Malignant Peritoneal Mesothelioma in Finland : Epidemiology, treatment, prognosis and diagnostics

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DISSERTATIONS | SILJA SALO | MALIGNANT PERITONEAL MESOTHELIOMA IN FINLAND | No 654

SILJA SALO

Malignant Peritoneal Mesothelioma in

Finland

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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MALIGNANT PERITONEAL MESOTHELIOMA IN FINLAND

EPIDEMIOLOGY, TREATMENT, PROGNOSIS AND DIAGNOSTICS

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Silja Salo

MALIGNANT PERITONEAL MESOTHELIOMA IN FINLAND

EPIDEMIOLOGY, TREATMENT, PROGNOSIS AND DIAGNOSTICS

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination

on December 3^rd, 2021, at 12 o’clock noon

Publications of the University of Eastern Finland Dissertations in Health Sciences

No 654

Department of Health Sciences, Institute of Clinical Medicine University of Eastern Finland, Kuopio

2021

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Series Editors

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Professor Tarja Kvist, Ph.D.

Department of Nursing Science Faculty of Health Sciences Professor Ville Leinonen, M.D., Ph.D.

Institute of Clinical Medicine, Neurosurgery Faculty of Health Sciences

Professor Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D.

School of Pharmacy Faculty of Health Sciences

Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland

www.uef.fi/kirjasto PunaMusta Oy

Joensuu, 2021

ISBN: 978-952-61-4350-7 (print/nid.) ISBN: 978-952-61-4351-4 (PDF)

ISSNL: 1798-5706 ISSN: 1798-5706 ISSN: 1798-5714 (PDF)

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Author’s address: Institute of Clinical Medicine University of Eastern Finland KUOPIO

FINLAND

Doctoral programme: Clinical doctoral programme Supervisors: Professor Tuomo Rantanen, Ph.D.

Department of Surgery University of Eastern Finland KUOPIO

FINLAND

Docent Ilkka Ilonen, Ph.D.

Department of General Thoracic and Oesophageal Surgery University of Helsinki

HELSINKI FINLAND

Reviewers: Docent Monika Carpelan-Holmström, Ph.D.

Department of Gastrointestinal Surgery University of Helsinki

HELSINKI FINLAND

Docent Maija Lavonius, Ph.D.

Department of Digestive Surgery

Turku University Hospital and University of Turku TURKU

FINLAND

Opponent: Docent Matti Kairaluoma, Ph.D.

Department of Surgery

Central Hospital of Central Finland JYVÄSKYLÄ

FINLAND

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Salo, Silja

Malignant Peritoneal Mesothelioma in Finland: Epidemiology, treatment, prognosis and diagnostics

Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 654. 2021, 100 p.

ISBN: 978-952-61-4350-7 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4351-4 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

Malignant peritoneal mesothelioma is cancer arising from the mesothelial cells of the peritoneum. Beyond peritoneum, mesothelioma can occur more commonly involving the pleura and rarely may involve pericardium or the tunica vaginalis testis. Association with asbestos exposure as well as nonspecific and diverse symptoms are typical to this disease. Due to its rarity and varying symptoms, a diagnosis of malignant peritoneal mesothelioma is challenging and often delayed, leading to a poor prognosis. Due to its atypical growth pattern, the traditional TNM staging is not well suited for malignant peritoneal mesothelioma. Therefore, several new staging systems have been introduced.

Studies concerning the epidemiology, diagnosis, treatment, and prognosis of malignant peritoneal mesothelioma are scarce. In addition, these topics have not been reported for Finland previously. The aim of this study was to clarify the epidemiology, treatment, diagnosis, and prognosis of malignant peritoneal mesothelioma in Finland. In addition, we also aimed to assess the effect of the radiological Peritoneal Cancer Index on patient prognosis.

Study data consisted of all new cases diagnosed with malignant peritoneal

mesothelioma between 2000 and 2012 in Finland. These data were gathered from the Finnish Cancer Registry, Statistics Finland, Workers’ Compensation Center, and patient medical records. For Study I, the final study group consisted of 90

malignant peritoneal mesothelioma patients regardless of treatment status. For

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Study II, patients not on treatment were excluded. This group comprised 50 patients. For Study III, all Study I patient computed tomography and magnetic resonance images on diagnosis were obtained and analysed by a board-certified gastrointestinal radiologist. The final study group in Study III comprised 53 patients.

