IntroductionAcquired cystic disease-associated renal cell carcinoma (ACD-RCC) was recently recognized by the World Health Organization(WHO) as a subtype of renal cell carcinoma (RCC) occurringexclusively in acquired cystic kidney disease (ACKD).1 ACD-RCC is the most common RCC subtype developing in ACKD.1,2

ACKD occurs in 80% of patients with end stage renal disease(ESRD) after 10 to 20 years of hemodialysis.1,3-5 The risk ofdeveloping ACD-RCC is directly proportional to length ofdialysis, ranging from 1.8% to 8%.1 ACD-RCC develops fromproximal renal tubule epithelial cells, and several hypothesesregarding the etiology and pathogenesis of ACKD and ACD-RCChave been developed.1 Studies have concluded that uremia, analtered renal chemical microenvironment, and oxidative stresspresent in ESRD may promote genetic instability andcarcinogenesis.1,4 The proto-oncogene c-Jun and tumorigenesiscontributors c-MET receptor tyrosine kinase (c-MET) and itsligand, hepatocyte growth factor (HGF), have been detected inACD-RCC and ACKD, respectively.4,6,7 ACD-RCC is mostcommonly incidentally detected as a small, low stage mass duringimaging or gross examination of a nephrectomy specimen forother indications.1,2 If symptomatic, it is most common forpatients to report flank pain and hematuria.1

Materials and MethodsThe grossing procedure followed by the pathologists’ assistantwas in accordance with the College of American Pathologists(CAP) Protocol of Macroscopic Examination Guidelines for theExamination of Specimens from Patients with Invasive Carcinomaof Renal Tubular Origin, with the following not included:8,9

• Presence of Gerota’s fascia• Three dimensional kidney size without perinephric fat, length

and diameter of the renal artery and vein• Measurements to the renal sinus, renal vein, renal artery, and

ureter margins• Sections of renal sinus fat

Formalin fixed, paraffin embedded sections of tumor nodules werestained with CK7, CD10, c-Kit, and racemase (p504s)immunostains to determine the subtype(s) of RCC present. Allslides were stained with hematoxylin and eosin (H&E). Slideswere examined with light and polarizing microscopy to assesscellular morphology and calcium oxalate crystal presence.

AcknowledgmentsThe author would like to extend her appreciation to Dr. Dongping Shi and Dr. Eman Abdulfatah for their contributions. Their help in acquiring the patient case and photomicrographs as well as interpretation of the clinical data is greatly appreciated.

Results Future ImplicationsAn important avenue of research for future treatment is thecarcinogenesis of ACD-RCC.1,7 Once understood, targetedtherapy can be effectively utilized.1,7 PTEN and c-MET are IHCpositive in ACD-RCC and are promising prospects for targetedtherapy.7 In addition, increasing the understanding of theimmunophenotype of ACD-RCC will assist in the differentiationfrom CCRCC and PRCC with the use of IHC.1 Further researchinto these aspects of ACD-RCC will improve diagnosis andtreatment of the disease.

Jamie L. Maurice, MLS(ASCP)CM

Wayne State University Pathologists’ Assistant Program

Reference List1. Foshat M, Eyzaguirre E. Acquired Cystic Disease-Associated Renal Cell Carcinoma. Arch Pathol Lab Med. 2017;141:600-606. doi:

10.5858/arpa.2016-0123-RS.2. Mehra R, Smith SC, Divatia M, Amin MB. Emerging Entities in Renal Neoplasia. Surg Pathol Clin. 2015; 8(4): 623-656. doi:

http://dx.doi.org/10.1016/j.path.2015.08.004.3. Sule N, Yakupoglu U, Shen SS, et al. Calcium Oxalate Deposition in Renal Cell Carcinoma Associated With Acquired Cystic Kidney

Disease. Am J Surg Pathol. 2005; 29(4):443-451. doi: http://dx.doi.org/10.1097/01.pas.0000152131.58492.97.4. Rahbari-Oskoui F, O’Neill WC. Diagnosis and Management of Acquired Cystic Kidney Disease and Renal Tumors in ESRD Patients.

