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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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9

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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15

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

18

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

19

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

20

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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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