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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Senior research fellow Jari Juuti
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-2332-2 (Paperback)ISBN 978-952-62-2333-9 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1523
AC
TAJari M
ällinen
OULU 2019
D 1523
Jari Mällinen
STUDIES ON ACUTE APPENDICITIS WITHA SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 5 2 3
JARI MÄLLINEN
STUDIES ON ACUTE APPENDICITIS WITH A SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES
Academic dissertation to be presented with the assent ofthe Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 2 of Oulu University Hospital, on 25 October2019, at 12 noon
UNIVERSITY OF OULU, OULU 2019
Copyright © 2019Acta Univ. Oul. D 1523, 2019
Supervised byProfessor Jyrki MäkeläProfessor Paulina SalminenDocent Tero Rautio
Reviewed byDocent Panu MentulaDocent Sari Venesmaa
ISBN 978-952-62-2332-2 (Paperback)ISBN 978-952-62-2333-9 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2019
OpponentProfessor Pauli Puolakkainen
Mällinen, Jari, Studies on acute appendicitis with a special reference toappendicoliths and periappendicular abscesses. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; Oulu UniversityHospitalActa Univ. Oul. D 1523, 2019University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Epidemiological and clinical data suggest that acute appendicitis might have two different formswith different disease severities. Uncomplicated and complicated acute appendicitis appear to bedistinct entities instead of consecutive events. Appendicitis does not always inevitably progress toperforation and most cases are uncomplicated by nature. This supports the importance of anaccurate differential diagnosis between uncomplicated and complicated acute appendicitisenabling treatment optimization.
This thesis consists of three studies. The first study evaluated the possibility to differentiatebetween uncomplicated and complicated appendicitis using only clinical symptoms andlaboratory markers with a special focus on predicting the presence of an appendicolith without theuse of modern imaging. We found neither sufficiently reliable to accurately estimate the severityof acute appendicitis or to determine the presence of an appendicolith, supporting the use ofcomputed tomography imaging to assess the disease.
The second study focused on clarifying the histopathological differences betweenuncomplicated acute appendicitis and acute appendicitis presenting with an appendicolith; acalcified deposit of faecal material in the appendiceal lumen. It’s presence has been shown topredict perforation and failure of conservative treatment. This study evaluated thehistopathological findings of computed tomography diagnosed uncomplicated acute appendicitisand appendicolith appendicitis without perforation. Acute appendicitis presenting with anappendicolith was histopathologically different from uncomplicated acute appendicitis on all theassessed histological parameters, indicating the potentially complicated nature of appendicolithappendicitis.
The third study was a randomized, multicentre clinical trial comparing interval appendectomywith follow-up with magnetic resonance imaging after successful initial non-operative treatmentof complicated acute appendicitis presenting with a periappendicular abscess. The studyhypothesis was that an interval appendectomy might not be necessary based on the previouslyreported low appendicitis recurrence rate after a periappendicular abscess. The original studyhypothesis was left unresolved, as an unexpectedly high rate of appendiceal neoplasms wasdetected in the study population and the study was prematurely terminated. The neoplasm rateafter a periappendicular abscess in this prematurely terminated study was high (20%). All theneoplasms were detected in patients over 40 years of age, strongly supporting an intervalappendectomy for all patients over 40 years of age if this rate of neoplasms is validated in futurestudies.
Keywords: appendicolith, complicated appendicitis, imaging, interval appendectomy
Mällinen, Jari, Tutkimuksia äkillisestä umpilisäkkeen tulehduksesta koskienerityisesti ulostekiveä ja umpilisäkkeen vieruskudoksen paisetta. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Oulunyliopistollinen sairaalaActa Univ. Oul. D 1523, 2019Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Aiemmat tutkimukset viittaavat siihen, että on olemassa kaksi erillistä akuutin umpilisäkkeentulehduksen muotoa: komplisoitumaton ja komplisoitunut. Nämä muodot eivät ole toistensa jat-kumo: umpilisäkkeen tulehdus ei aina johda umpilisäkkeen puhkeamiseen, vaan valtaosa umpili-säkkeen tulehdustapauksista on komplisoitumattomia. Oikean hoitotavan valinta edellyttää tark-kaa erotusdiagnostiikkaa tautimuotojen välillä
Tämä väitöskirjatyö koostuu kolmesta osatyöstä. Ensimmäisen osatyö selvitti, onko kompli-soitumaton ja komplisoitunut umpilisäkkeen tulehdus mahdollista erottaa ilman kuvantamistakliinisin löydöksin ja laboratoriokokein painottaen ulostekiven olemassaolon ennustamista.Umpilisäkkeen tulehduksen vaikeusasteen tai ulostekiven olemassaolon ennustaminen ei ollutmahdollista pelkästään kliinisten löydösten tai laboratoriokokeiden perusteella. Tämä korostaatietokonetomografian merkitystä taudin vaikeusasteen arvioinnissa.
Toinen osatyö selvitti histologisia eroja komplisoitumattoman umpilisäkkeen tulehduksen jaulostekiven sisältävän äkillisen umpilisäkkeen tulehduksen välillä. Ulostekiven tiedetään ennus-tavan umpilisäkkeen puhkeamaa ja konservatiivisen hoidon epäonnistumista. Tutkimuksessa sel-vitettiin histologisia löydöksiä potilailla, joilla oli tietokonetomografiatutkimuksella varmistettukomplisoitumaton äkillinen umpilisäkkeen tulehdus tai ulostekiven sisältävä äkillinen umpili-säkkeen tulehdus ilman puhkeamaa. Tutkimuksessa todettiin, että ulostekiven sisältävät tulehtu-neet umpilisäkkeet poikkeavat kaikkien tutkittujen parametrien osalta komplisoitumattomastaumpilisäkkeen tulehduksesta. Tämä tukee käsitystä ulostekiven sisältävän umpilisäkkeen tuleh-duksen komplisoituneesta luonteesta.
Kolmas osatyö oli randomoitu monikeskustutkimus, jossa verrattiin toisiinsa rauhallisessavaiheessa tehtyä umpilisäkkeen poistoa ja seurantaa magneettiresonanssikuvauksella potilailla,joilla oli onnistuneesti hoidettu konservatiivisesti umpilisäkkeen ympäryskudoksen paise. Hypo-teesina oli, että myöhempi umpilisäkkeen poisto ei ole tarpeen, koska tulehduksen uusiutumisenriski umpilisäkkeen vieruskudoksen paiseen hoidon jälkeen on aiemmin raportoitu matalaksi.Tutkimushypoteesi jäi avoimeksi, koska tutkimuksen aikana havaittiin runsaasti umpilisäkkeenkasvaimia, mikä johti tutkimuksen ennenaikaiseen keskeyttämiseen. Umpilisäkkeen kasvaintenilmaantuvuus oli 20%, kaikki yli 40-vuotiailla potilailla. Mikäli tutkimuksen tulokset vahvistu-vat tulevissa tutkimuksissa, kaikille yli 40-vuotiaille potilaille tulisi suositella umpilisäkkeenpoistoa sairastetun umpilisäkkeen vieruskudoksen paiseen jälkeen.
Asiasanat: komplisoitunut umpilisäkkeen tulehdus, kuvantaminen, rauhallisen vaiheenumpilisäkkeen poisto, ulostekivi
To my Family
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Acknowledgements
This doctoral thesis was carried out during years 2013 to 2019 in the Department
of Surgery, Oulu University Hospital, in close co-operation with the Department of
Surgery, Turku University Hospital. Collection of the patient data for studies I and
III took place also in Kuopio and Tampere University Hospitals and Seinäjoki
Central Hospital. Analysis of the data for study II was done in the Department of
Pathology, Oulu University Hospital.
I started my work in Oulu University Hospital in January 2012 after a long
period of working in Kainuu Central Hospital. Soon after, I was politely asked
about my willingness to contribute in scientific work as a part of my new position
as a university hospital gastrosurgeon. In the beginning I was doubtful. First of all,
despite my long experience as a surgeon, I was a complete rookie when it came to
scientific writing and methods. I admit, being a specialist for a long time makes it
less appealing to be suddenly the apprentice. Second, I was not completely sure
that research without clinical context would interest me enough to follow through
such a long process. Luckily my supervisors had the wisdom to guide me to this
specific topic which made very much sense for me to absorb in. Therefore, I want
to express my deepest gratitude to my supervisors. I thank Professor Jyrki Mäkelä,
M.D., Ph.D., for the supportive guidance during this work. I thank Docent Tero
Rautio, M.D., Ph.D. for his calm patience, when I was frustrated by my own
incompetence. Most heavily I owe to Professor Paulina Salminen, M.D., Ph.D.
Without her contribution and brilliant mind there would be no thesis. More than
once I have stolen her free time for my own benefit when struggling with various
manuscripts. Her help has been irreplaceable.
I warmly thank all my co-authors. Especially I want to wish my gratitude to
Elina Lietzén, M.D., Ph.D. Apart from her contribution in the study I, she also
played an essential role in planning and organizing the study II. Professor Markus
Mäkinen, M.D., Ph.D. and Siina Vaarala, M.B., offered their expertise and valuable
time in analyzing the histopathological samples in the study II as well as
participated in formulating the article. I want to express my appreciation to Pasi
Ohtonen, M.Sc. for his assistance with statistical analyses as well as explaining
them in a way I understood.
I want to thank Docent Juha Saarnio, M.D., Ph.D., the Head of the Division of
Gastrointestinal Surgery during this study. He has been a role model for me both in
scientific work and in practicing surgery. I also wish to thank all my brilliant
collegues in the Division of Gastrointestinal Surgery. Especially I want to thank
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Heikki Takala, M.D., Ph.D., Marjo Koskela, M.D., Ph.D., and Kai Klintrup, M.D.,
Ph.D., long-lasting colleagues as well as friends. Your humor inside and outside the
OR has improved my life for years now. I also wish to thank other roommates:
Mika Vierimaa, M.D., Heikki Karjula, M.D., Jukka Rintala, M.D., Ph.D., Jarmo
Niemelä, M.D., and Docent Vesa Koivukangas, M.D., Ph.D. I often miss our
discussions in our crowded little office.
I warmly thank my brothers, Jukka and Olli-Pekka, for being present in my
life. Jukka has taught me valuable lessons in life as older brother often does. Olli-
Pekka has patiently guided me during our hiking tours in Lapland as I have
followed him totally disoriented. The conversations during our common trips have
helped me gain much needed sense.
I want to thank my mother-in-law Maija Manninen and father-in-law Pertti
Manninen, whose help has been required uncountable times during the last year
when we have held a household with two surgeons, one thesis and one very lively
toddler, my dear daughter Elsa. Her presence has helped me stay rooted to normal
life even during most intensive writing sessions as she does not approve my
excuses, even if they are thesis -related, when there are drawings that need to be
inspected.
I also want to dedicate this work to my adult children, Aatu, Miina and Kalle.
It has been a great pleasure for me to follow you find your place in the world.
Especially I am grateful for Aatu and his Sonja for making me a double grandfather.
My deepest gratitude is for my wife Mari. You are a true miracle: a surgeon
and a mother but even more thesis- related, my English dictionary, tech support and
meal service. You are my confidence when I loose it and am ready to give up.
Without you this thesis would not exist. I love you.
This work was financially supported by Oulu University, Mary and Georg C.
Ehrnrooth Foundation, Instrumentarium Science Foundation and Finnish Medical
Foundation.
August 2019 Jari Mällinen
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Abbreviations
AAS Adult appendicitis score
AAST The American Association for Surgery of Trauma
AIR Appendicitis inflammatory response
APSI Appendicitis severity index
AUC Area under curve
CCL Chemokine CC motif ligand
CI Confidence interval
CRP C-reactive protein
CRS Cytoreductive surgery
CT Computed tomography
CXCL Chemokine ligand
DPAM Disseminated peritoneal adenomucinosis
HAMN High-grade appendiceal mucinous neoplasm
HIPEC Hyperthermic intraoperative chemotherapy
IAA Intra-abdominal abscess
IL Interleukin
INR International normalized ratio
LA Laparoscopic appendectomy
LAMN Low-grade appendiceal mucinous neoplasm
MMP Matrix metalloproteinase
MPO Myeloperoxidase
MPV Mean platelet volume
MRI Magnetic resonance imaging
NEC Neuroendocrine carcinoma
NET Neuroendocrine tumour
NOTES Natural orifice transluminal endoscopic surgery
NSAP Non-specific abdominal pain
OA Open appendectomy
OR Odds ratio
PAS Pediatric appendicitis score
PDW Platelet distribution width
PMCA Peritoneal mucinous carcinomatosis
PMCA-S Peritoneal mucinous adenomucinosis with signet ring cells
PMP Pseudomyxoma peritonei
PSOGI Peritoneal Surface Oncology Group International
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RCT Randomized controlled trial
RIPASA Raja Isteri Pengiran Anak Saleha appendicitis
RLQ Right lower quadrant
ROC Receiver operation characteristic
RR Relative risk
SAA Serum amyloid A
SILS Single-incision laparoscopy-assisted
SSI Surgical site infection
TIMP Tissue inhibitor of metalloproteinase
TNF Tumour necrosis factor
US Ultrasound
WBC White blood cell count
WHO World Health Organization
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List of original publications
This thesis is based on following articles, which are referred in the text by their
Roman numbers
I Lietzén, E.*, Mällinen, J.*, Grönroos, J. M., Rautio, T., Paajanen, H., Nordström, P., Aarnio, M., Rantanen, T., Sand, J., Mecklin, J. P., Jartti, A., Virtanen, J., Ohtonen, P., Salminen, P. (2016). Is preoperative distinction between complicated and uncomplicated acute appendicitis feasible without imaging? Surgery 160(3), 789–795. doi:10.1016/j.surg.2016.04.021
II Mällinen, J., Vaarala, S., Mäkinen, M., T., Lietzén, E., Grönroos, J., Ohtonen, P., Rautio T, Salminen, P. (2019). Appendicolith appendicitis is clinically complicated acute appendicitis - is it histopathologically different from uncomplicated acute appendicitis? Int J Colorectal Dis 34(8), 1393–1400. doi:10.1007/s00384-019-03332-z
III Mällinen, J., Rautio, T., Grönroos, J., Rantanen, T., Nordström, P., Savolainen, H., Ohtonen, P., Hurme, S., Salminen, P. (2019). Risk of appendiceal neoplasm in periappendicular abscess in patients treated with interval appendectomy vs follow-up with magnetic resonance imaging. JAMA Surgery 154(3), 200–207. doi:10.1001/jamasurg.2018.4373
* The original publication I has also been used in the thesis of Elina Lietzén.
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Contents
Abstract
Tiivistelmä
Acknowledgements 9
Abbreviations 11
List of original publications 13
Contents 15
1 Introduction 17
2 Review of the literature 21
2.1 History of the acute appendicitis ............................................................. 21
2.2 Epidemiology of acute appendicitis ........................................................ 22
2.3 Aetiology and pathogenesis of acute appendicitis .................................. 23
2.4 Classification of acute appendicitis ......................................................... 27
2.5 Role of appendicoliths ............................................................................ 30
2.6 Diagnosis of acute appendicitis ............................................................... 31
2.6.1 Clinical diagnosis ......................................................................... 31
2.6.2 Laboratory markers ...................................................................... 32
2.6.3 Diagnostic imaging ....................................................................... 34
2.6.4 Diagnostic scoring ........................................................................ 38
2.6.5 Differential diagnosis of uncomplicated and complicated
appendicitis ................................................................................... 39
2.7 Treatment of acute appendicitis .............................................................. 41
2.7.1 Non-operative treatment of acute uncomplicated
appendicitis ................................................................................... 41
2.7.2 Operative treatment of acute uncomplicated appendicitis ............ 44
2.7.3 Treatment of perforated appendicitis ............................................ 46
2.7.4 Treatment of a periappendicular abscess ...................................... 47
2.8 Appendiceal neoplasms ........................................................................... 50
2.8.1 Classification of appendiceal neoplasms ...................................... 50
2.8.2 Neoplasms associated with uncomplicated appendicitis
and periappendicular abscesses .................................................... 54
3 Aims of the study 57
4 Materials and methods 59
4.1 APPAC study .......................................................................................... 59
4.1.1 Study I .......................................................................................... 61
4.1.2 Study II ......................................................................................... 62
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4.2 Study III .................................................................................................. 62
4.3 Statistical analysis ................................................................................... 63
5 Results 65
5.1 Study I ..................................................................................................... 65
5.2 Study II .................................................................................................... 67
5.3 Study III .................................................................................................. 69
6 Discussion 71
6.1 Differential diagnosis of uncomplicated and complicated acute
appendicitis ............................................................................................. 71
6.2 Histopathological differences between uncomplicated acute
appendicitis and acute appendicitis presenting with an
appendicolith ........................................................................................... 73
6.3 Treatment options of periappendicular abscesses ................................... 75
7 Conclusions 79
References 81
Original publications 107
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1 Introduction
Acute appendicitis is globally the most common reason for surgical emergency
department visits. Traditionally, an urgent emergency appendectomy was
recommended after a clinical diagnosis of suspected acute appendicitis had been
made, based on the idea that all appendicitis cases inevitably progress to perforation
due to advancing inflammation. However, now it is universally accepted that acute
appendicitis does not invariably progress to perforation. Complicated and
uncomplicated cases of appendicitis follow different epidemiological patterns,
suggesting that there may be different pathophysiological processes behind these
two forms of appendicitis (Livingston, Woodward, Sarosi, & Haley, 2007;
Livingston, Fomby, Woodward, & Haley, 2011). There is evidence suggesting that
a patient’s susceptibility to acquire complicated appendicitis may be at least
partially gene-related (Rivera-Chavez et al., 2004). An appendectomy is still the
gold standard treatment for acute appendicitis, but recent emerging evidence has
shown that in most cases, acute uncomplicated appendicitis can be treated non-
operatively with antibiotics even over the long term (Hansson, Korner, Khorram-
Manesh, Solberg, & Lundholm, 2009; Salminen et al., 2015; Salminen et al., 2018;
Vons et al., 2011). The spontaneous resolution of acute uncomplicated appendicitis
is known to be possible (Morino, Pellegrino, Castagna, Farinella, & Mao, 2006).
There is evidence showing that symptomatic care without antibiotics may be as
effective as antibiotic treatment in patients with computed tomography (CT)
confirmed acute uncomplicated appendicitis (Park, Kim, & Lee, 2017). On the
other hand, complicated acute appendicitis requires an emergency appendectomy,
emphasizing the need for diagnostic accuracy. Perforation often occurs before
admission to the hospital. However, there is debate concerning the impact of in-
hospital delays on the rate of complicated appendicitis. Based mostly on
retrospective studies, researchers have stated that the potential in-hospital delay due
to possible imaging after admission to surgery does not increase the rate of
perforation (Abou-Nukta et al., 2006; R. E. Andersson, 2007; Drake et al., 2014).