Our results indicated that malignant peritoneal mesothelioma was a rare and fatal disease and, at the time of the study, its treatment and diagnosis were both heterogenous and varying in Finland. The survival time after diagnosis varied widely. A lower Peritoneal Cancer Index was reported to relate to prolonged survival after diagnosis. Our results are in line with earlier literature from other countries.

Keywords: Medical Subject Headings: Mesothelioma, Malignant/diagnosis;

Mesothelioma, Malignant/epidemiology; Mesothelioma, Malignant/mortality;

Mesothelioma, Malignant/therapy; Incidence; Prognosis; Survival Analysis; Finland

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Salo, Silja

Maligni peritoneaalinen mesoteliooma Suomessa: epidemiologia, hoitomuodot, ennuste ja diagnostiikka

Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 654. 2021, 100 s.

ISBN: 978-952-61-4350-7 (nid.) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4351-4 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Maligni peritoneaalinen mesoteliooma on vatsakalvon mesoteelisoluista lähtöisin oleva pahalaatuinen kasvain. Vatsakalvoa useammin mesotelioomaa tavataan keuhkopussissa, ja harvinaisempia sijainteja mesoelioomalle ovat sydänpussi ja kiveksen tuppikalvo. Tyypillisiä taudille ovat yhteys asbestille altistumiseen sekä epäselvät ja moninaiset oireet. Harvinaisuutensa ja epäselvien oireiden vuoksi malignin peritoneaalisen mesoteliooman diagnostiikka on haastavaa ja usein viivästyy, johtaen heikkoon ennusteeseen. Epätyypillisen kasvutapansa vuoksi maligni peritoneaalinen mesoteliooma ei sovellu perinteiseen TNM-

levinneisyysluokitukseen. Useita uusia levinneisyysluokituksia taudille on kehitetty.

Tutkimukset malignin peritoneaalisen mesoteliooman epidemiologiasta, diagnostiikasta, hoidosta ja ennusteesta ovat vähäisiä, eikä Suomessa ole aikaisemmin julkaistu lainkaan tutkimuksia näihin liittyen. Tämän tutkimuksen tavoitteena oli selvittää taudinn epidemiologiaa, hoitomuotoja ja diagnostiikkaa sekä ennustetta Suomessa. Lisäksi tavoitteena oli arvioida

tietokonetomografiakuvien löydösten perusteella laskettavan peritoneaalisen syöpäindeksin vaikutusta potilaan ennusteeseen.

Aineisto koostui kaikista vuosina 2000-2012 Suomessa diagnosoiduista

tautitapauksista. Potilasaineisto saatiin Suomen syöpärekisterin syöpärekisteri- ilmoituksista, Tilastokeskuksesta, Tapaturmavakuutuskeskuksesta sekä potilasasiakirjoista. Tutkimuksessa I lopullisen tapausmäärän koko oli 90

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kappaletta. Tutkimuksessa II jätettiin edellä mainitusta potilasaineistosta pois ne tapaukset, jotka eivät saaneet minkäänlaista hoitoa. Tutkimuksen II lopullinen tapausmäärä oli 50 kappaletta. Tutkimuksessa III kaikkien tutkimuksen I

henkilöiden diagnoosin aikaiset tietokonetomografia- ja magneettikuvat tilattiin gastroradiologin arvioitavaksi. Lopullinen tapausmäärä tutkimuksessa III oli 53 potilasta.

Tuloksemme osoittivat, että maligni peritoneaalinen mesoteliooma on harvinainen ja huonoennusteinen sairaus, jonka hoito ja diagnostiikka vuosina 2000-2012 oli Suomessa varsin monimuotoista ja vaihtelevaa. Diagnoosin jälkeinen

elossaoloaika vaihteli suuresti. Matalamman peritoneaalisen syöpäindeksin havaittiin olevan yhteydessä pidempään elossaoloaikaan. Tuloksemme olivat linjassa aikaisemmin muualla maailmassa julkaistujen tulosten kanssa.

