, Department of Infectious Disease, the First Affiliated Hospital of University of South China, Hengyang 421001, Hunan Province, China

ORCID number: Jian Tang (0000-0001-5345-3028); Zhen-Yu Wu (0000-0003-4478-0734); Rong-Juan Dai (0000-0001-9455-8328); Jing Ma (0000-0001-8925-7686); Guo-Zhong Gong (0000-0002-1824-1625).

Author contributions: Tang J, Wu ZY and Gong GZ wrote the manuscript; Dai RJ and Ma J performed critical revision and editing of the manuscript; all authors gave approval of the final version.

supported by Natural Science Foundation of China, No. 81500455.

Conflict-of-interest statement: The authors have no conflict of interest to declare.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invited manuscript

Correspondence to: Guo-Zhong Gong, PhD, Professor, Department of Infectious Disease, the Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Changsha 410011, Hunan Province, China. [email protected]: +86-731-85292105 Fax: +86-731-85292173

Submit a Manuscript: http://www.f6publishing.com

DOI: 10.12998/wjcc.v6.i9.233

World J Clin Cases 2018 September 6; 6(9): 233-241



Natural killer cells; Kupffer cells; Dendritic cells

© The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: This review covers the following core concepts of hepatitis B virus (HBV) persistence, according to the most up-to-date literature: Hepatocytes lack immune responsiveness to HBV; Innate immune cells display weak responses at the early stages of HBV infection; HBV impairs functions of innate immune cells and select signaling pathways to evade immune recognition and response.

Tang J, Wu ZY, Dai RJ, Ma J, Gong GZ. Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related? World J Clin Cases 2018; 6(9): 233-241 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/233.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.233

INTRODUCTIONHepatitis B virus (HBV) infection remains a global health concern, as about 257 million people worldwide are chronically infected with HBV currently[1]. Although the HBV infection rate has been partly controlled by various prophylaxis strategies, researchers have yet to discover a cure for chronic HBV infection. Chronic hepatitis B (CHB) is typically asymptomatic, but harbors the potential for development of life-threatening complications[2]. To overcome this threat, the mechanisms of HBV infection that underlie progression to chronicity need to first be fully elucidated.

HBV, a member of hepadnavirus family, acts as a “stealth” virus, not inducing any obvious innate immune responses in the early stage of infection[3]. Furthermore, the target cells (hepatocytes) do not recognize HBV efficiently through known signaling pathways, indicating the possibility of an HBV immune evasion mechanism[4]. HBV also has the ability to suppress functions of innate immune cells[5-7]. HBV interaction with innate immunity would suggest that HBV persistence is related to a multitude of host and viral factors.

Herein, we summarize the recent knowledge regarding HBV persistence and the evidenced and theorized relations with intrahepatocyte signaling pathways and innate immune cells. Collation of such information will provide a useful overview of the field today, possibly providing new insights into novel therapeutic treatments for CHB.

Fundamentally, the innate immunity system res-ponds to viral infection in three phases. In the first phase, various sensors in the cytoplasm recognize pathogen-associated molecular patterns, such as for-eign DNA or RNA, and send a warning message to

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Tang J et al . HBV-persistent infection and innate immunity defect

initiate downstream signals. The second phase involves the proteins of the downstream signaling pathways transmitting the danger message to the nucleus, activating effector elements. In the last phase, the consequently up-regulated effectors [i.e., inflammatory factors or interferon (IFN)-stimulating genes] degrade the exogenous viral elements. Defect or suppression of the involved sensors and signaling pathways tends to result in persistent existence of HBV in the host, since, under such circumstances, HBV cannot be recogni-zed and eliminated in a timely manner. We will begin this review by discussing several intra-hepatocelluar pathways that are closely related to HBV recognition and which exert an anti-HBV effect.

HEPATOCYTES LACK IMMUNE

RESPONSIVENESS TO HBV Pattern recognition receptorsPattern recognition receptors (PRRs) are the major sensors of exogenous pathogens, and they include the Tolllike receptors (TLRs), retinoic acidinducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MAD5)[8]. These molecules are able to recognize diverse pathogenassociated common loci of specific pathogens, subsequently activating downstream signaling pathways that induce IFNs and inflammatory factors to control virus replication[9]. However, a recent study of liver tis-sues from CHB patients found that hepatocytes do not respond to HBV, even though they were able to produce IFNs and induce expression of IFN-stimulating genes when stimulated by other infection-related factors, such as those related to TLR3 binding and Sendai virus infection. This finding suggested that HBV is invisible to PRRs on hepatocytes[10].

Stimulator of IFN genes Stimulator of IFN genes (STING) serves as the adaptor protein of multiple cytoplasmic DNA receptors that recognize exogenous pathogens[11]. It has been repor-ted that cytoplasmic DNA-activated cyclic GMP-AMP synthase (commonly known as cGAS) binds to STING, thereby inducing secretion of type Ⅰ IFN and other cytokines[12]. This pathway is of great importance for eukaryotes (eukaryotic cells) to defend against bacterial, viral and other eukaryotic pathogens[11].

In vivo and in vitro experiments have shown that STING is NOT expressed in human hepatocytes, which might explain the dysfunction of DNA sensing[4]. Hence, HBV DNA may have adapted to this particular “biological niche”, whereby it can escape immune detection. More interestingly, cGAMP is able to induce a robust cytokine response in a HBV-infected C3AhNTCP hepatoma cell line if added in cell culture, suggesting its capacities of in-hibiting HBV replication[13].



INNATE IMMUNE CELLS HAVE WEAK RESPONSIVENESS TO HBVNatural killer cellsNatural killer (NK) cells constitute 30%40% of the intrahepatic lymphocytes, and are believed to play an indispensable role in HBV clearance. The NK cells exert their direct antiviral effects via secretion of IFN-γ, tumor necrosis factor (TNF)-α, granulocyte-macrophage stimulating factor, interleukin (IL)10 and transforming growth factor-β to inhibit HBV replication or stimulate killing of infected cells[14,15]. However, studies of the functions of NK cells in early HBV infection have produced controversial results.

In the woodchuck model of acute hepatitis B, NK cells are activated within 48-72 h after infection, consequently leading to a transient reduction of HBV replication; but, this activation is unable to induce a timely adaptive T cell response[16]. Further, in chimpanzee models with self-limited HBV infection, NK cells do not become activated until the major histocompatibility complex-restricted α/β T cells enter the liver and recognize antigen; the Tspecific cells, for the most part, carry out the clearance of HBV[3]. Since these studies were carried out in animal models, it remains unclear to what extent the results mirror the human molecular processes.

In fact, the function of NK cells in early human HBV infection has proven very difficult to determine because the time frame from infection to diagnosis is typically more than 1012 wk[17]. Regardless of how the NK cells function in this process, Tspecific cells are the primary cell-types responsible for HBV clearance. Thus, the inaction of NK cells, along with immature or coincidently impaired functions of T cells, may explain how HBV infection progresses to chronicity.

In addition, in human CHB, immune responses of NK cells are known to be altered. These alterations include impaired cytolytic activity[18] and up-regulation of antiviral T cell death receptors, the latter of which renders the cell susceptible to targeting for destruc-tion by host mechanisms[19]. Given that several studi-es have demonstrated that activated NK cells and T cells can cause liver damage[20-23], the defective NK cells’ functions and the NK cellmediated disarming of T-specific cells might be protective for hepatocytes while simultaneously contributing to HBV persistence.

Kupffer cells Kupffer cells (KCs) are macrophages residing in the liver sinusoids. Programmed to screen and clear pathog-ens that they engage, the KCs serve as scavengers. They produce pro and antiinflammatory cytokines, as well as other molecules known to have antipathogen activities. In the early phase of HBV infection, KCs directly interact with HBV and produce proinflammatory cytokines (i.e., IL6, TNFα and IFN-α) to elicit their antiviral effects[24,25]. Subsequently, NK cells and HBV

specific immunity are also activated to aid in eradication of the virus. While the interaction between KCs and hepatitis B surface antigen (HBsAg) is mostly dependent upon the TLRs[25,26], expression of TLR3 is found to be significantly decreased in CHB patients (compared to that in healthy controls); this aberrant expression may contribute to HBV chronicity.

Moreover, if HBV infection progresses to chronicity, the role of KCs will change, just as that of NK cells. The major cytokines secreted by KCs shift towards an antiinflammatory profile (i.e., increased IL10, which is known to contribute to the persistent existence of HBV in the host). In virus-persistent mouse models, stimulation of TLR2 by the hepatitis B core antigen leads to upregulation of IL10 secretion by KCs, with the ultimate detrimental exhaustion of anti-HBV CD8+ T cells[27]. IL10 suppresses not only T cellmediated specific immunity but also humoral immunity[28]. As such, KC depletion or IL10 deficiency will lead to restoration of CD8+ T cell function, breaking the cycle of humoral immune tolerance and allowing for clearance of the HBV[29]. Thus, the collective results in the literature have revealed that KC secretes IL10 in chronic HBV infection to disarm humoral and cellular immunity, which leads to HBV persistence.

Dendritic cells Dendritic cells (DCs) represent the most efficient professional antigen-presenting cell type. As such, although they reside universally throughout the body, their frequency accounts for less than 1% of the total peripheral blood mononuclear cells. Classified by expression of specific surface markers, the DCs are divided into several types, with those most frequently studied in chronic HBV infection being the plasmacytoid (p)DCs and the myeloid (m)DCs.

Besides antigen processing and presenting, the pDCs produce appreciable amounts of IFN-α, which serves to inhibit viral replication via the TLR7/9 signaling pathways, when stimulated. However, some studies have demonstrated that the frequency of pDCs is reduced in CHB patients (as compared with normal controls)[30-32], indicating that HBV persistence is associated with pDC reduction. This hypothesis, however, has been doub-ted following the finding of pDC frequency in CHB pa-tients being similar to that in healthy individuals[33-36]. Considering the rarity of pDCs in blood, it is likely that different experimental protocols account for the incon-sistencies among these findings.

Regardless of the frequencies, the functions of pDCs are indeed hampered in chronic HBV infection. Most studies have reported a significant reduction of IFN-α secretion from pDCs[6,30-34]. Notably, the level of IFN-α has been found to be negatively correlated with alanine aminotransferase levels[33]. This finding could reflect a mechanism of HBV immune evasion and persistence, and an immune regulatory role for pDCs in this infection.




Nevertheless, findings from an exceptional study led the authors to argue that pDC function was not impaired in chronic HBV infection[35]. The overall question remains unanswered.

mDCs are primarily responsible for inducing T cell differentiation and producing TNF-α. Unlike the pDCs, most studies on this cell type have found no difference in mDC frequency between CHB patients and healthy people[34-36]. Similar to the pDCs, however, it has been observed that the capacity of TNF-α production is impaired in mDCs when stimulated by HBV[34]. The other primary ability of mDCs, that of inducing T cell differentiation and proliferation, has not yet been de-fined in CHB patients.

HBV VIRUS-MEDIATED DISRUPTION OF THE HOST IMMUNOLOGICAL RESPONSE RIG-IHBV-induced type Ⅲ IFN expression depends on RIG-I[37]. A recent study has suggested that over-expressed RIG-I could dramatically reduce the levels of HBV mRNA and DNA in vitro[9]. More interestingly, RIG-I can directly exert antivirus function by preventing the HBV P protein from binding with the HBV pregeno-mic RNA 5’ stem-loop region[37]. MAD5 and RIG-I can recognize many viral RNAs, subsequently initiating downstream signaling pathways by up-regulating the adapter protein mitochondria-antiviral signaling protein [MAVS, also known as virusinduced signaling adaptor (VISA) and interferon promoter stimulator1 (IPS1)]. In turn, the IFN regulatory transcription factor 3 (IRF3) and nuclear factorkappa B (NFκB), two of the most important proinflammatory transcription factors, be-come activated[38]. It has been reported, however, that the quantity of MDA5 is obviously decreased in CHB patients (compared to healthy controls)[39]. Moreover, a recent study revealed that HBV-induced miR146a attenuated innate immunity through targeting of RIG-I and RIG-G[40].

TLRsIn rat models, TLR3 activation has been shown to result in the production of type Ⅰ IFN to control HBV rep-lication[41]. In mammalian cells, TLR2 and TLR4 share the MyD88-dependent signaling pathway, so that they mediate activation of the same downstream signaling pathways, including the NF-κB, MAPK and PI3k/Akt pathways. Ultimately, the production of proinflamma-tory cytokines (i.e., TNF-α and IL8) are upregulated in hepatocytes, to inhibit the HBV replication[42].

Intriguingly, lower expression of TLR2 has been observed in hepatocytes, KCs and peripheral monocytes of hepatitis B e antigen (HBeAg)-positive CHB patients (compared with that in HBeAg-negative CHB and con-trols)[43]. Further research found that this down-regu-lated expression correlated with the levels of plasma

HBsAg[44] and that HBsAg was able to selectively inhibit TLR2–induced IL12 production from human monocytes/macrophages in a dose-dependent manner[45]. HBeAg was also shown to specifically inhibit the TLRmediated activation of NF-κB and IFN-β[46].

MAVSMAVS is a downstream signaling pathway protein of RIGⅠ and MAD5. Localized in mitochondria[47], mitochondria-associated endoplasmic reticular membranes[48] and peroxisomes[49], the protein contains an N-terminal CARDlike domain and a Cterminal transmembrane domain, anchoring to the mitochondrial membrane[47]. RIG-I and MAD5 detect exogenous RNA in lymphocytes, subsequently communicating with the mitochondrial membrane and interacting with MAVS. Consequently, NF-κB and IRF3 become activated and induce IFN. Thus, MAVS is regarded as the central hub of the RIGIFN axis.

In the absence of MAVS, cells do not produce type Ⅰ or Ⅲ IFN or proinflammatory cytokines upon infection with RNA virus[47]. This result was recapitulated in MAVS knockout mice[50]. In addition, the HBV X protein mediates the degradation of MAVS by utilizing Lys(136) ubiquitin (directly on the MAVS protein), thereby suppressing the induction of IFN-γ[51] (Figure 1).

HBV-MEDIATED DYSFUNCTION OF INNATE IMMUNE CELLS HBV alters NK cell functionA study group found that the pDCNK cell crosstalk was suppressed by HBV[5], which might explain why the reaction of NK cells in early HBV infection is dull. Activation of NK cells is strongly dependent on IFNα produced by pDCs[52]. HBsAg and HBeAg were also found to impair NK cell function, through the downregulation of IFN-γ expression[7,53]. In CHB patients, IFN-γ production is declined, and restoration of the IFN-γ-producing capacity is achievable after viral load reduction[54]. Consequently, the antiviral capacity of NK cells is compromised in chronic HBV infection[55-58]. In addition, HBV can stimulate generation of suppressive monocytes to initiate regulatory NK cell differentiation, resulting in T cell inhibition[59].

HBV suppresses the function of TLRs in KCsAs mentioned above, KCs’ ability to combat HBV infection mainly depends on expression of TLRs, but HBV itself can develop the ability to suppress TLRmediated innate immune responses in the liver[26,60]. Accordingly, HBV replication will be controlled when TLRs are stimulated by agonists; the effective TLRs that potently inhibit HBV replication have been identified as TLR3 and TLR4[41]. In addition, the expression of TLR3 displays restoration after antiviral therapy[61] and hepa-tic HBV infection triggers a TLR3dependent immune responses in the absence of HBsAg[62]. Thus, HBsAg




might be at the center of the yet-to-be-defined HBV evasion mechanism.

HBV hampers secretion of antiviral cytokines from DCsHBV lacks the capacity to activate pDCs, and many studies have also revealed that HBV could be able to inhibit IFN-α secretion from these cells[6,30-34]. Similarly, HBV can also reduce TNF-α production by mDCs[34]. Thus, HBV-mediated impairment of functions of both pDCs and mDCs suggests a potential mechanism of HBV persistence; but, the mechanism by which HBV induces such dysfunction remains elusive.

NOVEL THERAPEUTIC STRATEGIES THAT BOOST INNATE IMMUNITYCurrently, the most frequently applied strategy of CHB treatment is PEG-IFN-α/nucleoside analogs (NA) combination which works quite well. However, if altered NK cell functions are corrected, the outcome of the drug combination could possibly be improved. As described above, the functions and number of innate immune cells such as NK cells, KCs and DCs can be impaired in chronic HBV infection. Thus, replacing, restoring or boosting the functions of innate immune cells can be potential therapeutic targets for viral load reduction and further, HBV clearance. And in return, once viral load

reduction is achieved, the antiviral capacities of innate immune cells often restore.

IFN-γ is able to inhibit the HBV replication within hepatocytes in the absence of immune cells[63]. Given that IFN-γproducing capacity of NK cells restores after viral load reduction, it seems to be a positivefeedback when IFN-γ is used in HBV infection. What’s more, compared with IFN-α, IFN-γ serves as efficient as IFNα but causes less side effects[64]. However, how IFN-γ combat HBV independent from immune cells remains unclear.

Agents enhancing the recognition of HBV could be used to wipe out HBV in the early stages of infection. Some known PRR agonists and TLR agonists could trigger a series of reaction in infected hepatocytes via IRF or NFκB pathways; since PRRs and TLRs are abundantly expressed in innate immune cells, such agonists are capable of rendering immune cells more powerful in recognizing HBV, thus contributing to early HBV clearance[65,66]. Vesatolimod (GS9620), an oral TLR7 agonist, which was already involved in the 2nd phase clinical trial, was surprisingly found to be able to cause dose-dependent pharmacodynamic induction of ISG15 and a significant increase of serum cytokines[67].

Stimulation of certain innate immune cells to produce direct antiviral cytokines is another theoretical way to fight against human CHB. But in CHB patients,

NK cell

IFN-α

Kupffer cell

IFN-α

pDC

HBeAgHBsAg

HBxAgUpregulate/activate

Downregulate/suppress

Defective pathwayssTING

MAVs

HBV

IFNR

cGAs

HBV DNAIFN-α

ER

HBV

TLR2

TLR4

MyD88 MAPK and PI3K/AKT

IKKs

NF-κB

IRF3

HBV infected hepatocyte

TLR3

IRF3 Mitochrondrial

IsG

TNF-αIL-8

HBV DNA

RIG-Im

iR146a

PproteinpgRNA

5' ε

Figure 1 Relationships between hepatitis B virus and innate immunity system. NK cell: Nature killer cell; IFN-α: Interferon-α; IFNR: Interferon receptor; HBV: Hepatitis B virus; cGAS: Cyclic GMP-AMP synthase; TLRs: Toll-like receptors; pDC: Plasmacytoid dendritic cells; MyD88: Myeloid differentiation primary response 88; MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidylinositol-3 kinase; NF-κB: Nuclear factor-kappa B; IRF3: IFN regulatory transcription factor 3; ER: Endoplasmic reticulum; TNF-α: Tumor necrosis factor alpha; IL8: Interleukin 8; RIG1: Retinoic acid-inducible gene Ⅰ.




there is a balance between antiviral activity and anti-inflammatory activity. It is unknown whether the agents would break the balance and what consequences they would bring (Table 1).

CONCLUSIONThe crosstalk between innate immunity and HBV persistence has been a controversial topic for a num-ber of years. The collective findings we present in this review demonstrate that HBV is able to hamper innate immunity in many ways, and even to alter the functions of innate immune cells in order to suppress specific immune responses. This partly explains why HBV manages to progress to chronicity and to exist persistently. We hope the field will build upon these insights, leading to a deeper and more comprehensive understanding of HBV persistence and the role of innate immunity. Such knowledge will serve as a foundation for future development of effective immunomodulation treatment for chronic HBV infection. Indeed, therapeutic strategies that aim to restore innate immune respon-ses may represent remarkably potent tools for reducing HBV chronicity and, further, for eradicating HBV infection.

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Table 1 Cytokines and factors implicated in causing inflammation in atherosclerosis

Cytokines/factors Abbreviations

Hepatitis B virus HBVChronic hepatitis B CHBInterferon IFNPattern recognition receptors PRRsToll-like receptors TLRsMelanoma differentiation-associated gene 5 MAD5Retinoic acid-inducible gene I RIG IStimulator of IFN genes STINGCyclic GMP-AMP synthase cGASHuman sodium taurocholate cotransporting polypeptide hNTCPNatural killer cell NK cellTumor necrosis factor TNFInterleukin ILKupffer cells KCsDendritic cells DCsPlasmacytoid dendritic cells pDCMyeloid dendritic cells mDCMitochondria-antiviral signaling protein MAVSVirus-induced signaling adaptor VISANucleoside analogs NA




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P- Reviewer: Chiu KW, Goral V, Hashimoto N S- Editor: Ji FF L- Editor: A E- Editor: Tan WW



Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China. [email protected]: +86-817-2262218Fax: +86-817-2222856

Received: April 27, 2018Peer-review started: April 27, 2018First decision: May 23, 2018Revised: July 5, 2018Accepted: August 1, 2018Article in press: August 1, 2018Published online: September 6, 2018

AbstractPrimary hepatocellular carcinoma (PHC) includes hepa-tocellular carcinoma, intrahepatic cholangiocarcinoma and other pathological types and is characterized by rapid progression. Most of the clinical diagnoses are made at late stage or when distant metastasis occurs, increasing the difficulty of treatment and resulting in a poor prognosis. Therefore, the early diagnosis of PHC plays an important role in timely treatment and the improvement of prognosis. The gold standard for the diagnosis of primary liver cancer is liver biopsy, but it has limitations as an invasive examination. Presently, imaging has become the first choice for the diagnosis of liver cancer. We here summarize the new methods and techniques of imaging in diagnosis and evaluation of primary liver cancer in recent years, including ultra-sonography, computed tomography perfusion imaging, diffusion-weighted imaging technology-voxel incoherent motion, diffusion tensor imaging, iterative decomposition of water and fat with echo asymmetry and least squa-res estimation-iron quantification, dynamic enhanced magnetic resonance imaging and hepatocyte-specific contrast medium imaging. Imaging diagnosis can not only evaluate the degree of differentiation, blood supply and perfusion, and invasiveness of the lesion, but also predict the prognosis, evaluate liver function, and

Xing-Hui Li, Qi Liang, Tian-Wu Chen, Jian Wang, Xiao-Ming Zhang

MINIREVIEWS


Diagnostic value of imaging examinations in patients with primary hepatocellular carcinoma

Xing-Hui Li, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China

Xing-Hui Li, Jian Wang, Department of Radiology, Southwest Hospital of Army Medical University, Chongqing 400038, China

Qi Liang, Department of Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China

Tian-Wu Chen, Xiao-Ming Zhang, Sichuan Key Laboratory of Medical Imaging, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China

ORCID number: Xing-Hui Li (0000-0002-6351-3677); Qi Liang (0000-0002-7134-8210); Tian-Wu Chen (0000-0002-0759-6383); Jian Wang (0000-0001-9173-2538); Xiao-Ming Zhang (0000-0001-5327-8506).

Author contributions: Li XH wrote most of the paper; Liang Q provided input to write the paper; Wang J provided free literature; Chen TW revised the manuscript; Zhang XM outlined and coordinated the writing of the paper.

Conflict-of-interest statement: There is no conflict of interest associated with publication of this manuscript.



Correspondence to: Xiao-Ming Zhang, MD, PhD, Chief Doctor, Professor, Sichuan Key Laboratory of Medical Imaging, Department of Radiology, Affiliated Hospital of North Sichuan


DOI: 10.12998/wjcc.v6.i9.242




provide references for clinical diagnosis and treatment.

Key words: Diagnosis; Imaging; Magnetic resonance imaging; Primary hepatocellular carcinoma; Diffusion-weighted imaging


Core tip: Primary hepatocellular carcinoma (PHC) is one of the most serious malignant tumors with high morbidity and mortality. It is the fifth leading cancer worldwide and third most common cause of cancer-related death. Early diagnosis of PHC plays an important role in timely treatment and improvement of prognosis. An ideal imaging technique should be chosen early and used promptly to make a qualitative diagnosis. The progress made in imaging techniques has offered new diagnostic methods for the study of liver cancer. This review outlines the diagnostic value of imaging in patients with PHC.

Li XH, Liang Q, Chen TW, Wang J, Zhang XM. Diagnostic value of imaging examinations in patients with primary hepatocellular carcinoma. World J Clin Cases 2018; 6(9): 242-248 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/242.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.242

INTRODUCTIONPrimary hepatocellular carcinoma (PHC) is one of the most seriousmalignant tumors with high morbidity and mortality. It is the third most common cause of cancer death and fifth leading cancer worldwide[1-3]. According to cancer statistics, hepatocellular carcinoma (HCC) mortality has gradually increased, and the overall cure rate for HCC has not improved significantly over the past decade[4]. A few risk factors have been identified for PHC such as viral hepatitis, cirrhosis, aflatoxin, parasitic infection and genetic factors[5-9]. Due to its characteristic concealment, PHC has no specific early symptoms and rapidly progresses. Most of the clinical diagnoses are made at late stage or when distant metastasis occurs, increasing the difficulty of treatment and leading to a poor prognosis. Therefore, early diagnosis of PHC plays an important role in timely treatment and the improvement of prognosis.

The early diagnosis of PHC follows the guidelines of the American Association for the Study of Liver Diseases (AASLD)[10], European Association for the Study of Liver Disease (EASL)[11], Asia-Pacific Association Study of the Liver (APASL)[1] and EASL-EORTC Clinical Practice Guidelines[12]. Several imaging modalities have been identified for the clinical diagnosis of PHC, and this review outlines the diagnostic value of imaging in pati-ents with PHC.


Li XH et al . Diagnostic value of imaging in HCC patients

TRADITIONAL IMAGING DIAGNOSIS OF PHCTraditional imaging methods of liver cancer, such as ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI), can provide in-formation about lesions, including their location, size and nature. These methods can also make a clear diagnosis, assist staging, guide treatment and evaluate efficacy[13-15]. Liver cancer presents as a hypoechoic mass on ultrasonography, and color Doppler shows a star-spot and a short-line blood flow signal. Ultrasonography is radiation-free, is repeatable, occurs in real-time and is convenient in operation. However, the ultrasound field of vision is small, interference is large, single imaging can only observe one or several lesions, and the results are dependent on the operator’s skill and experience. CT is a wide-coverage, high-speed and unique examination technique, but it has the side effects of radiation and the contrast agent. MRI uses no radiation and has high soft-tissue resolution. It can display multiple sequences and parameters, leading to the display of lesions in multiple ways-conventional-weighted images and dynamic-enhanced images, which are excellent for displaying anatomical structures. However, MR images do not provide functional information, the MR scanning speed is slow, the patient’s breath holding requirement is high, and there are side effects of the contrast agent. The current guidelines vary among different societies for the diagnosis of liver cancer. Both AASLD and EASL recommended that the diagnosis should be based on the imaging findings and size of the lesions; APASL recommends that the diagnosis should be based on the blood supply only, regardless of the focus size and α-fetoprotein (AFP) level; the Japan Society of Hepatology recommends combining AFP and imaging findings and then making a diagnosis based on the characteristics of the blood supply of the lesion[16]. EASL guidelines show that contrast-enhanced ultrasonography is not as accurate as CT and MRI in detecting lesions. Dynamic-enhanced MRI and multiphase-enhanced CT are the most effective techniques to detect < 2-cm tumors, and approximately 25%-30% of cases are underestimated[17].