However, in a prospective study, a longer in-hospital delay was associated with an
increased risk of complicated appendicitis (Sammalkorpi, Leppaniemi, & Mentula,
2015), and attention should also be paid to the imaging logistics in acute care
surgery settings to avoid this problem.
The previous cornerstones in diagnosing acute appendicitis have traditionally
been clinical symptoms and laboratory markers of the white blood cell (WBC)
count and C-reactive protein (CRP). Elevated levels of both abovementioned
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laboratory markers together with typical acute lower right quadrant abdominal pain
often result in the suspicion of acute appendicitis. In addition, low levels of both
the WBC count and CRP may rule out acute appendicitis quite effectively, even in
the presence of typical clinical signs (Gronroos & Gronroos, 1999). However,
diagnosing acute appendicitis by clinical symptoms and laboratory markers is
associated with a high rate of negative appendectomies, defined as the surgical
removal of a histopathologically non-inflamed appendix. Before the era of modern
imaging, even 15–30% rates of negative appendectomies were considered
acceptable (R. R. Andersson, Hugander, & Thulin, 1992; Gilmore et al., 1975;
Hoffmann & Rasmussen, 1989). Together with the development and increasing
availability of modern imaging modalities, especially CT imaging, the negative
appendectomy rates have decreased to 2–6% when novel imaging modalities are
used comprehensively (Bhangu, Soreide, Di Saverio, Assarsson, & Drake, 2015;
K. Jones, Pena, Dunn, Nadalo, & Mangram, 2004; Lahaye et al., 2015; C. C. Lee,
Golub, Singer, Cantu, & Levinson, 2007). At the same time, the rate of perforated
appendicitis has not decreased (Krajewski, Brown, Phang, Raval, & Brown, 2011).
In 1999 Rao and colleagues found a decreased incidence of perforated appendicitis
after CT scanning became available, but as Andersson later in 2008 commented,
this decrease could be explained by the 146% increase in the incidence of
uncomplicated appendicitis cases: a CT scan was in fact “too accurate” at
diagnosing spontaneously resolving appendicitis cases (R. E. Andersson, 2008;
Rao, Rhea, Rattner, Venus, & Novelline, 1999). CT is considered the most accurate
imaging modality in suspected acute appendicitis. However, even though the
specificity of CT is very high in diagnosing acute appendicitis, its sensitivity to
show appendix perforation is limited (M. S. Kim et al., 2014; Verma et al., 2015).
The differential diagnosis between uncomplicated and complicated
appendicitis is essential for assessing all the potential effective treatment options,
ranging from supportive therapy to antibiotics and an appendectomy, for the
treatment of uncomplicated acute appendicitis. Several scoring systems involving
clinical findings and laboratory markers have been developed to assist in the
diagnosis of acute appendicitis (Alvarado, 1986; M. Andersson & Andersson, 2008;
Lintula et al., 2010; Sammalkorpi, Leppaniemi, Lantto, & Mentula, 2017). These
scoring systems assist in identifying appendicitis patients among all the patients
presenting with the clinical symptoms of appendicitis or in guiding the diagnostic
imaging, but they do not differentiate between uncomplicated and complicated
appendicitis. Atema and colleagues recently described a scoring system combining
clinical findings, laboratory markers and CT imaging showing promising results in
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differentiating between uncomplicated and complicated appendicitis (Atema, van
Rossem, Leeuwenburgh, Stoker, & Boermeester, 2015). The presence of an
appendicolith has been shown to predict both the failure of non-operative treatment
of acute appendicitis and to be associated with a more complicated course of the
disease, but further studies are needed to better define appendicolith appendicitis
(Alaedeen, Cook, & Chwals, 2008; Aprahamian, Barnhart, Bledsoe, Vaid, &
Harmon, 2007; Mahida et al., 2016; Shindoh et al., 2010; Vons et al., 2011).
Complicated appendicitis is traditionally defined as perforated appendicitis,
leading either to peritonitis or a closed, circumscribed periappendicular abscess.
Acute appendicitis is complicated by an associated neoplasm in 0.7–3% of cases
(R. E. Andersson & Petzold, 2007; Loftus et al., 2017; Murphy, Farquharson, &
Moran, 2006; Teixeira et al., 2017). There is evidence showing that the rate of
neoplasms differs in uncomplicated and complicated acute appendicitis. In a recent
systematic review, the overall appendiceal tumour rate was 1% after an
appendectomy, but in patients presenting with appendiceal inflammatory mass, the
neoplasm rate varied from 10% to 29% (Teixeira et al., 2017).
An appendicolith is detected in 14–30% of the CT-confirmed acute
appendicitis patients (Alaedeen et al., 2008). Based on the known-increased risk of
perforation associated with non-operative treatment of appendicolith appendicitis,
it is recommended to be treated operatively (Mahida et al., 2016; Salminen et al.,
2015; Shindoh et al., 2010). The treatment of a patient with perforated acute
appendicitis with peritonitis is an emergency appendectomy. Acute appendicitis is
complicated by a periappendicular abscess in 3–10% of patients (R. E. Andersson
& Petzold, 2007; Meshikhes, 2008). The traditional, clinically accepted and widely
used management of a periappendicular abscess is primary non-operative treatment
with antibiotics and drainage, allowing the acute inflammatory process to subside
in more than 90% of cases without surgery (R. E. Andersson & Petzold, 2007; Oliak
et al., 2001). However, the authors advocating for primary operative treatment of
periappendicular abscess have shown much higher failure rates for primary non-
operative treatment (Deelder, Richir, Schoorl, & Schreurs, 2014; Maxfield,
Schuster, Bokhari, McGillicuddy, & Davis, 2014; Mentula, Sammalkorpi, &
Leppaniemi, 2015). The need for a subsequent interval appendectomy after the
initial successful non-operative treatment of a periappendicular abscess has
recently been questioned, with the appendicitis recurrence rate varying in most
studies between 5% and 26% (Anderson, Bickler, Chang, & Talamini, 2012; R. E.
Andersson & Petzold, 2007; Darwazeh, Cunningham, & Kowdley, 2016;
Kaminski, Liu, Applebaum, Lee, & Haigh, 2005; Lai et al., 2006). However, the
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alarming rates of neoplasms recently reported in patients with an interval
appendectomy after initial conservative treatment of a periappendicular abscess,
may support the need for an interval appendectomy (Carpenter, Chapital, Merritt,
& Johnson, 2012; Furman, Cahan, Cohen, & Lambert, 2013; Lee et al., 2011;
Teixeira et al., 2017; Wright, Mater, Carroll, Choy, & Chung, 2015).
The goal of study I was to evaluate the feasibility of clinical and laboratory
findings in differentiating between uncomplicated and complicated acute
appendicitis without imaging with a special interest in predicting the presence of
an appendicolith. The goal of study II was to assess possible histopathological
difference between uncomplicated and complicated acute appendicitis presenting
with an appendicolith. The aim of study III was to compare an interval
appendectomy and follow-up with magnetic resonance imaging after the initial
successful nonoperative treatment of a periappendicular abscess.
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2 Review of the literature
2.1 History of the acute appendicitis
In the middle ages, the existence of the appendix was uncertain. For centuries, the
knowledge of anatomy relied mostly on the writings of Galen, dating back to 130–
201 AD. His anatomic studies were mainly done on monkeys (Barbary macaques),
which, unlike great apes (anthropoids), do not have an appendix. Leonardo da Vinci
described appendix in his painting dated 1492. In the 16th century, anatomists like
Berengario da Carpi were able to identify its structure within the body but could
only guess at its purpose. In 1521, da Carpi described an empty small cavity
(addentramentum) at the end of the cecum. In 1543, Andreas Vesalius characterized
the appendix as one of the three openings of the cecum together with the ileum and
the colon. Gabriel Falloppius was the first anatomist to compare the appendix to a
worm (vermiformis) in 1561 (G. R. Williams, 1983).
The first successful appendectomy was performed in 1735 by Dr Claudius
Amayand at St. George’s Hospital in London. The patient was an 11-year-old boy,
whose appendix, located in the right-sided scrotal hernia sac, had been perforated
by a pin he had swallowed. Amayand identified the appendix, ligated and removed
it (G. R. Williams, 1983). Jean Mestivier performed the first operation for acute
appendicitis in 1759 in Bordeaux. However, before the invention of general
anaesthesia in 1846 and an appreciation of the cause of infection, laparotomy was
justifiably considered as a last resort. In 1867, British surgeon Joseph Heller
published his paper “Antiseptic Principle of the Practice of Surgery”, which lead to
the widespread introduction of antiseptic surgical methods (Pitt & Aubin, 2012).
In 1886, Dr Reginald H Fitz published his paper, “Perforating inflammation of
the Vermiform Appendix; With Special Reference to Its Early Diagnosis and
Treatment” (Fitz Reginald, 1886). For the first time, the term “appendicitis” was
used in this article. In 1991 Charles McBurney described the typical symptoms and
clinical signs of acute appendicitis in his writing, “The indications for early
laparotomy in appendicitis” (McBurney, 1891). McBurney introduced the muscle-
splitting incision still carrying his name in 1894 (McBurney, 1894). An early
appendectomy was recommended to prevent inevitable perforation. However, Fitz,
who was a pathologist, noticed that in 30% of autopsies there was evidence of prior
appendiceal inflammation, suggesting the possibility of the spontaneous resolution
of appendicitis without surgery in some patients. Surgeons rapidly accepted
22
appendectomies for acute appendicitis. In 1904, Dr John B Murphy of Chicago
reported a personal experience with 2000 appendectomies (G. R. Williams, 1983).
In 1981, Kurt Semm performed the first laparoscopic appendectomy (Semm,
1983), which currently is the gold standard of appendectomies.
2.2 Epidemiology of acute appendicitis
In Western countries, the life-time risk of acute appendicitis is estimated to be 7–
8% (Addiss, Shaffer, Fowler, & Tauxe, 1990; Almstrom, Svensson, Svenningsson,
Hagel, & Wester, 2018). The incidence rates in developing countries are much
lower compared to developed countries. In Ghana, the reported incidence of acute
appendicitis is 0.2/100 000 (Ohene-Yeboah & Abantanga, 2009). In developed
countries, the reported incidence rate is 75–136/100 000 (Ilves, Paajanen, Herzig,
Fagerstrom, & Miettinen, 2011). A part of this marked difference is explained by
variations in health care systems and the accuracy of the information available as
well as different dietary manners. On the other hand, according to a Swedish cohort
follow-up study, the association of the incidence of appendicitis with geographic
origin remains over generations and is seen in adoptees and immigrants (Terlinder
& Andersson, 2016).
The incidence of acute appendicitis in Finland in 2008 was 9.8/100 000, which
is equal to the reported incidence rates in other Scandinavian countries (Ilves et al.,
2011). According to many studies from Europe and North America, the trend in the
incidence was decreasing in the late 20th century, both in adult and paediatric
populations (Aarabi, Sidhwa, Riehle, Chen, & Mooney, 2011; Addiss et al., 1990;
Andersen, Paerregaard, & Larsen, 2009; Kang, Hoare, Majeed, Williamson, &
Maxwell, 2003; Noer, 1975). In Finland, the mean overall incidence declined 32%
between 1987 and 2008 (Ilves et al., 2011). In the USA, increased rates of acute
appendicitis have been reported during the first decade of the 21st century (Buckius
et al., 2012; Livingston et al., 2007). One potential explanation for the declining
incidence of acute appendicitis is the increased diagnostic accuracy. It has been
shown that in the past, with less accurate diagnostic methods, more normal
appendices and at same time, more appendices with spontaneously resolving
appendicitis, were removed (R. Andersson, Hugander, Thulin, Nystrom, & Olaison,
1994).
The epidemiological studies support the concept of different pathophysiologies
behind uncomplicated and complicated appendicitis. In a large Swedish cohort
study with a paediatric population, a pronounced reduction was found in the
23
incidence of non-perforated appendicitis compared with perforated appendicitis
between 1987 and 2013 (Almstrom et al., 2018). In an adult patient population, a
similar disconnect between the incidence of non-perforated and perforated
appendicitis has been reported (Buckius et al., 2012; Livingston et al., 2007).
The incidence of acute appendicitis is highest in adolescents and young adults.
The highest incidence occurs in the age group of 10–19 years (Addiss et al., 1990;
Buckius et al., 2012). The mean age at diagnosis seems to be rising. According to
an American epidemiological study between 1993 and 2008, the incidence of
appendicitis decreased by 4.6% in the age group of highest occurrence (10–19 years
of age), while the incidence increased by 6.3% in the age group of 30–69 years
(Buckius et al., 2012). Appendicitis is uncommon after 70 years of age and before
the age of 5 years (Addiss et al., 1990; J. H. Lee, Park, & Choi, 2010). There is
male dominance in the incidence of acute appendicitis: the male/female ratio varies
from 1.1 to 3.2 (Ilves et al., 2011), being highest before the age of 30 years (Stein
et al., 2012). However, as the negative appendectomy rate is higher in women, the
lifetime risk of undergoing an appendectomy is higher in females, 23% vs 12%,
respectively (Addiss et al., 1990).
The incidence of appendicitis shows seasonal variability. According to most
studies from Europe and North America, the incidence is highest in the summer
and lowest in the wintertime (Ilves et al., 2014; Zangbar et al., 2016).
2.3 Aetiology and pathogenesis of acute appendicitis
Over 130 years after Reginald Fitz’s publication introducing the term appendicitis,
the aetiology and exact pathogenesis of acute appendicitis remain unclear. In an
editorial dated 1938, the same questions and problems were pondered as we are
currently dealing with: for example, the importance of luminal obstruction, the
infective agent and the role of an appendicolith (A, 1938; Fitz Reginald, 1886).
In the 1930s, it was shown in animal models that complete obstruction of the
appendix leads to the appendiceal inflammation (Pieper, Kager, & Tidefeldt, 1982;
Wangensteen & Dennis, 1939). This led to a long-standing dogma concerning the
pathogenesis of acute appendicitis: distension of the appendix caused by the
obstruction is followed by increased intraluminal pressure. The disturbance of the
circulation, ischaemia and finally bacterial invasion to the appendiceal wall through
the damaged mucosa was believed to explain the development of appendicitis.
Appendicoliths or lymphoid hyperplasia have been mentioned as possible
obstructive agents (Swischuk, Chung, Hawkins, Jadhav, & Radhakrishnan, 2015).
24
However, an appendicolith is often an incidental finding without any signs of
appendicitis (Andreou, Blain, & Du Boulay, 1990; Ramdass, Young Sing, Milne,
Mooteeram, & Barrow, 2015; Singh & Mariadason, 2013), and lymphoid
hyperplasia is more common in normal appendices than in acute appendicitis, in
which it occurs in only approximately 6% of cases (Chang, 1981). The Swedish
studies directly contradict the obstruction theory. They measured the intraluminal
pressures of patients undergoing appendectomies and found no increase in
intraluminal pressure in 19/21 patients with phlegmonous appendicitis, whereas
there was increased intraluminal pressure in 6/6 patients with gangrenous
appendicitis. As a result, they suggested that appendiceal obstruction with increased
intraluminal pressure is a result of the inflammation, not the cause and the
obstruction caused by increased pressure may be associated with the development
of gangrenous appendicitis (Arnbjornsson & Bengmark, 1983; Arnbjornsson &
Bengmark, 1984). Further evidence against the obstruction theory comes from a
study in which it was observed that appendiceal mucosal ulcers can be
demonstrated often before the dilatation of the appendix is demonstrable. They
suggested that the primary lesion in acute appendicitis is a superficial mucosal
ulceration (Sisson, Ahlvin, & Harlow, 1971).
Carr suggested that a mucosal ulceration could be caused by a viral infection,
which is then followed by a secondary bacterial invasion (Carr, 2000) or
alternatively, viral disease could result in lymphoid hyperplasia of the appendix
with resultant obstruction and mucosal injury followed by bacterial infection (Alder
et al., 2010). This theory gets some support from the epidemiological studies
showing seasonal variation in the incidence of appendicitis (Alder et al., 2010;
Stein et al., 2012) as well as the temporo-spatial clustering of appendicitis cases
noted in a Swedish study (R. Andersson, Hugander, Thulin, Nystrom, & Olaison,
1995). Lynch et al. (2017) found an association between adenovirus infections and
acute appendicitis in a military trainee population (Lynch et al., 2017). Other
viruses with potential associations to appendicitis include Coxsackie B,
Cytomegalovirus and measles (Neumayer, Makar, Ampel, & Zukoski, 1993; Searle
& Owen, 1990; Tobe, Horikoshi, Hamada, & Hamashima, 1967; Whalen, Klos,
Kovalcik, & Cross, 1980).
Microbiological samples from acutely inflamed appendices reveal mixed
growth of normal gut organisms (Garcia-Marin, Perez-Lopez, Martinez-Guerrero,
Rodriguez-Cazalla, & Compan-Rosique, 2018; Montuori, Santurro, Gianotti, &
Fattori, 2018). The most commonly recovered species are Escherichia Coli,
Streptococcus spp., Bacteroides fragilis, Enterococcus faecium, Pseudomonas
25
aeruginosa, Klebsiella pneumoniae and Proteus. There is debate about the
usefulness of intraoperative culture swabs (Foo, Beckingham, & Ahmed, 2008).
However, in complicated appendicitis, peritoneal fluid cultures may lead to a useful
change in antibiotic therapy (Garcia-Marin et al., 2018). In addition, by taking
routine microbiological samples, changes in the local microbial antibiotic
resistance can be detected, which enables empiric antibiotic therapy to be optimized
(Coccolini et al., 2016).
Genetic factors seem to affect patients’ susceptibility to appendicitis. The risk
of appendicitis is three times higher in members of families with a positive history
for appendicitis than in those with no family history (Ergul, 2007). In a Japanese
study, the risk of a child to get appendicitis was 40% if both parents had undergone
an appendectomy and 20% if one of the parents had undergone it (Hiraiwa,
Umemoto, & Take, 1995). In a Swedish study analysing genetic and environmental
influences on the risk of acute appendicitis in twins, it was estimated that genetic
effects accounted for 30% of the risk (Sadr Azodi, Andren-Sandberg, & Larsson,
2009). In a recent study from Taiwan, the familial relative risks (RRs) of
appendicitis and familial transmission were estimated. The study group consisted
of 788 042 individuals who had at least one first-degree relative with operated and
histopathologically proved appendicitis. The overall RR (95% CI) was 1.67 (1.64–
1.71) compared with the general population. The RR with an affected twin was 3.40
(2.66–4.35). The RR for an individual with 3 or more affected first-degree relatives
was 6.70 (4.22–10.63). The estimated familial transmission (genetic plus shared
environmental contribution to the total phenotypic variance) was 23.2% (H. M. Li
et al., 2018). The advancement of appendicitis to perforation may also be gene
related. In another study, the risk for developing appendiceal perforation was found
to potentially be determined by variation in the interleukin-6 (IL-6) gene: the
patients with genetically modified lower immune response with low plasma and
peritoneal fluid IL-6 concentrations had a decreased risk of complicated disease
(Rivera-Chavez et al., 2004).