Avainsanat: Yleinen suomalainen ontologia: mesoteliooma; diagnoosi;

epidemiologia; hoitomenetelmät; ennusteet; kuolleisuus

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ACKNOWLEDGEMENTS

This study was carried out in the Department of Surgery of the Kuopio University Hospital and in the Department of Lung and Esophageal surgery of the Heart and Lung Center of Helsinki University Hospital, during 2015-2021. Personal financial support was received from the Finnish Cultural Foundation’s North Savo Regional Fund, The Finnish Medical Foundation and The Heart and Lung Center of Helsinki University Hospital. In addition, this study was financially supported by the Finnish Work Environment Fund. I am thankful for the financial support that has enabled me to work on this PhD thesis.

I owe my deepest gratitude to my supervisors. I would like to acknowledge Professor Tuomo Rantanen for his continuous and friendly encouragement and guidance during this work. I am also sincerely grateful to Docent Ilkka Ilonen for suggesting the topic of this thesis and for patiently and warmly guiding and helping me move forward with my work. I want to thank both of my supervisors for always being there to answer my questions and helping me whenever needed.

I would like to express my warmest gratitude to the official reviewers of this thesis, Docent Monika Carpelan-Holmström ja Docent Maija Lavonius, for their interest in my work and the constructive comments, as well as their valuable guidance. I am also grateful to have Docent Matti Kairaluoma as an opponent in the public examination of this thesis.

I would like to thank all the people who have contributed to this work, especially my co-authors Professor Marjukka Myllärniemi, Docent Eila Lantto, Sanna

Laaksonen, MD, and Eric Robinson, BS, for their contributions for this work. Special thanks go to Tuomas Selander, MSc, for biostatistical assistance in my work, and Elli Andersson, for the illustrations in my thesis. I am grateful to Finnish Cancer Registry for the data used in this thesis.

I would like to express my warmest gratitude to all my colleagues in the Surgical Department of Porvoo hospital. Special thanks go to Aleksi Lähdesmäki, MD, PhD, Esko Glücker, MD, Dr. Med., and Claes Tötterman, MD, for creating a pleasant working environment as well as for offering me time to concentrate and work on my thesis.

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Finally, a special thanks goes to my family. I will always be grateful to my father, Professor Jarmo Salo and my late mother, Hanna Tuominen-Salo, PhD, for all your support and love. Thank you for introducing me to the world of medicine and science and for guiding and encouraging me throughout my life and this work. I am especially grateful to Lauri, for your companionship and bringing joy to my life.

Porvoo, October 2021 Silja Salo

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LIST OF ORIGINAL PUBLICATIONS

This dissertation was based on the following original publications:

I Salo SAS, Ilonen I, Laaksonen S, Myllärniemi M, Salo JA, Rantanen T.

Epidemiology of malignant peritoneal mesothelioma in Finland 2000-2012.

Cancer Epidemiology 51:81-85, 2017.

II Salo SAS, Ilonen I, Laaksonen S, Myllärniemi M, Salo JA, Rantanen T. Malignant peritoneal mesothelioma: Treatment Options and Survival. Anticancer

Research 39(2):839-845, 2019.

III Salo SAS, Lantto E, Robinson E, Laaksonen S, Myllärniemi M, Salo JA, Rantanen T, Ilonen I. Prognostic role of radiological peritoneal cancer index in malignant peritoneal mesothelioma: national cohort study. Scientific Reports

10(1):13275, 2020.

The publications were adapted with the permission of the copyright owners.