Considering these promising results, traditional imaging faces enormous challenges. First, according to a report[18], among 243 cases of HCC confirmed by pathology, only 137 cases (56.4%) showed typical enhancement and 106 cases (43.6%) showed atypical enhancement, including equal or low enhancement in the arterial phase and no contrast elution in the equilibrium phase. At the arterial stage, 53 cases showed equal or low enhancement, and 53 cases were not eluted by a contrast agent in the balanced phase. Atypical HCC is not uncommon, posing a challenge for a definite diagnosis. Second, for the diagnosis of borderline lesions (early HCC and high heteromorphic hyperplasia nodules),



most of the lesions are not enhanced in the arterial phase and show a low signal in the venous phase and delayed phase. They are not distinguishable on imaging. Third, for patients with arteriovenous fistula, the arter-ial phase is obviously enhanced, and the venous phase and equilibrium phase are isointense, similar to the enhancement of focal nodular hyperplasia and adenoma; thus, it is difficult to differentiate[18]. How to address this challenge requires continuous development of imaging.

PROGRESS IN CT DIAGNOSISCT perfusion imaging is a noninvasive functional imaging method to evaluate the perfusion status of organs and tissues. Typical CT perfusion imaging of liver cancer is characterized by increased blood flow, increased blood volume, increased hepatic artery perfusion, de-creased portal vein perfusion, and an increased he-patic artery perfusion index[19]. CT perfusion imaging can be used to evaluate the efficacy of transcatheter arterial chemoembolization. After lipiodol embolization, tumor survival can be determined by perfusion if CT enhancement does not reveal the area of residual tumor with abnormal enhancement. After perfusion, a small region of high blood flow around the edge of the lesion, a small blood volume area, increased hepatic artery perfusion, decreased portal perfusion, and increased hepatic artery perfusion index indicate tumor survival[20].

PROGRESS IN MR DIAGNOSISIn recent years, due to the advancement of MR hard-ware, new quantitative techniques regarding fun-ctional and metabolic directions have emerged and include diffusion-weighted imaging (DWI)-intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), iterative decomposition of water and fat with echo asymmetry and least squares estimation-iron quantification (IDEAL-IQ), MR spectroscopy, MR elastography, MR perfusion imaging and hepatocyte-specific contrast agent imaging. These new technolog-ies can provide information on metabolism, such as glycogen, fat, iron metabolism, as well as information on the density of hepatocytes, structural disorder and phagocytosis of Kupffer cells in terms of structure and cell function.

DWIDWI is based on the principle of the diffusion of water molecules. Due to various reasons, the gap between cells is narrowed, and the movement of water molecules is restricted. Abnormal proliferation of tumor cells lea-ds to a decrease in the extracellular space, and the diffusion of tissue fluid located between cells is more limited than that of normal cells. Conventional DWI can be used to judge the degree of tumor differentiation. Nakanishi et al[21] have shown that, in HCC confirmed

by surgery, the degree of differentiation is different: the degree of differentiation is high with a higher apparent diffusion coefficient (ADC) value, and the degree of differentiation is low with a lower ADC value. The ADC value in the necrotic area was significantly higher than that in the tumor area[21]. Studies have shown that, when the b value is 1000, the ADC value of HCC with different degrees of differentiation is significantly lower than that of highly differentiated HCC[22,23]. Conventional DWI can also be used to judge microvascular invasion, and Xu et al[24] showed that the ADC value of lesions with microvascular invasion was lower than that without microvascular invasion.

With further study of DWI, it was found that, if multi-b-value imaging is used, the tissue signal decreases with the increase in the diffusion-weighted b value. The characteristics of the diffusion signal are described in the IVIM double-exponential model; one part comprises the water molecule diffusion signal, and the other part comprises the microcirculation perfusion signal in the capillary. A low b value is generally considered ≤ 200, including diffusion and perfusion effects, but mainly the perfusion effect, and a high b value (> 200) reflects the true dispersion effect. IVIM-derived parameters contain the perfusion fraction (f), pseudodiffusion coe-fficient (D*) and pure diffusion coefficient (D) values. The f value is the perfusion fraction that is linked to the microcirculation. D* is the perfusion parameter that represents the perfusion-related incoherent microcircu-lation, and D is the diffusion coefficient representing true molecular diffusion[25]. Woo et al[26] showed that the ADC and D values were correlated with the clinical grade of Edmondson, but the ADC, F, D and D* values were not correlated with the enhancement of the arterial phase (no blood supply enhancement, no blood supply or no enhancement). The D value was superior to ADCs in differentiating high-grade and low-grade HCC, and the f value was significantly correlated with the percentage of arterial enhancement[26].

DTI is also a DWI technique that provides additional information on anisotropy diffusion and total diffusion orientations, which can obtain the diffusion degree in multiple dimensions using at least six or more gradi-ent directions[27,28]. Fractional anisotropy (FA) can be calculated by DTI in addition to the ADC value, which is a scalar value describing the anisotropy degree of the diffusion of extracellular water molecules[29]. The malignant cells contain more membranes, organelles and complicated fibers, causing the cells in PHC to be densely packed. However, it remains unknown whether diffusion in PHC is isotropic or anisotropic; moreover, no study has explored the feasibility of DTI for the PHC diagnosis. Therefore, our previous study evaluated the feasibility of distinguishing HCC from healthy liver using FA and ADC values, and we found that both FA and ADC could be used as indexes to differentiate HCC from healthy liver[30].




IDEAL-IQ sequenceFor liver magnetic resonance scans, t fast spoiled gra-dient recalled echo with antiphase imaging was used to diagnose hepatic steatosis. Using the same window and wide window, if the liver signal is high in the same phase image and low in the inverse phase image, then liver fatty degeneration is considered[31,32]. However, this method cannot be applied to patients with liver iron overload because iron sinks in the liver to accelerate the phase acceleration of the hydrogen protons so that, in the same phase image as that with a low signal, the reversed phase image shows a high signal, greatly interfering with the diagnosis whether or not the patient has liver fat degeneration. Thus, using IDEAL-IQ, a single scan can generate a pure water image, a pure fat image, an in-phase image, and an inverse phase image. The ratio of fat to fat is similar to the R2* relaxation rate of six groups of images to determine whether the liver has fatty degeneration and iron overload[33]. It was reported that the presence of intratumoral fat is up to 19.6% in HCCs on MRI[34], and Siripongsakun et al[35] claimed that fat-containing HCC, compared with nonfat-containing HCC on MRI, may predict a more favorable prognosis. Therefore, we predict that IDEAL-IQ exhibits great value to distinguish fat-containing HCC from nonfat-containing HCC.

DYNAMICENHANCED MRIWith the application of the LAVA sequence in high-field MRI, the detection rate of small HCC has been significantly improved by DWI combined with dynamic contrast-enhanced MR. The smallest lesion diameter of 0.4 cm could be detected[36]. The enhancement of LAVA could better capture the arterial blood supply of the tumor, and the contrast between the enhancement of the lesion at the arterial stage and surrounding normal hepatic parenchyma was optimal, being helpful to distinguish small liver cancer from the new vessels in the tumor and increase the detection rate of small HCC inliver cirrhosis . However, LAVA enhancement is difficult to detect small liver cancer with a lack of a hepatic artery blood supply[37].

HEPATOCYTE-SPECIFIC CONTRAST AGENTSThere are two types of hepatocyte-specific contrast agents: Gd-DTPA and Gd-EOB-DTPA. On the one hand, Gd-DTPA and Gd-EOB-DTPA can shorten the tissue T1 relaxation time and can produce a similar dynamic enhancement effect to traditional MR contrast agents to observe the conventional multiphase dynamic en-hancement mode and performance of liver lesions. On the other hand, the liver parenchyma that contains normal liver cells is enhanced, and double information of the liver specific phase can be obtained. Therefore, hepatocyte-specific contrast agents can provide dual

information on the liver dynamic phase and specific phase. Regarding Gd-EOB-DTPA, 50% is excreted thr-ough the liver, and 50% is excreted by the kidneys. Regarding Gd-DTPA, 2%-4% is excreted by the liver, and the remainder is excreted by the kidneys. Thus, the specificity of Gd-DTPA is lower than that of Gd-EOB-DTPA. Gd-EOB-DTPA application for 3 min was used, the normal hepatocytes began to ingest, and the dynamic phase was mixed with dual information, whereas the Gd-DTPA uptake started later, so Gd-DTPA could provide a pure dynamic phase. Hepatocyte-specific contrast agents can help radiologists to detect early liver cancer and some small lesions, and the detection rate of liver lesions is higher than that of conventional MR contrast agents[38,39]. Presently, Gd-BOPTA is widely used in cli-nical practice.

The experts from the radiology branch of the Chinese Medical Association have reached a consensus on the application of Gd-EOB-DTPA. For atypical HCC, especially in the early stage, Gd-EOB-DTPA-enhanced MR can also be performed, which will help to improve the diagnostic accuracy[40-43]. For patients with progressive elevation of AFP, especially with high-risk factors (such as hepatitis B- or hepatitis C-associated cirrhosis) and other patients with negative imaging examination (on ultrasonography or Gd DTPA-enhanced MRI), Gd-EOB-DTPA-enhanced MRI is recommended[44]. Contrast-enhanced CT in the decision of HCC surgery, if the detection of additional small lesions (maximum diameter ≤ 2.0) may change the established treatment plan, will help to improve the radical treatment of tumors and reduce postoperative recurrence and metastasis. In the diagnosis of HCC by Gd-DTPA-enhanced MR, no definite nodules, such as abnormal perfusion and early small HCC, were found in other hepatic lobes and in the preoperative evaluation of donors and recipients before liver transplantation, especially in the selection of recipients. The evaluation of the donor bile duct showed its superiority[45-48].

GD-EOB-DTPA can detect more liver lesions, likely changing the treatment plan. Some studies have shown that approximately 10% of HCC are found only in the GD-EOB-DTPA phase, and approximately 90% of HCC show low expression of OATP8 and a low signal of the liver-specific phase in the early stage[49,50]. Therefore, the detection rate of MR liver-specific phase imaging for early HCC with an oligoblood supply is very high. Ariizumi et al[51] found that the nonsmooth boundary of hepatocyte-specific lesions was closely related to portal vein invasion and intrahepatic metastasis and was significantly associated with recurrence within 1 year after HCC. Some studies have shown that the changes in liver cell membrane function were earlier than those of the neovascularization/blood supply in nodules[52,53]. Yamashita et al[54] and other studies showed that the expression of OATP1B3 and level of AFP were negatively correlated with the high expression level of OATP1B3. The low-expression cells came from stem cells/progenitor cells, and the differentiation was poor, resulting in the




increase in the T1 value of liver tissue in patients with liver cirrhosis and decrease in the hepatic parenchymal signal in the hepatobiliary phase[54]. Therefore, GD-EOB-DTPA is expected to assist in the diagnosis and differential diagnosis of liver function and to evaluate liver function at the segmental level.

BOLD-fMRIBOLD-fMRI is a new MRI imaging technology. Using en-dogenous hemoglobin as the contrast agent, the blood oxygen content of tissues is measured by the tissue hemoglobin content. The content of blood oxygen in tissue depends on the relative changes in the perfusion oxygen supply and metabolic oxygen consumption. Therefore, the content of blood oxygen can reflect the changes in the hemodynamics, structure and function of the tissue. It has a certain value in the diagnosis, and clinical stage and curative effect evaluation of the tumor[55]. Choi et al[56] found that liver cancer chem-oembolization and postoperative R2 changed signifi-cantly. Therefore, BOLD functional MRI has the potential value in the diagnosis of small HCC, but large samples are needed for further study.

CONCLUSIONAn ideal diagnostic imaging technique for the diagnosis of liver cancer should be chosen early and used pro-mptly to make a qualitative diagnosis[57-59]. Imaging progress has brought new opportunities for the study of liver cancer. The diagnosis can be established based on the presence or absence of a focus, lesion location, size, and nature including the degree of differentiation, blood supply and perfusion, and invasion of the lesion, and the imaging can also be used to assess the prognosis and liver function, making the diagnosis more accurate and providing more information for clinical treatment.

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P- Reviewer: Corrales FJ, Liao KF, Montalto G S- Editor: Ji FF L- Editor: Ma JY E- Editor: Tan WW



Osman Tanriverdi, Uzay Erdogan, Canan Tanik, Ilhan Yilmaz, Omur Gunaldi, Huseyin Utku Adilay, Ayca Arslanhan, Metehan Eseoglu

ORIGINAL ARTICLE


Impact of sorafenib on epidural fibrosis: An immunohistochemical study

Osman Tanriverdi, Uzay Erdogan, Omur Gunaldi, Department of Neurosurgery and Psychiatry, University of Health Sciences, Bakırky Prof. Dr. Mazhar Osman Training and Research Hospital for Neurology, İstanbul 34303, Turkey

Canan Tanik, Department of Pathology, University of Health Sciences, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul 34303, Turkey

Ilhan Yilmaz, Department of Neurosurgery, University of Health Sciences, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul 34303, Turkey

Huseyin Utku Adilay, Department of Neurosurgery, Medical Faculty, Balıkesir University, Balıkesir 31300, Turkey

Ayca Arslanhan, Institute of Neurological Science, Marmara University, İstanbul 34303, Turkey

Metehan Eseoglu, Department of Neurosurgery, Medical Faculty, Medipol University, İstanbul 34303, Turkey

ORCID number: Osman Tanriverdi (0000-0002-4846-4213); Uzay Erdogan (0000-0001-8268-6306); Canan Tanik (0000-0003-2435-7533); Ilhan Yilmaz (0000-0001-5548-2228); Omur Gunaldi (0000-0001-5071-1319); Huseyin Utku Adilay (0000-0003-4867-244X); Ayca Arslanhan (0000-0002-3980-0609); Metehan Eseoglu (0000-0003-0260-1988).

Author contributions: Tanriverdi O contributed to the con-ception, design, supervision and writing; Erdogan U contributed to the literature review and data collection; Tanik C contributed to the design, data collection, analysis and processing; Yilmaz I contributed to the writing and literature review; Gunaldi O contributed to the critical review and supervision; Adilay HU contributed to the data collection and materials; Arslanhan A contributed to the materials and data collection; Eseoglu M contributed to the literature review, materials and data collection.

Institutional animal care and use committee statement: Marmara University Local Ethics Committee for Animal Studies.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.


Manuscript source: Unsolicited manuscript

Correspondence to: Osman Tanriverdi, MD, Doctor, Department of Neurosurgery and Psychiatry, University of Health Sciences, Bakırköy Prof. Dr. Mazhar Osman Training and Research Hospital for Neurology, Tevfik sağlam cad, No. 1, İstanbul 34303, Turkey. [email protected]: +90-505-2964052

Received: April 27, 2018Peer-review started: April 27, 2018First decision: June 15, 2018Revised: June 23, 2018Accepted: July 31, 2018Article in press: August 1, 2018Published online: September 6, 2018

AbstractAIMTo determine if sorafenib, an antineoplastic agent, could prevent the development of spinal epidural fibrosis (EF).

METHODSThe study used CD105 and osteopontin antibodies


DOI: 10.12998/wjcc.v6.i9.249




Basic Study

in an immunohistochemical approach to quantify EF that occurred as a consequence of laminectomy in rats. Wistar albino rats (n = 16) were divided into two groups: control (L1-2 level laminectomy only) and so-rafenib treatment (L1-2 level laminectomy + topical sorafenib). The animals were euthanatized after 6 wk, and the EF tissues were examined for histopathological changes after immunohistochemical staining. The EF grades were assigned to the tissues, and the treatment and control groups were compared.

RESULTSThe EF thickness, inflammatory cell density, and ara-chnoid adherences determined by light microscopy were significantly higher in the control group compared to the sorafenib-treated group. Based on fibrosis scores, the extent of EF in the treatment group was significantly lower than in the controls. Immunohistochemical sta-ining for CD105 to identify microvessels revealed that the EF grades based on vessel count were significantly lower in the treatment group. Staining for osteopontin did not show any significant differences between the groups in terms of the extent of EF. The staging of EF based on vascular counts observed after immunohistochemical staining for CD105, but not for osteopontin, was com-patible with conventional staging methods. Neither toxic effects on tissues nor systemic side effects were observed with the use of sorafenib.

CONCLUSIONLocal administration of sorafenib significantly reduced post-laminectomy EF. Decreased neovascularization in spinal tissue may be due to the sorafenib-induced inhi-bition of vascular endothelial growth factor.

Key words: Vascular endothelial growth factor; CD105; Osteopontin; Sorafenib; Spinal epidural fibrosis


Core tip: This study addressed the prevention of spinal epidural fibrosis (EF) by sorafenib, an antineoplastic agent, though immunohistochemical analyses of EF as a consequence of laminectomy in rats. The study demonstrated for the first time that the fibrosis thickness, inflammatory cell density, arachnoid adherences, fibrosis scores, and vessel count were significantly lower in the treatment group. These findings indicate that locally administered sorafenib may help reduce spinal EF after laminectomy without any significant complications or side effects.

Tanriverdi O, Erdogan U, Tanik C, Yilmaz I, Gunaldi O, Adilay HU, Arslanhan A, Eseoglu M. Impact of sorafenib on epidural fibrosis: An immunohistochemical study. World J Clin Cases 2018; 6(9): 249-258 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/249.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.249


Tanriverdi O et al . Impact of sorafenib on epidural fibrosis

INTRODUCTIONOne of the complications that occurs most frequently after laminectomy is epidural fibrosis (EF)[1]. EF causes reoccurrence of symptoms because of post-operation nerve root tensioning or compression[2]. A second op-eration is often required to remove scar tissue, and it is both difficult and has a high rate of complications[1,3,4]. A majority of authors believe that to avoid surgical treatment, EF should be prevented before it occurs[5,6]. Several studies have previously addressed the effec-ts of various compounds on EF after laminectomy in rat[2,7-10] and rabbit[11] models, on renal fibrosis[12], and on liver fibrosis[13]. Many of these drugs are still in the development stage, and some of them are intended to inhibit the mechanism underlying fibrosis development.

The multi-kinase inhibitor sorafenib is an antineoplastic drug with secondary antifibrotic and antiangiogenic activity via inhibition of vascular endothelial growth factor (VEGF)[13]. Although the antifibrotic effectiveness of sorafenib is well known, there is no literature to our knowledge of its utilization in spinal surgery[12,13].

Chemotactic factors arising from the disintegration of erythrocytes and thrombocytes following bleeding in the epidural region after laminectomy, as well as fibroblast migration arising from paraspinal muscles, are the main causes of EF. Adhesions can also form due to fibrous connective tissue hyperplasia when fibroblasts are activated by inflammatory cytokines and growth factors, primarily transforming growth factor-β (TGF-β) and basic fibroblast growth factor, to repair the local defect in the vertebral lamina. With collagen fibril production, fibrous connective tissue is transformed into scar tissue, leading to the development of fibrositis[14].

Tyrosine kinase (TK) inhibitors are a group of small molecules that have gained considerable importance in recent years for the prevention of angiogenesis. Sora-fenib is one such antineoplastic drug, and it reduces the proliferation of tumor cells through its antiangiogenic effect via multi-kinase inhibition[15]. Its principal targets are the Raf/ERK, VEGFR and PDGFR-β pathways[13]. It has been shown that sorafenib can inhibit a great num-ber of intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-B) (Figure 1). It is therefore thought that some of these kinases may take part in tumor cell signal transmission, angiogenesis and apoptosis. Sorafenib selectively inhibits the VEGF receptor tyrosine kinase (TK). Due to this antiangiogenic effect, it has become one of the most effective drugs in cancer treatment[16]. Moreover, in recent years, sora-fenib has conspicuously improved liver transplantation and conventional treatment methods of all other non-malignant fibrotic diseases like fibrosis caused by end-stage liver cirrhosis[13,17,18]. In the current study, we have investigated whether the antiangiogenic effect of so-rafenib via VEGF receptor blockade could also prevent



the development of experimental EF without toxic effects when applied locally to peripheral tissues.

CD105, also known as endoglin, is a membrane glycoprotein that regulates the signaling of TGF-β1[19].

It was first defined as a human endothelial cell marker produced by pre-B cell leukemia cell lines[20]. Further studies have indicated that this cell surface antigen is also expressed by macrophages, erythroid precursors, syncytiotrophoblasts of terminal placenta and stromal cells[20-23]. Previous studies have revealed that in various models of EF, CD105 expression could prevent the fib-rogenic impact of TGF-β1[19,24]. In biopsies of patients with kidney and liver fibrosis, an excessive amount of CD105 expression was seen, and its role in regulating fibrogenesis was thus realized[20,25]. In the light of the above information, CD105 levels may be useful in de-termining the density of microvessels and the extent of angiogenesis in fibrosis. Unfortunately, there is no literature available to our knowledge on the use of CD105 immunostaining for the examination of EF after laminectomy. Given the role of CD105 in angiogenesis and its expression in fibrosis and in macrophages, we examined its use as a marker of EF post-laminectomy at different stages in the development of EF.

Osteopontin is a glycophosphoprotein that was first isolated from bone tissue and possesses a number of functions affecting various cells including macrophages, epithelial cells, smooth muscle cells and endothelial

cells. High levels of osteopontin have been found in bone tissue, blood, milk, urine and seminal fluid[26]. It is secreted from embryonic stroma and from fibroblasts during wound healing[27]. Since osteopontin is secreted from inflammatory cells, fibroblasts and endothelial cells, it may be helpful in determining the presence of fibrosis[28]. We therefore analyzed whether osteopontin expression post-laminectomy could be used for the im-munohistochemical detection of EF and if its use was compatible with conventional methods of EF assessment.

In the present study, we have investigated the pre-ventive effect of sorafenib on the development of EF after laminectomy. In addition to conventional methods showing the number of fibroblasts and the prevalence of fibrosis, we employed immunohistochemical staining for CD105 and osteopontin to analyze the extent of EF and assessed whether these methods were compatible with conventional EF staging methods.

MATERIALS AND METHODSThe study was performed at the Marmara University Experimental Animals Laboratory (İstanbul, Turkey) and was approved by the Marmara University Animal Exper-iments Research Ethics Committee (04.01.2016/001). All necessary precautions were taken to minimize pain and discomfort in animals throughout the procedures of the study. Male Wistar albino rats (n = 16, weight 250

EGF

VEGF

FGF

PDG

F

Blockage Sorafenib

EGER

VEGFR

FGFR

PDG

FR

1

1

2

MEK/ERKpathway

PI3K/AKTpathway SRC c-Abl RhoA

Fibroblastdifferentiation,

proliferation andmigration

Endothelial celladhesion and

migration,vascular

permeability

2Interaction between RTKs and intracelular pathwaysRTKs: Receptor tyrosine kynases

Interaction between RTKs and nRnRTKs: Nonreceptor tyrosine kyn

Figure 1 Fibrosis development mechanism and the stage at which sorafenib prevents fibrosis is indicated. VEGF: Vascular endothelial growth factor.




g ± 30 g, 10-12 mo) were housed in an air-conditioned room with an average temperature of 23 ± 2℃ and an average humidity of 65%-70%, under a 12-h light-dark cycle. Each animal was kept in a separate cage throughout the study with food provided ad libitum and without any medical treatment after the initial operation. Surgical intervention was performed using standard microsurgical instruments.

Surgical procedure A prophylactic dose of 50 mg/kg ceftriaxone (Roce-phine; Roche, İstanbul, Turkey) was intraperitoneally injected 30 min before surgery. General anesthesia was applied by intraperitoneal administration of 100 mg/kg ketamine hydrochloride (Ketalar, 50 mg/mL; Parke-Davis, Eczacıbaşı, İstanbul, Turkey) + 10 mg/kg xylazine hydrochloride (2% Rompun; Sigma-Aldrich, Merck, İstanbul). After fastening the rat to the operating table, the operating area was disinfected with povidone iodine (Poviod, 10% polyvinyl pyrrolidone-iodine com-plex; Saba, İstanbul, Turkey). The operating area was covered with sterile cloths. Upon determining the L1-2 level, an approximately 2-2.5 cm central line skin in-cision was made. Para-spinal muscles were stripped by blunt dissection. Under a surgical microscope, total laminectomy was performed within an approximately 4 mm2 area between L1 and L2, and the dural sac was revealed. Throughout the operation, the wound was irrigated with saline and hemostasis was ensured. Bipolar cautery, bone wax, surgical or other hemostasis materials were not used. Experimental animals were divided equally (n = 8 per group) between the control group (Group Ⅰ) with laminectomy performed at the L1-2 level and physiologic saline applied, and the treat-ment group (Group Ⅱ) with laminectomy performed at the L1-2 level and topical sorafenib (Nexavar; Bayer and Onyx Pharmaceutical, Berlin, Germany) applied. Because sorafenib is produced in the form of 200 mg tablets and its injectable type was not available, we administered sorafenib in the form of a diluted topical treatment. Following the advice of the manufacturer, a 200 mg tablet was dissolved in 5 cc saline and applied via impregnated cotton sponge to the laminectomy area for 5 min. The incision area was then sutured with 3/0 silk in conformity with its anatomy. Experimental and control animals were euthanatized by cervical disloca-

tion 6 wk later. The motor functions of all animals was normal at the time of euthanasia, and no postoperative infection or other systematic pathology was evident. The relevant vertebral columns were removed as a block to-gether with the paraspinal muscles. The tissue was fixed in 10% formalin (4% formaldehyde) solution.

Histopathological examination was performed by a qualified pathologist. The amount of fibrosis in the laminectomy area in relation to dura mater was assessed in conformity with standard immunohistochemical cri-teria and classifications in the literature. Comparisons were made within groups and between control and treat-ment groups, and results were compiled and statistically interpreted.

Histopathological assessment After fixation for 24 h in 10% buffered formalin, the vertebral column was removed as a block and decal-cified in 10% formic acid for 2 d. Three specimens were taken from the area in which laminectomy was performed, and these specimens were subjected to Leica 300S “autotechnikon” routine tissue monitoring after washing for 6 h under running water. Paraffin blocks were sectioned at a thickness of 3 mm, and sec-tions were stained with hematoxylin-eosin (HE) for inspection under a light microscope with respect to the prevalence of fibrosis, cellular density and arachnoid fibrosis. Fibrosis staging at the dura was performed according to He et al[29] (Table 1). Fibroblasts at 100 X magnification were counted by pathologists in three fields per specimen, one in the middle and two at the edge of the laminectomy (Figure 2A). The average number of fibroblasts and inflammatory cells in the three fields were graded as follows: Grade 1, less than 100 fibroblasts/inflammatory cells per field; Grade 2, 100–150 fibroblasts/inflammatory cells per field; Grade 3, more than 150 fibroblasts/inflammatory cells per field. To verify the quantification of fibroblast numbers, immunohistochemistry was performed using monoclonal anti-vimentin antibody 1:100 (Vimentin clone: V9, LEICA Biosystems Newcastle Upon Tyne, United Kingdom), and the density of vimentin was evaluated[6]. Similarly, inflammatory cell density was assessed at 40 X (Figure 2B and C). Furthermore, we evaluated the sections for bone renewal, winding of the nerve root and adhesions between dura and arachnoid.

Immunohistochemical assessmentMicrovessel density in the specimens was determined based on immunostaining with anti-osteopontin and anti-CD105 monoclonal antibodies. Paraffin-embedded tissues fixed in 10% formalin were sectioned at 3-5 mm and mounted onto poly-L-lysine-coated slides. The immunohistochemical study was done in the Leica Bond Ⅲ. The slides were kept at 80℃ in the incubator for 3 h and installed in the Bond Ⅲ device. For the primary antibodies, 1/400 dilution was prepared from CD105

Table 1 Grading criteria for histopathological assessment of scar tissue by He et al [29]

Grade Width of the scar tissue

0 No scar tissue in dura mater

1 Thin fibrosis bands present between scar tissue and dura mater

2 Adhesions holding 2/3 of the laminectomy defect present

3 Widespread scar. More than 2/3 of the laminectomy defect affected




(Clone EP274, catalog number AC-0243A, Epitomics, Burlingame, CA, United States) and 1/100 dilution was prepared for osteopontin (Clone EP106, catalog number AC-0102RUO; Epitomics, Burlingame, CA, United States). After automatized coloring, the slides were kept in xy-lene for 3 min and sealed.