It has been assumed that diet has a role in the aetiology of appendicitis, as
populations on a high-fibre diet have lower incidence of appendicitis than those on
a more Western-style diet. On the other hand, the marked decrease in the incidence
of appendicitis in Western societies during the second half of the 20th century was
not associated with any remarkable changes in the dietary fibre intake.
Furthermore, the studies from Sweden and South Africa have shown that a change
to a Western-style low-fibre diet does not necessarily lead to higher incidence of
26
appendicitis among immigrants in Sweden or urban blacks in Johannesburg, South
Africa (Segal, Paterson, & Walker, 1986; Terlinder & Andersson, 2016).
During the early 20th century the incidence of appendicitis rose, peaked in
about 1950 and thereafter fell down. The industrialization in the first half of 1900s
was associated with an improvement in hygiene, which, according to the hygiene
hypothesis, limited the exposure of infants to enteric infections and modified
response to virus infections, thereby triggering appendicitis. Further improvements
in hygiene during the second half of the 1900s diminished the exposure to
pathogens causing the incidence of appendicitis finally to decline. There is some
epidemiological data supporting this theory, although the data available are far from
conclusive (Carr, 2000; Walker & Segal, 1990).
In a histological study with an Indian population, eosinophils were more
widely distributed through the appendiceal wall than neutrophils in focal
appendicitis patients (Aravindan, 1997). The author suggested that a type I
hypersensitivity reaction to an allergen might be responsible for the development
of acute appendicitis.
The spontaneous resolution of acute appendicitis is known to happen in at least
5–8% of all CT- or US-verified appendicitis cases (Barber, McLaren, & Rainey,
1997; Cobben, de Van Otterloo, & Puylaert, 2000; Heller & Skolnick, 1993;
Kirshenbaum, Mishra, Kuo, & Kaplan, 2003; Migraine, Atri, Bret, Lough, &
Hinchey, 1997). The histolopathologic features of resolving appendicitis with
mixed infiltrate of lymphocytes and eosinophils have been described (Ciani &
Chuaqui, 2000). Spontaneous resolution has been documented in epidemiological
studies. In a meta-analysis, in clinics adopting an expectant approach to the
treatment of suspected appendicitis, fewer patients with non-perforated
appendicitis were diagnosed compared with clinics that apply a more active
attitude. The incidence of perforated appendicitis was not influenced by the
radicality of the approach (R. Andersson et al., 1994). This suggests that some
appendicitis cases do resolve spontaneously, supporting further research in
assessing both the different pathophysiology and clinical course of different forms
of acute appendicitis and the role of the patient’s immune response potentially
affecting the disease presentation. In studies comparing early laparoscopy (during
the first 12–18 hours from admission) with observation in patients with non-
specific abdominal pain (NSAP), significantly less appendicitis has been diagnosed
in observation groups, also suggesting that the spontaneous resolution of
appendicitis occurs within observation. The incidence of acute appendicitis in these
studies was 30–39% in the laparoscopy group vs 6–13% in the observation group,
27
suggesting that in practice even 70–80% of appendicitis patients with non-specific
symptoms may recover spontaneously (Decadt et al., 1999; Morino et al., 2006).
2.4 Classification of acute appendicitis
Acute appendicitis can be divided into uncomplicated and complicated forms. The
division is usually based on the absence or presence of a perforation of the appendix
and is aimed to be useful in clinical practise to facilitate optimal treatment.
However, in practice the definitions of both uncomplicated and complicated acute
appendicitis are not uniform, and the use of these different terms varies in the
literature. The pathologists are also inconsistent in their use of diagnostic criteria
(Bhangu et al., 2015; Herd, Cross, & Dutt, 1992; Riber, Tonnesen, Aru, &
Bjerregaard, 1999). Table 1. shows the classification system presented originally
by Carr and later modified by Bhangu et al., taking into account both the
macroscopic appearance noted during surgery and the microscopic appearance
described by the pathologist as well as the possible clinical relevance of these
findings (Bhangu et al., 2015; Carr, 2000).
The clinical relevance of intraluminal inflammation (intraluminal neutrophil
infiltrate) with or without mucosal ulceration has been questioned. It is a common
finding in incidentally removed appendices without any clinical signs of
appendicitis (Pieper, Kager, & Nasman, 1983). The same concerns the
inflammation extending to the submucosa but not muscularis propria, and therefore
appendiceal inflammation without transmural invasion is now classified as a
normal finding (Bhangu et al., 2015).
In the literature, various subjective terms are used describing different degrees
of the disease. The concept of complicated appendicitis is usually defined as
appendiceal perforation with or without abscess formation. Often gangrenous
appendicitis is included in complicated appendicitis. In a study comparing the
cytokine levels in suppurative and gangrenous appendicitis, the patients with
gangrenous appendicitis had increased levels of proinflammatory markers
interleukin-6 (IL-6), interleukin-7 (IL-7), matrix metalloproteinase-8 (MMP-8) and
matrix metalloproteinase-9 (MMP-9), supporting the hypothesis that suppurative
and gangrenous appendicitis are different entities with divergent immune
regulation (Ruber et al., 2010).
28
Table 1. Classification of acute appendicitis, modified from Carr (2000) and Bhangu et
al. (2015).
Class Macroscopic appearance Microscopic appearance Clinical relevance
Normal appendix
Normal underlying
pathology
No visible changes Absence of any
abnormality
Consider other causes
Acute intraluminal
inflammation
No visible changes Luminal neutrophils only
with no mucosal
abnormality
Might be the cause of
symptoms, but consider
other causes
Acute mucosal
(catarrhal)
inflammation
No visible changes Neutrophils within
mucosa and mucosal
ulceration, with or without
intraluminal neutrophils
Might be the cause of
symptoms, but consider
other causes
Acute mucosal and
submucosal
inflammation
No visible changes Mucosal or submucosal
neutrophils and/or
ulceration
Might be the cause of
symptoms, but consider
other causes
Simple appendicitis
Suppurative/
phlegmonous
Congestion, colour
changes, increased
diameter, exudate, pus
Transmural inflammation,
ulceration or thrombosis,
with or without
extramural pus
Likely cause of
symptoms
Complex appendicitis
Gangrenous
(necrotizing)
Friable appendix with
purple, green or black
colour changes
Transmural inflammation
with necrosis; extensive
mucosal ulceration
Impending perforation
Perforated Visible perforation Perforation; not always
visible in microscope
Increased risk of
postoperative
complications
Abscess Mass found during
examination or abscess
seen on preoperative
imaging or abscess
found at surgery
Transmural inflammation
with pus with or without
perforation
Increased risk of
postoperative
complications
Standardized intra-operative grading systems have been developed to facilitate the
communication between clinicians and to make the prediction of postoperative
course more precise. The Sunshine Appendicitis Grading Score System developed
by Reid et al. (2017) is based on the intra-operative estimate of the degree of
contamination. It avoids the use of subjective terms as ‘necrotic’, ‘gangrenous’ and
‘suppurative’ and has shown a high rate of inter-observer agreement (Garst et al.,
2013; Reid, Choi, Williams, & Chan, 2017). The American Association for the
29
Surgery of Trauma (AAST) has developed a grading system for 16 emergency
general surgery situations, among them for acute appendicitis, to facilitate reliable
scoring for risk stratification, outcome analysis, quality improvement and resource
management (Tominaga et al., 2016). The AAST grading system is shown in Table
2.
Table 2. The AAST grading system for acute appendicitis (Tominaga et al., 2016).
AAST
Grade
Description Clinical
criteria
Imaging
criteria
Operative
criteria
Pathologic criteria
I Acutely inflamed
appendix, intact
Pain, leucocytosis
and right lower
quadrant (RLQ)
tenderness
Inflammatory
changes localized
to appendix +/-
appendiceal
dilatation +/-
contrast nonfilling
Acutely inflamed
appendix, intact
Presence of
neutrophils at the
base of crypts,
submucosa +/- in
the muscular wall
II Gangrenous
appendix, intact
Pain, leucocytosis
and RLQ
tenderness
Appendiceal wall
necrosis with
contrast
nonenhancement
+/- air in
appendiceal wall
Gangrenous
appendix, intact
Mucosa and
muscular wall
digestion; not
identifiable on
hematoxylin-eosin
stain
III Perforated
appendix with
local
contamination
Pain, leucocytosis
and RLQ
tenderness
Above with local
periappendiceal
fluid +/- contrast
extravasation
Above, with
evidence of local
contamination
Gross perforation
or focal dissolution
of mucosal wall
IV Perforated
appendix with
periappendiceal
phlegmon or
abscess
Pain, leucocytosis
and RLQ
tenderness; may
have a palpable
mass
Regional soft
tissue
inflammatory
changes,
phlegmon or
abscess
Above, with
abscess or
phlegmon in the
appendix region
Gross perforation
V Perforated
appendix with
generalized
peritonitis
Generalized
peritonitis
Diffuse abdominal
or pelvic
inflammatory
changes +/- free
intraperitoneal
fluid or air
Above, with the
addition of
generalized
purulent
contamination
away from the
appendix
Gross perforation
Periappendicitis is defined as inflammation of the serosa and subserosa without no
mucosal or transmural involvement. It is due to an extra-appendicular pathology
30
resulting in serosal inflammation of the appendix, the most common reason being
a gynaecological infection (Bloch, Kock, Saxtoft Hansen, & Sandermann, 1988;
Chaudhary, Nabi, & Arora, 2014; Mukherjee et al., 2002; O'Neil & Moore, 1977).
The relevance of eosinophilic infiltrate in the muscularis propria is unclear. It
has been proposed that it may be an early event in appendicitis representing a type
I hypersensitivity reaction to an allergen (Aravindan, Vijayaraghavan, &
Manipadam, 2010).
2.5 Role of appendicoliths
Appendicoliths, also referred to as fecoliths, stercoliths and coproliths, are stone-
like, often calcified pieces of stool inside the appendiceal lumen. In 1886, a
mechanical obstruction caused by an appendicolith was supposed to be the major
etiological factor for appendicitis (Fitz Reginald, 1886). Sixty years ago, Robert
Carras recommended, that a prophylactic appendectomy should be considered if an
appendicolith was visible in a plain radiograph (Carras & Friedenberg, 1960). In
1966, Forbes and Lloyd-Davies divided appendicoliths into three categories
according to the amount of calcium they contained: non-calcified faecal pellets,
partially calcified appendicoliths and stony, fully calcified calculi. They also
recommended the removal of the appendix if an appendicolith was found
incidentally on a radiological examination of the abdomen, as in their patients, an
appendicolith was often associated with complicated appendicitis (Forbes & Lloyd-
Davies, 1966). Since then, the conception of its role has changed significantly. Now
it is well known that an appendicolith is often an incidental finding without any
signs of appendicitis (B. A. Jones, Demetriades, Segal, & Burkitt, 1985; Ramdass
et al., 2015; Singh & Mariadason, 2013). The prevalence of appendicoliths
discovered incidentally varies according to the method used. Appendicoliths were
discovered incidentally in 32% of patients when the appendix was palpated at
laparotomy (B. A. Jones et al., 1985). The prevalence was 29–35% when detected
from histopathologic specimens after a negative appendectomy (Ramdass et al.,
2015; Singh & Mariadason, 2013). The reported prevalence of incidental
appendicoliths detected by CT is lower, 0.4–13% (Huwart et al., 2006; Rabinowitz,
Egglin, Beland, & Mayo-Smith, 2007). Patients with an incidentally discovered
appendicolith on radiological imaging do not have a greater risk to develop
appendicitis than the general population (M. S. Khan et al., 2018; Rollins et al.,
2010).
31
Although an appendicolith may often be an incidental finding, it clearly affects
the outcome when associated with acute appendicitis. In several studies, the
presence of an appendicolith has been reported to be associated with appendiceal
perforation and a more complicated course of the disease (Alaedeen et al., 2008;
Ishiyama et al., 2013; Kondo & Kohno, 2009; Lin et al., 2005; Singh &
Mariadason, 2013; Vons et al., 2011; Yoon et al., 2018). It has been shown that the
size of the appendicolith and location at the root of the appendix are significant
factors in predicting the more complicated course of appendicitis (Ishiyama et al.,
2013; Yoon et al., 2018). In children, the prevalence of appendicolith in
appendicitis detected by CT is higher than in the adult population (30% vs 14%),
which may be one explanation for the higher perforation rates demonstrated in
paediatric appendicitis (Alaedeen et al., 2008). In their study, the perforation rate
in appendicitis was 21.6% in children compared to 11.1% in adult patients. The
prevalence of appendicoliths in perforated appendicitis was 56.1% in children
compared with 27.5% in adults. Reflecting the more severe nature of appendicolith
appendicitis, the rate of fever and the level of C-reactive protein have been reported
to be higher in appendicolith appendicitis than in no appendicolith appendicitis
(Yoon et al., 2018).
The presence of an appendicolith predicts a failure in non-operative treatment.
In one study the failure rate was 60% and the study was terminated prematurely for
concerns over patient safety. In another study, the failure rate was 41%; multivariate
analysis revealed that elevated C-reactive protein and the presence of an
appendicolith were significant risk factors for treatment failure (Aprahamian et al.,
2007; Mahida et al., 2016; Shindoh et al., 2010). If Vons and colleagues would have
excluded the patients with appendicoliths in their study comparing appendectomies
and antibiotic therapy in the treatment of CT-confirmed uncomplicated acute
appendicitis, no significant difference in posttreatment peritonitis would have been
found between the antibiotic and appendectomy groups (Vons et al., 2011).
2.6 Diagnosis of acute appendicitis
2.6.1 Clinical diagnosis
The clinical symptoms and signs have been the backbone of the diagnosis of acute
appendicitis. In diagnosing or excluding acute appendicitis, the most helpful signs
are migratory pain from the periumbilical area to the right lower quadrant,
32
abdominal rigidity and rebound tenderness at the McBurney’s point (Blomberg
sign), positive psoas sign, nausea, vomiting and often mild fever (Chen, Arad,
Chen, Storrar, & Christy, 2016; Eskelinen, Ikonen, & Lipponen, 1995; Rasmussen
& Hoffmann, 1991; Wagner, McKinney, & Carpenter, 1996). The presence of
vomiting before pain makes appendicitis less unlikely (Wagner et al., 1996).
According to a meta-analysis, the descriptors of peritoneal inflammation (rebound
and percussion tenderness, guarding and rigidity) and migration of pain were the
strongest clinical indicators of acute appendicitis. If the appendix is located
retrocaecally, these signs are often missing, as an inflamed appendix does not lean
on parietal peritoneum causing peritoneal inflammation. Pain on rectal palpation
had no discriminatory or predictive power (R. E. Andersson, 2004). The Rovsing
sign, originally defined as pain in the lower right quadrant when antiperistaltic
pressure is applied retrogradely to the colon along the descending part to the
transverse part, supports the diagnosis (Prosenz & Hirtler, 2014). In-hospital
observation and repeated clinical assessment are commonly used in patients with
equivocal diagnosis of appendicitis. Repeated laboratory tests together with
repeated clinical investigation have shown to improve the diagnostic accuracy. The
problem with clinical assessment is that it cannot be standardized, which leads to a
low interobserver reliability of clinical findings (R. E. Andersson et al., 2000; R. E.
Andersson, 2004).
2.6.2 Laboratory markers
The most often used laboratory markers in the diagnosis of acute appendicitis are
the white blood cell count (WBC) and C-reactive protein (CRP). An increased
WBC is an early indicator of appendiceal inflammation, but the WBC values do
not reflect the degree of inflammation (Gronroos, Forsstrom, Irjala, & Nevalainen,
1994; Schellekens et al., 2013). In a study comparing the diagnostic potential of the
WBC and CRP in different age groups, the WBC count was superior in all age
groups except infants and octogenarians in diagnosing uncomplicated acute
appendicitis (Paajanen, Mansikka, Laato, Kettunen, & Kostiainen, 1997).
CRP is an acute phase protein widely used in the differential diagnosis of acute
abdominal pain (Clyne & Olshaker, 1999). Inflammation or tissue destruction leads
to the production of CRP in hepatocytes by the stimulation of cytokines,
particularly IL-6, IL-1 and tumour necrosis factor (TNF). The CRP value rises
slower than the WBC count in acute appendicitis, which makes it less useful than
the WBC in detecting early appendicitis. On the other hand, repeated examinations
33
with increasing values of CRP refer to advancing appendicitis and high values of
CRP are associated with complicated appendicitis (Gronroos & Gronroos, 1999;
Ortega-Deballon, Ruiz de Adana-Belbel, J. C., Hernandez-Matias, Garcia-Septiem,
& Moreno-Azcoita, 2008; H. P. Wu, Lin, Chang, Chang, & Huang, 2005). The CRP
values exceeding 99 mg/L on hospital admission have shown to reach a 90%
specificity for complicated appendicitis (Sammalkorpi et al., 2015). Ortega-
Deballon and colleagues noted a slight increase in the WBC count associated with
advancing disease, but the WBC level was lower in the perforated than gangrenous
appendicitis, making it useless in differentiating between uncomplicated and
complicated appendicitis (Gronroos & Gronroos, 1999; Ortega-Deballon et al.,
2008; H. P. Wu et al., 2005).
Normal values of both the WBC and CRP quite reliably exclude the diagnosis
of acute appendicitis in adult population, while in children under 5 years of age the
CRP and WBC values may be normal in 8% of patients with proven appendicitis
(Gronroos & Gronroos, 1999; Paajanen et al., 1997; Sack et al., 2006).
An increased neutrophil count can be detected in patients with appendicitis.
However, its value in differentiating between uncomplicated and complicated
appendicitis is controversial. According to recent publications, an elevated
neutrophil-to-lymphocyte ratio predicts complicated appendicitis as accurately as
high CRP value (Jung et al., 2017; Kelly et al., 2015; A. Khan et al., 2018).
