UNIVERSITATIS OULUENSIS MEDICA ACTA D D 1523 ACTA Jari Mällinen OULU 2019 D 1523 Jari Mällinen STUDIES ON ACUTE APPENDICITIS WITH A SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; OULU UNIVERSITY HOSPITAL
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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Senior research fellow Jari Juuti
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-2332-2 (Paperback)ISBN 978-952-62-2333-9 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1523
AC
TAJari M
ällinen
OULU 2019
D 1523
Jari Mällinen
STUDIES ON ACUTE APPENDICITIS WITHA SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 5 2 3
JARI MÄLLINEN
STUDIES ON ACUTE APPENDICITIS WITH A SPECIAL REFERENCE TO APPENDICOLITHS AND PERIAPPENDICULAR ABSCESSES
Academic dissertation to be presented with the assent ofthe Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 2 of Oulu University Hospital, on 25 October2019, at 12 noon
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.
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.
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
10
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
11
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
12
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
13
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.
14
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
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
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.
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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.
108
A C T A U N I V E R S I T A T I S O U L U E N S I S
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