Assessment of microvessel density Using an Olympus (Shinjuku, Japan) CX41 light mi-croscope, tissue sections immunostained with anti-CD105 and anti-osteopontin were scanned at 40X and 100X in three different areas where the density of neovascularization was the highest (hot spot). A single brown-stained endothelial cell or interconnected en-dothelial cell cluster separate from fibrosis and other connective tissue components at 400 X magnification, irrespective of lumens, was considered a countable microvessel (Figures 3A and B; 4A and B). Every experi-mental animal was classified in accordance with the number of stained vessels (Table 2) observed at 400 X magnification as follows: Grade 1, ≤ 3 vessels; grade 2, 4-6 vessels; and grade 3, ≥ 7 vessels. Vessels in the muscle layer were not included in the counts. The average number of vessels in three areas was calculated as the vessel density.

Statistical analysisSPSS 15.0 for Windows (IBM, Armonk, NY, United

States) was used for statistical analysis. Descriptive statistics were given as percentages for categorical variables. Differences in the proportional rates of ca-tegorical variables between groups were tested by chi-square analysis. In cases where the conditions could not be ensured, Monte Carlo simulation was im-plemented. Statistical significance was accepted as P < 0.05. All statistical procedures were carried out by an experienced biostatistician at Arat Biostatistics LLC (Istanbul, Turkey) through outsourcing.

RESULTSSignificant differences (P < 0.001) in fibrosis score, fibroblast density, inflammatory cell density and CD105 immunostaining were observed between the sora-fenib and control groups (Table 3). All control animals (Group Ⅰ) received fibrosis scores of grade 3, while scores for sorafenib-treated animals (Group Ⅱ) did not exceed grade 1 (P < 0.001) (Figure 2A and B, Table 3). Fibroblast density was graded the highest in 100% of Group 1 animals but remained at grade 1 in Group Ⅱ. Scores for inflammatory cell density were lowest in Group Ⅱ but highest in Group Ⅰ, as were scores for microvessel density assessed by CD105 immunostaining (P < 0.001) (Figure 3A and B, Table 3). There was no significant difference in microvessel density scores between groups after osteopontin staining (P = 0.355)

Inflammatory cellsDural tissue

Neural tissue

Fibrous tissue

Dural tissue

Neural tissue

Fibrous tissue

A B

C

Figure 2 Histopathological tissue section stained by HE. A: Grade-3 fibrosis and inflammatory cells in Group I; B: Grade-3 fibrosis and fibrous tissue in Group I; C: Grade 1 fibrosis in Group II. Star: Neural tissues; black arrow: Dura; blue arrow: Fibrosis tissue.




(Figure 4A and B, Table 3). By light microscopy, it could be seen that EF thickness, inflammatory cell density and arachnoidal adhesions were greater in control animals compared to Group Ⅱ (Table 3).

DISCUSSIONEF is a major cause of failed back/lumbar surgery syn-drome, which is often witnessed post-laminectomy[1,2].

Because treatment of EF is difficult and complication rates are high, ongoing studies have examined how to prevent its development. The role of angiogenesis in the development of fibrosis is known, with VEGF acting as a potent angiogenic agent[30]. Sorafenib inhibits VEGF in neoplastic cells and blocks angiogenesis, causing the death of tumor cells. The same mechanism is also applicable in the development of EF, and it has been shown that sorafenib prevents or inhibits the develo-pment of fibrosis in the liver and the kidney[13,19,31].

In the present study, the level/degree of EF was classified separately based on fibrosis scores, the density of fibroblasts and inflammatory cells, and co-unts of microvessels immunostained for either CD105 or osteopontin. Our results showed that EF developed to various extents in all control animals, indicating that experimental EF was successfully produced. The local application of sorafenib reduced the level and degree of EF compared to the control animals. We also found that the scoring of EF based on counts of osteopontin-stained microvessels did not agree with other measures used.

EF is a normal process with respect to the local reparation of surgical laminectomy, but its role in the production of epidural scar tissue has been contro-versial[2,10,14]. Clinical studies and results from the animal experiments have shown that many factors are related to the development of post-operative peridural scar tissue including postoperative hematoma, laminectomy technique, amount of bone removed and the relation of lamina to other anatomic structures[2,32]. However, the main factor in the creation of peridural scar tissue is fibroblast migration to the surgical area[32]. Theoretically, the augmentation of vascular permeability in the early phase of wound repair allows for the accumulation of fibrin-rich matrix required for cellular migration and proli-feration[2,33]. The angiogenic response is characteristic of the early wound-repair phase and ensures vasculari-ty, which nourishes newly formed granulation tissue. The most potent stimulant of angiogenesis is VEGF. In addition, other growth factors including FGF, PDGF,

angiopoietin 1 and 2 and hepatocyte growth factor stimu-late angiogenesis through TK receptors[30]. Furthermore, it is known that VEGF is helpful for vascularization in the postoperative damaged area and plays a key role in adhesion formation[8,10].

Sorafenib, a TK inhibitor, has been certified by the FDA for use as an antineoplastic agent demonstrating VEGF inhibitory and antiangiogenic effects. In work carried out by Ma et al[12], it was reported that sorafenib exerted an antifibrotic effect on the kidney and that this effect occurred as the result of its prevention of macrophage migration. In the present study, we sh-owed through immunohistochemical staining that so-rafenib applied locally to the surgical area prevented neovascularization in damaged postoperative tissue, thereby inhibiting or preventing EF. Furthermore, sora-fenib did not produce any toxic effects on the dura, paraspinal muscles or other tissues.

One method to determine the level of angiogenesis in a tumor and/or fibrotic lesion is to directly measure the density of microvessels and veins in the tissue. An increase in the number of microvessels indicates that angiogenesis is strong[34]. Detection of microvessels in fibrotic tissue is possible by making the vessels vi-sible after staining for proteins in the membranes of endothelial cells using immunohistochemical methods. CD105 is a potential immunohistochemical marker for the detection of microvessel density, which is associated with endothelial cells in angiogenic tissues and usually produces little or only weak color when used for imm-unohistochemical staining in normal tissue. It is this fact that makes anti-CD105 a useful antibody for the evaluation of angiogenesis or angiogenic potential[35,36]. In our study, we showed that the staging of EF using fibroblast counts and fibrosis density produced similar results as counting CD105-stained microvessels. Thus, CD105 is a suitable marker for immunohistochemical detection of EF.

Another potential immunohistochemical marker for the detection of fibrosis is osteopontin. While osteopontin is expressed by epithelium, endothelium and smooth muscle cells, it is also expressed by macrophages and T cells with infiltration features[26]. Osteopontin plays a significant role during acute and chronic inflamma-tion when its anti-inflammatory effect can prevent inflammation or alleviate its severity[26]. Osteopontin is essential for cell viability and protects against apo-ptosis[26]. There are reports of excessive expression of osteopontin in human idiopathic pulmonary fibrosis, interstitial fibrosis in the diabetic kidney and alcoholic liver illness even though full deterioration did not occur in the healing wound and the number of irregular collagen fibrils was less than normal[27,28,31,37,38]; however, other reports claimed that the elimination of tissue debris was a slower than normal process[27]. Pereira et al[28] reported that osteopontin did not show equal distribution in all tissues and that its presence might be directly related

Table 2 Microvessels visualized by CD105 immunostaining

Grade Average number of microvessels (400 x)

1 ≤ 32 4-63 ≥ 7




to pathophysiology during wound healing and formation of scar tissue. Another study suggested that inhibition of osteopontin synthesis, oscillation or local activity after spinal surgery diminished EF and the frequency of symptoms[28]. In our study, osteopontin levels did not significantly correlate with histopathological EF evaluation methods or immunohistochemically determined CD105 levels. Consequently, osteopontin cannot be considered

a reliable marker for the immunohistochemical detection of EF.

To the best of our knowledge, there have not been any studies that investigate the impact of sorafenib on spinal EF. Nevertheless, other research on tumors has shown that the anti-angiogenic effect of VEGF inhibition can reduce neovascularization and make an affirmative contribution to life span[39]. We have reached

Table 3 Grading of fibrosis and statistical results based on various criteria

Control (Group 1) Sorafenib (Group 2)

Assessment measure Grade n % n % P

Fibrosis score0 0 0 4 50

< 0.0011 0 0 4 503 8 100 0 0

Fibroblast density1 0 0 8 100

< 0.0013 8 100 0 0

Inflammatory cell density1 0 0 6 75

< 0.0012 2 25 2 253 6 75 0 0

CD105-stained microvessels1 0 0 6 75

< 0.0012 2 25 2 253 6 75 0 0

Osteopontin-stained microvessels1 4 50 7 87.5

0.3552 2 25 1 12.53 2 25 0 0

CD105 surrounded artery CD105 surrounded artery

A B

Figure 3 Immunohistochemical tissue section stained with anti-CD105 antibody. A: Grade-3 fibrosis in Group Ⅰ; B: Grade-1 fibrosis in Group Ⅱ. blue arrow: Fibrosis.

Osteopontin surrounded arteryDuraNeural tissue

A B

Figure 4 Immunohistochemical tissue section stained with anti-osteopontin antibody. A: Grade-3 fibrosis in Group Ⅰ; B: Grade-1 fibrosis in Group Ⅱ. Star: Neural tissues; black arrow: Dura; blue arrow: Fibrosis tissue.


Osteopontin surrounded artery



a similar conclusion in our study. Sorafenib decreased neovascularization in damaged tissue and thus signi-ficantly reduced the development of EF as shown using the CD105 antibody, although osteopontin was not a reliable marker.

Secondary operations required because of EF are both challenging and have a high complication rate[1,3,4].

Braverman et al[40] reported a success rate of only 30%-35% in operations performed by them to correct EF and observed adverse results in 10%-20% of cases.

Rather than removing or relieving the pressure created by EF, it would be a far better approach to prevent EF from the start[5].

In conclusion, the data obtained from our study showed that when sorafenib was locally applied post-laminectomy, EF was significantly reduced. The staging of fibrosis evaluated by immunohistochemical staining for CD105 was compatible with conventional methods, but staging using osteopontin was not reliable. Neither toxic effects on tissues nor systematic side effects were observed with the use of sorafenib. Therefore, there should be no hindrance to the application of sorafenib for clinical purposes.

ARTICLE HIGHLIGHTSResearch background Spinal epidural fibrosis (EF) is a natural consequence of surgical trauma arising after laminectomy. In this study, we asked whether sorafenib can prevent the development of EF post-laminectomy using an immunohistochemical approach to quantify EF with CD105 and osteopontin antibodies.

Research motivationEF is one of most common causes of failed back surgery syndrome, which occurs after laminectomy. Numerous causes and mechanisms have been proposed to explain its development after laminectomy. As treatment approaches for EF are associated with high rates of complications and failed surgery, the main goal is the prevention of EF. Many methods and medicines have been tried in order to prevent the development of EF. Sorafenib is an antineoplastic medicine that has demonstrated preventive effects against fibrosis due to an antiangiogenic mechanism involving inhibition of vascular endothelial growth factor (VEGF).

Research objectivesThe goal of this study was to assess VEGF inhibition for the postoperative treatment of fibrosis.

Research methods Wistar albino rats (n = 16) were divided into two groups: control (laminectomy only) and sorafenib treatment (laminectomy + topical sorafenib). The animals were euthanatized after six weeks, and EF tissue was examined for histopathological changes after immunohistochemical staining and an EF grade was assigned. SPSS 15.0 for Windows (IBM, Armonk, NY, United States) was used for statistical analysis. Statistical significance was accepted as P < 0.05.

Research results By light microscopy, EF thickness, inflammatory cell density and arachnoid adherences were higher in the control group compared to sorafenib-treated animals. Immunohistochemical staining for CD105 to identify microvessels revealed that EF grade was lower in the treatment group based on vessel count. Staining for osteopontin did not show any statistically significant

differences in the extent of EF between groups. Significant differences in fibrosis score, fibroblast density, inflammatory cell density and CD105 immunostaining were observed between the sorafenib and control groups (P < 0.001). All control animals (Group I) received fibrosis scores of grade 3, while scores for sorafenib-treated animals (Group II) did not exceed grade 1 (P < 0.001). Fibroblast density was graded the highest in 100% of Group 1 animals but remained at grade 1 in Group II. Scores for inflammatory cell density were lowest in Group II but highest in Group I, as were scores for microvessel density assessed by CD105 immunostaining (P < 0.001). There was no significant difference in microvessel density scores between groups after osteopontin staining (P = 0.355). By light microscope, it could be seen that EF thickness, inflammatory cell density and arachnoidal adhesions were greater in control animals compared to Group II.

Research conclusions In this study, we examined the efficacy of topical treatment with sorafenib for the prevention of EF in an animal laminectomy model and analyzed immunohistochemical methods for the assessment of microvessel density in fibrotic lesions compared to conventional measures of fibrosis staging. Our results demonstrated that topical sorafenib was effective in reducing EF after laminectomy, likely due to decreased neovascularization resulting from the antiangiogenic effect of sorafenib on VEGF activity. We further show that immunohistochemical assessment of microvessel density using anti-CD105 antibodies provided a new measure of fibrotic development that was compatible with conventional methods of fibrosis staging.

Research perspectivesIn our study, the local application of sorafenib after laminectomy prevents EF. CD105 is a suitable marker for fibrosis, whereas osteopontin was not found to be reliable. Sorafenib was not observed to have any toxic effects or systemic side effects on normal tissues. Therefore, this application could be tested in clinical trials.

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258WJCC|www.wjgnet.com September 6, 2018|Volume 6|Issue 9|

39 Plastaras JP, Kim SH, Liu YY, Dicker DT, Dorsey JF, McDonough J, Cerniglia G, Rajendran RR, Gupta A, Rustgi AK, Diehl JA, Smith CD, Flaherty KT, El-Deiry WS. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res 2007; 67: 9443-9454 [PMID: 17909054 DOI:

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P- Reviewer: Chui YL, Tajiri K, Wang Y S- Editor: Cui LJ L- Editor: Filipodia E- Editor: Tan WW


Revised: July 18, 2018Accepted: August 6, 2018Article in press: August 7, 2018Published online: September 6, 2018

AbstractAIMTo review the conversion therapy for initially unresectable hepatocellular carcinoma (HCC) patients and the suitable timing for subsequent salvage surgery.

METHODSA PubMed search was undertaken from 1987 to 2017 to identify articles using the keywords including “unresectable” “hepatocellular carcinoma”, ”hepatectomy”, ”conversion therapy”, “resection”, “salvage surgery” and “downstaging”. Additional studies were investigated through a manual search of the references from the articles. The exclusion criteria were duplicates, case reports, case series, videos, contents unrelated to the topic, comments, and editorial essays. The main and widely used conversion therapies and the suitable timing for subsequent salvage surgery were discussed in detail. Two members of our group independently performed the literature search and data extraction.

RESULTS Liver volume measurements [future liver remnant (FLR)/total liver volume or residual liver volume/bodyweight ratio] and function tests (scoring systems and liver stiffness) were often performed in order to justify whether patients were suitable candidates for surgery. Successful conversion therapy was usually defined as downstaging the tumor, increasing FLR and providing subsequent salvage surgery, without increasing complications, morbidity or mortality. The requirements

ZeFeng Zhang, YuJun Luo, Quan Lu, ShiXue Dai, WeiHong Sha

SYSTEMATIC REVIEWS


Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular carcinoma: What is new?

ZeFeng Zhang, YuJun Luo, Quan Lu, ShiXue Dai, WeiHong Sha, Department of Gastroenterology and Hepatology, Guangdong Geriatrics Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China

ORCID number: Ze-Feng Zhang (0000-0002-2250-5435); Yu-Jun Luo (0000-0002-5149-6451); Quan Lu (0000-0002-9312-2450); Shi-Xue Dai (0000-0001-6428-3634); Wei-Hong Sha (0000-0001-6615-422X).

Author contributions: Zhang ZF and Luo YJ drew up the manuscript; Lu Q and Dai SX performed the literature search and data extraction; Sha WH revised the manuscript.

Conflict-of-interest statement: All the authors declare that they have no competing interests.

OpenAccess: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Correspondence to: WeiHong Sha, MD, PhD, Professor, Chief, Department of Gastroenterology and Hepatology, Guangdong Geriatrics Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Second Road, Guangzhou 510080, Guangdong Province, China. [email protected]: +86-20-83827812-61911Fax: +86-20-83827812-61922

Received: March 29, 2018Peerreview started: March 30, 2018First decision: April 26, 2018


DOI: 10.12998/wjcc.v6.i9.259




for performing salvage surgery after transcatheter arterial chemoembolization were the achievement of a partial remission in radiology, the disappearance of the portal vein thrombosis, and the lack of extrahepatic metastasis. Patients with a standardized FLR (sFLR) > 20% were good candidates for surgery after portal vein embolization, while other predictive parameters like growth rate, kinetic growth rate were treated as an effective supplementary. There was probably not enough evidence to provide a standard operation time after associating liver partition and portal vein ligation for staged hepatectomy or yttrium90 microsphere radioembolization. The indications of any combinations of conversion therapies and the subsequent salvage surgery time still need to be carefully and comprehensively evaluated.

CONCLUSIONConversion therapy is recommended for the treatment of initially unresectable HCC, and the suitable subsequent salvage surgery time should be reappraised and is closely related to its previous therapeutic effect.

Key words: Unresectable; Hepatocellular carcinoma; Hepatectomy; Conversion therapy; Salvage surgery; Downstaging


Core tip: Since the treatment for initially unresectable hepatocellular carcinoma (HCC) patients is still controversial, we emphasize the importance and effectiveness of different conversion therapies and subsequent salvage surgery. We also introduce the common conversion therapies including their indications, advantages and shortcomings. Challengingly we try to elaborate on the suitable subsequent salvage surgery timing. We advocate the reasonable unified application of these to have the full effect of complementary advantages, to promote their therapeutic effect, and to increase the survival rate of the initially unresectable HCC patients.

Zhang ZF, Luo YJ, Lu Q, Dai SX, Sha WH. Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular carcinoma: What is new? World J Clin Cases 2018; 6(9): 259-273 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/259.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.259

INTRODUCTIONHepatocellular carcinoma (HCC) is a primary cancer of the liver and is the fifth most prevalent cancer in men and the seventh in women worldwide[1]. The HCC incidence is the highest among malignancies in East Asia and sub-Saharan Africa and is closely related to


Zhang ZF et al . Unresectable HCC therapy

hepatitis B virus (HBV) prevalence or consumption of aflatoxins[2].

The current standard classification system for HCC, the Barcelona clinic liver cancer (BCLC) classification, suggests that patients with very early or early stage HCC are candidates for curative surgery[3]. Curative therapy often refers to partial hepatectomy or liver transplantation (LT), bringing a positive prognosis to the selected HCC patients. Numerous staging systems provide patients with an estimated life expectancy, but only the BCLC staging system links staging with therapies. For patients meeting the Milan criteria, orthotopic liver transplantation (OLT) can provide an excellent 5-year survival of 70% or better[4]. Unfor-tunately, the unavailability of liver grafts minimizes the utilization of OLT, and most patients fail to meet the Milan criteria when waiting for an OLT[5]. Thus, he-patectomy is currently the first-line curative therapy, but only about 30% of lesions are resectable at the time of diagnosis[6].

In this context, conversion therapy is used to incr-ease the resectability of initially unresectable HCC by increasing the size of the future liver remnant (FLR) or downstaging the tumor, followed by salvage surgery. It is usually defined as the therapy that renders some unresectable tumor surgical approachable in an attempt to improve the outcome of patients[7]. Recent studies have also demonstrated the 5-year survival rate after downstaging followed by hepatectomy varies from 24.9%-57%, which is comparable to primary liver re-section (30%-60%)[8-11].

To challenge the limits of resectability, transcatheter arterial chemoembolization (TACE) is commonly used in initially unresectable HCC, featuring tumor size shrinking, satellite lesions disappearing and liver hypertrophy[12]. Portal vein embolization (PVE) is indicated for patients who are considered to have inadequate FLR, which induces hypertrophy of the FLR in an attempt to avoid liver failure. Currently, associating liver partition and portal vein ligation (ALPPS) has been regarded as an alternative, allowing for more rapid hypertrophy of the remnant liver, which induces a mean volume increase of 78.4%[13]. Radiotherapy such as hepatic intra-arterial yttrium-90 microsphere treatment has also demon-strated a promising effect on downstaging initially un-resectable HCC and converting it into resectable HCC. Other conversion therapies can be any combination of the methods above. Tang et al[9] found that double and triple treatments produced a higher successful downstaging-resection rate and resulted in a better prognosis. Although various preoperative therapies provide initially unresectable HCC patients with the chance to undergo curative resection, the suitable timing of the subsequent salvage surgery remains uncertain and controversial. To review the selection of conversion therapy and the following suitable salvage surgery time, we conduct the review of the current literature.



MATERIALS AND METHODSA PubMed search was undertaken from 1987 to 2017 to identify articles using the keywords including “unresectable” “hepatocellular carcinoma”, ”hepatec-tomy”, ”conversion therapy”, “resection”, “salvage surgery” and “downstaging”. Additional studies were investigated through a manual search of the references from the articles. The exclusion criteria were duplicates, case reports, case series, videos, contents unrelated to the topic, comments, and editorial essays. The main and widely used conversion therapies and the suitable timing for subsequent salvage surgery were discussed in detail. Two members of our group independently performed the literature search and data extraction.

RESULTSConversion therapy for initially unresectable HCCThe typical procedures for a successful conversion therapy followed by salvage surgery are: (1) assessment of the patient’s condition, including tumor stage, liver function, FLR, and body tolerance; (2) selection of an effective conversion therapy to downstage the tumor, increase FLR and arrangement of long-term treatment by an experienced surgery; (3) assessment of timing for salvage surgery; and (4) an aggressive surgical approach to liver resection. The selection of conversion therapy depends on the tumor itself and the availability of expertise at the individual medical center, but we discuss the expertise or required skills here.

Preoperative assessmentsSimilar to other tumors within an organ, it is essential to perform a preoperative assessment of the liver. The liver is a vital organ that possesses the functions of metabolism, detoxification, bile secretion, hematopo-iesis and immune defense. Any therapies that may impair liver function can cause complications related to postoperative liver failure or increased mortality. As a result, liver insufficiency mostly occurs in patients with a decompensated liver, especially a cirrhotic liver. Based on this rationale, a liver assessment is performed in order to identify whether patients are suitable candidates for surgery, and the assessment typically consists of two aspects: Liver volume and function tests.

Liver volume test: FLR should be emphasized before any surgery as it is a significant predictor of post-hepatectomy liver failure (PHLF). With the advent of CT scans, a liver volumetric measurement can be achieved in a more accurate way. Although studies have verified that the difference between CT-guided liver volume assessment and real liver volume is minimal, the indi-vidual difference is not fully considered in CT-guided assessment[14,15]. In order to solve the problem, sFLR is

suggested instead of FLR, which can be achieved by the ratio of FLR to total liver volume (TLV), calculated on the basis of Urata’s formula allowing for a comparison between patients[16]. TLV can be calculated by a formula that uses either body surface area (BSA) or weight, which is also designated as standard liver volume (SLT)[17]. Current studies on the safe limits of surgery outline the necessity of sFLR, and the details will be articulated below.

In addition to FLR, Truant et al[18] advocated a new calculating method, residual liver volume (RLV) to bo-dyweight ratio (RLV/BWR), to predict the postoperative complications and found that non-cirrhotic patients with RLV-BWR < 0.5% carried a higher risk of developing liver failure or postoperative mortality. Truant et al[19]

further noted that RLV/BWR (0.5%) was as effective as the standardized RLV/sTLV (20%). From Lin et al[20], a retrospective study suggested that RLV/BWR (1.4%) had a certain predictive value for PHLF in patients with cirrhotic liver by a receiver operating characteristic curve (ROC). By dividing patients into an RLV/BWR > 1.4% group and an RLV/BWR < 1.4% group, a significant difference was found in the incidence of PHLF in the latter group (P = 0.006)[20].

Liver volume test is a viable and stable evaluation indirectly reflecting the quality and quantity of the he-patocyte and provide clinical guidance in a short time. But it still has its limitation under certain circumstance. For example, computed tomography-deriver liver vo-lume (CTLV) is larger than SLT when the liver is under the situation of acute hypertrophy such as liver failure, liver resection, resulting in the misjudgment of real liver assessment.

Liver function testIn general, liver function tests can be classified into 3 types (as shown in Table 1: Biochemical parameters, dynamic quantitative tests to make liver function quan-tifiable, and scoring systems that incorporate laboratory tests with quantitative tests).

Liver biochemical parameters often indicate its function of metabolism or synthesis. The aminotran-saminase enzymes, aspartate transferase (AST) and alanine transferase (ALT), are indicators of the extent of liver damage as well as necrosis. Usually the rise of these enzymes indicates the deterioration of the liver function. Albumin and clotting factors are synthesized by the liver whose concentration is closely related to the function of synthesis. Other parameters like plasma bilirubin, lactate dehydrogenase, and alkaline phosphatase can also reflect part of the liver function.

Relying too much on biochemical parameters is unreasonable, for that they only reflect the liver function indirectly and are easy to be influenced by other factors such as bile duct obstruction[21]. To assess the liver function more directly and quantitively, the dynamic quantitative liver function test is usually performed.




Indocyanine Green (ICG) clearance test has been prevalent in Eastern country, featuring its non-toxic, water-soluble dye. Through applying ICG intravenously, clinicians are able to evaluate the liver function acc-ording to the clearance of ICG whose elimination is associated with the quantity of healthy hepatocyte. 99-m TC-GSA scintigraphy and 99-m TC-GSA PET/CT both are quantitative liver function tests which evaluate the liver morphologically and physiologically.

Clinicians are now focusing on a combination of heterogeneous assessment modalities because none of the single laboratory values can predict postoperative complications precisely. Therefore, scoring systems of liver function may offer an optimal choice for the patients scheduled for surgery. Among them, Child-Turcotte-Pugh (CTP) is frequently utilized in Asia, which is based on serum albumin, total bilirubin, prothrom-bin time and the presence and grade of ascites and hepatic encephalopathy. Although patients with CTP C can benefit from resection through careful selection, patients with CTP A are commonly considered to be good candidates for surgery[22]. However, this evaluation cannot identify “high risk” and “low risk” members of the CTP A group[23,24]. To address the issue, a decision tree (Figure 1) for hepatectomy has been proposed by Makuuchi et al[25]; the decision tree incorporates the presence or absence of ascites, the total bilirubin level, and the Indocyanine Green Clearance Test (ICGR15) into the criteria. A retrospective cohort study analyzing 1056 resections had also demonstrated that hepatic resection could be safely performed in patients who met the Makuuchi criteria[24].

Liver stiffness (LS) measured by transient elas-tography (TE) is also used to predict PHLF. We demon-strated that patients with LS ≥ 16.2 kPa carried a higher risk of PHLF (sensitivity = 71.43%, specificity = 85.11%) and recommended LS ≤ 16.2 kPa as the safe cutoff for surgery[26]. Analogously, a safe cutoff of LS of 15.7 kPa and 11.25 kPa were recommended by Cescon et al[27] and Chong et al[28], respectively.

All in all, liver function test still has its own limitation. Unlike liver volumetric assessment, biochemical para-meters are too unstable to predict the PHLF. What’s more, clinicians should be cautious to use ICG clearance when patients have obstructive jaundice or cholestasis. ICG elimination combined with scoring systems or other

dynamic quantitative test is recommended to fully assess the liver function because it alone doesn’t work well in a situation where the functional distribution is heterogeneity, like a damaged liver, cirrhotic liver, or liver after PVE.