Platelets have a role in haemostasis, but also in regulating inflammatory
process. They are activated when inflammatory mediators are released. The mean
platelet volume (MPV) and platelet distribution width (PDW) are two parameters
of the complete blood count. The MPV is reduced and PDW increased in patients
with acute appendicitis. In particular, the PDW has shown to have potential
diagnostic significance (Boshnak, Boshnaq, & Elgohary, 2018; Fan et al., 2015).
Elevated serum bilirubin level is commonly observed in patients suffering from
septic conditions. Bacteraemia is known to cause endotoxaemia, leading to
impaired excretion from bile canaliculi (Franson, Hierholzer, & LaBrecque, 1985).
Thus, the clinical significance of hyperbilirubinaemia in acute appendicitis has
been evaluated in several studies. Hyperbilirubinaemia associated with acute
appendicitis has some value as a predictor of appendiceal perforation but does not
alone distinguish a perforation in acute appendicitis (Burcharth, Pommergaard,
Rosenberg, & Gogenur, 2013; Emmanuel, Murchan, Wilson, & Balfe, 2011;
Franson et al., 1985; Giordano, Paakkonen, Salminen, & Gronroos, 2013; M. S.
Khan et al., 2018).
34
An elevated international normalized ratio (INR) has been shown to be
associated with complicated appendicitis, showing activation of the clotting
pathway by inflammatory mediators. In a study from South Korea, an elevated INR
was a feasible way to predict complicated appendicitis (M. Kim, Kim, & Cho,
2016).
The usefulness of several other novel biomarkers in diagnosing acute
appendicitis have been studied. Interleukin-6 (IL-6) has been shown to be a good
predictor of complicated appendicitis (M. Andersson, Ruber, Ekerfelt, Hallgren,
Olaison, & Andersson, 2014; Anielski, Kusnierz-Cabala, & Szafraniec, 2010). In a
recent study, matrix metalloproteinases (MMPs) and tissue inhibitors of
metalloproteinases (TIMPs) were shown to have potential to estimate the
probability of complicated appendicitis (M. Andersson, Ruber, Ekerfelt, Hallgren,
Olaison, & Andersson, 2014). Andersson and colleagues studied the diagnostic
properties of six new inflammatory markers (IL-6, chemokine ligand (CXCL)-8,
chemokine CC motif ligand (CCL)-2, serum amyloid A (SAA), matrix
metalloproteinase (MMP)-9 and myeloperoxidase (MPO). They found that SAA,
MPO and MMP-9 were strongest discriminators for appendicitis and SAA was the
strongest discriminator for complicated appendicitis. However, they concluded that
compared to conventional diagnostic variables (WBC, CRP, neutrophils), the
addition of new inflammatory variables did not improve diagnostic performance
any further (M. Andersson et al., 2014). In a review and cost-benefit analysis
comparing IL-6, pro-calcitonin and urinary 5-HIAA with conventional laboratory
markers, no single test had sufficient diagnostic performance to be used in isolation.
In a cost analysis, novel biomarkers were associated with higher costs and often
longer process times. For example, the processing time for IL-6 is 168 hours and
for the WBC and CRP only 1 hour (Acharya, Markar, Ni, & Hanna, 2017).
2.6.3 Diagnostic imaging
CT imaging has become the most widely accepted imaging modality due to its
availability and high accuracy. It is easily performed and interpreted and rarely
affected by bowel gas, severe abdominal pain or the patient’s obesity (Rao, Rhea,
Novelline, Mostafavi, & McCabe, 1998; Sippola et al., 2018). The CT features of
a normal appendix, appendicolith appendicitis and periappendicular abscess are
shown in Figure 1. In a recent study from Finland, the experience of the interpreting
radiologist did not affect the accuracy of CT diagnosis (Lietzen, Salminen et al.,
2018). The CT findings of acute appendicitis are divided into appendiceal (e.g.
35
appendiceal diameter), caecal (e.g. caecal apical thickening) and periappendicular
changes (e.g. periappendicular fat stranding and extraluminal fluid) (Pinto Leite,
Pereira, Cunha, Pinto, & Sirlin, 2005). Out of the CT features for acute appendicitis,
the appendiceal enlargement (> 6 mm) has been shown to be the most specific CT
finding with the highest sensitivity and negative predictive value (Limon, Oray,
Ertan, Sahin, & Ugurhan, 2015; Rao, Rhea, & Novelline, 1997). The combination
of enlarged appendix with periappendiceal fat stranding occurred in 93% of CT-
diagnosed acute appendicitis patients and other signs were considered additional
findings (Rao et al., 1997). Recently reported rates show 94–98% sensitivity and
90–94% specificity for CT in diagnosing acute appendicitis (Kim et al., 2018a;
Kinner et al., 2017; Repplinger et al., 2018).
Fig. 1. CT features of a normal appendix (a), appendicolith appendicitis (b) and
periappendicular abscess (c)
36
In 1998, Rao and colleagues published their landmark study showing that
performing a CT scan in patients with suspected appendicitis resulted in the
prevention of unnecessary appendectomies and admissions to the hospital as well
as led to cost savings (Rao et al., 1998). Since then, the CT scanning rates in patients
with suspected appendicitis have increased. As a consequence of more
comprehensive use of CT, the negative appendectomy rate has decreased. In a meta-
analysis, Krajewski et al. (2011) showed that negative appendectomy rate
decreased from 21.5% in the pre-CT era compared to 10.0% during the CT era.
From the meta-analysis, it was estimated that 13 CT scans are needed to avoid 1
unnecessary surgery. Appendiceal perforation rates were unchanged by the use of
CT (Krajewski et al., 2011). In studies implementing mandatory CT in suspected
appendicitis, the rate of negative appendectomy has been even lower, varying
between 2 and 6% (Bhangu et al., 2015; Lee et al., 2007; Raja et al., 2010).
Mandatory CT imaging may increase the risk of cancer related to ionized radiation.
In one study, it was estimated that the benefit of mandatory CT imaging is to avoid
12 unnecessary appendectomies but the cost is one cancer death (Rogers, Hoffman,
& Noori, 2015). However, this estimation is probably exaggerated, as the radiation
dose used in the calculation was 8–11 mSv / 1 CT scan. Currently, the radiation
dose in the standard dose CT scan varies between 5.2 and 10.2 mSv and in the low-
dose CT scan between 1.2 and 5.3 mSv (N. E. Aly, McAteer, & Aly, 2016). Low-
dose CT in suspected acute appendicitis has been shown to be noninferior to
standard-dose CT regarding the diagnostic accuracy and the negative
appendectomy rate (K. Kim et al., 2012; S. Y. Kim et al., 2011). In the OPTICAP
study, patients with suspected acute appendicitis underwent both standard and low-
dose CT. The diagnostic accuracy of the low-dose CT was not inferior to the
standard-dose CT in diagnosing acute appendicitis or distinguishing between
uncomplicated and complicated acute appendicitis (Sippola et al., 2018). In the
LOCAT group, Kim HJ and colleagues showed that the radiation dose could be
reduced to 2 mSv from the standard 8 mSv without impairing clinical outcome
assessed by the negative appendectomy rate (LOCAT Group, 2017)
Other optional imaging modalities are ultrasound (US) and magnetic resonance
imaging (MRI). Using them, the exposure for ionizing radiation can be avoided. In
addition to the lack of ionizing radiation, the advantages of US as an imaging
modality are that it is non-invasive, fast and inexpensive. On the other hand, it is
highly operator-dependent and often unavailable out of hours. In obese patients,
localizing and visualization of appendix can be challenging (Kaewlai,
Lertlumsakulsub, & Srichareon, 2015). The normal appendix is not visualized in
37
over 50% of patients (Yabunaka, Katsuda, Sanada, & Fukutomi, 2007). In a meta-
analysis examining US in the diagnosis of equivocal appendicitis, the sensitivity
was 83.7% and the specificity 95.9% (Al-Khayal & Al-Omran, 2007). In several
studies applying the graded compression technique first introduced by Puylaert in
1986, even higher specificity rates have been reported (Puylaert, 1986; Shirah,
Shirah, Alhaidari, Elraghi, & Chughtai, 2017). In studies with paediatric patient
populations, lower diagnostic accuracy has been reported, with sensitivities ranging
from 44% to 94% and specificities ranging from 47% to 95% (Y. R. Yu & Shah,
2017). On the other hand, in a large retrospective study with children, the negative
predictive values of non-diagnostic and non-visualized US without leukocytosis
(WBC < 11.0 x 109/L) were 95.6% and 97.0%, respectively (Cohen et al., 2015).
According to a meta-analysis, US should not be used in patients with a high
probability of appendicitis due to the high false-negative rate. In the same meta-
analysis, US was not recommended for screening patients with a low probability of
appendicitis due to a high false-positive rate in this group (Orr, Porter, & Hartman,
1995). However, in children and pregnant women, US is recommended as the first-
line diagnostic modality (Doria et al., 2006; R. Williams & Shaw, 2007). US
imaging as a single imaging modality has limited value in diagnosing complicated
appendicitis due to its low sensitivity and operator-dependency, despite the high
specificity it can reach (Tseng et al., 2016; Tulin-Silver et al., 2015). In a study
comparing US with conditional CT scan in case of negative or inconclusive US
findings and immediate CT scan, appendicitis could be diagnosed with equal
accuracy using both methods, if there was a clinical suspicion of appendicitis. As a
consequence, half of the CT scans could be avoided using the conditional CT
strategy (Atema et al., 2015). In a study assessing how stratification with Adult
Appendicitis Score affects diagnostic performance of diagnostic imaging, the post-
test probability of appendicitis after positive US was 95% in the high probability
group and 91% in the intermediate probability group. However, in the low
probability group, the post-test probability of appendicitis after positive US was
only 42% (Sammalkorpi et al., 2017).
The use of MRI in diagnosing appendicitis eliminates the risks associated with
radiation. Despite the fact that performing an MRI is time-consuming and with
limited availability compared to a CT scan, the lack of radiation makes it a
competitive imaging modality, especially in children and during pregnancy. The
diagnostic accuracy of MRI to diagnose acute appendicitis is similar to CT
(Repplinger et al., 2016). The results from the studies examining the efficacy of
MRI in detecting perforated appendicitis are controversial. In a study from the
38
Netherlands, MRI was comparable to US with the conditional use of CT in
identifying perforated appendicitis. However, the sensitivities of both imaging
modalities were low. The sensitivity of MRI was 75% and the sensitivity of US/CT
was 48% (Leeuwenburgh et al., 2014). In some recent studies, MRI has been shown
to be able to discriminate between perforated and non-perforated appendicitis with
a sensitivity of 82–90% and specificity of 85–86% ( Church, Coughlin, Antunez,
Smith, & Bruch, 2017; Dillman et al., 2016; Rosenbaum, Askin, Beneck, &
Kovanlikaya, 2017). However, in most studies CT has been shown to be the most
accurate imaging modality in differentiating uncomplicated and complicated acute
appendicitis (H. Y. Kim et al., 2018; M. S. Kim et al., 2014; Verma et al., 2015).
2.6.4 Diagnostic scoring
As each clinical symptom or laboratory marker alone has a poor predictive value
for appendicitis, diagnostic scoring systems combining different data have been
developed. The main purpose of most available scoring systems is to identify the
patients at low, intermediate or high risk for appendicitis and thus to guide the
decision-making of the clinician. An ideal scoring system rules out appendicitis
effectively in the low-risk group and stratifies all the patients with appendicitis in
the high-risk group without false-positive patients. The first scoring system was
introduced by Alfredo Alvarado in 1986, before the era of CT. The original
Alvarado score based on eight signs: localized tenderness in the right lower
quadrant, leucocytosis, the migration of pain, a shift to the left in the WBC count,
temperature elevation, nausea or vomiting, anorexia and direct rebound pain
(Alvarado, 1986). In a meta-analysis reviewing 29 studies validating the Alvarado
score, it was concluded that the Alvarado score is a useful ‘rule out’ score at a cut-
off point of 5 but it cannot be used to ‘rule in’ a diagnosis of appendicitis without
surgical assessment and further diagnostic testing. Alvarado score seemed to over-
predict the probability of appendicitis in children in the intermediate- and high-risk
groups and in women in all strata of risk (Ohle, O'Reilly, O'Brien, Fahey, &
Dimitrov, 2011). On the other hand, a low Alvarado score does not always rule out
appendicitis. According to two studies, 8–13% of the patients with an Alvarado
score < 5 actually had appendicitis (Apisarnthanarak et al., 2015; Gwynn, 2001).
In a modified version of the Alvarado score, the Paediatric Appendicitis Score
(PAS), testing the rebound pain has been replaced by testing cough/percussion
tenderness and hopping tenderness; signs that less often lead to a loss of
cooperation of a paediatric patient (Samuel, 2002). Another diagnostic score
39
developed for children (Lintula score) led to significantly lower rate of negative
appendectomies (17% vs 29%) when compared with clinical assessment without a
score (Lintula, Pesonen, Kokki, Vanamo, & Eskelinen, 2005; Lintula, Kokki,
Kettunen, & Eskelinen, 2009).
The appendicitis inflammatory response score (AIR score), developed in
Sweden in 2008, added C-reactive protein in the values measured in the Alvarado
score (M. Andersson & Andersson, 2008). Compared to the Alvarado score, the
AIR score has been shown to be more accurate both at excluding appendicitis in
the low-risk patients and at predicting appendicitis in the high-risk patients (Kollar,
McCartan, Bourke, Cross, & Dowdall, 2015). Using receiver operating
characteristics (ROC) analysis, the AIR score was shown to be significantly more
accurate than the Alvarado score. The areas under the ROC curve for the AIR score
and the Alvarado score were 0.96 and 0.82, respectively, p < 0.05. (de Castro, Unlu,
Steller, van Wagensveld, & Vrouenraets, 2012).
The adult appendicitis score (AAS) was recently developed in Finland for
patients over 16 years of age (Sammalkorpi, Mentula, & Leppaniemi, 2014;
Sammalkorpi et al., 2017; Sammalkorpi, Mentula, Savolainen, & Leppaniemi,
2017). It has been shown to be more accurate than the Alvarado score and AIR
score. When the score was implemented in clinical practice, the histologically
confirmed negative appendectomy rate decreased from 18.2% to 8.7%. By using
the AAS score patients can be selected for imaging according the stratified risk.
Only the patients at intermediate risk are referred to mandatory imaging with CT,
whereas the patients at high risk are operated without imaging and the patients at
low risk are observed (Sammalkorpi et al., 2017).
The Raja Isteri Pengiran Anak Saleha appendicitis (RIPASA) score, originally
developed for Asian populations, has been demonstrated to be useful in predicting
acute appendicitis in a Western population (M. U. Malik et al., 2017).
A ruptured appendicitis score was constructed for paediatric patients. It
combined disease history, physical examination and laboratory markers with CT
findings. The scoring system improved the specificity of the preoperative diagnosis
of the paediatric surgeon from 83% to 98% (R. F. Williams et al., 2009).
2.6.5 Differential diagnosis of uncomplicated and complicated
appendicitis
As the treatment options in uncomplicated and complicated appendicitis vary,
differentiating between these two forms of appendicitis is of vital clinical
40
importance. Patients with complicated appendicitis tend to be older, have longer
duration of symptoms, elevated body temperature and clearly increased levels of
inflammatory markers. According to one study in patients over 55 years of age,
29% had perforated appendicitis at 36 h of symptoms and 67% at 36 to 48 h of
symptoms (Augustin, Cagir, & Vandermeer, 2011; Broker, van Lieshout, van der
Elst, Stassen, & Schepers, 2012; Guller, Rosella, McCall, Brugger, & Candinas,
2011). As a rule, in clinical decision making, modern imaging is needed to
accurately distinguish between uncomplicated and complicated acute appendicitis
(Atema et al., 2015). However, there are situations when the decision to operate
can be done without imaging (like a young male patient with typical clinical signs
of appendicitis and peritonitis and CRP value exceeding 100 mg/L, unless an
abscess is suspected due to a long duration of symptoms).
Combining information from clinical examination, laboratory findings and
imaging studies has been shown to be useful in differential diagnosis (Atema et al.,
2015). They developed two different scoring systems, one incorporating CT
features and one based on US features. The clinical variables and imaging features
of the scoring system are shown in Table 3. The optimal cut-off values (with a pre-
defined maximum false-negative rate of 5%) for scores implementing CT and US
were 7 and 6, respectively. The corresponding sensitivity and specificity for these
cut-off values were 90.2% and 70.3% (CT score); 96.6% and 45.7% (US score).
The discriminative capacity expressed as AUC was 0.88 for the model
incorporating CT and 0.82 for the model incorporating US. Recently, another
scoring system combining clinical and radiological parameters was developed (the
appendicitis severity index, APSI). The APSI was reported to have an even higher
discriminative capacity (AUC = 0.92) than Atema and colleagues had shown for
their model (Avanesov et al., 2018).
In previous trials reporting the diagnostic accuracy of CT for complicated acute
appendicitis, the CT imaging features used for differentiating complicated acute
appendicitis from uncomplicated acute appendicitis have often been demonstrated
indefinitely. Therefore, a systematic review and meta-analysis was performed to
find the most informative CT findings for complicated appendicitis. Ten
informative CT features were identified, most of which (e.g. appendiceal wall
enhancement defect, extraluminal appendicolith and extraluminal air) showed
pooled specificity greater than 70% (74–100%) but sensitivity was limited (14–
59%). Periappendiceal fat stranding was the only feature to show high sensitivity
(94%) but low specificity (40%). Implementing these features in future studies and
evaluating them as risk factors for a more complicated form of the disease may lead
41
to greater accuracy in interpreting the CT information available (H. Y. Kim et al.,
2018).
Table 3. Scoring system developed to differentiate between uncomplicated and
complicated acute appendicitis, based on clinical and imaging features for both CT and
US (Atema et al., 2015).