Semin Dial. 2017; 30(4): 373-379. doi: 10.1111/sdi.12605.5. Alpers CE, Chang A. The Kidney. In: Kumar V, Abbas Ak, Aster JC, Perkins JA, eds. Robbins and Cotran Pathologic Basis of Disease, 9th

Edition. Philadelphia, PA: Elsevier Inc.; 2015: 897-957.6. Scovell J, Hernandez J, Hollander A, Link R. Transposon mutagenesis drives renal cyst formation in vivo when combined with C-Met

hyperactivation: implications for acquired renal cystic disease. J Urol. 2017;197(4S):e494-e495. doi: https://doi.org/10.1016/j.juro.2017.02.1179.

7. Ahn S, Kwon GY, Cho YM, et al. Acquired cystic disease-associated renal cell carcinoma: further characterization of the morphologic and immunopathologic features. Med Mol Morphol. 2013;46:225-232. doi: 10.1007/s00795-013-0028-x.

8. Srigley JR, Zhou M, Allan R, et al. Protocol for the Examination of Specimens from Patients with Invasive Carcinoma of Renal Tubular Origin. College of American Pathologists. http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-kidney-17protocol-4011.pdf. Published June 2017. Accessed March 2018.

9. Lowell M, Cheek H, Davidson J, et al. Protocol for Examination of Specimens from Patients with Invasive Carcinoma of Renal Tubular Origin. American Association of Pathologists’ Assistants.

10. Cossu-Rocca P, Eble JN, Zhang S, Martignoni G, Brunelli M, Cheng L. Acquired cystic disease-associated renal tumors: an immunohistochemical and fluorescence in situ hybridization study. Mod Pathol. 2006;19:780-787. doi: 10.1038/modpathol.3800604.

11. Kuroda N, Hess O, Zhou M. New and emerging renal tumour entities. Diagn Histopathol. 2016;22(2):47-56. doi: http://dx.doi.org/10.1016/j.mpdhp.2016.01.005.

12. Rini BI, McKiernan JM, Chang SS. Kidney. In: Amin MB et al, eds. AJCC Cancer Staging Manual, Eighth Edition. Chicago, IL: Springer; 2017: 739-748.

DiscussionMacroscopic & Microscopic Morphology: ACD-RCC nephrectomy specimens are atrophic or normal in size with the renal cortex and medullaobliterated by multiple, small serous cysts.1,4,5 ACD-RCC is solitary or multifocal and typically around 3.0 cm in greatest dimension, well-circumscribed, firm,and arising within a cyst.1-4 The cut surface is yellow-tan, white, or brown and may demonstrate focal hemorrhage or necrosis.1-3 Cysts may exhibit papillarychanges.1,7,10 Microscopic tumor architecture can be papillary, tubulocystic, microcystic, macrocystic, solid, or cribiform; papillary and tubulocystic being mostcommon.1-3,10 The tumor cells are large with granular eosinophilic cytoplasm, ill-defined membrane borders, and Fuhrman Nuclear Grade 3 nuclei.1-3,7,10,11

Polarizing, birefringent intratumoral calcium oxalate crystals are extracellular within the tumor and kidney parenchyma.1,3 Intratumoral calcium oxalatedeposition is exclusive to ACD-RCC but is not always present; thus, it is not pathognomonic.1,3,10

Ancillary Testing: ACD-RCC tumor cells exhibit a unique immunophenotype.10 Positive immunohistochemistry (IHC) results for CD10, renal cellcarcinoma marker, and racemase (p504s) prove a proximal renal tubule phenotype.1,2,7,10,11 In this case, CD10, CK7, and racemase (p504s) confirmed thediagnosis of ACD-RCC. The use of IHC as a diagnostic tool for ACD-RCC is limited as the immunophenotype is not definitively known; however, IHC isuseful for differentiation from clear cell renal cell carcinoma (CCRCC).1,7 ACD-RCC commonly exhibits gains of chromosomes 3, 7, and 16.1,2,11

Chromosomal losses are less common, but may occur with chromosomes 2, 3, 16, and Y.1 Molecular studies can be used to rule out papillary renal cellcarcinoma (PRCC), as PRCC will exhibit a gain of chromosome 1q and no loss of chromosomes 3 and X.1