TACE and the subsequent salvage surgery time: Transarterial chemoembolization (TACE), which was firstly reported by Yamada et al[29] in 1987, is a regime involving the injection of an embolic agent and a chemotherapeutic agent into the hepatic artery, resulting in ischemic necrosis of the tumor[30]. The underlying mechanism produces a selective ischemic and pharmacologic effect on the tumor. TACE is in-dicated for massive HCC (< 70% liver volume), mul-tifocal tumors, major vascular invasion (MVI), and incomplete portal vein thrombosis (PVT), while it is contraindicated in patients with CTP C or extra-hepatic metastasis. According to the BCLC stage system, TACE is the standard therapy for BCLC stage B (intermediate HCC) patients and plays an important role in replacing other therapies that are not applicable regarding early or advanced HCC[31]. Many meta-analyses have demonstrated that pre-operative TACE has no signifi-cant effect on improving the survival of patients with resectable HCC[32-34], but none of them mentioned the effect on unresectable HCC.

TACE alone for initially unresectable HCC can achieve limited overall survival (OS). The 1-, 3-, 5- and 7-years survival rates were 82%, 47%, 26% and 16%, respectively, reported by Takayasu et al[35] in a prospective cohort study. The high recurrence rate may be because there are residual viable tumor cells after TACE that could not be detected radiologically. Thus, the subsequent salvage resection is needed to remove them to provide pathological evidence even when AFP normalizes after conversion therapy (≤ 20 mg/L). According to Zhang et al[36], the median OS in the S group (patients receiving resection after TACE) was 49 mo, which differed significantly from the median OS in the T group (not receiving resection after TACE), which was 31 mo. The 2-, 4-, and 5-year survival rates were 93%, 47%, and 26% in the S group and 74%, 18%, and 10% in the T group, respectively[36].

TACE followed by salvage surgery can prolong the OS of initially unresectable HCC patients. According

Table 1 Three types of liver function tests

Types Contents

Biochemical parameters Alanine transaminase-aspartate transaminase, gamma glutamyl transpeptidase, alkaline phosphatase, albumin, bilirubin (total and conjugated), coagulation test (INR), Serum glucose, lactate dehydrogenase,

platelet countDynamic qualitative tests 99-m TC-GSA scintigraphy (uptake), ICG test (clearance), aminopyrine breath test, MEGX, galactose

elimination, LiMAX (metabolism)Scoring systems Child-Turcotte-Pugh systems, Model for end-stage liver disease, Model for end-stage liver disease-Na

ICG: Indocyanine Green.




to Majno et al[12], the conversion rate of initially un-resectable HCC was 42%, but the OS was not men-tioned. Fan et al[8] reported that 65 patients who received TACE followed by salvage surgery had a 5-year survival rate of 56%. Majno et al[12] also indicated that improved disease-free survival (DFS) after liver resection was closely related to a good response to TACE. A good response can be downstaging of the tumor or total necrosis. Downstaging was further defined as a 50% reduction of the product of the perpendicular diameters of the largest lesion detected by CT. Patients who met this criterion seemed to have a promising DFS[12]. The absence of PVT was also regarded as a criterion for downstaging[12]. We hypothesized that the response to TACE is an independent prognostic factor for survival and possible timing for salvage surgery. Two studies have reported on the possibility of this hypothesis. A prospective nonrandomized analysis from Luo et al[37]

has revealed that subsequent resection prolonged survival time in patients who showed good response to TACE. However, this study was a nonrandomized study and it didn’t provide any details about which types of patients benefit a lot, CR or PR. In another study by Zhang et al[36], 82 patients with unresectable HCC were divided into 2 groups: S group (TACE followed by salvage surgery) and T group (TACE alone). The retrospect analysis showed that patients with TACE

followed by surgery had better OS than TACE alone (49 mo vs 31 mo, P = 0.027). Furthermore, the author also made a subgroup analysis in S group, showing that the median OS for patients in the complete respond (CR) which was defined as achieving CR according to mRECIST with AFP normalized and partial response (PR) defined as PR in mRECIST was not significantly different (50 and 49 mo, respectively, P = 0.699)[36]. It is remarkable that the OS of patients who achieved CR to TACE in S group (salvage surgery) was comparable to that in and T group (TACE alone) (50 mo vs 54 mo, respectively). And those who achieved PR benefited a lot from salvage surgery in comparison to TACE alone (49 mo vs 24 mo)[36]. These findings suggest the suitable timing of surgery is achieving PR after TACE rather than CR. Here, we consider that not all patients undergo salvage surgery after TACE, especially those who achi-eve CR with respect to necrosis. The rationality might be that patients achieving CR in terms of radiologic necrosis actually have no or few viable tumor cells which potentially induce tumor recurrence, resulting in better survival. We also believe that the subsequent salvage time after TACE to be the time when patients achieve PR in radiology, because the considerable quantity of tumor cell still active in liver and resection is expected to remove the viable tumor cell in order to prolong the DFS. In the future, more efforts should be put on the

Astices

None orcontrolled

Total Bilirubin level

Norma

ICGR15

Norma

TrisectorectomyBisectorectomy

1.11.5 mg/mL

Limited Resection

10%19%

Leftsided HepatectomyRightsided

Sectorectomy

1.61.9 mg/mL

Enucleation

20%29%

Segmentectomy

Not controlled

≥ 2.0 mg/mL

Not indicated for Hepatectomy

20%29% ≥ 40%

Limited Resection

Enucleation

Figure 1 A decision tree for hepatectomy proposed by Makuuchi. The presence or absence of ascites, total bilirubin level, and the Indocyanine Green Clearance Test (ICGR15) was used together to select good candidates for hepatectomy and to determine proper survey methods to ensure surgical quality and to reduce the risk of complications.




following to evaluate the timing for salvage surgery: (1) diminishment of large HCC; (2) FLR; (3) disappearance of PVT or MVI; and (4) margin with tumor clearance > 2 cm.

PVE and the subsequent salvage surgery time: Preoperative PVE, which increases FLR through in-ducing hypertrophy, has been introduced to expand the indications for major resection or insufficient liver function. PVE in an attempt to increase FLR was firstly reported by Makuuchi et al[38] for hilar bile duct carcinoma, and its function in preventing postoperative liver failure has also been proven[38,39]. A meta-analysis from Abulkhir et al[40] reported that about 85% patients after PVE could be undertaken surgery, while 0.8% patients died after acute liver failure. PVE may induce atrophy in the embolized lobe and compensatory hypertrophy of the future remaining lobe after hepa-tectomy. Thus, PVE offers alternatives to patients with insufficient FLR and makes resection possible.

Generally, the salvage surgery time associated with liver assessment after PVE, in other words the FLR, is evaluated by three-dimensional CT. It is currently recommended that the minimum sFLR after hepatic resection are 20%-25% in normal livers, but 40% in compromised livers (such as cirrhosis, steatosis or chronic hepatitis)[41-44]. In Japan, PVE is performed when the non-tumor resection rate is > 60% for patients with normal ICGR15 and > 40% for patients with 10% < ICGR15 ≤ 20%[45]. Furthermore, PVE is rarely performed before an extended left hepatectomy or left trisectionectomy because the right posterior section often occupies approximately 30% of the TLV[46].

The sFLR is usually assessed 4-8 wk after PVE[47]. It is expected that the rapid growth of FLR can be achieved in the next 30-40 d. For patients with a normal liver, a sFLR ranging from 20%-25% is the minimal safe volume for surgery[42,48-50]. Two large studies have confirmed the 20% sFLR as the safe cutoff for surgery[48,51]. Abdalla[51] showed that 50% of patients with sFLR < 20% of TLV had postoperative complications while only 13% of patients with an FLR > 20%TLV had complications. In the study by Kishi et al[48], the incidences of hepatic insufficiency and death due to liver failure were not different between patients with 20% ≤ sFLR < 30% and patients with a sFLR ≥ 30% and only patients with sFLR < 20% had increased rate of complications. In addition, a sFLR ≥ 40% in patients with cirrhosis is often proposed as a safe minimal volume[52-54].

Unfortunately, the majority of assays mixed the safe cutoff with PVE with safe cutoff without PVE and only a few assays took a close look at what the safe cutoff of sFLR after PVE is. Vauthey et al[16] launched a research on a safe cutoff of FLR, which showed that subjects after PVE with sFLR ≤ 25% was a risk of experiencing major complications (60%) (P = 0.002), while those whose sFLR > 25% were free of major complications. It cannot

formula a safe cutoff because the number of subjects in the study is only 5. Ribero et al[55] found that major and liver-related complications, hepatic dysfunction or insufficiency were greater in a patient with sFLR < 20% or with a degree of hypertrophy (DH) of not more than 5%. Both studies paid more attention to the difference between patients with PVE and patients without PVE, suggesting that the underlying risk of mixing them up.

It is very important to figure out what is the me-chanism of the regenerative ability of the liver after PVE, especially the relation between liver function improvement and liver volume increment. Meier et al[56] retrospectively compared post-right hepatectomy out-comes in 28 patients with and 53 without PVE in a non-randomized study, suggesting that the immediate post-operative liver function per unit of volume in patients with PVE was better than those without PVE. This finding was also similar to Farges et al[47] who found the improved post-operative liver function in patients with PVE compared with those without PVE in terms of the chronic liver. The study of Hoekstra et al[21] also revealed that the increase in FLR function after PVE was more pronounced than the increase in FRL volume. Based on these three studies, we hypothesize that PVE is able to increase not only the liver volume but also the post-operative function per unit of volume, which has not been fully elucidated and we presume that the safe cutoff for surgery after PVE ought to be revaluated.

Apart from FLR, other factors are also used to predict post-operative complications. Leung et al[57] retrospectively analyzed 153 patients who underwent a major hepatectomy after PVE and calculated growth rate (GR = DH/weeks since PVE), finding that no patient with GR > 2.66%/wk developed liver failure. Shindoh et al[58] used degree of hypertrophy at initial volume assessment divided by number of weeks elapsed after PVE defined as the kinetic growth rate (KGR) to predict overall and liver-specific postoperative morbidity and mortality, whose study indicated that KGR of less than 2% per week vs ≥ 2% per week correlate with rates of hepatic insufficiency (21.6% vs 0%, P = 0.0001) and liver-related 90-d mortality (8.1% vs 0%, P = 0.04).

Methods to evaluate the suitable timing for sur-gery seem various, but the best remains uncertain. Technetium-99m-galactosyl human serum albumin (Tc-99m-GSA) scintigraphy might be a good candidate to assess the timing. In previous studies, Tc-99m-GSA scintigraphy is able to detect Tc-99m-GSA agent and determine the liver functional reserve in various physiological and pathological states which is usually performed 2 wk after PVE[59-61]. Hirai et al[59] reported that the functional increase in 99mTc-GSA uptake after PVE is superior to the degree of morphologic, which is similar to previous studies. It was shown in his study that patients with the ratio of the left lobe volume to the standard liver volume < 35% and a low 99mTc-GSAuptake (< 25%) in the non embolized lobe after




PVE were a risk of developing postoperative liver failure. Beppu et al[61] prospectively performed an analysis on patients undergoing PVE and found that increment in the percentage of functional remnant liver volume was 7.5% greater for that of the non-tumorous RLV (P < 0.001). Kubo et al[62] performed 99mTc-GSA scintigraphy on 16 patients undergoing percutaneous transhepatic portal vein embolization (PTPE) and found that 12 patients with the left receptor index ≥ 0.35 were free of any major postoperative complication, which was calculated by dividing the radioactivity of the left lobe of the liver regions of interest (ROI) by that of the entire liver plus heart ROIs 15 min after the injection of the 99mTc-GSA[62]. Nishiyama et al[63] devised an original predictive residual index (PRI) by combining the k-value with functional liver volume which was measured by liver dynamic SPET for pre-operative assessment relevant to PTPE and reported that patients with PRI above 0.4 had a low incidence of hepatic failure after hepatectomy. As far as we are concerned, 99mTc-GSA scintigraphy is a good diagnostic tool for evaluation of functional liver volume and some safe cutoff could be used in assessing the suitable timing for surgery after PVE.

Wakabayashi et al[64] had previously noted a negative prognosis (complications or liver failure) for patients after PVE but prior to surgery was closely related to 5 factors: (1) a hypertrophic ratio of the left lobe < 1.21; (2) anICGR15 > 16% after PVE; (3) a portal pressure > 25 cmH2O immediately after PVE; (4) a post-PVE serum cholinesterase < 160 U/L; and (5) a serum hyaluronate > 160 ng/mL after PVE; however, we cannot obtain further information.

In our opinion, sFLR is usually used for evaluation of the appropriate surgery time; surgery may be safe when sFLR is > 20% for normal livers after PVE. Other predictive parameters like GR, KGR are treated as an effective supplementary to the assessment. Tc-99m-GSA scintigraphy might be a good candidate to accurately evaluate the suitable salvage surgery time.

ALPPS and the subsequent salvage surgery time: Associating liver partition and portal vein ligation (PVL) for staged hepatectomy (ALPPS) is a revolutionary strategy that combines liver partition with PVL followed by a second resection of the tumor part of the liver[65]. ALPPS consists of 2 stages. Stage 1 comprises surgical exploration, in situ splitting (ISS) of the liver parenchyma and exposure of the inferior vena cava. Stage 2 includes performing extended resection and ligating the disease-side hepatic artery, right bile duct, and hepatic vein. Unlike conventional PVE or PVL procedures, ALPPS occludes the blood supply (usually the portal vein) to the tumor part of the liver, blocks the collateral flow, and induces rapid growth of sFLR (40%-160%) in only 1 or 2 wk, while it takes more than 4 wk in PVE/PVL[66,67]. Therefore, ALPPS is often regarded as not only a remedy for PVE or PVL to accelerate FLR regeneration but also

a strategy to prevent tumor progression. According to Erik Schadde et al[68], patients in the ALPPS group showed a 77% increase in FLR on average between stages compared to an increase of 34% in the PVE/PLE group. Moreover, patients in the ALPPS group (48/48) all achieved a 30% increase in FLR, which was the cut off proposed for safe liver resection, while the PVE/PVL group did not[68]. ALPPS could achieve a 100% feasibility of R0 resection by pathology, which was the aim of ALPPS and expanded the indication for extended resection[13]. It was also indicated that 83.3% of patients (10/12) achieved R0 in monosegment ALPPS hepatectomy[69].

ALPPS is often indicated for colorectal liver meta-stases (CRLM) or initially unresectable HCC with an insufficient FLR. Patients with a sFLR ≤ 30% in normal liver or a sFLR ≤ 40% in injured livers (such as livers with cirrhosis or macrosteatosis) are usually candidates for ALPPS. During the ALPPS, preoperative assessments before stage 2 will be performed 6-9 d after stage 1 to evaluate the FLR. CT is usually used for volumetric measurement. Studies have suggested an sFLR over 20% = 30% in patients with normal livers and over 40% = 50% in patients with diseased livers are safe for surgery[44,54,68,70-73]. We show in Table 2 (ALPPS over nearly five years, including FLR% changes between stage 1 and stage 2, morbidity and mortality) below in an attempt to determine the best cutoff. It seems that high morbidity occurs frequently when the sFLR is over 30%, indicating the safe cutoff in PVE might not be suitable for ALPPS. In view of this finding, Nadalin et al[70] used the growth rate of RLV/TLV > 30% or the RLVBWR > 0.5 as the safe cutoff for stage 2, for which morbidity and mortality were 66.7% and 28.7%, respectively. A multicenter study suggested that the 90-d mortality rate was 9%, and most deaths were related to liver failure[74]. Patients in the interval between stage 1 and stage 2 in ALPPS were reported to have a higher liver failure rate than those who underwent PVE[75]. The dis-crepancy between rapid volumetric hypertrophy and a high incidence of liver failure indicates a need to assess the intrinsic function of the liver.

Hepatobiliary scintigraphy (HBS) with 99-m TC-GSA is a quantitative regime that assesses the uptake function of the liver mass by calculating the density of specific receptors. Truant et al[76] identified a notable delay in a functional increase (12.5%) by HBS in ALPPS inter-stages phase, while the liver volume had achieved a remarkable rate of hypertrophy (41.7%). The hypothesis was presumably that the early stage of hypertrophy was carried by immature hepatocytes that lacked functional capacity. These findings suggest that liver failure could even occur after stage 1, which is supported by the International Study Group of Liver Surgery (ISGLS) criteria[77]. Although HBS is promising to assess the intrinsic liver function objectively, the lack of extensive studies makes it difficult to establish




a safe cutoff for surgery. In previous studies, CTP Cor stages B, C and D of BCLC were regarded as predictors of death[23]. Schadde et al[68] proposed that liver failure meeting the ISGLS criteria after stage 1, or over 10 points of the model of end-stage liver disease (MELD) before stage 2, was an independent factor of a poor prognosis.

We believe that ALPPS may increase resectability and reduce unsatisfactory morbidity and mortality. There is insufficient evidence to sustain a safe cutoff not only in sFLR but also in intrinsic liver function. It is risky to apply the safe cutoff standard of FLR from PVE to ALPPS[78]. HBS combined with traditional assessments might be effective in distinguishing suitable candidates for stage 2.

Yttrium-90 microsphere radioembolization and the subsequent salvage surgery time: Yttrium-90 microsphere RE, a novel conversion therapy for initially unresectable HCC, is always indicated for insufficient FLR and lesions with close proximity to important structures such as portal veins that make R0 resection impossible. Nevertheless, yttrium-90 microsphere RE is inferior to PVE regarding the hypertrophy rate. PVE showed a higher hypertrophy compared with RE (PVE: 61.5% vs SIRT: 29.0%) within a shorter period [PVE: 33 (24-56) d vs SIRT: 46 (27-79) d][79].

We briefly classified the preoperative evaluation after RE into FLR and tumor response. Two previous studies had demonstrated that the increased rate of hypertrophy was unfavorable in RE[80,81]. To elucidate the dynamic change of FLR, one study observed that the FLR hypertrophy rate was 24% at 1.5-3 mo, 35% at 3-6 mo, and 45% after 9 mo. Despite the slow hypertrophy kinetic outcome, 9 of the 18 individuals achieved a sFLR > 25%. Additionally, the study indicated the volumetric hypertrophy after RE was likely to result in enough FLR for salvage surgery, although at a slow rate[79]. Regarding the tumor response, yttrium-90 microsphere RE is able to induce tumor necrosis. It is reported by

many studies that the rate of CR and PR are 0%-10% and 35%-47% respectively according to WHO criterion in a patient with HCC after yttrium-90 microsphere RE[82-91]. However, the majority of the litertures took RE as a neoadjuvant therapy rather than conversion therapy. Only a few mentioned about the rate of do-wnstaging to LT or resection, which is ranging from 29%-50%[92-94].

In our opinion, there are insufficient studies on the efficiency of the yttrium-90 microsphere RE as a conversion therapy for surgery. Also, the indications for yttrium-90 microsphere RE in an attempt to con-version therapy are uncertain. Due to the risk of tumor progression in patients undergoing PVE, we suggested that yttrium-90 microsphere RE might be considered when patients are contraindicated for PVE or vital structure is likely to get invaded because of tumor progression. In terms of those who only need adequate FLR, PVE is prior to RE.

As for safe cutoff, no prospective or retrospective study on timing for surgery is reported. A sFLR > 25% with a normal liver might be the safe cutoff[95]. For patients with cirrhosis, a sFLR > 40%is recommended. The tumor response evaluation is based on size (WHO criterion) or necrosis (EASL criterion) and ranges from 20% to 99%[88,90,96]. In spite of its promising effect on tumor necrosis, none of the studies evaluated the timing for surgery.

Sequential TACE and PVE and the subsequent salvage time: The feasibility and effectiveness of PVE to induce compensatory hypertrophy of the contra-lateral parenchyma for patients with insufficient FLR have been documented in numerous studies[42,97,98]. However, since the capacity for regeneration in cirrhotic patients is impaired, the hypertrophy rate often fails to meet the safe criterion for surgery. On the other hand, tumor progression could possibly occur based on the fact that the liver is a double blood-supply organ. In other words, when the portal vein is embolized, a

Table 2 Studies on associating liver partition and portal vein ligation for staged hepatectomy and future liver remnant % changes between stage 1 and stage 2 over nearly 5 years

Ref. Year Cases FLR%1 FLR%2 FLR%3 Morbidity Mortality Feasibility

[106] 2017 20 15 41 (24-67) 88 NM 0 100[107] 2016 295 26 39 74 NM 7.5 NM[108] 2016 17 24.2 38.5 (27.9-56.9) - 11.8 5.9 100[69] 2015 12 15 35 (26-53) 160 NM 0 100[109] 2015 9 21.1 32.2 (26.5-37.9) 96 66.7 1 100[110] 2015 62 24.2 39.1 (22.3-72.2) 48.6 80 12.9 95.2[111] 2015 11 33.9 46.3 (36.2-55.8) 140 45 9.1 100[70] 2014 15 22.6 36.3 (30-59.2) 87.2 66.7 28.7 100[68] 2014 48 23 41 (34-47) 77.4 NM 17 100[13] 2013 15 27 46.9 (31.7-67) 78.4 53 0 100[112] 2013 9 22.9 NM 87.2 68 12 100[66] 2012 10 27.8 NM 82 40 0 100

1FLR% before stage 1; 2FLR% before stage 2; 3FLR% between stage 1 and stage 2. NM: Not mentioned; FLR: Future liver remnant.




compensatory increase in artery flow might occur[99]. To improve the insufficient FLR and reduce the risk

of tumor progression, sequential TACE followed by PVE has been proposed. The rationale is that TACE not only augments the effect of PVE but also prevents the progression of the tumor through the double occlusion. An animal study of rabbit VX2 has documented that the TACE + PVE group has higher levels of IL-6, TNF-α and HGF than the TACE or PVE groups alone, indicating that combined treatment might induce stronger liver regeneration[100]. The reported rate of conversion to surgery is appreciable, ranging from 72% to 100% (Table 3). The 5-year OS rate was over 40%, which is comparable to the resection for resectable HCC[101,102]. It should be noted that TACE + PVE features not only a higher rate of increases in the percentage of FLR than PVE alone (12% vs 8%, respectively, P = 0.022) but also a better 5-year recurrence-free survival rate (37% vs 19%, respectively)[102]. A possible rationale for the appreciable hypertrophy is that TACE might attenuate the compensatory arterial flow in area embolized by PVE and induce severe damage in the embolized area, resulting in atrophy of FLR, which we also call double occulation effect[99]. However, Peng et al[103] reported that combined treatment did not induce significant increase in percent FLR compared with PVE alone [percent increase in FLR (PVE alone, 7.9% vs sequential intra-arterial therapy (IAT) + PVE, 7.4%; P = 0.203)] and the author assumed the different conclusion to the embolism agent and techniques[103]. Given the anti-tumor effect, TACE + PVE might induce more com-plete necrosis of tumor burden. It was reported by Ogata et al[102] that sequential TACE and PVE induced complete tumor necrosis in more than 80% of patients, compared with only 5% after PVE alone. The study also detected a higher 1-, 3- and 5-year recurrence-free survival rates in TACE + PVE group than PVE group (93%, 37% and 37% vs 63%, 19% and 19%; P = 0.041)[102].

This combined approach was used for patients with unilobar HCC or impaired livers (such as livers with cirrhosis, fibrosis, steatohepatitis or steatosis) to undergo major hepatectomy. Patients with CTP A with a good performance status were simultaneously evaluated (ECOG 0-2)[104].

The TACE + PVE procedure usually consists of 2

steps: (1) TACE performed on selected patients; and (2) a follow-up PVE performed with measurements (liver volumetric assessment, ICGR15 and liver fun-ction tests) after an interval ranging from 1 wk to 4 wk[101,102,105]. Aoki et al[101] recommended two standards for resection: (1) the volumetric ratio of future remnant segments was nearly 40% (in cases with an ICGR15 of less than 10%) or 60% (in cases with an ICGR15 of 10%-20%) of the total liver parenchyma; and (2) the liver function test results had returned to the baseline. The results proved that patients who followed this cut-off had promising 5-year disease-free and OS rates of 46.7% and 55.6%, respectively[101]. Tumor progression, insufficient FLR hypertrophy (< 5%) and liver failure were used as exclusion criteria, and patients who met any of those criteria could achieve a median OS of 41 mo[104]. Ogata et al[102] identified F4 fibrosis and an increase in the percentage of FLR volume less than 10% as two important complication-related factors. In this study, he stratified the patients with cirrhosis and noted that a 5% and 10% increase in FLR should be achieved in F3 fibrosis and F4 fibrosis, respectively[102].

In the interval between TACE and PVE, the ALT and AST of almost all the patients were elevated but soon returned to a normal level over a short period; this finding could be explained by the necrosis of the liver parenchyma[105]. According to this rationale, careful selection of the timing for PVE is crucial. In other words, a short interval between TACE and PVE is likely to cause PHLF, while a long interval might result in disease progression. Here, we strongly advocate that a 5% increase in FLR and a normalized liver function tests can be used to determine a safe cutoff for salvage surgery time. If the patients can undergo liver cirrhotic assessment, then the safe cutoff of F4 fibrosis should be reappraised. Any patient who develops liver failure or tumor progression after conversion therapy should be excluded from the surgery list.

DISCUSSION Are there any remaining problems that need to be solved? Firstly, the definition of unresectable is still subjective once T1 and T4 stages are excluded. Howe-ver, the distribution of the nodules to both hepatic lobes, the presence of high alpha-feto levels, and the vascular

Table 3 Studies on transcatheter arterial chemoembolization + portal venous embolizations and the rate of conversion to resection

Ref. Year Cases Types of tumor Convert to surgery (%) 5-yr disease-free survival rates (%)

Median survival time (mo)

[101] 2004 17 Hepatocellular carcinoma 94 46.7 NM[102] 2006 18 Hepatocellular carcinoma 100 37 NM[113] 2011 71 Hepatocellular carcinoma 95.7 61 NM[103] 2012 29 Hepatocellular carcinoma and metastatic disease 93.1 NM 58[104] 2016 54 Hepatocellular carcinoma 72 NM 41

NM: Not mentioned.




involvement are substantial tumoral parameters that help in the evaluation of resectability beside residual liver function and patients general conditions. Moreover, the limit of unresectability depends on the level of the hospital and the experience of the operator or their expertise in surgery.

For the initially unresectable HCC patients, conver-sion therapies such as TACE, PVE, ALPPS, yttrium-90 RE, and sequential TACE and PVE have been demons-trated to be effective and should be performed. Both morphological and functional examinations need to be undertaken to estimate the therapeutic effect before salvage surgery. Controlling a good operative time and selecting a reasonable procedure are important for improving the operative efficacy. The reasonable unified application of conversion therapy and salvage surgery can improve the curative effect and increase the survival rate of patients.

ARTICLE HIGHLIGHTSResearch backgroundHepatocellular carcinoma (HCC) is a primary cancer of the liver and is the fifth most prevalent cancer in men and the seventh in women worldwide. Hepatectomy is currently the first-line curative therapy, but about 30% of lesions are resectable at the time of diagnosis. Conversion therapy is used to increase the resectability of initially unresectable HCC by increasing the size of the future liver remnant (FLR) or downstaging the tumor, followed by salvage surgery. Although various preoperative therapies provide initially unresectable HCC patients with the chance to undergo curative resection, the suitable timing of the subsequent salvage surgery remains uncertain and controversial.

Research motivationOnly 10%-30% HCC patients can obtain the chance to undergo surgery at the time of diagnosis. Those who are not suitable for curative surgery may benefit from conversion therapy and seize the opportunity to undergo salvage surgery when they reach the “timing”. Therefore, we review the types of conversion therapy and the suitable timing for salvage surgery.

Research objectivesTo review the conversion therapy for initially unresectable HCC patients and the suitable timing for subsequent salvage surgery, and we finally hope to increase the 5-year survival rate of HCC patients.