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ABBREVIATIONS

ALK Anaplastic lymphoma kinase

BAP1 BRCA-associated protein 1

CC Completeness of cytoreduction

CD141 Thrombomodulin

CEA Carcinoembryonic antigen

ChT Chemotherapy

CK5/6 Cytokeratin 5/6

CRS Cytoreductive surgery

CT Computed tomography

EGFR Epidermal growth factor

EPIC Early postoperative chemotherapy

FCR Finnish Cancer Registry

HIIC Heated Intraoperative Chemotherapy

HIPEC Hyperthermic Intraperitoneal chemotherapy

ICD10 10^th version of International Classification of Diseases

IPHC Intraperitoneal hyperthermic chemoperfusion

MM Multicystic mesothelioma

MPeM Malignant peritoneal mesothelioma

MRI Magnetic resonance imaging

PCI Peritoneal cancer index

PD-1 Programmed death ligand 1

PET Positron emission tomography

PIPAC Pressurised intraperitoneal aerosol chemotherapy

PS Palliative surgery

R Radiation

RS Radical surgery

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SEER Surveillance, Epidemiology and End Results

SF Statistics Finland

SIC Sequential chemotherapy

SRMP Serum mesothelin-related protein

SV40 Simian virus 40

VATS Video-assisted thoracic surgery

VEGF Vascular endothelial growth factor

WCC Workers’ Compensation Center

WDPM Well-differentiated papillary mesothelioma

WHO World Health Organization

WT1 Wilms’ tumour 1 protein

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1 INTRODUCTION

Malignant peritoneal mesothelioma (MPeM) is a rare and malignant primary peritoneal cancer that arises from peritoneal mesothelial cells. MPeM was first described by Miller and Wynn in 1907 in The Journal of Pathology and Bacteriology (Miller, Wynn, 1908). The first reported case of MPeM was in a 32-year-old man suffering from ascites and abdominal pain.

The most common site of mesothelioma is the pleura. Rarely, malignant mesothelioma occurs in other body parts containing mesothelial cells, such as pericardium, tunica vaginalis testis, or peritoneum. Peritoneal cases comprise approximately 7-30% of all mesothelioma cases (Price, Ware, 2009, Henley et al., 2013, Moolgavkar, Meza & Turim, 2009, Price, 1997)

Asbestos exposure is connected to 33-50% of all MPeM cases. Other risk factors have been reported, such as Simian virus 40 (SV40) infection, mineral fibre

exposure, ionising radiation exposure, and repeated bouts of peritonitis (Boffetta, 2007).

The symptoms of MPeM are heterogenous and nonspecific: MPeM usually presents with abdominal distension, weight loss, abdominal pain, and dyspnoea.

Ascites is found in most MPeM patients. These nonspecific symptoms are related to MPeM’s atypical way of spread along involved surfaces. Computed tomography (CT) plays an important role in identifying MPeM. Diagnosis should be made following solid tissue biopsy. Ascitic fluid assessment is not reported to give a diagnostic benefit. Nonspecific symptoms and unusual extent within the

abdominal cavity make MPeM challenging to both suspect and diagnose. MPeM is therefore usually diagnosed when already in the advanced stage.

MPeM fits poorly with the classic TNM staging due to its lack of distant metastases and its manner of spread through the abdominal cavity. Thus, several different staging methods have been introduced (Jacquet, Sugarbaker, 1996b, Jacquet, Sugarbaker, 1996a, Yan et al., 2011, Schaub et al., 2013, Magge et al., 2014). One of these methods, the Peritoneal Cancer Index (PCI) assesses the extent of disease, scored as 0-3 points on 13 different abdominal areas, resulting in a total score of between 0-39 points (Jacquet, Sugarbaker, 1996).

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The treatment of MPeM also varies greatly. Resistance to radiation and systemic chemotherapy is typical in MPeM. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), when combined with careful patient selection, has prolonged survival of MPeM patients up to 92 months (Sugarbaker, Paul H., 2017).

To date, MPeM and its characteristics have not previously been studied in Finland.

Therefore, the primary purpose of this study was to clarify the epidemiology and treatment of MPeM in Finland. Also, we aimed to assess the predictive value of radiological PCI among MPeM patients and to clarify the radiological assessment of MPeM. Finally, our study aimed to confirm findings published in earlier literature.