Variable Clinical and CT features Clinical and US features
Age > 45 years 2 2
Body temperature (Celsius)
< 37.0 0 0
37.1–37.9 2 2
> 38.0 4 4
Duration of symptoms > 48 h 2 2
WBC count > 13 x 109 2 2
C-reactive protein mg/l
< 50 0 0
51–100 2 4
> 100 3 5
Extraluminal free air on imaging 5 -
Periappendiceal fluid on imaging 2 2
Appendicolith on imaging 2 2
Maximum score 22 19
2.7 Treatment of acute appendicitis
2.7.1 Non-operative treatment of acute uncomplicated appendicitis
Although an appendectomy has been the accepted treatment standard for acute
appendicitis for over 130 years, the spontaneous resolution of appendicitis has been
observed and described for as long. In the 1950s, shortly after the invention of
antibiotics, case reports and short series of successful treatment of acute
appendicitis with antibiotics were reported (Coldrey, 1956; Harrison, 1953). The
results of a review of conservative treatment in 252 patients with acute appendicitis
on ships of the Kalingrad Fishing Industry from 1975 to 1987 were published with
a recovery rate of 84.1% (Gurin, Slobodchuk, & Gavrilov, 1992). To date, the
option of treating appendicitis with antibiotics has been tested in only a few
randomized clinical trials including CT imaging for the diagnosis only in the more
recent RCTs (Eriksson & Granstrom, 1995; Hansson et al., 2009; A. A. Malik &
Bari, 2009; Salminen et al., 2015; Styrud et al., 2006; Talan et al., 2017; Turhan et
42
al., 2009; Vons et al., 2011). In a meta-analysis of five RCTs using a 1-year follow-
up, an inevitably higher rate of treatment efficacy was found for an appendectomy
compared with antibiotic therapy (98.3% vs 75.9%, p < 0.0001) and appendicitis
recurrence after antibiotic treatment was reported in 22.5% of patients. The rate of
complicated appendicitis identified at time of surgical operation was higher in the
antibiotic treatment group (19.9% vs 8.5%, p = 0.02) (Podda et al., 2017). One
explanation for this difference is that older trials relied on the clinical diagnosis of
acute appendicitis (Hansson et al., 2009; Styrud et al., 2006). The first study to use
CT confirmation of acute uncomplicated appendicitis was published in 2011 (Vons
et al., 2011). However, despite the CT-scan assessment, 18% of the patients in the
appendectomy group were unexpectedly identified at surgery to have complicated
appendicitis with peritonitis. Furthermore, they did not exclude patients with
intraluminal appendicolith from their study population. In their antibiotic-treated
group, appendicoliths were associated with failed antibiotic treatment. If they had
excluded the patients with appendicoliths, no significant difference in
posttreatment peritonitis would have been found between the antibiotic and
appendectomy groups (Vons et al., 2011). In a more recent RCT from Finland
(APPAC trial) with CT-confirmed diagnosis and the exclusion of patients with
intraluminal appendicolith, 27.3% (70/257) of the patients in the antibiotic group
underwent an appendectomy due to suspected recurrent appendicitis within a 1-
year follow-up (Salminen et al., 2015). In a meta-analysis of nine RCTs with both
adult and paediatric patients, the overall recurrence rate in antibiotic treatment
group was 18.2%, but the risk of complications was significantly lower in the
antibiotic treatment group (Poprom et al., 2018). This is in line with a meta-analysis
showing a 22.6% recurrence rate but a lower rate of both minor and major
complications in the antibiotic group (Sallinen et al., 2016). On the contrary, in
another meta-analysis comparing surgical and conservative treatment for acute
appendicitis, overall postoperative complications were comparable, whereas the
rate of adverse events and the incidence of complicated appendicitis were
significantly higher in the antibiotic treatment group (Harnoss et al., 2017).
Hansson and colleagues aimed to assess antibiotic therapy in a setting where
consecutive patients with suspected acute appendicitis were all offered antibiotic
therapy if the surgeon on call did not evaluate an appendectomy as necessary or the
patient did not insist on primary surgery, with 79% of the study patients receiving
antibiotics as the first-line therapy. They reported a 77% treatment success rate, and
the proportions of phlegmonous, gangrenous and perforated appendicitis did not
43
differ between patients who had primary surgery and those who had rescue surgery
(Hansson et al., 2012).
Recently, the long-term outcome of the APPAC trial was published. In the first
year following randomization, 70 of the 256 patients in the antibiotic group
underwent an appendectomy. During the years 2–5, 30 more patients underwent an
appendectomy, resulting in a 39.1% (100/256) cumulative incidence of recurrence
at 5 years. However, not all these patients had a true recurrence, as the patients with
a clinically suspected recurrence underwent an appendectomy based on the study
protocol without further imaging. Out of the 85 patients operated on for suspected
recurrence, 78 had a true recurrence at histopathology, resulting in a 32.4% true
recurrence rate (78 true recurrences after initial hospitalization out of 241 patients
in the antibiotic group with initial successful treatment). No patient initially treated
with antibiotics, who later underwent an appendectomy, had any severe or
increased complications related to the delay of surgery, i.e. antibiotics was a safe
treatment option (Salminen et al., 2018).
The antibiotic used varies significantly in published studies. To succeed, the
antibiotic must provide broad-spectrum coverage for all the pathogens that might
cause appendicitis, especially Escherichia coli. The resistance of Escherichia coli
to amoxicillin-clavulanic acid is increasing, which is why it should not be used (de
Kraker et al., 2011). In the T.E.A study, ertapenem was efficient in treating localized
intra-abdominal infections (Catena et al., 2013). In a meta-analysis, the lowest risk
of complications was associated with studies using beta-lactam antibiotics as
ertapenem (Poprom et al., 2018). It was used in one of recent major RCTs
(Salminen et al., 2015), but future studies should likely aim for a more restricted
spectrum antibiotic therapy, and optimization of the antibiotic therapy is under
active research (Haijanen et al., 2018).
Acute appendicitis may resolve spontaneously in a subgroup of patients. This
was shown recently in a trial in which patients with CT-confirmed uncomplicated
acute appendicitis were randomized to antibiotic treatment and observation without
antibiotics. After a median follow-up time of 19 months, 20.7% of the antibiotic-
treated and 23.4% of the observation-only patients had undergone an
appendectomy. This suggests that in selective patients, supportive care may be a
valid treatment option in the future (Park et al., 2017).
Comparing two treatment methods as different as operative and non-operative
treatment is difficult. Non-operative treatment will naturally be inferior compared
to the treatment efficacy of surgery when defined as a successful appendectomy.
Assessment of the best possible treatment option should also include appendectomy
44
related morbidity, the recurrence rate after non-operative therapy, the patient’s
preference and treatment costs. In some studies, antibiotic treatment has been
shown to be less expensive than an appendectomy. In an economic evaluation of
the APPAC randomized clinical trial at one-year follow-up, overall societal costs
were 1.6 times higher than those in the antibiotic group (Sippola et al., 2017). This
is in line with other reports regarding both paediatric and adult patient populations
(J. X. Wu, Dawes, Sacks, Brunicardi, & Keeler, 2015; J. X. Wu, Sacks, Dawes,
DeUgarte, & Lee, 2017). However, in a United States register study, non-operative
treatment was associated with a higher overall cost of care due to more frequent
readmissions and follow-up visits, but in this retrospective study the diagnosis of
uncomplicated acute appendicitis was based solely on diagnosis codes creating a
major bias in their analysis, as they also had a higher abscess rate in the antibiotic
group in their study associated with the inclusion of complicated acute appendicitis
patients (Sceats, Trickey, Morris, Kin, & Staudenmayer, 2018).
As a conclusion, the choice between non-operative and operative treatment
should be individual, depending on the patient’s values and preferences as well as
the expected risks associated with the chosen treatment option. At least in selected
patients like the patients at a high operative risk, non-operative treatment might be
considered as a treatment option (Abongwa et al., 2017). According to the WSES
Jerusalem guideline, antibiotic therapy can be successful in selected patients with
uncomplicated appendicitis who wish to avoid surgery and accept the risk of
recurrence up to 38% (Di Saverio et al., 2016). The Cochrane analysis concludes
that an appendectomy remains the standard treatment for acute appendicitis and
antibiotic treatment might be used in a good quality RCT or in specific patients or
conditions were surgery is contraindicated (Di Saverio et al., 2016; Wilms, de
Hoog, de Visser, & Janzing, 2011). Further studies are needed to assess the
feasibility of non-operative treatment of uncomplicated acute appendicitis
(antibiotic therapy and symptomatic treatment) to better understand their optimal
use in the treatment paradigm of uncomplicated acute appendicitis.
2.7.2 Operative treatment of acute uncomplicated appendicitis
An open appendectomy (OA) was initially described by Charles McBurney in 1894
and it has been the gold standard for 100 years. In 1983, Semm published the first
laparoscopic appendectomy (LA), which has since then been adopted worldwide,
where appropriate facilities are available (Semm, 1983). In the United States, 95%
of all appendectomies are performed laparoscopically (Dumas et al., 2018). In
45
Finland, the percentage of LAs between 2008 and 2010 was 21.3% (Kotaluoto et
al., 2017). In Germany, the rate of LAs increased from 33% in 1997 to 86% in 2009
(Sahm et al., 2013). During the last years, LAs have gained popularity as in Finland.
In a recent multicentre observational study performed in 116 worldwide surgical
departments from 44 countries over a 6-month period (April 1, 2016–September
30, 2016), 51.7% of patients underwent an LA (Sartelli et al., 2018).
Antibiotic prophylaxis is essential in preventing surgical site infection (SSI)
associated with an appendectomy. It has been estimated that 40–60% of SSIs are
preventable with proper prophylaxis. According to guidelines in appendectomies,
a combination of cephalosporin plus metronidazole administered within 1 hour
before incision is the first-choice option (Garcell et al., 2017).
An appendectomy has been considered a safe operation, associated with quite
low mortality and morbidity. In a large Finnish register study with a total of 164 579
appendectomies between 1990 and 2010, the overall 30-day mortality rate was
0.21%. In a multivariate analysis there was a significant increase in mortality
related to negative appendectomies (OR 4.2, 95% CI 3.2–5.5) and OAs (OR 6.0,
95% CI 1.9–18.8). Male gender was associated with a 1.5-fold increase in mortality
risk. Not surprisingly, in elderly patients over 65 years of age, there was a 39-fold
increase in mortality. During the study period, the mortality declined from 0.26%
to 0.1% (Kotaluoto et al., 2017). The mortality associated with a negative
appendectomy was in line with earlies reports (M. N. Andersson & Andersson,
2011; R. E. Andersson, 2013). The increased mortality related to negative
appendectomies hardly reflects that a negative appendectomy is a dangerous
procedure per se. More likely is that missing an underlying disease while removing
innocent appendix causes the increased mortality. A large register study from
Sweden reported a similar 30-day mortality in LAs and OAs but a lower long-term
mortality in laparoscopic than an OA (R. E. Andersson, 2013). The high mortality
rate in elderly patients after an appendectomy was noticed in this and in an earlier
study from Sweden (Blomqvist, Andersson, Granath, Lambe, & Ekbom, 2001).
Multiple RCTs, meta-analyses and reviews comparing OAs and LAs have been
published. In a large review from the United States with 32 683 appendectomy
patients, the overall morbidity was significantly higher in OAs than in LAs (8.8%
vs 4.5%, p < 0.0001). The incidence of superficial and deep incisional infections
was lower in LA than in OA (3.9% and 1.0% versus 1.3% and 0.2%, respectively,
p < 0.0001 (Ingraham et al., 2010). Cochrane Reviews comparing LAs and OAs
have been published in 2010 and in 2018. Further, their results show that wound
infections are less likely after LAs than after OAs (OR 0.42, 95% CI -1.04 to -0.45).
46
Conversely, the incidence of intra-abdominal abscesses (IAAs) was almost two
times higher in LA than in OA (Jaschinski, Mosch, Eikermann, Neugebauer, &
Sauerland, 2018; Sauerland, Jaschinski, & Neugebauer, 2010). However, in a
recent meta-analysis LAs did not increase the rate of postoperative IAA
(OR = 0.79; 95% CI: 0.45–1.34, p = 0.40) (M. C. Yu et al., 2017). According to the
Cochrane Reviews, the pain intensity on day 1 in adults and the length of hospital
stay were significantly lower in LA. Obese and old patients in particular have been
shown to benefit from the laparoscopic approach (Ciarrocchi & Amicucci, 2014;
Yeh et al., 2011). In conclusion, the laparoscopic technique has clearly shown to be
superior to OA when treating uncomplicated acute appendicitis. However, OA is a
good alternative if the operating surgeon is not familiar with laparoscopic
technique, or in the case of conversion. In a large American register study with over
2 500 000 appendectomies, the overall conversion rate from LA to OA was 6.3%
(Masoomi et al., 2014).
The first single-incision laparoscopy-assisted (SILS) appendectomy was
reported in 1992(Pelosi & Pelosi, 1992). SILS offers better cosmesis at the cost of
a longer operation time and higher conversion rate (O. E. Aly, Black, Rehman, &
Ahmed, 2016) Natural orifice transluminal endoscopic surgery (NOTES) provides
a scarless appendectomy either via a transvaginal or transgastric approach. Even
though a transvaginal appendectomy is the second-most frequently performed
NOTES procedure after cholecystectomy, its role is controversial and debated
(Bingener & Ibrahim-zada, 2014).
2.7.3 Treatment of perforated appendicitis
The rate of perforated appendicitis in adult patient populations is 7–34% (Chamisa,
2009; Colson, Skinner, & Dunnington, 1997; Gerard, Kielhorn, Petersen, Mullard,
& McCahill, 2018; Sartelli et al., 2018). The incidence in children is higher; in
children under 5 years of age it is 69–74% and in children over 8 years of age 30–
40% (Nance, Adamson, & Hedrick, 2000). Accurate diagnosis guiding operative
treatment is of utmost importance regarding these patients. Perforated appendicitis
with peritonitis is treated with fluid resuscitation, IV antibiotic therapy and
emergency appendectomies. The use of intra-abdominal drainage after an
appendectomy for perforated appendicitis is not beneficial and is associated with
an increased rate of overall complications and a longer hospital stay (Z. Li, Zhao,
Cheng, Cheng, & Deng, 2018; Rather, Bari, Malik, & Khan, 2013). There is
evidence suggesting that short antibiotic therapy following source control by an
47
appendectomy does not result in a worse primary outcome. In a small RCT
comparing a 24-hour antibiotic therapy with extended administration (average
length of antibiotic therapy 6 ± 3 days) the overall complication rates were 17.9%
and 29.3% in short and extended therapy groups, respectively (Saar et al., 2018).
Similarly, there were no differences in surgical-site infections, recurrent intra-
abdominal infections or deaths in a study comparing 4 and 8 day-long antibiotic
therapies after surgical source control of an intra-abdominal infection (Sawyer et
al., 2015).
2.7.4 Treatment of a periappendicular abscess
Primary treatment of a periappendicular abscess
Primary non-operative treatment
The clinically established practice of a periappendicular abscess is antibiotic
therapy and drainage, if necessary. According to mostly retrospective studies, this
approach has been shown to be safe and effective, allowing the acute inflammatory
process to subside in more than 90% of cases without surgery (R. E. Andersson &
Petzold, 2007; Simillis, Symeonides, Shorthouse, & Tekkis, 2010). In a systematic
review and meta-analysis with almost 60 000 patients with suspected acute
appendicitis, the proportion of patients with a periappendicular mass was 3.8%.
The failure rate of primary non-operative treatment was 7.2% and drainage of an
abscess was needed in 27.6% of the patients with an abscess diagnosed by CT or
US. The overall morbidity related to primary nonsurgical treatment was 13.5%. (R.
E. Andersson & Petzold, 2007). One limitation of the meta-analysis was that most
of the reviewed studies were retrospective, causing a remarkable risk for selection
bias, and the diagnosis based on clinical signs in most patients. In a retrospective
study with CT-verified abscess diagnosis, the failure rate of conservative treatment
was 5.8% and the complication rate related to nonsurgical treatment was 17%
(Oliak et al., 2001). In a more recent systematic review with 1943 patients, the
failure rate of primary nonoperative treatment was 12.4% and the morbidity 13.3%
(Darwazeh et al., 2016). In a meta-analysis comparing conservative treatment
versus an appendectomy for an appendiceal abscess or phlegmon, conservative
treatment was associated with significantly fewer overall complications, abdominal
or pelvic abscesses, bowel obstructions and reoperations (Simillis et al., 2010).
48
However, worse results regarding primary non-operative treatment have been
published. In a retrospective study, 71% of the patients experienced at least one
recurrence and 54% of the patients ultimately needed an acute surgical or
radiological intervention (Deelder et al., 2014).
Primary operative treatment
According to a large meta-analysis reviewing mostly retrospective studies
published between 1964 and 2005, immediate surgery of a periappendicular
abscess was associated with a three-fold increase of morbidity compared with
conservative management. An ileocecal resection or a right-sided hemicolectomy
due to technical reasons or a suspicion of malignancy was needed in 3% of patients
(R. E. Andersson & Petzold, 2007; Tannoury & Abboud, 2013). A prospective RCT
from Finland with a small number of patients (n = 60) compared immediate LA and
conservative treatment as the first-line treatment of a periappendicular abscess. It
showed that in experienced hands, there was no difference in hospital stay between
the two groups and in the laparoscopy group, there were significantly fewer
unplanned readmissions (3% versus 27%, p = 0.026). The rate of uneventful
recovery was 90% in the laparoscopy group and 50% in the conservative group.
However, even in skilled hands, there was a 10% risk for bowel resection and a
13% risk for an incomplete appendectomy in the laparoscopy group (Mentula et
al., 2015). In a small randomized trial with 40 paediatric patients comparing an
immediate appendectomy with primary non-operative treatment and an interval
appendectomy, there were no differences in the length of total hospitalization,
recurrent abscess rates or overall costs (St Peter et al., 2010). According to the
WSES Jerusalem guidelines, non-operative management is a reasonable first-line
treatment for appendicitis with phlegmon or abscess, but in experienced hands,
operative management is a safe alternative (Di Saverio et al., 2016). Regarding the
recently reported alarming rates of appendiceal neoplasms associated with a
periappendicular abscess, appendectomy in the acute phase should perhaps be
approached with caution, as it may transform a restricted tumour perforation to an
unlimited peritoneal spreading, countering the principles of the oncologic approach
to cancer surgery. However, there are no studies comparing the oncologic outcome
of acute phase operations or planned interval appendectomies (Carpenter et al.,
2012; Furman et al., 2013; Teixeira et al., 2017).
49
Secondary treatment of periappendicular abscesses
The treatment options after the successful primary non-operative treatment of a
periappendicular abscess are a planned interval appendectomy and follow-up. The
factors supporting an interval appendectomy are the risks of recurrence and
possible underlying neoplasms and in the follow-up strategy avoiding operative
morbidity. The need for a subsequent interval appendectomy in complicated acute
appendicitis presenting with a periappendicular abscess has recently been
questioned, with the appendicitis recurrence risk varying between 5 to 26%
(Quartey, 2012). Most of the recurrences occur within 6 months after the primary
treatment, and after the first year the risk of recurrence decreases down to 2%
(Anderson et al., 2012; R. E. Andersson & Petzold, 2007; Darwazeh et al., 2016;
Kaminski et al., 2005; Lai et al., 2006). The reported morbidity rate of interval
appendectomies varies between 11% and 23% (Eriksson & Styrud, 1998; Quartey,
2012; Tannoury & Abboud, 2013; Willemsen, Hoorntje, Eddes, & Ploeg, 2002). In
a meta-analysis, the risk of underlying malignant neoplasm was 1.2% (R. E.