Research methods A PubMed search was undertaken from 1987 to 2017 to identify articles using the key words including “unresectable” “hepatocellular carcinoma”, ”hepatectomy”, ”conversion therapy”, “resection”, “salvage surgery” and “downstaging”. Additional studies were investigated through a manual search of the references from the articles. The exclusion criteria were duplicates, case reports, case series, videos, contents unrelated to the topic, comments, and editorial essays. The main and widely used conversion therapies and the suitable timing for subsequent salvage surgery were discussed in detail. Two members of our group independently performed the literature search and data extraction.

Research resultsLiver volume measurements (FLR/total liver volume or residual liver volume/bodyweight ratio) and function tests (scoring systems and liver stiffness) were often performed in order to justify whether patients were suitable candidates for surgery. Successful conversion therapy was usually defined as downstaging the tumor, increasing FLR and providing subsequent salvage surgery, without

increasing complications, morbidity or mortality. The requirements for performing salvage surgery after transcatheter arterial chemoembolization (TACE) were the achievement of a partial remission in radiology, the disappearance of the portal vein thrombosis (PVT), and the lack of extrahepatic metastasis. Patients with a standardized FLR (sFLR) > 20% were good candidates for surgery after portal vein embolization (PVE), while other predictive parameters like growth rate (GR), kinetic growth rate (KGR) were treated as an effective supplementary. There was probably not enough evidence to provide a standard operation time after associating liver partition and portal vein ligation for staged hepatectomy (ALLPS) or yttrium-90 microsphere radioembolization (RE). The indications of any combinations of conversion therapies and the subsequent salvage surgery time still need to be carefully and comprehensively evaluated.

Research conclusionConversion therapy is recommended for the treatment of initially unresectable HCC, and the suitable subsequent salvage surgery time should be reappraised and is closely related to its previous therapeutic effect.

Research perspectivesFor the initially unresectable HCC patients, conversion therapies such as TACE, PVE, ALPPS, yttrium-90 RE, and sequential TACE and PVE have been demonstrated to be effective and should be performed. Both morphological and functional examinations need to be undertaken to estimate the therapeutic effect before salvage surgery. Controlling a good operative time and selecting a reasonable procedure are important for improving the operative efficacy. The reasonable unified application of conversion therapy and salvage surgery can improve the curative effect and increase the survival rate of patients.

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avoid postoperative liver failure? J Gastrointest Surg 2013; 17: 956-961 [PMID: 23288719 DOI: 10.1007/s11605-012-2132-y]

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P- Reviewer: Agrawal S, Barone M, Ho MC, Memeo R S- Editor: Ji FF L- Editor: A E- Editor: Tan WW



Received: April 2, 2018Peer-review started: April 2, 2018First decision: May 8, 2018Revised: May 31, 2018Accepted: June 7, 2018Article in press: June 8, 2018Published online: September 6, 2018

AbstractSystemic air embolism through a bronchovenous fistula (BVF) has been described in patients undergoing positive-pressure ventilation. However, no report has mentioned the potential risks of systemic air embolism through a BVF in patients undergoing extracorporeal membrane oxygenation (ECMO). Positive-pressure ven-tilation and ECMO support in patients with lung injury can increase the risk of systemic air embolism through a BVF. Increased alveolar pressure, decreased pulmonary venous pressure, and anticoagulation are thought to be the factors that contribute to this complication. Here, we present a case of systemic air embolism in a patient with ECMO and mechanical ventilator support.

Key words: Air embolism; Extracorporeal membrane oxygenation; Cerebral embolism; Positive-pressure ventilation; Cardio-pulmonary resuscitation


Core tip: Sudden deterioration of patients during ex-tracorporeal membrane oxygenation support is not unusual. Usually, it is thought to result from the critical illness of the patients. This report suggests that some such cases may be related to bronchovenous fistula, which causes cerebral and coronary air embolisms.

Se-Min Ryu, Sung-Min Park

CASE REPORT


Unexpected complication during extracorporeal membrane oxygenation support: Ventilator associated systemic air embolism

Se-Min Ryu, Sung-Min Park, Department of Thoracic and Cardiovascular Surgery, Kangwon National University Hospital, School of Medicine, Kangwon National Univerity, Chuncheon 24289, South Korea

ORCID number: Se-Min Ryu (0000-0003-2290-5778); Sung-Min Park (0000-0003-0959-1276).

Author contributions: Ryu SM wrote the report; Park SM designed the report, analyzed the data, and performed the literature search.

Supported by 2014 Research Grant from Kangwon National University.

Informed consent statement: This case report was exempt from the Institutional Review Board standards at Kangwon National University Hospital.

Conflictofinterest statement: All authors reported no conflict-of-interest to disclose.

CARE Checklist (2013) statement: The authors have read the CARE Checklist (2013), and the manuscript was prepared and revised according to the CARE Checklist (2013).

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial(CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Correspondence to: Sung-Min Park, MD, PhD, Doctor, Full Professor, Department of Thoracic and Cardiovascular Surgery, Kangwon National University Hospital, School of Medicine, Kangwon National Univerity, 200-722, Baengnyeong-ro 156, Chuncheon 24289, South Korea. [email protected]: +82-33-2582294Fax: +82-33-2582182


DOI: 10.12998/wjcc.v6.i9.274




Ryu SM, Park SM. Unexpected complication during extra-corporeal membrane oxygenation support: Ventilator associated systemic air embolism. World J Clin Cases 2018; 6(9): 274-278 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/274.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.274

INTRODUCTIONAir in the extracorporeal membrane oxygenation (ECMO) circuit (1.4%-4.6%) can lead to systemic air embolism[1-3]. In most cases, the air source is the venous system, and massive systemic air embolism is rare. The known origins of air embolism include the venous cannula, central venous catheter, membrane oxygena-tor, and cavitation[4]. In most studies, the lung is not considered a source of air embolism in ECMO support. However, massive systemic air embolism can occur in patients with positive pressure ventilation[5,6]. When there is an injury to the lung and the alveolar pressure exceeds pulmonary venous pressure, air can enter the systemic circulation through the pulmonary vein. This is known as bronchovenous fistula (BVF) and causes massive cerebral and myocardial air embolism[7,8]. No previous report has considered the possibility that ECMO can contribute to the development of air embolism through BVF. We present a case of systemic air embolism in a patient undergoing ECMO support and mechanical ventilation.

CASE REPORTA 47-year-old man was admitted to the emergency room for chest pain. He had a medical history of hy-pertension and diabetes mellitus. His initial blood pressure and heart rate were 80/50 mmHg and 124/min, respectively. Electrocardiography (ECG) showed STsegment elevation on leads V2V4. The troponin Ⅰconcentration was 102 ng/mL. Cardiac arrest developed and cardiac massage was initiated. The patient was intubated with a 7.5 Fr endotracheal tube and was manually ventilated with an ambu bag. During bagging, bloody secretion was observed in the endotracheal tube. An intra-aortic balloon pump was inserted through the left femoral artery. Because of severe cardiac dysfunction and ventricular arrhythmia, ECMO (Capiox EBS, Terumo Corp., Tokyo, Japan) was applied through the right femoral vein and artery. Emergency coronary angiography (CAG) revealed total occlusion of the pro-ximal left anterior descending artery and up to 40% diffuse stenosis of the right coronary artery (RCA). A coronary artery stent was inserted into the left anterior descending artery. After the procedure, the patient was supported with mechanical ventilation. The ventilator was set in the pressurecontrol mode with an FiO2 of 0.8, peak end expiratory pressure of 6 cmH2O, peak pressure of 26 cmH2O, and respiratory rate of 12/min. The follow-up chest X-ray revealed haziness in the right


Ryu SM et al . Bronchovenous fistula in ECMO

upper lung field (Figure 1). The patient’s hemodynamic condition and consciousness level gradually improved; he became able to follow commands and open his eyes in response to stimulation. His hourly urine output increased, and the inotropic agent was withdrawn. ECMO flow was decreased from 3.5 L/min to 1.0 L/min. Five hours after percutaneous coronary intervention (PCI), he experienced a sudden decrease in blood pressure from 120/70 mmHg to 60/40 mmHg and bradycardia, as low as 15/min, which recovered after administration of atropine and epinephrine. The ECMO circuit was immediately examined for any flow disturbance, but no abnormal sign or dysfunction was found. ECMO flow was increased up to 3.0 L/min. The 12lead ECG results suggested acute inferior and anteroseptal wall ischemia (Figure 2). The followup CAG showed no evidence of occlusion or significant stenosis of coronary vessels. Echocardiography did not show any evidence of an intracardiac shunt or pericardial tamponade, but severe dysfunction of the left ventricle was detected. Acute neurological deterioration was also present; his Glasgow Coma Scale score was 4. Because of the unexplained neurologic dysfunction, a computed tomo-graphic brain scan was taken, revealing a massive cerebral air embolism (Figure 3). The patient was placed in the Trendelenburg position. Although he did not have a central venous catheter (Figure 1), all indwelling catheters, including the ECMO circuit, were inspected for a possible origin of the air embolism, but we found no defect. Despite resuscitation measures, the patient’s condition became aggravated and he died 10 h after the sudden deterioration.

DISCUSSIONSystemic air embolism is a dreaded complication in ECMO support. Several sources of air emboli are known: The venous cannula, central venous catheter, membrane oxygenator, and cavitation[4]. In this case, there was a massive cerebral air embolism. If such a large amount of air originated from the venous system, air should have been detected in the ECMO circuit. However, no air was detected in the ECMO circuit, including the oxygenator and the cone of the centrifugal pump. The systemic air embolism could not be explained until a pulmonary origin of the air embolism was suspected.

No previous report has mentioned the lung as a source of systemic air embolism in patients with ECMO support. However, systemic air embolism can result from the interface between the alveoli and pulmonary veins known as BVF[5-8]. BVF causes massive cerebral and coronary air embolism in neonates with mechanical ventilation and in adults who have lung injury and are supported by positive pressure ventilation[9,10]. The underlying mechanism is increased alveolar pressure exceeding pulmonary venous pressure and shift of air through the damaged pulmonary vasculature[6]. Loss of consciousness from cerebral air embolism and sudden bradycardia from RCA occlusion with air emboli are the



prominent signs of air embolism caused by BVF[6-8]. These clinical features closely resemble those of our case.

There are a number of ECMO-related factors that might contribute to the increased risk of systemic air embolism originating from a BVF. One factor is decreased venous return to the heart. ECMO (VA mode) drains venous blood, thereby decreasing venous return, and lowers pulmonary venous pressure, which consequent-ly increases the chances of alveolar air entering the vascular system. Many patients receive CPR before ECMO support. Manual ambu bagging with cardiac massage during CPR can cause lung injury, forcing air to enter the pulmonary vein[11]. The use of anticoagulation prevents sealing of the injured vascular bed of the lung, increasing the risk of air embolism. When these patients are supported by positive pressure ventilation, which is often the case, the air can enter the vascular system through the injured alveoli. LV diastolic pressure can fall below zero in mitral stenosis patients[12]. Under ECMO support where LV diastolic volume is reduced, the diastolic LV pressure may drop to negative pressure when the LV function returns to normal (e.g., after PCI). Consequently the risks of BVF air embolism will increase. Because of these clinical conditions, patients with ECMO support have increased risk of developing air embolism originating from BVF.

Although there are a number of factors that can increase the risk of air entrance into the pulmonary vein, it seems that the actual systemic air embolism does not occur until there is sufficient left ventricular blood flow. The patient did not show any sign of sys-temic air embolism when fully supported with EC-MO. The systemic air embolism developed after we decreased ECMO flow. In a case report about ECMO-related systemic air embolism, the author described a large oscillating air bubble detected in the aortic root immediately after initiation of the IABP[13]. These clinical features suggest that the air embolism might take place in two phases. First, the air in the alveolar space enters into the pulmonary vein. It is trapped in the pulmonary vein, left atrium, or left ventricle depending on the po-

sition of the patient. Secondly, when there is enough left ventricular blood flow, the air bubbles move into the aorta and peripheral arteries, causing systemic air embolism.

Evidence of air entrance through BVF in patients with ECMO support has not been reported except in a pediatric patient who had total anomalous pulmonary venous return (TAPVR) and was supported with ECMO[2]. In that case, air was detected in the venous cannula during ambu bagging because there was a residual pulmonary veinSVC connection. Air embolism through the lung during CPB has been reported[14,15]. These air embolisms were detected after left ventricular beat-ing was started during open heart surgery. Common features of these cases include anticoagulation, lung injury, CPB, and positive pressure ventilation. We searched for cases of air embolism through BVF in ECMO support. There is one case report to compare with our case[13]. The case was similar to our case in that the patient had AMI and received CPR followed by ECMO support and PCI[13]. According to that report, IABP was inserted through the femoral artery in the intervention room to enhance coronary perfusion and decrease afterload. Immediately after IABP was started, a large air bubble was detected in the aortic root. The author admitted that the origin of the air was unknown and suggested the IABP sheath would be a possible source of the air. However, air entering the arterial system without a pressure gradient is unlikely. Considering the clinical conditions, which resembled those in our case, we believe that a BVF was the origin of the air embolism in that case.

One might wonder why there have been no reports about ECMOrelated BVF air embolism. Gas in the systemic circulation is extremely difficult to document[5]. As is our experience, sudden deterioration of patients with AMI prompts a search for cardiac problems, and the possibility of cerebral air embolism might be overlooked. Even though scarce in the literature, there might be more ECMOrelated BVF air embolisms than we think because CPR and ECMO support followed by PCI is common clinical practice. Sudden loss of consciousness and bradycardia in a patient with ECMO support might be a sign of cerebral and coronary air embolism caused by BVF. Avoiding high pressure ventilation setting might help to lower the risk of this complication. Because systemic air embolism is often lethal and there is no effective treatment available, prevention of this complication is of key importance. To reveal the true incidence of BVF air embolism in ECMO support and to prevent this devastating complication, clinicians should be aware of the possibility of air embolism from BVF in patients with ECMO support.

ARTICLE HIGHLIGHTSCase characteristicsA 47-year-old male with extracorporeal membrane oxygenation (ECMO)

Figure 1 Chest X-ray in the critical care unit. Right upper lung field infil-tration is visible. There is no central venous catheter.


ARTICLE HIGHLIGHTS



support developed sudden cardiogenic shock and loss of consciousness.

Clinical diagnosisThe electrocardiography finding suggested acute inferior and anteroseptal wall ischemia, and the loss of consciousness was thought to be the consequence of the cardiogenic shock because the ECMO flow was low.

Differential diagnosisDifferential diagnosis includes acute myocardial infarction, cerebral thromboembolism, and cerebral hemorrhage.

Imaging diagnosisBrain CT showed massive cerebral air embolism.

TreatmentThe patient was placed in the Trendelenburg position.

Related reportsBronchovenous fistula (BVF) can cause systemic air embolism when the alveolar pressure exceeds pulmonary venous pressure.

Term explanation BVF is a connection between alveolar and pulmonary vein caused by pulmonary injury.

Experiences and lessonsECMO support can increase the risk of systemic air embolism caused by BVF fistula, and this complication should be suspected when there is sudden

bradycardia with loss of consciousness.

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Figure 2 Electrocardiogram after the development of sudden hypotension and loss of consciousness. The electrocardiogram shows inferior wall infarction.

Figure 3 Brain computed tomography image after the development of sudden hypotension and loss of consciousness. A massive cerebral air embolism is observed.




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P- Reviewer: Auzinger G, Ono M S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW



Published online: September 6, 2018

AbstractCarpal tunnel syndrome (CTS) is well recognized as the most common type of peripheral neuropathy. A rare cause of CTS is tophaceous gout. Tophi deposits can accumulate in various structures including the flexor tendons, tendon sheaths, the carpal tunnel floor, transverse carpal ligament, and even the median nerve, causing various symptoms such as pain, numbness, and weakness. Tophi forming in the carpal canal can compress the median nerve, leading to CTS. Here, we describe a 25-year-old male with a family history of tophaceous gout who presented with typical CTS symptoms. Although he had chronic numbness in his right hand, he failed to present with any obvious palpable masses on his forearm or hand. However, his family history, laboratory, clinical, and magnetic resonance imaging findings were consistent with tophi deposits. CTS symptoms were eased through surgical removal of tophi and decompression of the median nerve. No recurrences of gout and CTS symptoms were reported at a one-year follow-up. This case shows that CTS symptoms could be the initial manifestation of tophaceous gout. In patients with a family history of gout and with CTS symptoms, imaging examinations are critical for early diagnosis and selecting appropri-ate treatment. Surgical removal of “covert” tophi and decompression of the median nerve is an effective op-tion for eliminating symptoms.

Key words: Carpal tunnel syndrome; Tophaceous gout; Family medical history; Surgery; Flexor Tendon


Core tip: A rare cause of carpal tunnel syndrome

PengBo Luo, ChangQing Zhang

CASE REPORT


Chronic carpal tunnel syndrome caused by covert tophaceous gout: A case report

PengBo Luo, ChangQing Zhang, Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai 200233, China

ORCID number: Peng-Bo Luo (0000-0002-4837-0495); Chang-Qing Zhang (0000 -0002-7408-4126).

Author contributions: All the two authors contributed to this manuscript.

Informed consent statement: Our hospital does not need patient consent to publish a single case.

Conflictofinterest statement: None of the authors have any conflict of interest related to the article.

CARE Checklist (2013) statement: The authors have read the CARE Checklist (2013), and the manuscript was prepared and revised according to the CARE Checklist.


Manuscript Source: Unsolicited Manuscript

Correspondence to: ChangQing Zhang, MD, PhD, Full Professor, Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. [email protected]: +86-21-64701361

Received: April 3, 2018Peer-review started: April 3, 2018First decision: May 21, 2018Revised: May 26, 2018Accepted: June 7, 2018Article in press: June 8, 2018


DOI: 10.12998/wjcc.v6.i9.279




(CTS) is tophaceous gout. This report represents the first case, to our knowledge, of a patient presenting with typical CTS symptoms, yet lacking any visible or palpable signs of gout in any part of his body. Only after magnetic resonance imaging, surgical inspection, and pathological analysis was it clear that the 25-year-old patient had a large gouty tophus attached to the surface of the distal volar radius adjacent to the digital flexor tendons. Surgical removal of the “covert” tophi and decompression of the median nerve is an effective option for eliminating CTS symptoms.

Luo PB, Zhang CQ. Chronic carpal tunnel syndrome caused by covert tophaceous gout: A case report. World J Clin Cases 2018; 6(9): 279-283 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/279.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.279

INTRODUCTIONCarpal tunnel syndrome (CTS) is the most commonly diagnosed compression neuropathy of the upper limb[1]. It is usually caused by excessive pressure on the median nerve as it travels through the wrist at the carpal tunnel. The confined anatomic space makes the nerve vulnerable to compression. The causes of CTS include local trauma to the wrist, bleeding disorders, spaceoccupying lesions, rheumatoid arthritis, diabetes mellitus, and multiple myeloma[13]. Deposition of gouty tophi in flexor tendons can also cause chronic and acute CTS. This is extremely rare, with a reported incidence of 0.6%[4]. For the patient of this case report presenting with CTS, it was particularly exceptional that he had no visible tophi in any part of the body. To our limited knowledge, the literature has yet to report tophi-associated chronic CTS in a patient who lacks visible signs of tophi but has a family medical history of gout. Here, we describe such a case of CTS without significantly visible tophi in a 25-year-old male.

CASE REPORTA 25-year-old male who was referred to our department presented with typical CTS symptoms of his right hand. The symptoms worsened with extension of the wrist. Intermittent numbness in the three radial fingers of the right hand developed three years ago, but he did not recall a history of trauma or tophaceous gout. The patient reported no previous gouty attack. He did not accept medical treatment during the first two years. His condition worsened, and the numbness in his right hand became significantly aggravated over the previous three months before seeking treatment at our department.

Medical treatment with mecobalamin aimed to ease the numbness began three months ago, but without significant improvement. The patient had normal hand function activities but decreased grip strength. On


Luo PB et al . CTS and covert gouty tophi

local physical examinations, joint pain, palpable mass, and redness of the wrist and hand were absent. Obvious atrophy of the thenar muscle was also absent. Phalen’s test and Tinel’s sign were positive. Neurologic examination revealed numbness in the thumb, index finger, middle finger, and half of the ring finger of his right hand. Electromyography revealed reduced conduction velocity and impaired sensory function of the median nerve. Laboratory analyses, including complete blood count and electrolytes, were normal. Creactive protein was elevated (17.17 mg/L), as was erythrocyte sedimentation rate (28 mm/h). A diagnosis of hyperuricemia was made with an elevated uric acid level of 568 µmol/L.

Radiographs revealed no bone erosion or tophi deposition in his hands (Figure 1). Magnetic resonance imaging (MRI) showed a sizable mass adhering to the surface of the distal volar radius with a wide base, and a mass adjacent to the digital flexor tendons at the level of the proximal carpal tunnel; this mass appeared to be pressing on the median nerve (Figure 2). The mass had lowtointermediate signal intensity on T1weighted images and high signal intensity on T2-wei-ghted images. Given the gout history of the patient’s father, and the laboratory, clinical, and imaging findings, we speculated this was a case of tophaceous gout compressing the median nerve, resulting in numbness in the hand.

On the basis of imaging findings and the failure to ease numbness through mecobalamin therapy, we decided to perform surgery two days after hospital admission. During the operation, an upper arm tourniquet was applied (inflated to 200 mmHg) without exsanguinating the extremity. A longitudinal incision was made over the carpal tunnel, distal to the wrist flexion crease and proximal to the forearm. With the transverse carpal ligament exposed, the median nerve was identified. We observed a significant bulge in the portion of the median nerve within the canal and a distal impression on the nerve (Figure 3). Large tophi were observed next to the ulnar side of the median nerve, and in the flexor digitorum superficialis and flexor digitorum profundus tendon sheaths of the middle finger, ring finger, and digitus minimus (Figure 4). With the median nerve and flexor tendons protected by the drainage tubes, large gouty tophi were found embedded deep into the distal volar radius (Figure 4). The gouty tophi had irregular boundary shapes, and their surface was soft but without inflammation or ulceration. Thus, we performed a synovectomy of all the affected flexor tendons and we removed the deep gouty tophi (Figures 5 and 6). A definite diagnosis of tophaceous gout was confirmed by the pathology report. The wound was irrigated with saline until clear effluent was observed. Epineurium neurolysis of the median nerve was then performed. Rubber drainage tubes were removed one week later.

The day after surgery, the patient reported marked



lessening of numbness in the thumb, index finger, middle finger, and half of the ring finger of his right hand. We then encouraged him to actively flex and extend his hand; uric acidlowering medication was recommended. The patient was followed closely as an outpatient under orthopedic surgery services and rheumatology services. Longterm management of gout involved daily maintenance medication with allopurinol. With respect to diet, the patient was advised to decrease consumption of meat high in purine content, high fructose corn syrup, and alcohol, especially beer.

Six months after the surgery, the patient recovered full sensory and motor function of the right median nerve, and his uric acid level was normal. As of the 12-mo follow-up, the patient reported no gouty attacks and no recurrence of numbness. Gouty tophi in the operated hand were also absent at the 12-mo exam (Figure 7).

DISCUSSIONThe carpal tunnel is a narrow rigid tube at the base of the hand composed of ligaments and bones. It encompasses the median nerve and the tendons that move the fingers. The confined anatomic space makes the nerve susceptible to compression. Tophaceous gout is a well recognized, but uncommon, cause of CTS. Tophi can be deposited in various structures, including the flexor tendons, tendon sheaths, the carpal tunnel floor, transverse carpal ligament, and even the median nerve[5]. These can cause symptoms associated with these deposits[5]. In the current case, several flexor digitorum superficialis and flexor digitorum profundus tendons were affected by tophi, and more deep tophi were found adhering to the distal volar radius. Interestingly, in this patient the pronator quadratus muscle was also affected, which had never been reported in the literature.

Carpal tunnel compression may be the initial manifestation of gout[6]. Because of its rare frequency, gouty involvement of the flexor tendons and CTS may be overlooked in the differential diagnosis[7]. It was

particularly exceptional for this patient, because there were no visible tophi in any part of his body. Gout is more likely to develop in patients whose family mem-bers have had gout. It is possible that their genetic makeup predisposes them to gout[8]. Since our patient reported no problem with overconsumption of alcohol, no history of gout, and no visible tophi when he visited our department for local examinations, we diagnosed him as a typical CTS patient. He took mecobalamin but experienced little relief for months. Given the imaging findings and his father’s history of gout, gouty tophi were finally considered to be the likely cause of CTS.

Chen et al[9] performed a retrospective CT and MRI review of patients with a documented diagnosis of gout and who presented with goutrelated CTS. This review revealed that gouty tophi should be entertained as a cause of CTS in the appropriate patient population. Ultrasound has also been used in diagnosing CTS caused by gouty tophi of the flexor tendons of the fingers[10]. It is well known that a delayed diagnosis can lead to irreversible nerve injury and complications, including articular changes, tendon rupture, and tenosynovitis[11]. Thus, it is imperative to consider all possibilities when entertaining causes of CTS.

In the present case, surgical intervention was postponed because of a lack of imaging data and our ignorance about his family history of gout. Thus, physicians need to be familiar with tophiassociated CTS and aware of the patient’s family history of gout, as both are critical for differential diagnosis. In addition, imaging examinations, including ultrasound, CT, and MRI are recommended for an early accurate diagnosis. Surgical intervention is recommended to relieve symptoms and to avoid permanent damage.

Poor healing of surgical wounds in gouty patients is well recognized because of the phlogistic characteristics of gout[12]. This did not pose a problem in our case. Complete removal of visible and wellconfined tophi, lack of inflammatory lesions, satisfactory rinsing of the area and use of uric acidlowering agents may explain why this was averted. The disease may recur due to residual tophi. Complete removal of the tophi achieved a good result in our patient. Uric acidlowering medication, including uricosuric agents and allopurinol, is necessary to avoid recurrence of gout[13]. The target serum urate levels should be less than 6 mg/dL[14]. Reducing the consumption of meat rich in purine content, high fructose corn syrup, and alcohol also was helpful in our case, likely because poor compliance with low-purine diet the-rapy and consumption of seafood and beer increases the risk of gout[7].

In conclusion, prompt diagnosis accompanied by CT or MRI is necessary to identify the specific causes of CTS in patients with a family history of gout and medication failure. To relieve symptoms and to avoid permanent damage, surgical decompression of the median nerve and complete removal of gouty tophi are recommended

Figure 1 Radiograhic posteroanterior projection images of the patient’s hands. Radiographs showed no bone erosion or tophi deposition.




whenever a patient presents with symptomatic median nerve compression. Postoperatively, uric acidlowering

therapy should be instituted.

ARTICLE HIGHLIGHTSCase characteristicsA young man with a family history of tophaceous gout who presented with typical carpal tunnel syndrome symptoms.

Clinical diagnosisNumbness in the thumb, index finger, middle finger, and half of the ring finger of the right hand. The symptoms worsened with extension of the wrist. Normal

ARTICLE HIGHLIGHTS

*

* *

A B C

Figure 2 Magnetic resonance images of the patient’s right hand and wrist. A: Lateral projection; B: Posteroanterior projection; C: Transverse projections. Magnetic resonance imaging revealed a giant mass adhering to the surface of the distal volar radius. The base of the mass was wide (A, B, white arrows). There was also a mass adjacent to the digital flexor tendons at the level of the proximal carpal tunnel. These were pressing on the median nerve (C, red asterisks).

Figure 3 Photomicrograph of the surgical field. After exposing the transverse carpal ligament, we identified the median nerve. The section of the median nerve coursing through the carpal canal had a significant bulge (white arrow) and a distal impression (black arrow).