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2 REVIEW OF THE LITERATURE

2.1 PERITONEUM

2.1.1 Anatomy and physiology

The peritoneum covers the abdominal cavity and is considered the most extensive serous membrane of the human body, with a surface area of approximately 1.8 m² in adults (Healy, Reznek, 1998, van Baal et al., 2017). During embryogenesis, the peritoneum is formed from the mesoderm (Blackburn, Stanton, 2014). The

peritoneum consists of two layers: the parietal layer, which lines the body wall, and the visceral layer, surfacing the abdominal organs. The peritoneal cavity is located between these layers. The peritoneal cavity carries a physiological amount of 5- 100 ml of peritoneal fluid, which consists of plasma transudate and ovarian exudate (Pannu, Oliphant, 2015, van Baal et al., 2017).

Abdominal organs can be divided into intraperitoneal organs, such as liver, spleen, and stomach, and retroperitoneal organs, such as suprarenal glands, aorta, duodenum, pancreas, ureters, kidneys, distal oesophagus, and rectum.

Intraperitoneal organs are surrounded by the peritoneum, whereas in

retroperitoneal organs, the peritoneum covers only the anterior wall of the organs.

The function of the peritoneum is to support and protect the abdominal organs and the nerves, blood vessels, and lymphatics within the abdominal area (Kalra, A., Wehrle & Tuma, 2021).

The peritoneum’s visceral and parietal layers consist of three layers, the mesothelium, a basal lamina, and the submesothelial stroma. In the literature, peritoneum has been described to consist of either three different layers or a single layer of mesothelial cells (van Baal et al., 2017, Melichar, Freedman, 2002, Michailova, Usunoff, 2006).

The parietal peritoneum receives arterial blood from the epigastric, intercostal, lumbar, and iliac arteries, while venous blood drains into the inferior vena cava.

Additionally, the visceral peritoneum receives its arterial blood from both the superior and inferior mesenteric arteries, while its venous blood is drained into

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the portal vein (Solass et al., 2016). The parietal peritoneum is somatically innervated from spinal nerves Th10, Th11, Th12, and L1, whereas the visceral peritoneum derives its autonomic innervation from the vagus nerve (Blackburn, Stanton, 2014, Sheehan, 1933).

Mesothelial cells are squamous cells, which, beyond the peritoneum, can be found within the pleura, pericardium, and tunica vaginalis testis. (Sugarbaker, P. H. et al., 2006). The primary function of mesothelial cells is to decrease the friction between adjacent organs doing peristaltic and beating movements by excreting and

circulating peritoneal fluid (Judge et al., 2016, Blackburn, Stanton, 2014).

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Figure 1. Sagittal view of the abdominal cavity. 1. Diaphragm, 2. Parietal peritoneum, 3. Liver, 4. The small intestine, 5. Urinary bladder, 6. Rectum, 7.

Abdominal aorta, 8. Pancreas, 9. Oesophagus. The visceral peritoneum lies on the abdominal organs.

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Figure 2. Axial view of the abdominal cavity. 1. Visceral peritoneum, 2. Parietal peritoneum, 3. Epigastric artery and vein, 4. Liver, 5. Linea alba, 6. Rectus

abdominis muscle, 7. Gastric artery and vein, 8. Stomach, 9. Spleen, 10. Intercostal muscles, 11. Parietal peritoneum, 12. Left kidney, 13. Latissimus dorsi muscle, 14.

Abdominal aorta, 15. Azygos vein, 16. Inferior vena cava

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2.2 PERITONEAL MESOTHELIOMA

2.2.1 Definition

Peritoneal mesothelioma (MPeM) is a rare cancer arising from the peritoneal mesothelial cells (Judge et al., 2016, Raza, Huang & Takabe, 2014, Gilani et al., 2013). Pleural mesothelioma is the most common site of malignant mesothelioma, covering 75-80% of all diagnosed cases of malignant mesothelioma (Inai, 2008).

The peritoneum is the second most common location of mesothelioma. In previous studies, peritoneal mesothelioma has been reported to cover 7–30 % of malignant mesotheliomas (Dayal, Ghosh & Moran, 2014, Sugarbaker et al., 2006, Claimon et al., 2015, Kim, Bhagwandin & Labow, 2017, Mirarabshahii et al., 2012).