Staging, Prognosis, & Treatment: ACD-RCC staging falls under the American Joint Committee on Cancer (AJCC) kidney cancer staging system inthe eighth edition of the AJCC Cancer Staging Manual.12 Staging depends on tumor size, extent of invasion, extension into vasculature, regional lymph nodemetastasis, and distant metastasis.12 The bone, liver, lung, brain, adrenal glands, and distant lymph nodes are common metastatic sites.12 Renal vein extensionis a concern when evaluating RCC, as inferior vena cava and right atrium involvement may result.12 Compared to sporadic RCC, ACD-RCC is less aggressivewith a good prognosis.1-4,10,11 Sarcomatoid differentiation and rhabdoid characteristics indicate a more aggressive cancer and poorer prognosis.1,2,11 The RCCfive-year survival rate is 70% with metastases, 95% with no metastases, and 60% with perinephric fat invasion.5 ACD-RCC tumors are discovered at a lowergrade and stage due to ESRD patient management.2,3,11 First-line treatment is partial or total nephrectomy.1,5 Radiographic surveillance of high risk ESRDpatients has been suggested to diagnose ACD-RCC at an early stage.1 Frequent radiographic surveillance of known ACD-RCC patients and ESRD patientsundergoing dialysis for more than 10 years is currently the only recommendation.1,3

Macroscopic ExaminationThe 455 gram, 15.0 x 8.5 x 7.0 cm right radical nephrectomy consisted of attached perinephric fat,kidney, renal vein, renal artery, one accessory vessel, and 2.0 x 0.5 cm ureter. The specimen surfaceappeared markedly cystic with several disrupted areas. The specimen was bivalved to reveal multiplesmooth-walled cysts occupying the entire renal parenchyma, consistent with ACKD. Papillaryexcrescences were not identified. The cysts contained serosanguineous fluid, gelatinous material, andclotted blood. Three well-circumscribed nodules were confined within the kidney parenchyma: 1.5 x0.8 x 0.8 cm and 0.8 x 0.8 x 0.7 cm tan, firm nodules located in the superior pole and central kidney,respectively; 0.8 x 0.8 x 0.7 cm golden yellow and dark brown nodule located in the inferior pole.Invasion of the renal artery, renal vein, and perinephric fat was not grossly identified. Macroscopicimages were not available for this case, see Image 1.2

Microscopic ExaminationH&E stained sections of the superior pole nodule exhibited tumor cells witheosinophilic cytoplasm, ill-defined cell borders, and uniform nuclei, consistentwith an oncocytoma. The remaining two nodules exhibited papillary,micropapillary, microcystic, and solid tubular microscopic architectures, seeImage 2A. Tumor cells with moderate to abundant eosinophilic cytoplasm andFuhrman Nuclear Grade 3 nuclei were present, see Image 2B. The nodulesstained strongly and diffusely positive for CD10 and racemase (p504s) andscattered positive for CK7, see Image 2C. Intratumoral calcium oxalate crystalswere identified with polarizing microscopy, see Image 2D. The morphology andIHC are consistent with ACD-RCC. The kidney parenchyma exhibited cysticstructures and glomerulosclerosis, consistent with ESRD and ACKD. All threetumor nodules were microscopically confirmed as confined to the kidneywithout sarcomatoid features, margin involvement, tumor necrosis, orlymphovascular invasion. The ACD-RCC was staged as pT1a, pNX, pM0.13

Image 2: A. Low power view of ACD-RCC nodule with eosinophilic cells and microcysticarchitecture (H&E). B. High power view of ACD-RCC cells with abundant eosinophiliccytoplasm, ill-defined cell borders, dysplastic nuclei, and prominent nucleoli (H&E).C. Strong, diffuse positivity of ACD-RCC cells with racemase (p504s). D. Low power viewof birefringent intratumoral calcium oxalate crystals with polarizing microscopy.

Image 1: ACD-RCC with a similar morphologic appearanceto this patient case.2 The renal parenchyma is replaced bycysts. A well-circumscribed, hemorrhagic ACD-RCC tumornodule is present in the superior pole of the kidney.

Patient CaseThe patient presented is a 71 year-old male with a history ofESRD due to hypertension, 15 years of hemodialysis, prostatecancer, and left chest wall sarcoma. The patient presented to theemergency department anuric with gross hematuria lasting onemonth, but denied dysuria, suprapubic pain, fever, chills, nausea,vomiting, and trauma. A CT scan revealed multiple, bilateralrenal cysts. This and the patient’s history of ESRD and dialysisare compatible with ACKD. A right retrograde pyelogramindicated a displaced collecting system, likely due to renal cysts.The patient underwent an elective right radical nephrectomy.