MN

Figure 4 Photomicrograph of the surgical field, with the wrist rotated medially. An impressive large mass (3.2 cm in diameter; black arrow) was observed on the ulnar side of the median nerve (MN); in the flexor digitorum superficialis and flexor digitorum profundus tendon sheaths of the middle finger, ring finger; and in the digitus minimus. With the median nerve and flexor tendons protected by the drainage tubes, we observed another large mass (7.0 cm in diameter; white arrows) embedded deep into the distal volar radius. The masses were irregularly shaped and their surface was soft but without inflammation or ulceration.

Figure 5 Synovectomy of all affected flexor tendons was performed and deep masses were removed.

Figure 6 Chalk-like liquid was found in the gouty mass.




hand function activities with decreased grip strength.

Differential diagnosisTophaceous gout.

Laboratory diagnosisComplete blood count and electrolytes were normal. Creactive protein, erythrocyte sedimentation rate and uric acid level were elevated.

Imaging diagnosisRadiographs showed no bone erosion or tophi deposition in the hands. Magnetic resonance imaging showed a sizable mass adhering to the surface of the distal volar radius, and a mass adjacent to the digital flexor tendons at the level of the proximal carpal tunnel.

Pathological diagnosisTophaceous gout in the digital flexor tendons.

TreatmentSurgical removal of the gouty tophi, synovectomy of all the affected flexor tendons, and decompression of the median nerve were performed.

Related reportsTo our limited knowledge, this is the first case report to describe tophi-associated chronic carpal tunnel syndrome without visible signs of tophi but has a family medical history of gout.

Term explanationCarpal tunnel syndrome is the most commonly diagnosed compression neuropathy of the upper limb, which is usually caused by excessive pressure on the median nerve by many causes. Deposition of gouty tophi in flexor tendons is a rare cause.

Experiences and lessonsTophaceous gout is a rare cause of carpal tunnel syndrome (CTS). Physicians need to be familiar with tophiassociated CTS and aware of the patient’s family

history of gout. Prompt imaging examinations including computed tomography or magnetic resonance imaging are necessary to identify the specific causes of CTS.

REFERENCES1 Levin RA, Felsenthal G. Handcuff neuropathy: two unusual cases.

Arch Phys Med Rehabil 1984; 65: 41-43 [PMID: 6691797]2 Rayan GM, Conner S. Posterior interosseous nerve paralysis and

amyloid neuropathy of multiple myeloma. Clin Orthop Relat Res 1982; 202-205 [PMID: 7140071 DOI: 10.1097/00003086-198211000-00036]

3 Schnetzler KA. Acute carpal tunnel syndrome. J Am Acad Orthop Surg 2008; 16: 276-282 [PMID: 18460688 DOI: 10.5435/00124635-200805000-00006]

4 Rich JT, Bush DC, Lincoski CJ, Harrington TM. Carpal tunnel syndrome due to tophaceous gout. Orthopedics 2004; 27: 862-863 [PMID: 15369009]

5 Chuang HL, Wong CW. Carpal tunnel syndrome induced by tophaceous deposits on the median nerve: case report. Neurosurgery 1994; 34: 919; discussion 920 [PMID: 8052395 DOI: 10.1227/00006123-199405000-00023]

6 Ogilvie C, Kay NR. Fulminating carpal tunnel syndrome due to gout. J Hand Surg Br 1988; 13: 42-43 [PMID: 3361205 DOI: 10.1016/0266-7681(88)90049-6]

7 Lu H, Chen Q, Shen H. A repeated carpal tunnel syndrome due to tophaceous gout in flexor tendon: A case report. Medicine (Baltimore) 2017; 96: e6245 [PMID: 28248892 DOI: 10.1097/MD.0000000000006245]

8 Bardin T, Richette P. [The epidemiology and genetic of gout]. Presse Med 2011; 40: 830-835 [PMID: 21752574 DOI: 10.1016/j.lpm.2011.04.012]

9 Chen CK, Chung CB, Yeh L, Pan HB, Yang CF, Lai PH, Liang HL, Resnick D. Carpal tunnel syndrome caused by tophaceous gout: CT and MR imaging features in 20 patients. AJR Am J Roentgenol 2000; 175: 655-659 [PMID: 10954446 DOI: 10.2214/ajr.175.3.1750655]

10 Therimadasamy A, Peng YP, Putti TC, Wilder-Smith EP. Carpal tunnel syndrome caused by gouty tophus of the flexor tendons of the fingers: sonographic features. J Clin Ultrasound 2011; 39: 463-465 [PMID: 21412783 DOI: 10.1002/jcu.20799]

11 Yü TF, Gutman AB. Principles of current management of primary gout. Am J Med Sci 1967; 254: 893-907 [PMID: 4863805 DOI: 10.1097/00000441-196712000-00019]

12 Tsai CY, Yu CL, Tsai ST. Bilateral carpal tunnel syndrome secondary to tophaceous compression of the median nerves. Scand J Rheumatol 1996; 25: 107-108 [PMID: 8614765 DOI: 10.3109/03009749609069218]

13 Gutman AB. Uricosuric drugs, with special reference to pro-benecid and sulfinpyrazone. Adv Pharmacol 1966; 4: 91-142 [PMID: 5333771 DOI: 10.1016/S1054-3589(08)60098-8]

14 Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R; American College of Rheumatology. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonph-armacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64: 1431-1446 [PMID: 23024028 DOI: 10.1002/acr.21772]

P- Reviewer: Alimehmeti RH, Itrat M, Jiang B, Shen J S- Editor: Wang JL L- Editor: A E- Editor: Tan WW

Figure 7 Magnetic resonance imaging of lateral projection of the patient’s right wrist. Magnetic resonance imaging showed no recurrence of gouty tophi 12 mo after synovectomy of all the affected flexor tendons, removal of deep gouty tophi, and epineurium neurolysis of the median nerve of the patient’s right wrist.



Department of Gastroenterology, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan 250012, Shandong Province, China. [email protected]: +86-531-82166090Fax: +86-531-82166090

Received: February 27, 2018Peer-review started: February 27, 2018First decision: March 30, 2018Revised: June 27, 2018Accepted: June 28, 2018Article in press: June 28, 2018Published online: September 6, 2018

AbstractHere, we report a rare case of primary gastrointestinal amyloidosis in a stable condition after being followed up for three years. The patient was admitted to the hospital in 2014. Tests showed decreased levels of hemoglobin and ferritin. Transoral and transanal enteroscopy showed multiple nodular protuberances in the esophagus, ileum, colon and rectum. Endoscopic ultrasonography indicated the nodular protuberances stemmed from the submu-cosa and partially invaded the intrinsic myometrium. Pathological examinations found multiple small nodules in the submucosa and dyed structures, which were positive for special Congo red dyeing. After treatment with oral iron supplements, the levels of hemoglobin and ferritin became normal. It is concluded that the patient represents a case of primary gastrointestinal amyloido-sis with multiple nodular protuberances in the digestive tract with controllable moderate abdominal discomfort and anemia and a benign course. Enteroscopy and endoscopic ultrasonography play an important role in the diagnosis of primary gastrointestinal amyloidosis.

Key words: Enteroscopy; Primary gastrointestinal amyloidosis; Endoscopic ultrasonography; Pathological diagnosis

Yi-Pin Liu, Wei-Wei Jiang, Guo-Xun Chen, Yan-Qing Li

CASE REPORT


Case report and review of the literature of primary gastrointestinal amyloidosis diagnosed with enteroscopy and endoscopic ultrasonography

Yi-Pin Liu, Yan-Qing Li, Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China

Yi-Pin Liu, Wei-Wei Jiang, Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai 264100, Shandong Province, China

Guo-Xun Chen, Department of Nutrition, University of Tennessee, Knoxville, TN 37996, United States

ORCID number: Yi-Pin Liu (0000-0002-2958-6354); Wei-Wei Jiang (0000-0002-2298-2522); Guo-Xun Chen (0000- 0001-6226-4050); Yan-Qing Li (0000-0001-9325-4808).

Author contributions: Liu YP performed the endoscopy examinations and wrote the manuscript; Jiang WW participated in the patient management and followed up the patient after discharge; Chen GX was involved in the writing and responsible for language editing of the manuscript; Li YQ planned and gave guidance to the research.

Informed consent statement: Written informed consent was obtained from the individual participant included in the study.

Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.




Correspondence to: Yan-Qing Li, MD, PhD, Professor,


DOI: 10.12998/wjcc.v6.i9.284





Core tip: A 48-year-old woman was admitted with moderate abdominal discomfort for two years and decreased hemoglobin and ferritin levels. Transoral and transanal enteroscopy showed multiple nodular protuberances in the digestive tract. Endoscopic ul-trasonography indicated the nodular protuberances stemmed from the submucosa and partially invaded the intrinsic myometrium. Pathological examinations showed the nodules were positive for special Congo red dyeing. It is concluded that the patient represen-ts a case of primary gastrointestinal amyloidosis with multiple nodular protuberances in the digestive tract with controllable symptoms and a benign course during three-year follow-up. Enteroscopy and endoscopic ul-trasonography play an important role in the diagnosis.

Liu YP, Jiang WW, Chen GX, Li YQ. Case report and review of the literature of primary gastrointestinal amyloidosis diagnosed with enteroscopy and endoscopic ultrasonography. World J Clin Cases 2018; 6(9): 284-290 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/284.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.284

INTRODUCTIONAmyloidosis is a rare disorder characterized by the extracellular deposition of an abnormal fibrillar protein. The pathogenesis is due to abnormal protein folding, which leads to the formation of a fibrous structure and disruption of tissue function. These misfolded proteins are deposited in the extracellular space of tissues. The excessive accumulation of these misfolded proteins leads to various degrees of organ dysfunction[1,2]. The disease is named amyloidosis because the color reaction of the accumulated substances to iodine and sulfuric acid is similar to that of starch to the same reagents, and the name has been used to date[3,4]. Epidemiological investigations in Latin America and Europe found that the incidence of amyloidosis is lower than ten cases per million people, which is considered a rare clinical disease[57]. The probability of involvement of the digestive system for amyloidosis is 70%80%, and the lesions can occur throughout the gastrointestinal tract from the mouth to the rectum[8].

Currently, the prognosis of amyloidosis is primarily associated with a high mortality rate due to the progressive nature, especially with heart failure[9]. We encountered a case of primary amyloidosis in the digestive tract, which was diagnosed with enteroscopy and endoscopic ultrasonography. After a close followup of three years, it was considered a rare and unique case with a benign nature. Therefore, we wish to share our experience and opinions regarding diagnosing and treating such a case.


Liu YP et al . Rare case of primary gastrointestinal amyloidosis

CASE REPORTA 48-year-old woman was admitted into Yantai Affiliated Hospital of Binzhou Medical University on December 7, 2014 for the first time with a history of moderate daily “abdominal discomfort for two years”. She had a history of cesarean section. She had no unhealthy diet habits. Her family members had no gastrointestinal diseases, except that her father had a history of “gastric cancer” with surgical resection. Gastroscopy and colonoscopy in the outpatient department of the hospital reported multiple nodular protuberances in the esophagus, colon and rectum.

After admission, a comprehensive physical examination demonstrated upper abdominal tenderness and moderate anemia. The laboratory tests showed low plasma levels of hemoglobin (84 g/L, normal range 110150 g/L) and ferritin (1.2 ng/mL, normal range 10291 ng/mL) and normal values for urine and stool routines. Specifically, the levels of the only urine parameters Bence Jones protein and blood parameters such as digestive tract tumor markers, blood glucose, liver and kidney function, myocardial enzymes, coagulation function, thyroid function, Streptococcus hemolysin O, rheumatoid factor, erythrocyte sedimentation rate, C reactive protein, and β2 microglobulin, were all within normal ranges. Electrocardiogram, computed tomography and ultrasound in the chest and abdomen showed no abnormalities.

We conducted enteroscopy and endoscopic ultrasonography in the patient. Enteroscopy through the mouth and the anus performed on December 11, 2014 showed many yellowish nodular protuberances with diameters of approximately 0.20.5 cm in the esophagus, ileum, colon and rectum (Figure 1). The mucosa of the stomach, duodenum and jejunum appeared to be normal.

Endoscopic ultrasonography was obtained on December 8, 2014. The nodular protuberances of the esophagus stemmed from hypoechoic lesions of the submucosa, and the layer of the origin was clear (Figure 2A). The nodular protuberances of the colon stemmed from the submucosa and partially invaded the intrinsic myometrium with a hypoechoic structure, which is a partly hypoechoic fusion and inhomogeneous echo (Figure 2B).

Pathological examination was performed with hematoxylin and eosin staining on samples collected from the digestive tract. In the esophagus, the squamous epithelium in the tissue was mildly proliferative and there were multiple small nodules in the submucosa. Figure 3A shows that the central portion of an esophagus biopsy sample contained a homogeneous powder and dyed structure, which is surrounded by inflammatory cells and fibrous tissues. In the ileum and descending colon, chronic inflammation was observed in the mucous tissue. Figure 3B shows that the biopsy sample of the ileum contained multiple homogeneous powder dyeing without structural small nodules in the submucosal layer.



Moreover, staining of samples from the esophagus with Congo red, Masson Blue, and Periodic AcidSchiff was positive (Figure 4).

According to the above findings, the patient was diagnosed with primary amylolysis in the digestive tract[10,11]. An oral iron supplement (Ferrous fumarate, 0.2 g one time, 34 times/d) was prescribed for one year for anemia between December 2014 and December 2015, along with medications such as esomeprazole magnesium (Nexium®), Talcid®, Domperidone for the treatments of abdominal discomfort. The anemia gradually improved and was eventually cured.

The patient was regularly followed up for three years. Blood tests performed in October 2017 showed that the hemoglobin and serum ferritin were restored to 124 g/L (normal range 110150 g/L) and 39.8 ng/mL (normal range 10291 ng/mL), respectively, without abnormalities for other routine parameters. During this period, the patient only occasionally reported mild abdominal discomfort. Gastroscopy and colonoscopy performed on October 2017 showed that the numbers and sizes of nodular protuberances in the mucosa of the esophagus, ileum and colon had no obvious change compared with those observed three years ago (Figure 5).

A B

C D

Figure 1 Representative images of enteroscopy at admission. A: Nodular protuberances (arrows) in the esophagus; B: Nodular protuberances (arrows) in the ileum; C: Nodular protuberances (arrows) in the hepatic area of the colon; D: Nodular protuberances (arrows) in the rectum.

A B

Figure 2 Images of endoscopic ultrasonography. A: Nodular protuberances in the esophagus stemming from hypoechoic lesions of the submucosa, and the layer of origin was clear; B: Nodular protuberances in the colon stemming from the submucosa, partially invading the intrinsic myometrium with a hypoechoic structure, which is partially hypoechoic fusion and inhomogeneous echo.




DISCUSSIONAmyloidosis is categorized into primary, secondary and inheritable based on the types of deposited proteins, and primary amyloidosis is the most common type[1113]. Clinically, primary amyloidosis is mainly due to the deposition of immunoglobulin light chain, which commonly occurs in the digestive system and affects its functions[14,15]. Gastrointestinal involvement by amyloidosis has been reported as common. The most common gastrointestinal manifestations were weight loss, abdominal pain/dyspepsia, and nausea/vomiting[16]. The frequency of amyloid deposition was highest in the duodenum, and the duodenal biopsy is sensitive for diagnosing amyloidosis[17]. Amyloidosis in the small intestine may be characterized by diarrhea, fat diarrhea, bleeding, obstruction, constipation, and similar symptoms[18,19]. Colonic amyloidosis manifests similarly to inflammatory bowel disease and ischemic bowel disease, and is characterized by mucous congestion, erosion, ulcer, nodular protuberance or polypoid changes[2022]. Our patient had multiple nodular protuberances in the esophagus, ileum, colon and rectum, with a history of moderately daily abdominal discomfort for two years, which was improved by symptomatic treatment. Thus, the case was characterized by multiple nodular protu

berances covering the upper, middle and lower digestive tract, as well as relatively mild, non-specific and stable clinical symptoms.

Due to the lack of specificity in the clinical manifestation of primary amyloidosis in the digestive tract, laboratory and imaging examinations are prone to misdiagnosis and missed diagnosis. At present, auxiliary examinations for gastrointestinal amyloidosis mainly rely on gastroscopy and colonoscopy. In our case, transoral and transanal enteroscopy was applied. Theoretically, enteroscopy specifically covers the entire small intestine and extends the examination to the whole digestive tract, and thus, would improve the diagnosis of amyloidosis in the whole digestive tract. Moreover, endoscopic ultrasonography performed on the case showed that the lesions involved the submucosa, and a partial invasion of the intrinsic myometrium was hypoechoic, which is consistent with the pathological examinations. Endoscopic ultrasonography has unique characteristics that enable a diagnosis of amyloidosis of the digestive tract and reduces the rate of misdiagnosis. We propose that accurate and multisite biopsy of the digestive tract under the guidance of endoscopic ultrasonography enhances the pathological diagnosis. If eosinophil infiltration and waxlike substance deposition are found in the pathological routine, hematoxylin and eosin staining, as well

A B

Figure 3 Pathological examination with hematoxylin and eosin staining. A: The central portion of an esophagus biopsy sample containing a homogeneous powder and dyed structure (arrows), which is surrounded by inflammatory cells and fibrous tissues (magnification 10 × 4); B: The biopsy sample of ileum containing multiple homogeneous powder dyeing (arrow) without structural small nodules in the submucosal layer (MAGNIFICATION 10 × 4).

A B C

Figure 4 Positive staining of Esophagus biopsy sample. A: With Congo red; B: With Masson blue; C: With Periodic Acid-Schiff.




as specific Congo red staining should be performed to assist the diagnosis. In our opinion, enteroscopy and endoscopic ultrasonography play important roles in the diagnosis of the amyloidosis disease, and pathology is the gold standard for diagnosis. These techniques are highly recommended techniques for the diagnosis of digestive tract amyloidosis. Specifically, for a case with a moderate abdominal discomfort and anemia for a couple of years, the physician should take digestive tract amyloidosis into consideration and apply transoral and transanal enteroscopy, along with endoscopic ultrasonography and pathological examinations for the diagnosis. Several factors, such as the clinical and endoscopic features, the qualification and experience of the evaluating endoscopist, the choice of reasonable endoscopic and pathological examinations, may influence the diagnosis of dig-estive tract amyloidosis. For example, we usually apply gastroscopy and colonoscopy to diagnose gastrointestinal amyloidosis; however, the lesions are prominent in the small intestine in some patients. Therefore, transoral and transanal enteroscopy is required in these cases in order to avoid misdiagnosis and missed diagnosis. It should be mentioned that the procedure of transoral and transanal enteroscopy needs special equipment and an experienced endoscopist, and thus may not be applied in the other settings. However, it is important for a physician, especially a gastroenterologist, to be aware of the existence of digestive tract amyloidosis and refer the suspected patients to enteroscopy, along with endoscopic ultrasonography in clinical practice to diagnose or rule out digestive tract amyloidosis.

Chemotherapy and stem cell transplantation are currently the standard of treatment for primary amyloidosis[23]. For patients with primary amyloidosis in the digestive tract, studies have shown that a risk stratification score using cardiac troponin T, Nterminal probrain natriuretic peptide, and uric acid is helpful to identify patients at risk of early mortality, and prospective identification of these patients allows the development of riskadapted strategies and help develop riskadapted therapies[24,25]. In our case, the patient had no bad diet habits without a family history of a similar disease. The

two major symptoms were abdominal discomfort and anemia. The former was treated symptomatically and relieved to a great extent, and the latter was treated and cured with an iron supplement. Close followup was maintained for three years after admission. The condition of the patient remained stable, clinical symptoms were not progressively aggravated, and endoscopic observation showed no obvious changes in the digestive tract, indicating a benign disease course. Ideally, the subtype of the amyloidosis should be further investigated to rule out multiple myeloma. We indeed tried to persuade the patient to take bone marrow examination during the course, but the patient refused. Nevertheless, there was no manifestation of multiple myeloma during the 3year followup, and thus multiple myeloma could be ruled out.

The prognosis of primary gastrointestinal amyloidosis is usually poor but largely depends on the underlying etiology for amyloid deposition and the degree of organ involvement. A prospective study of a cohort of 155 patients with systemic amyloidosis found that the median survival time was 16 mo for 131 cases without gastrointestinal involvement and 8 mo for 24 cases with gastrointestinal involvement[19]. The patient presented here was a rare case of gastrointestinal amyloidosis with a benign clinical course, and the prognosis was deemed as good. However, the mechanism linking the pathogenesis and prognosis is unknown, and needs to be further investigated. We will continue to closely follow up the case and conduct protein mass spectrometry analysis to identify the deposited proteins and genetic analysis to explore the genes involved in the development of amyloidosis.

We acknowledge that the threeyear followup is still short to determine the future outcome of the patient, and it remains too early to make a final conclusion on whether multiple organ dysfunctions, such as heart, liver, lung and kidney, which were normal in the previous admission examination, will occur in the future. Therefore, more tests and careful analysis of clinical reports are needed in the followup visits.

In conclusion, the present patient represents a case

A B C

Figure 5 Representative images of enteroscopy three years after admission. A: Nodular protuberances (arrows) in the esophagus; B: Nodular protuberances (arrows) in the ileum; C: Nodular protuberances (arrows) in the colon.




of primary gastrointestinal amyloidosis with multiple nodular protuberances in the digestive tract with controllable moderate abdominal discomfort and anemia and a benign course. Enteroscopy and endoscopic ultrasonography, which are used for the diagnosis of this case, may play an important role in the diagnosis of primary gastrointestinal amyloidosis, although pathology remains the gold standard for diagnosis.

ARTICLE HIGHLIGHTSCase characteristicsA case with multiple nodular protuberances in the digestive tract with controllable moderate abdominal discomfort and anemia and a benign course.

Clinical diagnosisAfter admission, a comprehensive physical examination demonstrated upper abdominal tenderness and moderate anemia.

Differential diagnosisTheoretically, enteroscopy specifically covers the entire small intestine and extends the examination to the whole digestive tract and thus would improve the diagnosis of amyloidosis in the whole digestive tract, and endoscopic ultrasonography has unique characteristics that enable a diagnosis of amyloidosis of the digestive tract and reduces the rate of misdiagnosis.

Laboratory diagnosisThe laboratory tests showed low plasma levels of hemoglobin (84 g/L, normal range 110-150 g/L) and ferritin (1.2 ng/mL, normal range 10-291 ng/mL) and normal values for urine and stool routines at administration, and normal plasma levels of hemoglobin 124 g/L and 39.8 ng/mL without abnormalities for other routine parameters at three-year follow-up.

Imaging diagnosisTransoral and transanal enteroscopy showed multiple nodular protuberances in the esophagus, ileum, colon and rectum, and endoscopic ultrasonography showed the nodular protuberances stemmed from the submucosa and partially invaded the intrinsic myometrium.

Pathological diagnosisPathological examinations found multiple small nodules in the submucosa and dyed structures.

TreatmentAn oral iron supplement (Ferrous fumarate, 0.2 g/time, 3-4 times/d) were prescribed for one year for the anemia, along with medications such as esomeprazole magnesium (Nexium®), Talcid®, Domperidone for the treatment of abdominal discomfort.

Term explanation Amyloidosis is categorized into primary, secondary and inheritable, and primary amyloidosis is the most common type.

Experiences and lessonsPrimary gastrointestinal amyloidosis can be presented with controllable moderate abdominal discomfort and anemia and a benign course. Enteroscopy and endoscopic ultrasonography may play an important role in the diagnosis.

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2 Picken MM. Modern approaches to the treatment of amyloidosis: the critical importance of early detection in surgical pathology. Adv Anat Pathol 2013; 20: 424-439 [PMID: 24113313 DOI: 10.1097/PAP.0b013e3182a92dc3]

3 Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins PN. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346: 1786-1791 [PMID: 12050338 DOI: 10.1056/NEJMoa013354]

4 Lavatelli F, Vrana JA. Proteomic typing of amyloid deposits in systemic amyloidoses. Amyloid 2011; 18: 177-182 [PMID: 22080761 DOI: 10.3109/13506129.2011.630762]

5 Aguirre MA, Boietti BR, Nucifora E, Sorroche PB, González Bernaldo de Quirós F, Giunta DH, Posadas-Martínez ML. Incidence rate of amyloidosis in patients from a medical care program in Buenos Aires, Argentina: a prospective cohort. Amyloid 2016; 23: 184-187 [PMID: 27470486 DOI: 10.1080/13506129.2016.1207626]

6 Hemminki K, Li X, Försti A, Sundquist J, Sundquist K. Incidence and survival in non-hereditary amyloidosis in Sweden. BMC Public Health 2012; 12: 974 [PMID: 23148499 DOI: 10.1186/1471-2458-12-974]

7 Pinney JH, Smith CJ, Taube JB, Lachmann HJ, Venner CP, Gibbs SD, Dungu J, Banypersad SM, Wechalekar AD, Whelan CJ, Hawkins PN, Gillmore JD. Systemic amyloidosis in England: an epidemiological study. Br J Haematol 2013; 161: 525-532 [PMID: 23480608 DOI: 10.1111/bjh.12286]

8 Levy DJ, Franklin GO, Rosenthal WS. Gastrointestinal bleeding and amyloidosis. Am J Gastroenterol 1982; 77: 422-426 [PMID: 6979925]

9 Gilowski W, Stryjewski P, Gilowska M, Liszniański P, Nowak J. [The rapid progress of heart failure due to systemic amyloidosis with cardiac involvement--case report]. Przegl Lek 2015; 72: 697-700 [PMID: 27012134]

10 Djunić I, Tomin D, Perunicić M, Vidović A, Cemerikić V, Djurasinović V, Jaković L, Janković G. [Diagnosis and the treatment of primary amyloidosis]. Vojnosanit Pregl 2010; 67: 781-785 [PMID: 20954418 DOI: 10.2298/VSP1009781D]

11 Pinney JH, Hawkins PN. Amyloidosis. Ann Clin Biochem 2012; 49: 229-241 [PMID: 22402917 DOI: 10.1258/acb.2011.011225]

12 Hemminki K, Li X, Försti A, Sundquist J, Sundquist K. Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases. BMC Med Genet 2013; 14: 88 [PMID: 24138840 DOI: 10.1186/1471-2350-14-88]

13 Czeyda-Pommersheim F, Hwang M, Chen SS, Strollo D, Fuhrman C, Bhalla S. Amyloidosis: Modern Cross-sectional Ima-ging. Radiographics 2015; 35: 1381-1392 [PMID: 26230754 DOI: 10.1148/rg.2015140179]

14 Freudenthaler S, Hegenbart U, Schönland S, Behrens HM, Krüger S, Röcken C. Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients. Virchows Arch 2016; 468: 569-577 [PMID: 26915034 DOI: 10.1007/s00428-016-1916-y]

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16 Said SM, Grogg KL, Smyrk TC. Gastric amyloidosis: clinico-pathological correlations in 79 cases from a single institution. Hum Pathol 2015; 46: 491-498 [PMID: 25649008 DOI: 10.1016/j.humpath.2014.12.009]

17 Yilmaz M, Unsal A, Sokmen M, Harmankaya O, Alkim C, Kabukcuoglu F, Ozagari A. Duodenal biopsy for diagnosis of renal involvement in amyloidosis. Clin Nephrol 2012; 77: 114-118 [PMID: 22257541 DOI: 10.5414/CN107139]

18 Gould M, Zarrin-Khameh N, Sellin J. Small bowel amyloidosis. Curr Gastroenterol Rep 2013; 15: 350 [PMID: 24065604 DOI: 10.1007/s11894-013-0350-4]

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Intern Med 2015; 30: 496-505 [PMID: 26161016 DOI: 10.3904/kjim.2015.30.4.496]

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C, Laumann K, Zeldenrust SR, Leung N, Dingli D, Greipp PR, Lust JA, Russell SJ, Kyle RA, Rajkumar SV, Gertz MA. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012; 30: 989-995 [PMID: 22331953 DOI: 10.1200/JCO.2011.38.5724]

25 Kumar SK, Gertz MA, Lacy MQ, Dingli D, Hayman SR, Buadi FK, Short-Detweiler K, Zeldenrust SR, Leung N, Greipp PR, Lust JA, Russell SJ, Kyle RA, Rajkumar SV, Dispenzieri A. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc 2011; 86: 12-18 [PMID: 21193650 DOI: 10.4065/mcp.2010.0480]

P- Reviewer: Amornyotin S, Nakajima N, Osawa S S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW



Received: March 25, 2018Peer-review started: March 25, 2018First decision: April 26, 2018Revised: June 18, 2018Accepted: June 27, 2018Article in press: June 27, 2018Published online: September 6, 2018

AbstractAcute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-year-old woman presented with nausea and vomiting for 12 h, but no abdominal pain following an overdose of eight Tylenol tablets containing acetaminophen (325 mg acetaminophen per tablet). Laboratory results on admission showed abnormal amylase and lipase levels but completely normal liver function. Magnetic resonan-ce cholangiopancreatography revealed mild swelling of the pancreas without fluid collection around the pancreas. The patient complained of severe abdominal pain five days after admission when attempting to drink water and liquids. Eight days after admission, fluid around the pancreas was observed by computed to-mography. The patient was subsequently diagnosed with acetaminophen-induced acute pancreatitis after exclusion of common causes. Routine treatment for pancreatitis and N-acetylcysteine were administered to prevent disease progression. The patient was discharged in good condition.