Tunica vaginalis testis and pericardium as primary sites of malignant

mesothelioma are extremely rare (Boffetta, 2007). MPeM can occur at any age, but over half of patients are aged 45–65 years when the disease is diagnosed (Claimon et al., 2015). MPeM is the most common malignant peritoneal primary tumour among developed countries (Mirarabshahii et al., 2012). MPeM can occur either involving the parietal or the visceral part of the peritoneum. Macroscopically, MPeM presents as diffuse or, more seldomly, as local mesothelioma. MPeM has the code C45.1 in the tenth version of the International Classification of Diseases (ICD10) (Conti et al., 2015).

2.2.2 Epidemiology

The incidence of MPeM has been reported to be at 0,2–3 cases per million per year worldwide (Judge et al., 2016, Sugarbaker, 2017, Mirarabshahii et al., 2012) Per the RARECARE database, the European incidence and mortality of MPeM have been reported to be at 1.3 and 1.2 cases per million per year from 1995 to 2002 (Conti et al., 2015). The incidence of MPeM is increasing in Genoa, a harbour city in the shipbuilding industry from Italy, with an annual incidence of 5.5 cases per million among men (Sugarbaker, 2017). MPeM has been suggested to be more common among men (Gilani et al., 2013, Boffetta, 2007, Mirarabshahii et al., 2012, Price, 1997). However, it is unclear if this results from different asbestos exposure rates between male and female patients, or genetic factors (Gao et al., 2015). This has been suggested to be from increased occupational asbestos exposure during the last decades (Claimon et al., 2015, Baratti et al., 2009). In the United States, over

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90% of MPeM patients have been reported to be non-Hispanic whites, whereas 4,6% of patients were black (Miura et al., 2014).

The incidence of MPeM has been rising since 1970 (Sugarbaker, 2017). The incidence has either already reached, or is reaching its peak in the United States, Europe, and Australia (Peto et al., 1995, Peto et al., 1999, Sugarbaker, 2017). The mean age during diagnosis has been reported to be 64 years. However, MPeM can occur at any age (Li, C. Y., Alexander, 2018). Even cases during childhood have been published (Moran, Albores-Saavedra & Suster, 2008, Cioffredi, Janne &

Jackman, 2009, Niggli et al., 1994).

2.2.3 Histology and pathogenesis

Most of the peritoneal tumours are secondary, originating from another primary location, such as colorectal cancer or pseudomyxoma peritonei (Piso et al., 2015).

Primary peritoneal tumours can be divided into MPeM, serous carcinoma of the peritoneum, well-differentiated papillary mesothelioma (WDPM), and multicystic mesothelioma (MM). Additionally, mesothelial cell proliferation can be found because of tissue damage or inflammatory factors from previous ascites, termed reactive mesothelial hyperplasia (Wei et al., 2017, Kawai et al., 2016).

Macroscopically MPeM tumour nodules are thick and heterogenous, spreading widely throughout the peritoneum. MPeM can form peritoneal plaques, masses, overlapping layers, or even cover the whole peritoneal surface (Elias et al., 2007, Sugarbaker et al., 2006). The World Health Organization (WHO) has divided MPeM into three histological subtypes by haematoxylin-eosin histological examination:

epithelial, sarcomatoid, and the biphasic subtype, also called the mixed subtype. A group of positive and negative markers leads to the diagnosis of MPeM (Levy et al., 2008, Husain et al., 2013).

Epithelial MPeM cells look like normal mesothelial cells, and their mitotic activity is scarce. (Levy et al., 2008, Husain et al., 2013). The epithelial subtype has been stated to be the most common histological subtype, comprising 75% of all cases (Liu et al., 2014). Differential diagnoses of epithelial mesothelioma and carcinoma, such as primary serous carcinoma of the peritoneum, require

immunohistochemistry (Chapel et al., 2020, International Academy of Pathology, 2021). The Finnish Department of the International Academy of Pathology has suggested certain immunohistochemical panels to distinguish epithelial

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mesothelioma from lung adenocarcinoma. These panels are used also in

differentiating peritoneal epithelial mesothelioma and primary serous carcinoma of the peritoneum (Chapel et al., 2020, International Academy of Pathology, 2021).