Andersson & Petzold, 2007). However, more recent studies have reported much
higher rates of neoplasms associated with periappendicular abscesses, especially in
patients over 40 years of age (Carpenter et al., 2012; Furman et al., 2013; Teixeira
et al., 2017; Wright et al., 2015). In this regard, appendicitis is a similar condition
with acute diverticulitis, which also can be graded as uncomplicated and
complicated, with an increased risk of colon cancer up to 11.4% in patients with
acute diverticulitis and an abscess on CT scan (Sallinen, Mentula, & Leppaniemi,
2014).
In a retrospective study from Taiwan, the efficacy of interval appendectomies
was evaluated based on a cost-effectiveness analysis reporting that routine interval
appendectomies increased the cost per patient by 38% compared with follow-up
and appendectomies after recurrence (Lai, Loong, Wu, & Lui, 2005). Thus far, the
need for interval appendectomies has only been assessed in one randomized clinical
trial. It is a study from India with a small number of patients (n = 60) and no CT
confirmation of the diagnosis. The patients were randomized after primary
nonsurgical treatment to a planned interval appendectomy, delayed appendectomy
and follow-up. The follow-up group had the lowest morbidity and the shortest
length of stay in the hospital (Kumar & Jain, 2004).
Currently, there is no consensus regarding the optimal management after the
successful primary non-operative treatment of a periappendicular abscess.
Regarding the reported low recurrence rates and lower costs associated with follow-
50
up, available evidence supports the idea of not performing a routine interval
appendectomy. On the other hand, follow-up carries the risk of missing possible
underlying neoplasms, especially in patients over 40 years of age. In the WSES
Jerusalem guidelines, an interval appendectomy is not routinely recommended.
However, recognizing the risk of neoplasms, the guidelines recommend that
appendiceal and colonic neoplasms should be excluded when the follow-up option
is chosen (Di Saverio et al., 2016). Colonoscopy is an effective method to diagnose
colonic neoplasms whereas appendiceal neoplasms seldom are visualized in
colonoscopy and in CT scan a small appendiceal tumour is easily masked by the
inflammatory process.
2.8 Appendiceal neoplasms
2.8.1 Classification of appendiceal neoplasms
Appendiceal neoplasms are rare. They have been reported to appear in 0.3–1.7 %
of all appendectomy specimens and constitute under 0.5% of all gastrointestinal
neoplasms (Benedix et al., 2010; Charfi et al., 2014; Kunduz et al., 2018). Acute
appendicitis is the initial presentation of an appendiceal neoplasm in more than
50% of cases (Connor, Hanna, & Frizelle, 1998). The classification of appendiceal
neoplasms has been controversial, as several classification systems exist. The lack
of universal standard terminology for both benign and malignant neoplasms has
confounded comparisons between studies. The World Health Organization (WHO)
classification (2010) classifies appendiceal neoplasms in two main groups:
appendiceal carcinomas (epithelial origin) and neuroendocrine (NET) tumours
(Table 4) (Teixeira et al., 2017).
51
Table 4. The WHO classification of primary appendiceal neoplasms (Teixeira et al.,
2017).
WHO class
Appendiceal carcinomas
Adenocarcinoma
Mucinous adenocarcinoma
Low-grade mucinous neoplasia
Signet-ring cell formation carcinoma
Undifferentiated carcinoma
Neuroendocrine appendiceal neoplasms
Neuroendocrine tumours (NET)
NET G1 (carcinoid)
NET G2
Neuroendocrine carcinomas (NEC)
NEC large cell type
NET small cell type
Mixed tumours
Mixed adenoneuroendocrine carcinoma
Serotonin-producing endocrine carcinoma
Goblet cell carcinoid
Tubular carcinoid
Peptide-producing/glucagon-producing large cell type tumour
The Peritoneal Surface Oncology Group International (PSOGI) formulated a
classification for appendiceal neoplasms of epithelial origin in 2012 (Table 5) (Carr
et al., 2017)
The annual incidence of appendiceal neuroendocrine tumours (NET) is
0.15/100 000 with equal frequency in men and women, and these are often
diagnosed incidentally (Yao et al., 2008). In 70% of cases, the tumour is in the tip
of the appendix and 60–80% of NETs are smaller than 1 cm (T1a). Tumours larger
than 2 cm carry a risk of metastases in 25–40% of patients. The prognosis of NET
located in the tip of the appendix and having a diameter smaller than 1 cm is
excellent with 100% of 5-year overall survival after a simple appendectomy.
Tumours located at the base of the appendix, larger than 2 cm or invading
macroscopically in the mesoappendix, should be treated with a right
hemicolectomy. Mixed tumours with goblet cell morphology and neuroendocrine
features are rare and carry a poorer prognosis with 40–70% 5-year overall survival
(Teixeira et al., 2017).
52
Table 5. Classification of epithelial neoplasms of the appendix.
Terminology Histological features
Low-grade appendiceal mucinous neoplasm
(LAMN) if atypia is low-grade.
High-grade appendiceal mucinous neoplasm
(HAMN) if atypia is high-grade
Mucinous neoplasm without infiltrative invasion but
with any of the following
- loss of muscularis mucosae
- fibrosis of submucosa
- ‘pushing invasion’ (expansile or diverticulum-like
growth)
- dissection of acellular mucin in the wall
- undulating or flattened epithelial growth
- rupture of the appendix
- mucin and/or cells outside the appendix
Serrated polyp with or without dysplasia (low- or
high-grade)
Tumour with serrated features confined to the
mucosa, muscularis mucosae intact
Tubular, tubulovillous or villous adenoma, low- or
high-grade dysplasia
Adenoma resembling the usual colorectal type,
confined to the mucosa, muscularis mucosae intact
Mucinous adenocarcinoma – well, moderately or
poorly differentiated
Mucinous neoplasm with infiltrative invasion
Adenocarcinoma – well, moderately or poorly
differentiated
Non-mucinous adenocarcinoma resembling the
usual colorectal type
Poorly differentiated (mucinous) adenocarcinoma
with signet ring cells
Signet-ring cells present in adenocarcinoma
According to a large register study from the Netherlands with 167 744
appendectomies performed between 1995 and 2015, the incidence of epithelial
neoplasms of the appendix (both benign and malignant) was 0.9/100 000 with a
slight female predominance (59% vs 41%). Of these neoplasms, 56% were
mucinous and 47% non-mucinous. The proportion of adenocarcinomas was 25%.
Interestingly, in 13% of the patients with an epithelial neoplasm of the appendix,
an additional epithelial neoplasm was found in the colon (Smeenk, van Velthuysen,
Verwaal, & Zoetmulder, 2008). This in in line with earlier observations of a high
incidence of synchronous and metachronous colorectal tumours associated with
appendiceal neoplasms (in 10% associated with carcinoids and in 89% associated
with primary appendiceal malignancies) (Connor et al., 1998).
Epithelial neoplasms of the appendix range from benign adenomas to invasive
adenocarcinomas. Compared with cancer of the colon, appendiceal colonic-type
invasive adenocarcinoma carries a poorer prognosis with a 5-year disease-free
survival of 58% and 85%, respectively (Son et al., 2016). Patients with a perforated
appendiceal mucinous neoplasm are especially at risk to develop pseudomyxoma
53
peritonei (PMP). The term PMP was first introduced in 1884, indicating peritoneal
implants and mucinous ascites leading finally to progressive abdominal distension
known as “jelly belly” (Smeenk et al., 2008). PMP is a clinical syndrome in which
the mucinous neoplasm grows within the peritoneal cavity following the normal
flow of peritoneal fluid within the abdominal cavity, ‘redistributing’ the mucin and
the cells it contains (Sugarbaker, 1994). PMP is an uncommon phenomenon with
an incidence of approximately 0.2/100 000 (Smeenk et al., 2008).
Histopathologically, PMP may contain acellular mucin or mucin with epithelial
neoplastic cells with various grades of malignancy. Table 6 shows the PSOGI
diagnostic criteria for PMP (Carr et al., 2017).
Table 6. Diagnostic criteria for intra-abdominal mucin and pseudomyxoma peritonei
(Carr et al., 2017).
Lesion Criteria
Acellular mucin Mucin within the peritoneal cavity without neoplastic epithelial cells
Low-grade mucinous carcinoma
peritonei/DPAM1
- Epithelial component typically scanty
- Strips, gland-like structures or small clusters of cells
- Minimal cytological atypia
- Not more than occasional (sporadic) mitosis
- Invasion into underlying organs is generally of the ‘pushing’ type
High-grade mucinous carcinoma
peritonei/PMCA2
- Relatively more cellular
- Cribriform growth
- High-grade cytological atypia
- Numerous mitoses
- Destructive infiltrative invasion of underlying organs
High-grade mucinous carcinoma
peritonei with signet ring cells/
PMCA-S3
- Any lesion with a component of signet ring cells, i.e. round cells
with intracytoplasmic mucin pushing the nucleus against the cell
membrane
- (Degenerating cells within pools of mucin that mimic signet ring
cells should be discounted)
1 disseminated peritoneal adenomucinosis, 2 peritoneal mucinous carcinomatosis, 3 peritoneal mucinous
carcinomatosis with signet ring cells
Low-grade appendiceal mucinous neoplasm (LAMN) is often diagnosed
incidentally after an appendectomy. Most patients with negative margins and
normal tumour marker levels (CEA, CA19-9, CA12-5) do not experience disease
recurrence after an initial appendectomy. However, PMP occurs in 17% of patients
with LAMN without any signs of perforation or extra-appendicular mucin during
the initial appendectomy. As PMP can occur up to 10 years after the initial
54
appendectomy, i.e. patients with completely excised LAMN should be systemically
followed (Fournier et al., 2017; Honore et al., 2015). The established treatment for
PMP from appendiceal origin is removal of all visible tumour with necessary organ
excisions (cytoreductive surgery, CRS) combined with hyperthermic intraoperative
chemotherapy (HIPEC) (Cioppa et al., 2008; Fournier et al., 2017; Jarvinen,
Jarvinen, & Lepisto, 2010; Mirnezami, Moran, & Cecil, 2009; Moran, Baratti, Yan,
Kusamura, & Deraco, 2008). The 10-year survival of all PMP patients after
cytoreductive surgery and HIPEC is 63%. Patients with high-grade mucinous
carcinoma, especially with signet ring cells, carry a poorer prognosis. In a large
register study with 5655 appendiceal malignancies, the 5-year disease-free survival
for mucinous adenocarcinoma and adenocarcinoma with signet cells were 58% and
27%, respectively (Chua et al., 2012; Turaga, Pappas, & Gamblin, 2012).
2.8.2 Neoplasms associated with uncomplicated appendicitis and
periappendicular abscesses
The different neoplasm rates associated with uncomplicated and complicated acute
appendicitis reflect the different nature of these two disease entities. The reported
neoplasm rates associated with acute appendicitis are low, varying between 0.7%
and 1.7% (Charfi et al., 2014; Smeenk et al., 2008). In the APPAC study with CT-
confirmed uncomplicated acute appendicitis patients, the incidence of neoplasms
was 1.5% (Salminen et al., 2015). Accordingly, in a recent systematic review of
retrospective cohort studies with 13 244 acute appendicitis patients, the overall
appendiceal neoplasm rate was 1%. However, in patients presenting with a
periappendicular abscess or phlegmon, the neoplasm rate varied from 10% to 29%
(Teixeira et al., 2017). A retrospective review with 3744 appendectomies revealed
0.7% incidence of appendiceal neoplasms and 80% of these neoplasms presented
with periappendiceal abscess (Lee et al., 2011). In a retrospective cohort study with
6038 appendectomy patients, an appendectomy was performed in 5851 (97%)
patients at the index admission. Of the 188 patients initially treated non-operatively,
89 (47%) underwent an interval appendectomy. Appendiceal neoplasms were
identified in 11 of 89 patients (12%). The rate of neoplasms in patients over 40
years of age was 16%. In patients undergoing an appendectomy at the index
hospital admission, the rate of neoplasms was 0.5%. There was a significant
difference in the histopathological diagnosis of the neoplasms between the two
groups. The neoplasms found in the index appendectomy group, mostly in patients
with uncomplicated appendicitis, were carcinoid tumours in 74% of patients. In the
55
interval appendectomy group with initial nonoperative treatment of complicated
appendicitis, the neoplasms were mucinous in 55% of patients (Wright et al., 2015).
A similar increased risk of mucinous neoplasms in patients undergoing an interval
appendectomy was reported in an earlier study with a smaller patient population
(Furman et al., 2013). In a nationwide Finnish population-based registry study, the
associated neoplasm risk was significantly higher in complicated acute appendicitis
compared with uncomplicated acute appendicitis (3.24% vs. 0.87%, p < 0.001). In
a subgroup analysis, the neoplasm risk associated with a periappendicular abscess
was 4.99% (Lietzen, Gronroos et al., 2018).
56
57
3 Aims of the study
The aims of this study were:
1. To assess the feasibility of clinical history and findings and common laboratory
tests in the differential diagnosis of complicated and uncomplicated acute
appendicitis with a special focus on predicting the presence of an
appendicolith.
2. To assess possible histopathological differences between uncomplicated acute
appendicitis and acute appendicitis presenting with an appendicolith.
3. To compare an interval appendectomy and follow-up with MRI after initial
successful non-operative treatment of a periappendicular abscess.
58
59
4 Materials and methods
4.1 APPAC study
The APPendicitis ACuta (APPAC) trial was a randomized, controlled, open-label,
non-inferiority multicentre trial designed to compare antibiotic therapy with an
emergency appendectomy in the treatment of acute uncomplicated appendicitis.
The APPAC trial was performed from November 2009 until June 2012 in 6 Finnish
hospitals (Turku, Oulu and Tampere University hospitals and Mikkeli, Seinäjoki
and Jyväskylä central hospitals). Patients aged 18–60 years admitted to the
emergency department with a clinical suspicion of uncomplicated acute
appendicitis confirmed by a CT scan were enrolled in the study. Patients with
complicated appendicitis, which was defined as the presence of an appendicolith,
perforation, abscess or suspicion of a tumour on the CT scan, were excluded. The
trial protocol was approved by the ethics committees of all the participating
hospitals. The study was conducted in accordance with the Declaration of Helsinki.
All patients gave written informed consent to participate in the study.
Patients were randomized by a closed envelope method either to undergo OA
or to receive antibiotic therapy with intravenous ertapenem for three days followed
by oral levofloxacin and metronidazole for seven days. The clinical status of the
patients in the antibiotic group was re-evaluated and if the surgeon suspected
progressive infection, the patient underwent an appendectomy. The primary end
point for patients in the antibiotic therapy group was resolution of acute
appendicitis without recurrent appendicitis during a minimum follow-up of 1 year.
Treatment success in the appendectomy group was defined as a patient successfully
undergoing an appendectomy without complications. During the recruitment
period, 1379 patients were assessed for eligibility. A total of 849 patients were
excluded – 337 patients for complicated acute appendicitis; 530 patients were
randomized – 273 patients to receive an appendectomy and 257 patients to receive
antibiotic therapy. The patient flow in the APPAC trial is shown in Figure 2. During
the enrolment period, a total of 4380 appendectomies were performed at the 6 trial
hospitals. Of these, 3667 patients had appendicitis, 3120 (85%) had uncomplicated
acute appendicitis and 347 (15%) had complicated appendicitis presenting with
perforation or an abscess. The negative appendectomy rate was 16% (713/4380).
60
Fig. 2. Path of patients in the Appendicitis Acuta (APPAC) Trial.
1379 Patients assessed for eligibility
530 Randomized
849 Excluded733 Did not meet inclusion criteria
351 Other finding in computedtomography337 Complicated acute appendicitisa
18 Patient age either < 18 yor > 60 y
27 Other reasons116 Refused to participate
275 Randomized to receive antibiotic therapy242 Received antibiotic as randomized15 Did not receive antibiotic as randomized
8 Uncomplicated acute appendicitisat surgery
7 Complicated acute appendicitisat surgery
273 Randomized to receive appendectomy272 Received appendectomy as
randomized1 Did not receive appendectomy as
randomized (resolution of symptoms)
1 Lost to follow‐up (died on fifth post‐operative day due to cardiomyopathy)
0 Discontinued intervention
1 Lost to follow‐up (died due trauma)55 Discontinued intervention
50 Uncomplicated recurrent acuteappendicitis
5 Normal appendix, no acute appendicitis
272 Included in primary analysis 256 Included in primary analysis
215 Included in assessment of secondaryoutcomes
57 Lost to follow‐up (could not be reachedby telephone or at clinic follow‐up)
1 Died
277 Included in assessment of secondaryoutcomes
29 Lost to follow‐up (could not be reached by telephone or at clinic follow‐up)
1 Died
a Includes appendicolith, perforation, abscess orsuspicion of tumor
61
4.1.1 Study I
Study I was based on the APPAC trial. Data used in the study were collected from
the patients who underwent a CT scan performed according to the APPAC trial
protocol. The surgeon on call examined all patients admitted to the emergency
department with a clinical suspicion of acute appendicitis. Age, sex, body
temperature and the duration of symptoms (< 12 hours, 12–24 hours or > 24 hours)
before admission to the hospital were recorded. If acute appendicitis was suspected
based on clinical history and physical examination, blood tests (haemoglobin,
WBC, CRP, creatinine, serum human chorionic gonadotropin) and urine analysis
were undertaken. All patients aged 18–60 years were invited to participate in the
APPAC trial and informed of the study protocol. A total of 1379 patients were
evaluated for the enrolment in the APPAC trial. In study I, we included all the
patients excluded from the APPAC trial for a CT-verified complicated appendicitis
(337 patients) and all the patients operated on for uncomplicated acute appendicitis
(368 patients). The group with uncomplicated acute appendicitis included the
patients randomized to receive an appendectomy according to the APPAC study
protocol as well as the patients with uncomplicated acute appendicitis who were
over 60 years of age or who refused to participate the APPAC trial.
The patients in study I were divided into complicated and uncomplicated acute
appendicitis according to the CT findings. In the trial, acute appendicitis was
considered complicated when the CT scan showed an appendicolith, perforation,
periappendicular abscess or suspicion of a tumour. The criteria for uncomplicated
acute appendicitis included an appendiceal diameter exceeding 6 mm with mural
thickening and at least 1 of the following findings: abnormal contrast enhancement
of the appendiceal wall, inflammatory oedema or fluid collection around the
appendix. For further analyses, we divided the complicated acute appendicitis
group into 2 subgroups: complicated acute appendicitis with appendicolith and
complicated acute appendicitis with perforation and/or periappendicular abscess.