Key words: Pancreatitis; Cholangiopancreatography; Acetaminophen; Acute pancreatitis; Drug-induced acute pancreatitis


Ya-Hong He, Lei Lu, Yu-Fang Wang, Jin-Song Huang, Wei-Qin Zhu, Yan Guo, Chun-Xia Li, Hua-Ming Li

CASE REPORT


Acetaminophen-induced acute pancreatitis: A case report and literature review

Ya-Hong He, Yu-Fang Wang, Jin-Song Huang, Wei-Qin Zhu, Yan Guo, Chun-Xia Li, Hua-Ming Li, Department of Gastroenterology, Hangzhou Third People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China

Lei Lu, Department of Gastroenterology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou 310000, Zhejiang Province, China

ORCID number: Ya-Hong He (0000-0001-9756-3130); Lei Lu (0000-0001-9407-2555); Yu-Fang Wang (0000-0003-1597- 3289); Jin-Song Huang (0000-0002-3774-6178); Wei-Qin Zhu (0000-0001-5272-7111); Yan Guo (0000-0001-7038-7472); Chun-Xia Li (0000-0002-8369-6562); Hua-Ming Li (0000 -0003-4352-9601).

Author contributions: All authors contributed to the acquisition of data, writing, and revision of this manuscript.

Informed consent statement: The patient and her family provided informed written consent.

Conflict-of-interest statement: All the authors have no conflicts of interests to declare.



Correspondence to: Hua-Ming Li, MAMS, Doctor, Department of Gastroenterology, Hangzhou Third People’s Hospital, Zhejiang Chinese Medical University, No. 548 Binwen Road, No. 38 West Lake Road, Hangzhou 310000, Zhejiang Province, China. [email protected]: +86-571-87823158


DOI: 10.12998/wjcc.v6.i9.291




Core tip: This case shows that a dose of acetaminophen of less than 4 g can cause acute pancreatitis without liver damage, and that the mechanism of pancreatitis is different from that of hepatitis, and acetaminophen-induced acute pancreatitis may not be related to the drug dose. Although drug-induced acute pancreatitis is rare and the detailed underlying mechanism is unknown, physicians should consider this etiology after ruling out other causes of pancreatitis, especially in young women who are at high risk of overdosing on Class Ⅰ and Class Ⅱ drugs.

He YH, Lu L, Wang YF, Huang JS, Zhu WQ, Guo Y, Li CX, Li HM. Acetaminophen-induced acute pancreatitis: A case report and literature review. World J Clin Cases 2018; 6(9): 291-295 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/291.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.291

INTRODUCTIONAcute pancreatitis is a common disease in the clinic, and the mortality rate in patients with severe pancreatitis is high. Biliary stones, alcohol consumption, metabolic disorders and tumors are the most frequent causes of acute pancreatitis. Drug-induced acute pancreatitis is implicated in only a minority of cases, with an incidence of 0.1%-2%[1]. To date, over 130 kinds of drugs have been reported to cause acute pancreatitis, including acetaminophen[2]. It is well known that acetaminophen overdose causes hepatic toxicity, but it is a rare cause of acute pancreatitis. Only 11 cases of pancreatitis and hepatic impairment have been associated with acetaminophen at doses ranging from 4 to 120 g. Unlike previous reported cases, we report a case of acute pancreatitis caused by low doses of acetaminophen but without liver damage (Tables 1 and 2).

CASE REPORTA 32-year-old woman presented with nausea and vomiting for 12 h associated with dizziness and epi-gastric pain. Before attending the hospital, she took eight Tylenol tablets containing acetaminophen (325 mg acetaminophen per tablet) after quarreling with her husband. She denied taking other drugs, alcohol consumption, gallbladder stones, trauma, autoimmune diseases and diabetes mellitus. The upper abdomen was soft with mild tenderness. Jaundice, hepatosplenome-galy, ascites, and Murphy’s sign were absent.

Laboratory examinations showed the following: Hemoglobin 10.8 g/dL, white blood cells 5.5 × 10-9/L, neutrophils 65%, and platelets 169 × 10-9/L. Emergency biochemical tests showed aspartate aminotransferase 13 U/L (7-40 U/L), glutamic oxaloacetic transaminase 13 U/L (13-35 U/L), serum albumin 3.3 g/dL, serum amylase 990 U/L (0-96 U/L), serum lipase 49.5 U/L (13-60 U/L) and triglycerides 0.6 mmol/L (0.34-1.70


He YH et al . Acetaminophen-induced acute pancreatitis

mmol/L). Two days later, blood biochemistry showed aspartate aminotransferase 13 U/L, glutamic oxaloa-cetic transaminase 13 U/L, alkaline phosphatase 52 U/L (35-100 U/L), serum albumin 40.9 g/L, serum amylase 433 U/L, serum lipase 136.6 U/L, triglycerides 0.6 mmol/L, and serum creatinine 53 μmol/L (45-84 μmol/L). Viral hepatitis markers (A, B, C, D and E), antinuclear antibody Hep-2, antineutrophil cytoplasmic antibody (ANCA), peripheral-ANCA and cytoplasmic-ANCA were negative. Serum IgG4 was 1.08 (0.03-2) g/L. Abdominal ultrasonography showed no abnormali-ties in the pancreas. However, magnetic resonance cholangiopancreatography (MRCP) showed that the pancreas was bulky without exudation. In addition to routine treatment for pancreatitis, N-acetylcysteine was administered to the patient to prevent disease progression. Five days after admission, she was able to drink water and take a liquid diet. Her serum amylase level decreased and abdominal pain resolved. However, that night she complained of severe upper abdominal pain radiating to the midcentral back with nausea and hypoglycemia. Contrast-enhanced computed tomo-graphy (CT) demonstrated swelling of the pancreas, especially the head of the pancreas, with fluid collection around the pancreas (Figure 1). Therefore, the patient was fasted again. In the following days, abdominal pain gradually alleviated and her diet gradually transitioned to semi-liquids as laboratory examinations revealed serum amylase of 281 U/L and lipase of 263.7 U/L with normal aminotransferase (13 U/L) after three days of pancreatic secretion/enzyme activity suppression and symptomatic treatment. On day 10 after admission, the patient requested early discharge as she had no abdominal pain or other feelings of discomfort. The patient was seen as an outpatient and laboratory exa-minations revealed serum amylase of 97 U/L and lipase of 15 U/L two weeks later. The patient refused further CT examination.

DISCUSSION Drug-induced acute pancreatitis is rare with a reported incidence of 0.1%-2%, but should not be overlooked[1,3]. However, drug-induced pancreatitis remains a difficult and challenging diagnosis due to atypical clinical and laboratory tests, which is usually established by excluding other causes. A positive rechallenge is the most effective proof but cannot be performed due to ethical reasons. Our patient took an overdose of a drug containing ace-taminophen in a suicide attempt. However, during the follow-up period, the typical conditions associated with acetaminophen overdose did not occur. In general, drug-induced acute pancreatitis is more frequent in children, women, the elderly, and in patients with advanced HIV infection and inflammatory bowel disease[4,5]. A single-center study with about 328 patients with acute pancreatitis from Australia revealed that drug-induced acute pancreatitis appeared to be more common in middle-aged women, which was attributed to the es-



trogens by an unclear mechanism[6]. Our patient was a young woman and thus a high-risk individual. Based on the weight of evidence including the presence of a rechallenge, latency, and the number of case reports, Badalov et al[3] divided drugs into five categories including acetaminophen, which was categorized as Class Ⅱ. It has been reported that drugs belonging to Class Ⅰ and Class Ⅱ have the “most evidence” of causing acute pancreatitis as shown by published case reports[2].

Acetaminophen is frequently used for pain and fever

in the clinic and is easily obtained from any pharmacy without prescription. Acetaminophen, when taken in an overdose, is a well-known cause of hepatic toxicity, but is rarely the etiologic agent of acute pancreatitis. To date, 11 case reports have been published descri-bing acetaminophen-induced pancreatitis (Table 1)[7-17]. The first case was reported by Gilmore and Tourvas in 1977. Since then, another ten cases of acetaminophen-induced pancreatitis have been described. In most of these cases, a positive rechallenge was not performed. However, Hisato Igarashi et al[14] reported a 35-year-old

Table 1 Summary of 11 cases of acetaminophen-induced acute pancreatitis

Year Age/gender APAP (g) Serum APAP AMS (IU/L) ALT (IU/L) TBil NAC Ref.

1977 31/F 60 NA 1440 300 H No [7]1977 41/F 25 NA 1250 NA H No [8]1986 19/M 25 62 μg/mL 1500 380 NA Yes [9]1991 34/F 9.37-13 77.7 μg/mL 936 225 NA Yes [10]1995 48/F 25 NA 300 8700 NA No [11]1997 74/F NAa 31 μg/mL 787 3070 H Yes [12]2001 47/M 4 NA 498 408 H No [13]2009 35/F 3.97-5.3b NA 1414 75 (H) Normal No [14]2009 17/F 15 Below 529 Normal Normal No [15]2012 40/F H NA NAc Normal Normal Yes [16]2014 19/F 78-120 208.4 μg/mL 638 9689 H NA [17]

aA detailed medical history was difficult to obtain from this patient due to her confused mental state; b3.97-5.3 g/d for 1 mo; cAbdominal CT showed features suggestive of acute pancreatitis, AMS was not available. APAP: Acetaminophen; AMS: Serum amylase; ALT: Alanine aminotransferase; TBil: Total bilirubin; NA: Not available; NAC: N-acetylcysteine; H: High.

A

B

Figure 1 Magnetic resonance cholangiopancreatography and computed tomography findings. A: MRCP shows the bulky pancreas without exudation on admission; B: CT demonstrates swelling of the pancreas, especially the head of the pancreas, with fluid around the pancreas 8 d after admission. MRCP: Magnetic resonance cholangiopancreatography; CT: Computed tomography.




woman who experienced a similar situation each time after three overdoses of acetaminophen due to severe pain in the lower limbs after experiencing high levels of stress. In our case, the diagnosis of acute pancreatitis was made based on clinical findings in combination with blood test results and confirmed by image examinations. MRCP indicated pancreatitis by its advantage over CT or ultrasound (US) because of its T1-weighted images with an advantage to differentiate between simple effusion and hemorrhagic necrosis of the peripancreatic fatty tissue and to depict acute pancreatic hemorrhage and its T2-weighted images with better sensibility of upper abdominal fluid collections[18,19]. Secondly, the diagnosis of acetaminophen-induced pancreatitis was establish-ed by excluding common etiologies such as gallstone pancreatitis, hyperlipidemic pancreatitis and ethanol-induced acute pancreatitis and other suspicious drugs that have been reported to cause pancreatitis.

In nine of these cases, different degrees of abnor-mal liver function were present and two cases had no evidence of hepatotoxicity (Table 1). Our patient showed no liver damage but pancreatitis, which may be related to the dose of acetaminophen and the different underlying mechanisms of liver toxicity and pancreatic toxicity. The recommended maximum thera-peutic dose of acetaminophen is 4 g/d for an adult, and asymptomatic elevations in aminotransferases are sometimes seen with chronic use at the maximum recommended daily dose of 4 g[20,21]. In our patient, the maximum therapeutic dose was not reached and was lower than 3 g. In contrast, all other patients took more than 3 g acetaminophen, the highest dose being 120 g and the lowest dose approximately 4 g[17,13]. A reliable dose-dependent relationship between acetaminophen poisoning and severity of acute pancreatitis is lacking, which was also stated in the case reported by Praveen Jinnur[16,17,22]. He believed that normal liver function was attributed to individual susceptibility rather than dose-related drug toxicity[16]. Similarly, a retrospective study, which included 814 patients with acetaminophen poisoning, showed that acetaminophen-associated acu-te pancreatitis occurred in patients without fulminant hepatic failure and in two patients without significant hepatotoxicity[23]. Consistent with these findings is the theory that acetaminophen-induced pancreatitis is related to an idiosyncratic reaction rather than intrinsic drug toxicity, which is in line with Gilmore and Tour-vasa who considered that pancreatitis and hepatitis have different viral causes, as did Hisato Igarashi and Zachary Cavanaugh[7,14,17]. Interestingly, 5 of 11 cases were similar to ours that patients took an excess of

acetaminophen at a time, which made us doubt whether the frequency and single overdose of acetaminophen were related with pancreatic toxicity. Unfortunately, no adequate evidence-based basis has been found because understanding of drug-induced acute pancreatitis is largely based on case reports and critical reviews.

This patient was fortunately taken to the hospital in time and treated with N-acetylcysteine, which can pre-vent hepatotoxicity following acetaminophen overdose by replenishing hepatic glutathione stores. In patients who receive N-acetylcysteine within the first eight hours after an acute overdose, the risk of hepatotoxicity is less than 5%, whereas delays beyond 10 h are associated with an increased risk of hepatic injury[20]. In other cases, they either took a large dose of acetaminophen or did not receive timely treatment, or they were patients at high risk, such as those with known alcohol consumption, which may have led to drug-induced pancreatitis with different levels of liver damage.

In conclusion, less than 4 g acetaminophen can cause acute pancreatitis without liver damage, which indicates that the mechanism of pancreatitis is differ-ent from that of hepatitis, and the severity of acute pancreatitis may not have a reliable dose-dependent relationship. Although drug-induced acute pancreati-tis is rare and easily ignored, we should be aware of this condition in high-risk patients with a history of drug overdose, especially Class Ⅰ and Class Ⅱ drugs, and both timely and appropriate treatment should be administered.

ARTICLE HIGHLIGHTSCase characteristicsA 32-year-old woman presented with nausea and vomiting for 12 h associated with dizziness and epigastric pain.

Clinical diagnosisAcetaminophen-induced acute pancreatitis.

Differential diagnosisBiliary pancreatitis, alcohol-induced pancreatitis, hyperlipidemic pancreatitis and codeine-induced pancreatitis.

Laboratory diagnosisLaboratory workup revealed a significant elevation of serum amylase of 990 U/L but normal aminotransferases.

Imaging diagnosisMagnetic resonance cholangiopancreatography showed that the pancreas was bulky without exudation. Computed tomography demonstrated swelling of the pancreas, especially the head of the pancreas, with fluid collection around the pancreas.

TreatmentAbrosia, routine treatment for pancreatitis, and N-acetylcysteine were administered to the patient.

Related reportsA total of eleven cases of acetaminophen-induced acute pancreatitis have been

Table 2 Causes of acute pancreatitis

Causes of acute pancreatitis

Common causes Gallstones, alcohol misuse, hyperlipidemiaOther causes Hypercalcemia, autoimmune, idiopathic, drugs,

trauma, tumor


ARTICLE HIGHLIGHTS



reported in the literature but this case took the lowest dose of acetaminophen without liver damage.

Experiences and lessonsAcetaminophen-induced acute pancreatitis is rare and should be considered in the differential diagnosis of acute pancreatitis, especially in high-risk patients with an overdose of suspected drugs.

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P- Reviewer: Dambrauskas Z, Zaky A S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW





Correspondence to: Yue-Yong Zhu, MD, PhD, Professor, Liver Research Center, the First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Taijiang District, Fuzhou 350005, Fujian Province, China. [email protected]: +86-591-87981660Fax: +86-591-87981028

Received: March 10, 2018Peer-review started: March 10, 2018First decision: April 18, 2018Revised: May 4, 2018Accepted: June 7, 2018Article in press: June 8, 2018Published online: September 6, 2018

AbstractVon Meyenburg complexes (VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abnormal echographic presentation of the liver. She received magnetic resonance imaging (MRI) examina-tion and liver biopsy, and the results showed she had VMCs. Histologically proved hepatocellular carcinoma was found 1 year after the diagnosis of VMCs. Proband B was a 57-year-old woman with intrahepatic diffuse

Su Lin, Tian-Yu Shang, Ming-Fang Wang, Jian Lin, Xiao-Jian Ye, Da-Wu Zeng, Jiao-Feng Huang, Nan-Wen Zhang, Yi-Long Wu, Yue-Yong Zhu

CASE REPORT


Polycystic kidney and hepatic disease 1 gene mutations in von Meyenburg complexes: Case report

Su Lin, Tian-Yu Shang, Ming-Fang Wang, Da-Wu Zeng, Jiao-Feng Huang, Yi-Long Wu, Yue-Yong Zhu, Liver Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China

Jian Lin, Department of Hepato-Biliary-Pancreatic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China

Xiao-Jian Ye, Department of Ultrasound, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, China

Nan-Wen Zhang, Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350005, Fujian Province, China

ORCID number: Su Lin (0000-0001-7517-9859); Tian-Yu Shang (0000-0002-0976-8951); Ming-Fang Wang (0000-0001-7306-955X); Jian Lin (0000-0003-4584-6045); Xiao-J ian Ye (0000-0001-5563-3321); Da-Wu Zeng (0000-0003-3818-0062); Jiao-Feng Huang (0000-0003-1383- 6897); Nan-Wen Zhang (0000-0002-6711-1560); Yi-Long Wu (0000-0001-8650-3458); Yue-Yong Zhu (0000-0002-0746-4911).

Author contributions: All authors designed the report and wrote the paper.

Supported by Pilot Project of Fujian Science and Technology Department, No. 2015Y0057; Fujian Medical Innovation Project, No. 2018-ZQN-54; and Science and Technology Project of Fujian Education Department, No. JAT160211.

Informed consent statement: Written informed consent was obtained from the probands and families for this study, and direct sequencing of PKHD1 was performed.

Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.



DOI: 10.12998/wjcc.v6.i9.296




lesions displayed by abdominal ultrasonography. Her final diagnoses were VMCs, congenital hepatic fibrosis, and hepatitis B surface e antigen-negative chronic he-patitis B after a series of examinations. Then, all the family members of both proband A and proband B were screened for VMCs by MRI or ultrasonography. The re-sults showed that four of the 11 family members from two families, including two males and two females, were diagnosed with VMCs. DNA samples were extracted from the peripheral blood of those 11 individuals of two VMCs pedigrees and subjected to polymerase chain reaction amplification of the polycystic kidney and hepatic dis-ease 1 (PKHD1) gene. Two different mutation loci were identified. Heterozygous mutations located in exon 32 (c.4280delG, p.Gly1427ValfsX6) in family A and exon 28 (c.3118C>T, p.Arg1040Ter) in family B were detected. We speculate that PKHD1 gene mutations may be res-ponsible for the development of VMCs.

Key words: Von Meyenburg complexes; Ductal plate malformations; PKHD1; Gene mutation; Fibrosis


Core tip: Von Meyenburg complexes (VMCs) are a rare type of ductal plate malformation. Although generally benign, VMCs have been found to correlate with malig-nant diseases and progress towards adenocarcinomas. Mutations of the PKHD1 gene have been demonstrated to cause autosomal recessive polycystic kidney disease, a type of ductal plate malformation. In this study, muta-tions of the PKHD1 gene located in exon 28 and exon 32, respectively, were identified in two Chinese VMCs families, with four VMCs patients reported in total.

Lin S, Shang TY, Wang MF, Lin J, Ye XJ, Zeng DW, Huang JF, Zhang NW, Wu YL, Zhu YY. Polycystic kidney and hepatic disease 1 gene mutations in von Meyenburg complexes: Case report. World J Clin Cases 2018; 6(9): 296-300 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/296.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.296

INTRODUCTIONVon Meyenburg complexes (VMCs), or biliary hamartomas, are a rare type of ductal plate malformation (DPM). Although generally benign, VMCs have been found to correlate with malignant diseases and progress towards adenocarcinomas[1]. Family cluster of VMCs has been observed clinically, indicating a genetic background of this disease. However, the gene mutation associated with this rare disorder has not been reported until now.

Mutations of the polycystic kidney and hepatic disease 1 (PKDH1) gene are confirmed to incur autosomal recessive polycystic kidney disease (ARPKD), a severe type of DPMs. Epigenetic changes in the liver and bile


Lin S et al . PKHD1 gene mutations in VMCs

ducts vary from different exon mutation regions of PKHD1. Herein, we reported the PKHD1 gene sequences in two families of VMCs.

CASE REPORTTwo probands with histologyproved VMCs were included in this study. None of the family members/offspring in pedigree died or had clinical fullblown ARPKD.

Pedigree 1 (VMC1): Proband A was a 62yearold woman with no medical history, who was referred due to abnormal echographic presentation of the liver (Figure 1A, Ⅰ: 2). Laboratory examinations showed 36 U/L alanine aminotransferase (ALT), 32 U/L aspartate aminotransferase (AST), 13.2 µmol/L total bilirubin, 2.22 ng/mL α-fetoprotein (AFP), positive hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), and 3.13 × 106 copies/mL HBV DNA, and hepatitis C virus and human immunodeficiency virus antibodies were both negative. Magnetic resonance imaging (MRI) displayed a typical feature of VMCs (Figure 1B); however, no renal cysts were found. She denied a history of alcohol consumption or drug administration. Liver biopsy confirmed the diagnosis of VMCs and chronic hepatitis B. The woman was given entecavir for successive 6 mo, and a 1year followup by MRI displayed carcinoma in the right lobe of liver (Figure 1C). The subsequent intraoperative pathology revealed a moderately differentiated hepatocellular carcinoma (HCC) and the existence of VMCs (Figure 1D). The woman reported that one of her siblings was also diagnosed with HCC and VMCs 2 years ago and died of HCC. Subsequently, her five family members received MRI scans, and VMCs were identified in two members, without renal kidney cysts seen.

Pedigree 2 (VMC2): Proband B was a previously healthy 57yearold woman (Figure 1F, Ⅲ: 2), and abdominal ultrasonography displayed intrahepatic diffuse lesions (Figure 1G and H) with no kidney cysts. Laboratory tests showed 34 U/L ALT, 32U/L AST, 10.8 µmol/L total bilirubin, 3.8 ng/mL AFP, 1310.95 IU/mL HBsAg, 0.02 s/co HBeAb, 11.57 s/co HBeAb, and < 500 copies/mL HBV-DNA viral load. She was finally dia-gnosed with VMCs, congenital hepatic fibrosis (CHF), and HBeAg-negative chronic hepatitis B after MRI and histopathological examinations. Liver ultrasonography was performed in three members of her family, and her husband, also her cousin (Figure 1F, Ⅲ: 1), reported an abnormal echographic presentation (Figure 1H).

The method of proteinase K and phenol were applied to extracted genomic DNA from venous blood of the members. Seventytwo primers were designed (Shanghai Genesky Biotechnology Co., Ltd.; Shanghai, China), adopting an online software (http://frodo.wi.mit.edu/cgibin/primer3/ primer3_www.cgi) to amplify exons 167 and the ambient introns of the PKDH1 gene (supplementary Table 1).



OutcomesVenous blood samples were collected for amplifying exons 167 and the ambient intronic sequences of the PKDH1 gene, and genomic DNA from the proband A and Ⅱ: Two were sequenced for the entire coding

region and splice sites of PKHD1. One heterozygous deletion mutation was detected at exon 32 in the PKHD1 gene (c.4280delG), leading to p.Gly1427ValfsX6 at protein level (Figure 1E). Further sequencing analysis of the entire family 1 revealed that other affected

Ⅰ

Ⅱ

1

1 2 3 4

2 3

HCC HCC

A B C

D E

F G H

I J

Ⅳ

Ⅰ

Ⅱ

Ⅲ

1 2 3

1

90 95 100 105 110

Figure 1 Genetic, clinical, and molecular findings. A: Pedigree of the family cluster with five von Meyenburg complexes (VMCs) patients of two generations, with affected status indicated by black shading. The arrow indicates the proband; B: MRI findings display a typical feature of VMCs; C: A 1-year follow-up by MRI shows carcinoma in the right lobe of liver; D: Intraoperative pathology diagnoses a moderately differentiated HCC and VMCs; E: Electropherograms show a heterozygous deletion mutation at exon 32 in the PKHD1 gene (c.4280delG) in the proband (Ⅰ: 2); F: Pedigree of the family cluster with one von Meyenburg complexes (VMCs) patient of four generations, with affected status indicated by black shading. The arrow indicates the proband; G and H: B ultrasound findings of proband B; Ⅰ: B ultrasound findings of Ⅲ: 1; J: Electropherograms show a heterozygous deletion mutation at exon 28 in the PKHD1 gene (p.Arg1040Ter) in the proband B (Ⅲ: 2). HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging




individuals (Ⅱ: 1, Ⅱ: 2) were also heterozygous for 4280delG, while unaffected siblings were wild type at the sequence position. Another mutation was located in exon 28 (p.Arg1040Ter) from proband B (Figure 1Ⅰ), while mutations of PKHD1 of the remaining members of family 2 were not detected.

DISCUSSIONDuctal plate arises from single or doublelayered epithelial structures of hepatoblasts around the portal vein in the embryonic stage. Ductal plate undergoes remodeling (molding process from large bile ducts to microscopic bile ducts) and gives rise to the formation of bile ducts. DPM is defined as the developmental abnormalities considered to be resulted from the lack of ductal plate remodeling during bile duct morphogenesis. The congenital DPM diseases incorporate congenital hepatic fibrosis, autosomal dominant polycystic kidney disease (ADPKD), autosomal dominant polycystic liver disease (ADPLD), ARPKD, Caroli’s disease, Caroli’s syndrome, and VMCs[2]. ADPLD is a heritable disease characterized by the malformation of medium sizes ducts, which ultimately generate cysts full of fluid. This malformation is usually underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis, manifestations, and management[3]. Liver cysts are more frequently found in patients with ADPKD and adulttype polycystic liver disease, where the development of renal cysts precedes hepatic cysts[4]. Dissimilar to ADPLD, hepatic cysts in ADPKD are originated from peribiliary bile duct glands and dilated biliary microhamartomas[5]. By contrast, VMCs are caused from malformations of the smallsized intrahepatic duct[4] and are considered a histopathological lesion that transforms into cysts[6].

Often found as small, symptomless and scattered cysts[7], VMCs are diagnosed accidentally upon their special radiologic appearance and sometimes in a manner of either not exact abdominal symptoms or the onset of liver sepsis[8]. A consecutive autopsy study indicates that the incidence in adults was about 5.6% and in children was 0.9%[9]. In another biopsy series, the incidence was only 0.6%[10]. Our previous study showed that the prevalence in patients subjected to diagnostic liver biopsy was 0.35%[11].