Acute appendicitis was diagnosed on CT in 705 patients. Of them, 368 patients had
uncomplicated acute appendicitis and 337 patients had complicated acute
appendicitis. Out of the 337 complicated acute appendicitis patients, 256 had
appendicolith appendicitis, 78 had perforation and/or periappendicular abscess.
Three patients had appendiceal tumours on CT and were excluded from the study.
In study I, we assessed the clinical value of the laboratory tests and body
temperature in separating patients with uncomplicated acute appendicitis from
those with complicated acute appendicitis. Comparisons between groups were
62
performed using ROC curves, calculating the area under curve (AUC) for each
assessed variable.
4.1.2 Study II
Study II was also based on the APPAC trial. We compared the appendiceal
histopathological findings of either from patients with an uncomplicated acute
appendicitis and randomized to an appendectomy, or the patients with complicated
acute appendicitis presenting with an appendicolith excluded from the study. The
appendicolith appendicitis patients presenting also with perforation or
periappendicular abscess were excluded from analysis. A total of 344 patients were
included in this study from the two largest university hospitals participating in the
APPAC study (Turku University Hospital and Oulu University Hospital). The
uncomplicated acute appendicitis group consisted of 187 patients and complicated
acute appendicitis with an appendicolith group consisted of 157 patients.
The histopathological specimens were examined end evaluated by a
pathologist who was blinded to the primary CT diagnosis and other clinical data.
The following parameters were assessed: the depth of inflammation, possible
microabscesses and the number of eosinophils and neutrophils in the appendiceal
wall, the status of epithelial surface and the appendiceal diameter. The presence of
appendicolith of faecal material in the appendiceal lumen was also assessed,
recognizing that the appendicolith may be already discarded by the surgeon, i.e. the
presence of an appendicolith was always initially confirmed by a CT scan.
4.2 Study III
The PeriAPPAC study was a multicentre, non-inferiority, randomized clinical trial
designed to test the hypothesis that an interval appendectomy is not necessary after
initial successful non-operative treatment of periappendicular abscess. The primary
endpoint for the study was treatment success at one year after the intervention. In
the interval appendectomy group treatment success was defined as both a
successful appendectomy and non-complicated recovery and in the follow-up
group as the absence of recurrence during the follow-up period. The predefined
secondary endpoints included possible appendiceal or colonic neoplasms, possible
inflammatory bowel disease diagnosis (ulcerative colitis or Crohn’s disease), the
length of hospital stay and sick leave. According to the sample size calculation, our
aim was to enrol 122 patients.
63
The trial was conducted from January 2013 to February 2016 in five Finnish
hospitals (Turku, Oulu, Kuopio and Tampere University Hospitals and Seinäjoki
Central Hospital). After the initial successful non-operative treatment of
periappendicular abscess, the patients were randomized to an interval
appendectomy or to follow-up with magnetic resonance imaging. Patients between
18–60 years of age admitted to the emergency department with a CT or MRI
diagnosed with a periappendicular abscess were evaluated for study enrolment.
Patients randomized to operative treatment were scheduled to undergo an LA at 3
months after the initial non-operative treatment. Prior to the randomized
intervention, colonoscopy was performed in both study groups to rule out a caecal
tumour. Patients randomized to follow-up underwent an abdominal MRI at three
months after the initial non-operative treatment. In cases of suspected recurrence
or persistent symptoms, the patients were scheduled for either an emergency or
elective appendectomy depending on patient’s clinical condition. Baseline patient
characteristics were recorded during the initial hospital stay. The follow-up data
were collected by telephone interview at one week, two months and one year after
an interval appendectomy and at two months and one year in the follow-up group.
Potential complications in both study groups were registered.
Study III was approved by the ethical committee of all participating hospitals.
The study was conducted in accordance with the declaration of Helsinki. All
participating patients gave written informed consent. The PeriAPPAC trial had no
independent data monitoring committee and there was no planned interim analysis.
4.3 Statistical analysis
In study I, comparisons between groups were performed using Student’s t-test or
χ2 test (categorical variables). The area under the receiver operating characteristic
curve (AUC) was calculated. An AUC value ≥ 0.70 was considered a clinically
meaningful diagnostic test. Cut-off points were assessed according to the Youden
index (sensitivity + specificity -1) and sensitivities of 80% and 90%. Positive and
negative likelihood ratios (LR±) were used to calculate post-test probabilities for
the combinations of clinically meaningful tests. A pre-test probability of 0.2 was
used to calculate post-test probabilities. Two-tailed p-values < 0.05 were
considered statistically significant. Analyses were performed using SPSS for
Windows (IBM SPSS Statistics for Windows, version 21.0, 2012; IBM Corp.,
Armonk, NY).
64
In study II, summary measurements were presented as mean with standard
deviation (SD) unless otherwise stated. Between-group comparisons for continuous
variables were performed with Student’s t-test or Welch t-test, the latter if the
variances differed significantly. Categorical variables were compared using
Pearson’s χ2 – test or Fisher’s exact test. Multivariable logistic regression models
were created to assess the impact of each histopathologic parameters separately on
acute appendicitis presenting with an appendicolith. The logistic regression models
were adjusted with age, sex and duration of symptoms. Odds ratios (ORs) with 95%
confidence intervals are presented as a result. Two-tailed p-values < 0.05 are
considered statistically significant. Analyses were performed using SPSS for
Windows (IBM Corp. Released 2018. IBM SPSS Statistics for Windows, Version
25.0. Armonk, NY: IBM Corp.).
In study III, Student’s t-test (continuous variables) and Pearson’s χ2-test or
Fisher’s exact test (categorical variables) were used for between-group
comparisons. Two-tailed p-values < 0.05 were considered statistically significant.
All analyses were performed according to intention-to-treat (ITT) principle.
Analyses were performed using SPSS for Windows (IBM Corp. Released 2014.
IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.).
65
5 Results
5.1 Study I
The baseline characteristics of the study population are presented in Table 7.
Table 7. Demographic, clinical and laboratory characteristics of the patients (n = 705).
Character Uncomplicated
appendicitis
acuta group
(UA)
(n = 368)
Complicated
appendicitis
acuta group
(CA)
(n = 337)
p-value1 Appendicolith
appendicitis
acuta group
CA1
(n = 256)
Perforated
appendicitis
acuta/abscess
group CA2
(n = 78)
p-value2
Male, (%) 229 (62.2) 215 (63.8) 0.67 171 (66.8) 43 (55.1) 0.15
Age, mean (SD) 36.8 (12.4) 37.6 (13.0) 0.36 36.4 (13.0) 41.7 (12.5) 0.004
CRP3, mean (SD) 47.4 (47.0) 66.3 (74.6) < 0.001 48.3 (57.5) 122.2 (92.9) < 0.001
WBC4, mean (SD) 12.0 (4.0) 13.7 (0.9) < 0.001 13.8 (3.5) 13.5 (4.8) < 0.001
Temperature,
mean (SD)
37.5 (0.7) 37.7 (0.9) 0.004 37.6 (0.9) 38.0 (0.8) 0.001
Duration of
symptoms (%)
< 0.001 < 0.001
< 12 h, n (%) 69 (19.0) 69 (20.5) 63 (24.6) 6 (7.7)
12–24 h, n (%) 157 (43.1) 87 (25.8) 78 (30.5) 9 (11.5)
> 24 h, n (%) 138 (37.9) 181 (53.7) 115 (44.9) 63 (80.8)
1 between UA and CA, 2 between UA, CA1 and CA2, 3 C-reactive protein (mg/L), 4 white blood count
The UA patients were similar to CA patients with respect to sex, age, WBC and
body temperature. The mean CRP was significantly greater in only in group CA2
when compared with group UA (122 mg/L versus 47 mg/L, p < .001). Regarding
the duration of symptoms, there was no clinically significant difference between
the groups UA, CA and CA1, in contrast to the statistically and clinically significant
difference between UA and CA2 groups, as 81% of CA2 group patients had
symptoms > 24 hours before admission (p < .001).
The clinical value of the laboratory tests and temperature in separating patients
with UA from those with CA, CA1 and CA2 according to ROC curves is presented
in Table 7. The CRP values and body temperature were greater in CA2 patients
compared with UA patients (AUC > 0.7 in ROC analysis). The results of the
optimal cut-off of the CRP value and temperature in separating patients with UA
from those with CA2 are shown in Table 8. The cut-off points assessed with the
Youden index led to fairly good discrimination between groups UA and CA2, if
66
CRP > 84 mg/L or temperature > 37.8ºC. A cut-off point with maximal sensitivity
is considered most useful in clinical situations. When using a sensitivity of 90%,
the cut-off points (CRP > 13 mg/L and temperature > 37.1ºC) lead to a poor
separation. The post-test probabilities are also shown in Tables 9 and 10. None of
the combinations was a useful positive test, with the maximum post-test probability
being 0.61. After negative test results in both CRP and temperature, the post-test
probability is 0.03–0.05, ruling out the presence of perforated appendicitis and/or
periappendicular abscess.
Table 8. Clinical value of the laboratory tests and body temperature in separating
patients with uncomplicated acute appendicitis in CT scan from those with complicated
appendicitis in CT scan according to ROC7 curves.
Value Complicated acute
appendicitis
group CA2
Appendicolith
group CA13
Perforated acute
appendicitis group/abscess
group CA24
AUC1 CI5 95% AUC CI 95% AUC CI 95%
CRP6 0.53 0.49–0.58 0.45 0.41–0.50 0.77 0.70–0.84
WBC8 0.65 0.59–0.67 0.64 0.60–0.68 0.60 0.53–067
Temperature 0.61 0.54–0.67 0.57 0.50–0.64 0.70 0.61–0.79
1 area under the ROC curve, 2 complicated appendicitis; 3 appendicolith appendicitis; 4 perforation and/or
periappendicular abscess, 5 confidence interval, 6 C-reactive protein (mg/L), 7 receiver operating
characteristics, 8 white blood cell count
Table 9. Evaluation of optimal cut-off of the CRP in separating patients with
uncomplicated appendicitis from those with perforated acute appendicitis or
periappendicular abscess (in CT scan).
CRP2 Sensitivity Specificity LR3+ LR- Post-test probability
Temp4 ≥ 37.4 Temp < 37.4
CRP+ CRP- CRP+ CRP-
≥ 841 0.65 0.84 4.1 0.41 0.61 0.13 0.31 0.04
≥ 40 0.81 0.53 1.7 0.36 0.39 0.12 0.15 0.04
≥ 13 0.91 0.24 1.2 0.37 0.31 0.12 0.11 0.04
Cut-off points were assessed for these parameters as maximum of sensitivity + specificity-1 and with
(approximately) 80% and 90% sensitivity. A pre-test probability of 0.2 was used for post-test calculations. 1 Youden index, 2 C-reactive protein (mg/L), 3 likelihood ratio, 4 temperature (ºC)
67
Table 10. Evaluation of optimal cut-off of the temperature in separating patients with
uncomplicated appendicitis from those with perforated acute appendicitis or
periappendicular abscess (in CT scan).
Temp4 Sensitivity Specificity LR3+ LR- Post-test probability
CRP2 ≥ 40 CRP < 40
Temp+ Temp- Temp+ Temp-
≥ 37.81 0.60 0.75 2.4 0.53 0.50 0.18 0.18 0.05
≥ 37.4 0.80 0.47 1.5 0.43 0.39 0.12 0.15 0.04
≥ 37.1 0.90 0.27 1.2 0.38 0.34 0.10 0.14 0.03
Cut-off points were assessed for these parameters as maximum of sensitivity + specificity-1 and with
(approximately) 80% and 90% sensitivity. A pre-test probability of 0.2 was used for post-test calculations. 1 Youden index, 2 C-reactive protein (mg/L), 3 likelihood ratio, 4 temperature (ºC)
5.2 Study II
The baseline patient characteristics of study II are shown in Table 11.
Table 11. Baseline characteristics of the patients
Character Uncomplicated acute
appendicitis n = 187
Appendicolith appendicitis
n = 157
p-value
Male, n (%) 114 (51.4) 108 (48.6) 0.14
Age, years, mean (SD) 35.3 (11.9) 35.1 (12.9) 0.73
CRP, mean (SD) 46.9 (43.7) 43.4 (50.7) 0.61
WBC, mean (SD) 12.2 (3.9) 13.7 (3.5) < 0.001
Duration of symptoms 0.021
< 12 h, n (%) 32 (17.1) 44 (28.0)
12–24 h, n (%) 46 (24.6) 44 (28.0)
> 24 h, n (%) 106 (56.7) 69 (44.0)
The results of the histopathological measurements are presented in Table 12. As
shown in Table 12, there were differences in every measured parameter. The depth
of inflammation was less in appendicolith appendicitis, but in appendicolith
appendicitis patients, the measurements were made more often from destroyed
epithelial surface and the crypt morphology of the luminal epithelium was more
often destroyed. The inflammation reached the serosa or mesoappendix in almost
every patient in both patient groups. Microabscesses were more often present in
appendicolith appendicitis patients. The maximal appendiceal diameter was larger
in appendicolith appendicitis patients. The number of neutrophils in the
appendiceal wall was higher and the number of eosinophils lower in the
68
appendicolith appendicitis patients. An appendicolith or not clearly delineated
faecal material was detected by a pathologist more often in appedicolith
appendicitis patients, but no faecal material was found by a pathologist in 40% of
appendicolith appendicitis patients. As we wanted to separately assess the impact
of each histopathological measurement, we created multivariable regression
models for each individual histopathological parameter. The results of logistic
regression analysis adjusting for age, sex and the duration of symptoms are shown
in Table 13.
Table 12. The measured histopathological parameters.
Parameter Uncomplicated acute
appendicitis,
n = 187
Appendicolith
appendicitis,
n = 157
p-value
Max diameter of appendix, mm, mean (SD),
n/N (%)
7.954
138/187
(1.682)
(73.8)
9.181
141/157
(2.107)
(89.8)
< 0.001
Depth of inflammation, mm, mean (SD),
n/N (%)
3.641
165/187
(1038)
(88.2)
3.325
145/157
(1001)
(92.4)
0.007
≤ 2.8 mm, n/N (%) 33/165 (20.0) 51/145 (35.2) 0.003
Superficial mucosal damage, n/N (%) 44/187 (23.5) 75/175 (47.7) < 0.001
Deep mucosal damage, n/N (%) 27/187 (14.4) 77/156 (49.0) < 0.001
Neutrophils, n/mm2 < 0.001
< 150, n/N (%) 144/179 (80.4) 82/143 (57.3)
≥ 150, n/N (%) 35/179 (19.6) 61/143 (42.7)
Eosinophils, n/mm2, mean (SD) 11.0 (14.5) 6.9 (9.8) 0.001
Microabscesses 0.016
No abscesses, n/N (%) 162/187 (86.6) 119/156 (76.3)
One or multiple abscesses, n/N (%) 25/187 (13.4) 37/156 (23.7)
Presence of faecal material < 0.001
No faecal material n/N (%) 155/187 (82.9) 63/156 (40.4)
Appendicolith n/N (%) 9/187 (4.8) 26/156 (16.7)
Faecal material n/N (%) 23/187 (12.3) 67/156 (42.9)
69
Table 13. The results of logistic regression analysis for the presence of acute
appendicitis with an appendicolith. The results are presented as ORs with a 95% CI.
Variable Univariate OR Adjusted1 OR 95% CI p-value
Microabscess 2.02 2.16 1.22 to 3.83 0.008
Eosinophils, n/mm2 0.97 0.97 0.95 to 0.99 0.013
Neutrophils, ≥ 150/mm2 3.06 3.04 1.82 to 5.09 < 0.001
Faecal material 5.37 6.05 3.45 to 10.59 < 0.001
Depth of inflammation 2.17 2.18 1.29 to 3.71 0.004
1 Adjusting variables age, sex and duration of symptoms
5.3 Study III
During the study recruitment, a clinical suspicion of increased neoplasm risk in the
study population prompted an interim analysis, performed in April 2016, which was
not originally included in the study plan. At the time of interim analysis, there were
60 randomized patients out of the originally planned 122 patients. After interim
analysis, the trial was terminated prematurely due to ethical concerns based on high
neoplasm incidence. Before interim analysis, 60 patients with a CT scan confirmed
periappendicular abscess and a successful initial non-operative treatment were
randomized from January 2013 until February 2016 with 30 patients in each
treatment group.
Upon interim analysis, the incidence of neoplasms in the whole study
population was 17% (10/60) and the neoplasm rate in patients over 40 years of age
was 24% (10/41). All neoplasms were diagnosed in patients over 40 years of age
with a median age of 53 years (range 40 to 61 years). Upon study termination, all
the patients randomized to the follow-up treatment arm were re-evaluated, and an
LA was recommended to all patients. Two more low-grade appendiceal mucinous
neoplasms were found after re-evaluation. After study termination and re-
evaluation of the follow-up arm, the overall incidence of neoplasms in the study
population was 20% (12/60), and the rate of neoplasms in patients over 40 years of
age was 29% (12/41). All the neoplasms were diagnosed in patients over 40 years
of age. The characteristics of the patients with neoplasms in the study population
are shown in detail in Table 14.
Based on the premature termination of this trial, we failed to reach our initial
sample size, and our study remained underpowered to draw conclusions concerning
the initial primary endpoint.
70
Table 14. Neoplasms found in the study population.
Patient
Sex/Age, y
Reason for
intervention
Intervention Histological findings Secondary intervention
F/56 Allocated
intervention
Appendectomy LAMN2 and
pseudomyxoma peritonei
Cytoreductive surgery
and hyperthermic
intraperitoneal
chemotherapy
M/47 Allocated
intervention
Appendectomy LAMN Surveillance
M/59 Allocated
intervention
Appendectomy Sessile serrated
adenoma
Surveillance
M/59 Recurrent
symptoms
Ileocecal resection Adenocarcinoma of the
appendix
Right hemicolectomy
M/59 Recurrent
symptoms
Appendectomy LAMN Ileocecal resection
M/61 Recurrent
symptoms
Appendectomy Mucinous cystadenoma Surveillance
M/55 Recurrent
symptoms
Appendectomy Goblet cell carcinoid Cytoreductive surgery
and hyperthermic
intraperitoneal
chemotherapy
F/58 MRI3 tumour
suspicion
Appendectomy Sessile serrated adenoma Surveillance
F/53 CT1 tumour
suspicion
Chemotherapy Caecal adenocarcinoma
and sessile serrated
appendiceal adenoma
Right hemicolectomy
(palliative)
M/61 Recommended Appendectomy LAMN Surveillance
F/41 Recommended Appendectomy LAMN Surveillance
1 computed tomography, 2 low-grade appendiceal mucinous neoplasm, 3 magnetic resonance imaging
71
6 Discussion
6.1 Differential diagnosis of uncomplicated and complicated acute
appendicitis
Differentiating between uncomplicated and complicated appendicitis is important,
as the treatment options for these two disease entities are different. Using the data
from the APPAC trial, we evaluated the feasibility of clinical history and clinical
and laboratory findings in the differential diagnosis between uncomplicated and
complicated acute appendicitis without imaging. We had a special interest in
predicting the presence of an appendicolith, as it has been shown to be associated
with a more complicated course of the disease and to constitute a risk factor in the
failure of nonoperative management of acute uncomplicated appendicitis (Mahida
et al., 2016; Shindoh et al., 2010; Singh & Mariadason, 2013; Vons et al., 2011).
The analysed parameters included the duration of symptoms (< 12 h, 12–
24 h, > 24 h), temperature, plasma CRP and WBC count. In our study population,
the CRP value was significantly higher in patients with perforated appendicitis
and/or periappendicular abscess. A higher temperature and longer duration of
symptoms also suggested perforated appendicitis in our study population. Optimal
cut-off points with reasonable values of sensitivity and specificity could not be
identified for any one of these parameters or a combination of two of them even
though the identification of a threshold value for CRP could be of clinical use and
there are other trials reporting such values (Sammalkorpi et al., 2015). In our study
no difference in CRP values could be found between patients with uncomplicated
acute appendicitis and acute appendicitis presenting with an appendicolith. This is
in contrast with a United States study, where higher CRP values were reported in
paediatric appendicitis patients presenting with an appendicolith (Alaedeen et al.,
2008). This may reflect differences in an acute phase reaction between children and
adults.
CT is the most effective imaging modality in differentiating uncomplicated and
complicated appendicitis (H. Y. Kim et al., 2018; M. S. Kim et al., 2014; Verma et
al., 2015). However, it has limitations. The most informative CT findings were
identified in a recent systematic review (H. Y. Kim et al., 2018). There was a general
tendency for these characteristics to show relatively high specificity but low
sensitivity: CT imaging cannot reliably exclude complicated appendicitis.
Periappendiceal fat stranding was the only feature with high sensitivity (H. Y. Kim
72
et al., 2018). More uniform implementation of the recognized diagnostic features
in future studies and evaluating them as risk factors for a more complicated form
of the disease may increase the accuracy of CT.
Scoring systems combining information from clinical signs, laboratory
findings and imaging studies have been designed to achieve better differential
diagnostic potential. Two scoring systems were developed – one based on CT
features and an the other using US. The sensitivity and specificity of the CT score
with optimal cut off values were 90.2% and 70.3%, respectively. The scoring
system predicted the correct diagnosis in 95% of patients (Atema et al., 2015).
More recently, another scoring system was published combining clinical and
radiological data. Interestingly, unlike in the previous scoring system, no laboratory
findings were incorporated in the final version of their model. The detected
parameters were age, temperature and duration of symptoms together with assessed
CT features. However, they achieved a competitive discriminative capacity
compared to the model of Atema and colleagues (Avanesov et al., 2018). In another
study, the CT findings in the pelvic retroperitoneal space were assessed. The results
showed that complicated appendicitis could be predicted by a combination of
clinical variables, the number of involved segments of retroperitoneal space,
appendiceal diameter, appendicolithiasis and CRP level (Kitaoka, Saito, &
Tokuuye, 2014).
The presence of an appendicolith is associated with failure in the non-operative
treatment of acute appendicitis. Therefore, patients with CT-verified appendicoliths
were considered at risk for complicated appendicitis and were excluded from the
APPAC study (Salminen et al., 2015). The fact that in our study the appendicolith
appendicitis patients could not been identified by clinical signs or laboratory
findings emphasizes the role of CT in choosing the patients suitable for non-
operative treatment in future studies.
The limitations of this study include the retrospective study design in a
prospectively collected patient material. The APPAC trial had difficulties in
recruiting patients. Only 31.5% of all acute appendicitis patients and 20% of the
patients treated for uncomplicated acute appendicitis were recruited. However, the
study population closely resembled the patients who did not participate the trial and
underwent an appendectomy during the recruiting period in the study hospitals.
73
6.2 Histopathological differences between uncomplicated acute
appendicitis and acute appendicitis presenting with an
appendicolith
The role of an appendicolith in the pathogenesis of acute appendicitis has been
debated for over a century. During the last century, the clinical association of
appendicoliths to a more complicated course of the disease was detected in small
case series. The removal of the appendix was recommended if an appendicolith was
found incidentally on abdominal radiological examination, as an appendicolith was
often shown to be associated with a complicated appendicitis (Carras &
Friedenberg, 1960; Forbes & Lloyd-Davies, 1966). As a result of improved
diagnostic imaging, especially CT, we now know that an appendicolith may be an
incidental finding without any signs of appendicitis and when detected incidentally,
does not increase the risk of developing appendicitis compared to general
population (Huwart et al., 2006; B. A. Jones et al., 1985; M. S. Khan et al., 2018).
However, when presenting together with acute appendicitis, the role of an
appendicolith in predicting a worse outcome of the disease is clear. The presence
of an appendicolith has been identified as an independent prognostic risk factor for
treatment failure in the non-operative treatment of uncomplicated acute
appendicitis and has also been shown to be associated with appendiceal perforation
(Alaedeen et al., 2008; Mahida et al., 2016; Shindoh et al., 2010; Singh &
Mariadason, 2013; Vons et al., 2011; Yoon et al., 2018).
Despite the clinical findings indicating the important role of an appendicolith
in developing complicated acute appendicitis, little is known about the possible
histopathological differences between uncomplicated acute appendicitis and acute
appendicitis presenting with an appendicolith. In our study, we showed significant
histopathological differences between these two forms of acute appendicitis,
further supporting the concept of appendicolith as a risk factor for complicated
acute appendicitis.
In our study, acute appendicitis presenting with an appendicolith was
associated with a shorter duration of symptoms and signs of more severe
inflammation, such as mucosal ulcerations and microabscesses, than
uncomplicated appendicitis (Table 12). In appendicolith appendicitis, appendiceal
diameter was larger, the mucosa more often ulcerated, and the appendiceal wall
was thinner. This, together with the higher WBC count (Table 11), may reflect the
more abrupt and complicated nature of appendicolith appendicitis.
74
The epithelial surface was significantly more often destructed in appendicolith
appendicitis. As the measurement of the thickness of the inflamed appendiceal wall
was more often performed from a destructed epithelial surface, the thickness of the
wall (equalling the depth of inflammation as the diagnostic criterion for acute
appendicitis was transmural inflammation) was significantly lower in appendicolith
appendicitis. The crypt morphology was more often destructed (deep mucosal
damage, Table 12) in appendicolith appendicitis. The number of neutrophils was
significantly higher in appendicolith appendicitis. This finding is in line with a
recent study in which uncomplicated and complicated appendicitis cases were
compared in a paediatric patient population (Gorter et al., 2017). The number of
eosinophils was significantly lower in appendicolith appendicitis specimens. This
may reflect underlying individual differences in immunological responses,
explaining part of the differences in the pathophysiology of uncomplicated and
complicated appendicitis. The immune system is regulated by T-helper (Th) cells,
which develop different immune responses according to different cell types, type I
Th-cells (Th1) and type II Th-cells (Th2). Th1-cells induce the activation of
phagocytes and cytotoxic cells, and Th-2 cells induce secretion of antibodies and
activation of mast cells, eosinophils and basophils. In previous studies complicated
appendicitis has been suggested to be associated with a Th1-mediated immune
response and uncomplicated appendicitis to a Th2-mediated immune response
(Ruber, Berg, Ekerfelt, Olaison, & Andersson, 2006; Ruber et al., 2010). This is
supported by the histopathological findings showing eosinophilic infiltration in
resected appendices with uncomplicated appendices as well as the detected
eosinophilia in peripheral blood in paediatric patients with uncomplicated
appendicitis (Minderjahn, Schadlich, Radtke, Rothe, & Reismann, 2018;
Reismann, Schadlich, Minderjahn, Rothe, & Reismann, 2019; Yaeger, Cheng,
Tatishchev, & Whang, 2018).
The strengths of study II include the large prospective patient material with
prospectively collected clinical data and the availability of the CT-confirmed
differential diagnosis between uncomplicated acute appendicitis and appendicolith
appendicitis as well as the blinding of the histopathological specimens and the use
of a single senior specialist in pathology. The limitations include the retrospective
study design despite the prospective data collection, as, for example, we did not
have all the appendicoliths detected available for the histopathological assessment.
Another limitation of our study was the lack of grading and reporting gangrenous
appendicitis cases in each study group.
75
6.3 Treatment options of periappendicular abscesses
The management of a periappendicular abscess has been a matter of debate for
decades. Traditionally, the initial treatment has been conservative. According to
mostly retrospective data immediate operation prior to initial inflammatory mass
resolution is associated with risks that can be avoided by non-operative treatment
with antibiotics and possible drainage of the abscess. In a systematic review with
3772 patients and a total of 48 studies, immediate operation carried a risk of
complications up to 57% and a risk of unnecessary bowel resection in 5–25 % of
patients (Olsen, Skovdal, Qvist, & Bisgaard, 2014). Conservative treatment was
associated with a treatment failure rate of 8–15%. Drainage of the abscess,
recommended if the abscess diameter was > 5 cm, carried the risk of complications
in 2–15% of patients. A more recent systematic review and meta-analysis was
published in 2019 (Gavriilidis, de'Angelis, Katsanos, & Di Saverio, 2019). The
authors included 1864 patients in 17 retrospective studies, one prospective study
and three RCTs in the analysis, which showed clear differences between published
retrospective studies and RCTs with a laparoscopic approach regarding
complications. In previous, retrospective studies, overall complications,
abdominal/pelvic abscesses, wound infections and unplanned procedures were
significantly lower in the conservative treatment cohort. However, in contrast with
the retrospective studies, no significant difference was noticed between the LA and
conservative treatment cohort regarding the abdominal or pelvic abscesses or the
duration of hospital stay. The authors concluded that the present meta-analysis
demonstrates a shift in the treatment paradigm towards a more widespread use of a
laparoscopic approach for the management of complicated appendicitis. However,
they emphasized that the management of complicated appendicitis remains
controversial, as specific expertise and skill are required for the laparoscopic
approach.
Following successful conservative treatment of a periappendicular abscess,
“classical management” involves performing an interval appendectomy after
resolution of the abscess. It was first proposed by JB Murphy in 1904, and the same
method was favoured by 75% of the consultant surgeons questioned in the UK in
2005 (Deakin & Ahmed, 2007). An interval appendectomy provides a definite
diagnosis and rules out possibly underlying malignancy as well as prevents a
recurrent disease. However, recently an interval appendectomy has been
questioned, as the risk of recurrence is fairly low, varying between 5% and 26%
(Anderson et al., 2012; R. E. Andersson & Petzold, 2007; Darwazeh et al., 2016;
76
Kaminski et al., 2005; Lai et al., 2006). An interval appendectomy also is not
without morbidity. The reported complication rates range between 11% and 23%
(Eriksson & Styrud, 1998; Quartey, 2012; Tannoury & Abboud, 2013; Willemsen
et al., 2002). In a cost-effectiveness analysis, a 38% cost reduction was found if an
appendectomy was performed only after recurrence compared to a routine interval
appendectomy (Lai et al., 2005). The reported risk of a malignant disease associated
with a periappendicular abscess was 1.2% in a large meta-analysis (R. E. Andersson
& Petzold, 2007).
As there was only one published RCT comparing nonsurgical follow-up with
an interval appendectomy, we designed a multicentre non-inferiority randomized
clinical trial to test the hypothesis that an interval appendectomy is not necessary
after initial successful treatment of a periappendicular abscess. Originally, no
interim analysis was planned. However, as the incidence of appendiceal tumours in
the study population was higher than expected, an interim analysis was performed,
and the trial was terminated prematurely based on ethical concerns. The rate of
neoplasms was 20% in the whole study group, and as all the neoplasms were
diagnosed in patients older than 40 years, the neoplasm rate in this age group was
even 29%. Due to the premature termination of the study, we did not reach the
intended sample size, and therefore the study was underpowered to draw
conclusions on the initial primary end point, which was treatment success evaluated
at one year after intervention.
Recent data regarding the rate of appendiceal neoplasms in periappendicular
abscess patients differs from older reports, which may reflect varying definitions
of complicated appendicitis. In a large meta-analysis reviewing studies from 1964
to 2005 the risk of malignancy associated with a periappendicular mass was 1.2%
(R. E. Andersson & Petzold, 2007). However, the diagnosis of a periappendicular
abscess was made based on clinical examination in 93.5% of the patients. The
diagnosis was CT-or US-verified in only 6.5% of the large patient population. In a
more recent systematic review including over 13 000 patients with acute
appendicitis, the overall neoplasm rate was 1%, but in patients with a
periappendicular abscess, the rate varied from 10% to 29%. The proportion of
mucinous neoplasms (LAMN or mucinous adenocarcinoma) varied between 20%
and 100% in the analysed studies (Teixeira et al., 2017). This was in line with our
results, as 42% of all neoplasms in the study population were LAMNs. In our trial,
all the neoplasms were detected in patients over 40 years of age. This is in
accordance with previous retrospective case series. In a study by Wright et al.
(2015) the rate of appendiceal neoplasms in patients over 40 undergoing an interval
77
appendectomy was 16% and in patients under 40 the rate was 4% (Wright et al.,
2015).
An appendiceal tumour associated with a periappendicular abscess always
equals tumour perforation, which carries a risk of peritoneal dissemination.
Specifically, in the case of LAMN, the patient is at risk of pseudomyxoma peritonei
(Honore et al., 2015; Yantiss et al., 2009). In a report of 22 patients with LAMN
detected incidentally in an appendectomy, the rate of pseudomyxoma peritonei was
23%, and in 80% of the patients with peritoneal dissemination the CT was not able
to show peritoneal dissemination (Foster et al., 2016). In our study population, two
appendiceal neoplasms were diagnosed only after recurrent acute appendicitis
despite the fact that both patients had undergone MRI and colonoscopy. This is in
accordance with previous studies, as appendiceal tumours are not generally
suspected preoperatively (Lee et al., 2011). In a large Finnish population-based
registry study assessing the neoplasm risk associated with complicated acute
appendicitis, none of the appendiceal tumours were suspected preoperatively in
patients operated on for suspected acute appendicitis. In the same study, only 11%
of tumour patients had a preoperative diagnosis (Lietzen et al., 2018). This
highlights the need for better preoperative diagnostic modalities as well as the need
for operative treatment. As the patients’ compliance to follow-up and an interval
appendectomy varies and imaging studies do not reliably diagnose appendiceal
tumours, an immediate appendectomy may prove to be a good option. In our study
population, 11/60 patients declined surgery, thereby being exposed to a risk of a
tumour in the future. As concluded in the recent meta-analysis, the treatment
paradigm is seemingly shifting towards an immediate LA. However, the
management of periappendicular abscesses is still debated, considering the special
expertise required in the immediate laparoscopic approach (Gavriilidis et al., 2019).
Even in skilled hands, the rate of incomplete appendectomies was 13% (Mentula
et al., 2015).
In conclusion, based on the findings of our study, patients older than 40 years
of age with a periappendicular abscess carry a remarkable risk of an appendiceal
neoplasm. If further trials with larger patient populations are done to assess the
need for an interval appendectomy, patients over 40 years of age should be
excluded from the follow-up arm. Future trials are needed to assess the tumour
incidence associated with periappendicular abscess, and this could be performed
by having a prospective cohort study with an interval appendectomy for all
consecutive patients at least above 40 years of age. Future studies should also
78
include an immediate appendectomy treatment arm and assess the potential of only
follow-up in perhaps younger and asymptomatic patients.
The major limitation of this study is the small number of patients, which was
the result of the premature termination of the study. The high incidence of
appendiceal tumours in the study population prompted an interim analysis that was
not originally planned. The premature termination of the study resulted in an
underpowered trial, and thus the study was inconclusive regarding the trial
hypothesis and primary end point.
79
7 Conclusions
The following conclusions can be made from the present data:
1. Clinical signs or laboratory findings cannot reliably recognize complicated
appendicitis or to determine the presence of an appendicolith, highlighting the
need for modern imaging in differentiating between uncomplicated and
complicated appendicitis.
2. Significant histopathological differences were detected between
uncomplicated acute appendicitis and acute appendicitis presenting with an
appendicolith, supporting the complicated nature of appendicolith
appendicitis.
3. Based on the high rate of neoplasms in our study population resulting in
premature study termination, careful evaluation of interval appendectomy is
necessary, at least in patients over 40 years of age suffering from a
periappendicular abscess.
80
81
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Original publications
This thesis is based on following articles, which are referred in the text by their
Roman numbers
I Lietzén, E., Mällinen, J., Grönroos, J. M., Rautio, T., Paajanen, H., Nordström, P., Aarnio, M., Rantanen, T., Sand, J., Mecklin, J. P., Jartti, A., Virtanen, J., Ohtonen, P., Salminen, P. (2016). Is preoperative distinction between complicated and uncomplicated acute appendicitis feasible without imaging? Surgery 160(3), 789–795. doi:10.1016/j.surg.2016.04.021
II Mällinen, J., Vaarala, S., Mäkinen, M., Lietzén, E., Grönroos, J., Ohtonen, P., Rautio T., Salminen, P. (2019). Appendicolith appendicitis is clinically complicated acute appendicitis - is it histopathologically different from uncomplicated acute appendicitis? Int J Colorectal Dis 34(8), 1393–1400. doi:10.1007/s00384-019-03332-z
III Mällinen, J., Rautio, T., Grönroos, J., Rantanen, T., Nordström, P., Savolainen, H., Ohtonen, P., Hurme, S., Salminen, P. (2019). Risk of appendiceal neoplasm in periappendicular abscess in patients treated with interval appendectomy vs follow-up with magnetic resonance imaging. JAMA Surgery 154(3), 200–207. doi:10.1001/jamasurg.2018.4373
Reprinted with permission from Elsevier Inc.(I), Springer (II) and American
Medical Association (III).
Original publications are not included in the electronic version of the dissertation.
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U N I V E R S I TAT I S O U L U E N S I S
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D 1523
AC
TAJari M
ällinen
OULU 2019
D 1523
Jari Mällinen
STUDIES ON ACUTE APPENDICITIS WITHA SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;OULU UNIVERSITY HOSPITAL
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