Mutations of the PKHD1 gene have been demonstrated to cause ARPKD, a type of DPM[12]. PKHD1 gene contains 76 exons and more than 300 types of mutation. PKHD1 exon 2-deficient mice exhibit hepatic, pancreatic, and renal abnormalities, grossly cystic and fibrotic livers, and progressive bile duct dilatation as well as structural abnormalities and shortening of primary cilia in the bile ducts relative to the wildtype animals[13]. Deletion of exon 40 on the PKHD1 gene resulted in bile duct abnormality in mice[14]. In addition, mutation of the PKHD1 gene by disrupting exon 4 downregulated fibrocystin/polyductin (FPC) expression, resulting in in-

trahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis in mice[15]. Herein, we examined the genetic mutations of two VMCs pedigrees. Two mutations (c.4280delG and c.3118C>T) of the PKHD1 gene located on exons 32 and 28 were detected, respectively, both of which led to early termination of synthesis. These heterozygous deletion mutations may result in a single-dose deficiency of the PKHD1 gene, which affects the development of bile ducts. The exon 2832 of PKHD1 gene mainly encodes the IPT/TIG (Iglike, plexins, transcription factors), IPT_PCSRP (plexins and cell surface receptors), and initial G8 (this domain is named G8 after its 8 conserved glycines) domains of the fibrocystin protein. These domains are involved in the regulation of cell growth, signal transduction, proliferation, and adhesion. Our previous study also showed that silencing of the PKHD1 gene promoted the proliferation, migration, and invasion of human intrahepatic cholangiocarcinoma HuCCT1 cells via the PI3K/Akt signaling pathway, indicating that PKHD1 may contribute to the development and progression of intrahepatic cholangiocarcinoma[16]. It is therefore hypothesized that the protein component encoded by exon 2832 of the PKHD1 gene may have a closer correlation with the development of bile duct than with renal tubules. The mutation in exon 2832 may lead to the malformations of the ductal plate alone without kidney involvement.

In summary, our report provides four cases to the literature of VMCs associated with PKHD1 gene mutations. To be more persuasive, more clinicopathologic and molecular studies are needed to validate the findings and test the hypothesis from the present study.

ARTICLE HIGHLIGHTSCase characteristicsA 62-year-old woman and a 57-year-old woman were both previously healthy, who were referred due to abnormal echographic presentation of the liver.

Differential diagnosisLiver cirrhosis, metastases, microabscesses, and simple liver cysts.

Laboratory diagnosisProband A and B were diagnosed with chronic hepatitis B and HBeAg-negative chronic hepatitis B, respectively, by laboratory examinations of positive hepatitis B surface antigen (HBsAg), negative anti-hepatitis C virus and anti-human immuno-deficiency virus tests, and normal liver function tests.

Imaging diagnosisAbdominal ultrasonography displayed intrahepatic diffuse lesions and magnetic resonance imaging (MRI) showed cystic lesions that shared no connection with the intra- and extra-hepatic bile duct system and were of normal size for von Meyenburg complexes (VMCs). A carcinoma in the right lobe of the liver was also found in proband A. No kidney cyst was seen in the imaging examinations of any family member.

Pathological diagnosisPathological diagnosis confirmed the diagnoses of hepatocellular carcinoma VMCs and chronic hepatitis B in proband A and of congenital hepatic fibrosis


ARTICLE HIGHLIGHTS



(CHF) and VMCs in proband B.

TreatmentProband A was given entecavir and complete surgical resection of the hepatocellular carcinoma lesion. Proband B did not receive any medication and was followed up regularly.

Related reportsIn most of cases, VMCs are incidentally detected, focusing on the location of the disease (liver surface, extrahepatic), relative symptoms, mimicking metastatic disease or malignancy, and association with liver tumor.

Term explanation PKHD1 gene is located on chromosome 6p12. It encodes a protein named fibrocystin/polyductin (FPC). FPC protein is involved in the maintenance of the normal tubular structure of intrahepatic bile duct epithelial cells. Mutation of PKHD1 may cause the structural and functional disorder of FPC, leading eventually to the development of renal and hepatic cysts. VMCs are benign neoplasms characterized by the disorderly arrangement of biliary epithelium, which form abnormal biliary ducts surrounded by ample fibrous stroma.

Experiences and lessonsThe PKHD1 gene mutations were identified in two VMCs patients, providing new insights into the pathogenesis, diagnosis, and progression of the VMCs.

REFERENCES1 Song JS, Lee YJ, Kim KW, Huh J, Jang SJ, Yu E. Cholang-

iocarcinoma arising in von Meyenburg complexes: report of four cases. Pathol Int 2008; 58: 503-512 [PMID: 18705771 DOI: 10.1111/j.1440-1827.2008.02264.x]

2 Desmet VJ. Congenital diseases of intrahepatic bile ducts: var-iations on the theme “ductal plate malformation”. Hepatology 1992; 16: 1069-1083 [PMID: 1398487 DOI: 10.1002/hep.1840160434]

3 Qian Q, Li A, King BF, Kamath PS, Lager DJ, Huston J 3rd, Shub C, Davila S, Somlo S, Torres VE. Clinical profile of autosomal dominant polycystic liver disease. Hepatology 2003; 37: 164-171 [PMID: 12500201 DOI: 10.1053/jhep.2003.50006]

4 Venkatanarasimha N, Thomas R, Armstrong EM, Shirley JF, Fox BM, Jackson SA. Imaging features of ductal plate malformations in adults. Clin Radiol 2011; 66: 1086-1093 [PMID: 21840516 DOI: 10.1016/j.crad.2011.05.008]

5 Kida T, Nakanuma Y, Terada T. Cystic dilatation of peribiliary glands in livers with adult polycystic disease and livers with soli-tary nonparasitic cysts: an autopsy study. Hepatology 1992; 16: 334-340 [PMID: 1639342 DOI: 10.1002/hep.1840160209]

6 Karhunen PJ. Adult polycystic liver disease and biliary micro-

hamartomas (von Meyenburg’s complexes). Acta Pathol Microbiol Immunol Scand A 1986; 94: 397-400 [PMID: 3811921 DOI: 10.1111/j.1699-0463.1986.tb03011.x]

7 Tohmé-Noun C, Cazals D, Noun R, Menassa L, Valla D, Vilgrain V. Multiple biliary hamartomas: magnetic resonance features with histopathologic correlation. Eur Radiol 2008; 18: 493-499 [PMID: 17934738 DOI: 10.1007/s00330-007-0790-z]

8 Sinakos E, Papalavrentios L, Chourmouzi D, Dimopoulou D, Drevelegas A, Akriviadis E. The clinical presentation of Von Meyenburg complexes. Hippokratia 2011; 15: 170-173 [PMID: 22110302]

9 Redston MS, Wanless IR. The hepatic von Meyenburg complex: prevalence and association with hepatic and renal cysts among 2843 autopsies [corrected]. Mod Pathol 1996; 9: 233-237 [PMID: 8685220]

10 Thommesen N. Biliary hamartomas (von Meyenburg complexes) in liver needle biopsies. Acta Pathol Microbiol Scand A 1978; 86: 93-99 [PMID: 696321 DOI: 10.1111/j.1699-0463.1978.tb02019.x]

11 Lin S, Weng Z, Xu J, Wang MF, Zhu YY, Jiang JJ. A study of multiple biliary hamartomas based on 1697 liver biopsies. Eur J Gastroenterol Hepatol 2013; 25: 948-952 [PMID: 23510964 DOI: 10.1097/MEG.0b013e32835fb9ee]

12 Bergmann C, Senderek J, Küpper F, Schneider F, Dornia C, Windelen E, Eggermann T, Rudnik-Schöneborn S, Kirfel J, Furu L, Onuchic LF, Rossetti S, Harris PC, Somlo S, Guay-Woodford L, Germino GG, Moser M, Büttner R, Zerres K. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat 2004; 23: 453-463 [PMID: 15108277 DOI: 10.1002/humu.20029]

13 Woollard JR, Punyashtiti R, Richardson S, Masyuk TV, Whelan S, Huang BQ, Lager DJ, vanDeursen J, Torres VE, Gattone VH, LaRusso NF, Harris PC, Ward CJ. A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int 2007; 72: 328-336 [PMID: 17519956 DOI: 10.1038/sj.ki.5002294]

14 Moser M, Matthiesen S, Kirfel J, Schorle H, Bergmann C, Senderek J, Rudnik-Schöneborn S, Zerres K, Buettner R. A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD). Hepatology 2005; 41: 1113-1121 [PMID: 15830394 DOI: 10.1002/hep.20655]

15 Gallagher AR, Esquivel EL, Briere TS, Tian X, Mitobe M, Menezes LF, Markowitz GS, Jain D, Onuchic LF, Somlo S. Biliary and pancreatic dysgenesis in mice harboring a mutation in Pkhd1. Am J Pathol 2008; 172: 417-429 [PMID: 18202188 DOI: 10.2353/ajpath.2008.070381]

16 Lin S, He C, Wang MF, Wu YL, Lin J, Liu Y, Zhu YY. shRNA-mediated silencing of PKHD1 gene promotes proliferation, migration and invasion of human intrahepatic cholangiocarcinoma HuCCT-1 cells. Int J Clin Exp Pathol 2017; 10: 2496-2509

P- Reviewer: Burgesser MV, Cheungpasitporn W, Rangan G S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW



Liaoning Province, China. [email protected]: +86-24-83283333Fax: +86-24-83283333

Received: March 31, 2018Peer-review started: April 2, 2018First decision: May 24, 2018Revised: June 1, 2018Accepted: June 26, 2018Article in press: June 27, 2018Published online: September 6, 2018

AbstractThe clivus is an atypical metastatic site for renal clear cell carcinoma (RCCC). Here we report a 54 year old man with acute cavernous sinus syndrome. Brain magne-tic resonance imaging identified a clival-based lesion with associated bony erosion. The patient underwent endoscopic endonasal biopsy and partial resection of the clival mass. Because histologic examination of the resected specimen resulted in a diagnosis of RCCC, contrast-enhanced computed tomography scan of the abdomen was performed and showed an enhanced left renal mass. The patient subsequently underwent laparoscopic left radical nephrectomy and gamma knife was planned for the residual clival lesion. We also re-trospectively reviewed available published reports on clival metastases, specifically those from RCCC, since 1990.

Key words: Clival metastases; Endoscopic skull base surgery; Renal clear cell carcinoma; Renal; Carcinoma


Core tip: Clival metastasis is an extremely rare pre-sentation of renal clear cell carcinoma. The symptom of sudden onset of cranial neuropathy, most commonly

Wei-Qi Zhang, Yue Bao, Bo Qiu, Yong Wang, Zhi-Peng Li, Yi-Bao Wang

CASE REPORT


Clival metastasis of renal clear cell carcinoma: Case report and literature review

Wei-Qi Zhang, Yue Bao, Bo Qiu, Yong Wang, Zhi-Peng Li, Yi-Bao Wang, Department of Neurosurgery, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China

ORCID number: Wei-Qi Zhang (0000-0003-3150-0756); Yue Bao (0000-0003-1977-2652); Bo Qiu (0000-0003-2907-3169); Yong Wang (0000-0002-3933-8936); Zhi-Peng Li (0000- 0002-6674-9482); Yi-Bao Wang (0000-0001-7908-4777).

Author contributions: Zhang WQ and Bao Y examined the patient and collected clinical data; Wang YB and Wang Y performed surgical resection and follow up; Zhang WQ and Li ZP wrote the paper; Qiu B and Wang YB edited the manuscript and had final approval.

Institutional review board statement: The authors’ institution does not require IRB approval to publish a single case report.

Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Conflict-of-interest statement: The authors declare that they have no conflict of interest.


Open-Access: This article is an open-access article, which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Correspondence to: Yi-Bao Wang, MD, Professor, De-partment of Neurosurgery, First Affiliated Hospital of China Medical University, Floor # 18, Room # 1801, Shenyang 110001,


DOI: 10.12998/wjcc.v6.i9.301




involving the abducens nerve, and findings on radiologic examination are crucial for making an early diagnosis. Histopathological diagnosis and resection of the clival mass can be safely achieved through an endoscopic endonasal approach. Multidisciplinary management, including surgery, stereotactic radiotherapy and tumor-targeted agents, is often required to prolong survival and maximize the quality of life for patients with me-tastatic renal cell carcinoma.

Zhang WQ, Bao Y, Qiu B, Wang Y, Li ZP, Wang YB. Clival metastasis of renal clear cell carcinoma: Case report and literature review. World J Clin Cases 2018; 6(9): 301-307 Available from: URL: http://www.wjgnet.com/2307-8960/full/v6/i9/301.htm DOI: http://dx.doi.org/10.12998/wjcc.v6.i9.301

INTRODUCTIONRenal cell carcinoma (RCC) is the ninth most common cancer in men, and the fourteenth most common in women[1]. Approximately 90% of kidney cancers are RCCs[2,3]. The most common subtype is renal clear cell carcinoma (RCCC), comprising about 75%-80% of RCCs in surgical series[4]. Almost one-third of patients with RCC present with metastatic disease. The usual metastatic sites are lungs (45.2%), bone (29.5%), lymph nodes (21.8%), liver (20.3%), adrenal gland (8.9%), and brain (8.1%)[5]. Tumors originating primarily in the clivus region are very rare. Chordomas, which are the most frequent tumor affecting that region, represent only 0.15% of all intracranial tumors and 6% of all skull base tumors[6,7]. Common differential diagnoses of clival neoplasms are meningioma, chordoma, lymphoma, pituitary adenoma, nasopharyngeal carcinoma, bone marrow reconversion, and metastatic lesions[8]. Clival metastases from RCCC account for a small proportion of clival tumors. Few cases have been reported.

CASE REPORTA 54-year-old man presented to the ophthalmology outpatient clinic of our institution with asthenia for one month and acute onset drooping of his right eyelid with diplopia for fourteen days. He had smoked ten cigarettes daily for 30 years. On admission, physical examination revealed palsies of right cranial nerves Ⅲ, Ⅳ, Ⅵ, and V2 manifesting as right-sided ptosis, diplopia, and decreased sensation over the right cheek. Both pupils were normal in size and reacted to light.

Results of routine laboratory tests were normal apart from a high urinary red blood cell (RBC) of 14.80/hpf. A non-contrast brain magnetic resonance imaging (MRI) showed a mass with irregular margins in the clivus. The mass was invading the sphenoid and cavernous sinuses bilaterally and encasing both carotid arteries. It was isointense on T1-weighted images and slightly hyperintense on T2-weighted images (Figure 1). Brain


Zhang WQ et al . Clival metastatic renal clear cell carcinoma

computed tomography (CT) scan showed obvious os-teolysis of the cranial base involving the clivus and both petrous apexes. There was marked enhancement of the clival lesion following intravenous contrast injection (Figure 2).

To obtain a tissue diagnosis and decompress the cavernous sinus, the patient underwent endoscopic endonasal transclival resection of the lesion. Intrao-peratively, the tumor was noted to be firm and highly hemorrhagic. Massive bleeding necessitated interrup-tion of the procedure and caused a marked drop in blood pressure. Hemostasis was achieved once the tumor had been partially resected and 400 mL of blood transfused. An early postoperative CT scan showed no evidence of major complications. Immediately after the procedure, the patient’s right-sided ptosis and diplopia improv-ed slightly. Pathological examination of the operative specimen resulted in a diagnosis of clear cell carcinoma (Figure 3A). Ki67 was expressed in 10%-20% of the neoplastic cells and immunohistochemical staining was positive for cytokeratin, vimentin, CK8/18, paired box gene 8 and cluster of differentiation 10. On the sixth postoperative day, the patient underwent a contrast-enhanced CT scan of the abdomen, which showed a slightly inhomogeneous, enhancing, roundish mass in the upper pole of the left kidney. No tumor thrombus in the left renal vein or retroperitoneal lymphadenopathy was detected. Contrast-enhanced thoracic CT scan showed no pulmonary metastases (Figure 4). Laparo-scopic left radical nephrectomy was performed twelve days after the clival surgery. A 4 cm × 4 cm × 4.5 cm tumor and a 2 cm × 2.5 cm × 2.5 cm isolated tumor satellite focus were noted in the posterosuperior part of the left kidney. The patient did not develop any pos-toperative complications such as abdominal infection and was discharged ten days after the second surgery. Histopathologic examination of the resected kidney resulted in a diagnosis of RCCC consistent with that of the intracranial tumor (Figure 3). The patient underwent gamma knife for the residual clival lesion one month later. An MRI performed one month after this procedure demonstrated expected postoperative changes. At the four month follow-up, the patient was in good general condition, though his right cavernous sinus syndrome had not improved. Further follow-up is ongoing.

DISCUSSIONMost reports of metastases to the clivus have been in the form of case reports, case images, or small series[9]. We performed an extensive review of available reports on clival metastases from RCCC and identified nine patients, including the present case (Table 1). The male/female ratio was 5:4 and mean age was 54 years (range 27-62 years). The clival metastasis was diagnosed first in seven of the nine patients. The main clinical manifestations were sixth nerve palsy, headache, and diplopia. Our results are similar to those reported by Dekker et al[10]. All reported primary RCCCs were



unilateral.The clivus, part of the skull base, is located between

the foramen magnum and dorsum sellae and lies deep in the midline in intimate relationship with various

critical neurovascular structures[9,11]. In particular, the sixth nerve is very prone to involvement by tumors gr-owing from the clivus and petroclival regions because of its long serpentine course from the brainstem to the

Table 1 Case reports of clival metastasis from renal clear cell carcinoma

Ref. Age/sex Symptoms First diagnosis and interval

Position and size of Primary

Tumor

Surgery for clival metastasis

Surgery for primary tumor

Additional treatment

Follow-up

Fumino et al[28] 58/M Diplopia Clival metastasis, NA

The left kidney, 6 cm × 4 cm

None Left radical nephrectomy

Radiotherapy to the clivus

NA

Endo et al[29] 59/M Occipital pain, dysarthria, CN

XII palsy

Clival metastasis, NA

The right kidney, 9 cm

None None Radiotherapy for the clivus

DOD (6 mo)

Sepúlveda et al[30] 62/M Sixth nerve palsy,

dysarthria, right tongue

deviation and right facial paralysis


The right kidney, NA

Biopsy None Radiotherapy and palliative care

NA

Patel et al[31] 59/F Headaches and acute onset

cranial nerve neuropathies


The left kidney, NA

Endoscopic endonasal

near complete resection

None Palliative radiation treatment

NA

Mendelson et al[32] 59/F Headaches and dropping of left eye with double

vision


The left kidney, NA

Endoscopic decompression of clival lesion

None Palliative radiotherapy for

renal mass

NA

Mani et al[12] 55/M Headache and diplopia

photophobia of right eye


The left kidney, 6.5 cm × 6.0 cm

× 5.5 cm

None Biopsy External beam radiation therapy and supportive palliative care

DOD (6 mo)

Gil Salu et al[33] 56/F Diplopia Primary RCCC, 8 yr


Endoscopic endonasal

partial resection

Right nephrectomy

NA NA

Santhosh et al[34] 27/F Pain in right lower limb

Primary RCCC, NA


None Right radical nephrectomy

Immunotherapy AWD (28 mo)

Zhang et al 54/M Asthenia and drooping of

his right eyelid with diplopia

Clival metastasis, 6 d

The left kidney, 4 cm × 4 cm ×

4.5 cm

Endoscopic endonasal biopsy and

partial resection

Laparoscopic left radical

nephrectomy

Gamma knife for residual clival

lesion

AWD (4 mo)

F: Female; M: Male; NA: Not available; AWD: Alive with disease; DOD: Dead of disease.

A B C

Figure 1 Brain magnetic resonance images. A: Axial T1-weighted magnetic resonance imaging (MRI) showing isointense mass (white arrow) with encasement of the bilateral carotid arteries; B: Sagittal T1-weighted MRI showing sphenoid sinuses involvement (white arrow); C: Axial T2-weighted MRI showing hyperintense central areas suggest cyst degeneration or central necrosis (white arrow).




superior orbital fissure[12]. Abducens nerve palsy was the presenting manifestation in 46% of patients with chordoma and 47% of those with chondrosarcoma repor-ted by Deconde et al[13]. Above 40% of clival metasta-ses present with isolated sixth nerve palsy according to the review conducted by Dekker et al[10]. That our patient’s tumor extended into the right cavernous sinus may explain the presence of multiple cranial nerve palsies. The possibility of metastatic RCCC should be

considered in patients with a clival lesion and cranial neuropathies. Patients with RCC usually present with the classical triad of macroscopic hematuria, abdominal mass, and flank pain. However, many such tumors are asymptomatic and detected incidentally on health check-ups or imaging examinations[2].

Most reported diagnoses of clival metastases are based on imaging examinations including CT, MRI, posi-tron emission tomography scan with CT (PET-CT) and

A B C

Figure 2 Brain computed tomography scans. A: Axial computed tomography (CT); B: Sagittal CT showing obvious osteolysis at the cranial base with clivus and bilateral petrous apexes (white arrow); C: Axial CT angiogram showing obvious enhancement (white arrow) after intravenous contrast injection.

A B

Figure 3 Histological findings. A: H and E stain of the clival lesion, 200 ×; B: H and E stain of the left renal mass, 200 × showing clear cells with alveolar growth and separated by reticular separation of thin wall vessels. The two lesions demonstrated similar histopathologic features.

A B

Figure 4 Contrast-enhanced computed tomography scans of abdomen. A: Coronal contrast-enhanced computed tomography (CT) showing slightly inhomogeneous enhancing round-like mass (white arrow) located at the upper pole of the left kidney; B: Axial contrast-enhanced CT showing no tumor thrombus in the left renal vein (white arrow) and retroperitoneal lymphadenopathy revealed.




radionuclide bone scans using technetium or gallium[14]. The superior sensitivity of MRI in detecting bone marrow diseases allows precise localization and evaluation of the signal characteristics of clival lesions[8]. Because of its central location, the clivus is best seen on a midsagittal view on MRI. A normal clivus characteristically shows mild enhancement. Low-intensity clival lesions in the marrow tend to be isointense with normal marrow on contrast enhancement. Thus, unenhanced images are more sensitive for detecting clival lesions[8,15]. The usual normal adult clival signal is iso- or hyperintense compared with the pons on T1-weighted images and approximately isointense with the pons on T2-weighted images. Replacement of fatty bone marrow by clival lesions may explain why most clival lesions appear hy-pointense on T1-weighted images and hyperintense on T2-weighted images[8,12]. Integrated PET-CT has been shown to be an effective means of preoperative staging and follow-up surveillance of patients with skull base tumors (overall sensitivity of 77% and specificity of 81%)[14]. However, clival metastases do not appear to have any distinctive radiological features. Radiologic examinations alone have limited ability to distinguish metastases from primary lesions such as chordomas and chondrosarcomas[16].

An endoscopic endonasal approach is reported as a promising option for managing clival lesions with mini-mal morbidity[17]. With the use of a rigid endoscope and angled telescopes, an endoscopic endonasal approach provides a significantly wider and better-illuminated surgical field than traditional open surgeries[18]. In the articles we reviewed, an endoscopic endonasal approach was used in four patients to obtain a biopsy or achieve partial resection. Endoscopic skull base surgeries aided by surgical navigation systems based on preoperative imaging, such as CT and MRI, allow the surgeon to recognize critical structures and maximize the precision of the resection[18]. The application of intraoperative navigated angiosonography techniques for skull base surgery may be helpful in approaching the tumor and avoiding vascular damage[19]. However, endoscopic en-donasal approaches have some limitations, including limited working space, reduced maneuverability, and the need for special instrumentation. It is important to carefully select the most appropriate approach for each patient on the basis of patient- and tumor-related factors as well as the experience of the surgeon.

RCC can be associated with a favorable outcome when diagnosed at an early stage[20]. Unfortunately, 30% of these patients have metastatic disease at diagnosis or after treatment of local disease[20]. The largest published retrospective study comprised 286 patients with brain metastases from RCC and their median survival was 9.63 mo[21]. Diseasespecific prognostic factors include Karnofsky performance sta-tus and the number of brain metastases. A study by Vickers et al[22] revealed that histologic diagnoses of RCCC are more common in patients with brain metas-tases than in those with metastases to other sites (96%

of these patients had clear cell histology). The median survival of patients with brain metastases from RCC is reportedly 14.4 mo, whereas that of patients with RCC without brain metastases is 19.0 mo[22].

Although multiple advances have been made in systemic therapy for RCC, management of metastatic RCC (mRCC) is still challenging[4]. Surgical treatment of our patient, namely partial removal of the metastatic lesion, nephrectomy, and gamma knife treatment were performed successively because he had a solitary metastasis and his physical status was good. The role of radiotherapy in the treatment of RCC remains unclear and it is not recommended[23]. However, several case series have reported that stereotactic radiotherapy is a valuable means of reducing local symptoms from tumor bulk and stabilizing the growth of metastatic lesions in both cranial and extracranial sites[2,24]. Approximately 70% of RCCCs are associated with loss of function of the von Hippel-Lindau gene (VHL). VHL can resu-lt in high concentrations of hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF), which facilitates tumor-associated angiogenesis[25].

Tumor-targeted therapies for RCCC can combat tumor angiogenesis and inhibit tumor cell proliferation. Ex-tended clinical trials of sunitinib and sorafenib have shown that these targeted drugs improve the efficacy of treatment of brain metastasis from RCCC[26,27]. A combination of surgery, stereotactic radiotherapy, and non-targeted and/or targeted agents is often required for management of mRCC. Clinicians should always fo-cus on the goals of treatment and tailor an individual treatment plan to ensure the best possible outcomes.

ARTICLE HIGHLIGHTSCase characteristicsA 54-year-old man with a history of smoking presented with asthenia and acute right cavernous sinus syndrome.

Clinical diagnosisPalsies of right cranial nerves Ⅲ, Ⅳ, Ⅵ, and V2, likely caused by intracranial lesions.

Differential diagnosisDifferential diagnoses included clival chondroma, clival chondrosarcoma, intraosseous lymphoma, and meningioma.

Laboratory diagnosisResults of routine laboratory tests were normal, apart from a high urinary red blood cell of 14.80/hpf.

Imaging diagnosisNon-contrast brain magnetic resonance imaging demonstrated a mass lesion in the clivus with irregular margins that had invaded the sphenoid and cavernous sinus bilaterally. Brain computed tomography (CT) scan showed obvious osteolysis of the cranial base involving the clivus and both petrous apexes. Contrast-enhanced CT scan of the abdomen showed a slightly inhomogeneous, enhancing, roundish mass in the upper pole of the left kidney.

Pathological diagnosisHistopathological examination of the operative specimens revealed clear cells


ARTICLE HIGHLIGHTS



in an alveolar pattern, being separated by a reticular meshwork of thin walled vessels.

TreatmentEndoscopic endonasal partial resection of the clival metastasis. Laparoscopic left radical nephrectomy of the primary renal clear cell carcinoma (RCCC). Gamma knife for the residual clival lesion.

Related reportsFew reports of clival metastasis from RCCC have been published. These tumors tend to be very aggressive, as evidenced by presentation at an advanced stage of the disease. Multidisciplinary management is necessary.

Term explanationThe Karnofsky Performance Scale is a means of classifying patients’ functional impairment. Scores can be used to compare effectiveness of different therapies and assess the prognosis of individual patients. The lower the Karnofsky score, the worse the prognosis.

Experiences and lessonsClival metastasis from RCCC should be considered in the differential diagnosis of bony lesions of the clivus in patients with cranial neuropathy of sudden onset. Early diagnosis, clinical experience, and multidisciplinary management are crucial for effective treatment of such lesions.

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P- Reviewer: Budai B, Vidal EIO S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW



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