In epithelial MPeM, immunohistochemically positive markers, such as calretinin and podoplanin, are important. In the diagnosis of epithelial MPeM, several immunohistochemical tests are performed. The selection of different markers is based on histological appearance and patient potential previous malignancies. The result of multiple immunohistochemical tests and a combination of several

markets confirm the diagnosis (International Academy of Pathology, 2021, WHO Classification of tumours, 2021, Zhang, Brambilla, Molyneaux, Rice, Robertus, Jordan, Lim, Lang-Lazdunski, Begum, Dusmet, Anikin, Beddow, Finch, Asadi, Popat, Cookson et al., 2020, Zhang, Brambilla, Molyneaux, Rice, Robertus, Jordan, Lim, Lang-Lazdunski, Begum, Dusmet, Anikin, Beddow, Finch, Asadi, Popat, Quesne et al., 2020, Nicholson et al., 2020, Schulte, Husain, 2020). In previous literature, epithelial mesothelioma has been divided into low-grade and high-grade epithelial mesothelioma (Nicholson et al., 2020).

The biphasic subtype comprises 10% or more epithelial and sarcomatoid subtypes (Levy et al., 2008, Husain et al., 2013). When diagnosing biphasic MPeM, the pathologist should estimate the percentage of both subtypes. Especially in the diagnosis of biphasic mesothelioma, GATA-3 is a useful immunohistochemical positive marker. The prognosis of biphasic MPeM is mainly determined by the tumour percentage of the sarcomatoid subtype (International Academy of Pathology, 2021).

To date, no specific immunohistochemical markers have been found to diagnose sarcomatoid MPeM. For the sarcomatoid subtype, positive markers in the

epithelial subtype, such as calretinin and podoplanin, are usually negative. Low molecular weight cytocetarins can be considered as a positive

immunohistochemical marker in the sarcomatoid subtype (International Academy of Pathology, 2021, WHO Classification of Tumours Editorial Board, 2020). The sarcomatoid subtype has been reported to be the rarest MPeM subtype (Liu et al., 2014).

Primary serous carcinoma of the peritoneum is a primary peritoneal tumour but does not arise from mesothelial cells (Comin, Saieva & Messerini, 2007). Primary

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serous carcinoma often presents similarly to advanced serous ovarian carcinoma (Wang, Chen, 2010), but with no primary tumour identified, also presenting as abdominal carcinomatosis, commonly involving the omentum (Jha et al., 2020).

WDPM and MM are benign and usually originate from peritoneal surfaces within the pelvis area. They occur especially among women of fertile and middle ages (Takeshima et al., 2008, Gonzalez-Moreno et al., 2002, Weiss, Tavassoli, 1988, Katsube, Mukai & Silverberg, 1982). No connection between WDPM and asbestos exposure has been reported (Hoekman et al., 1996). Similar to primary serous carcinoma of the peritoneum, WDPM and MM can be treated by hyperthermic intraperitoneal chemotherapy (HIPEC) (Noiret et al., 2019). Rare subtypes, such as tubule-papillary non-glandular (solid), undifferentiated, desmoplastic, lympho- histiocytoid, small cells, and deciduous subtypes have been reported (Weiss, 1994, Noiret et al., 2019).

Even though MPeM is reported to be highly invasive, it usually does not seed lymph nodes or involve organ metastases beyond the peritoneum. However, distant metastases have been found in autopsy studies. In most MPeM patients, the disease stays within the peritoneal area (Gilani et al., 2013, Sugarbaker et al., 2006, Zha et al., 2015, Deraco, M. et al., 2006). In 2019, Jiang et al. reported a case of a 60-year-old woman in China, suffering from MPeM with meningeal metastasis (Jiang et al., 2019). Skin and subcutaneous metastases have also been reported (Ordonez, Smith, 1983, Pappa et al., 2006). Interleukin-8 (IL-8) has been suggested to be the main transmitter in MPeM (Judge et al., 2016).

2.2.4 Aetiology and the role of asbestos

Asbestos is a commercial term used for six different fibrous silicate minerals.

These minerals include actinolite, amosite (also known as brown asbestos), crocidolite (also known as blue asbestos), chrysotile (also known as white asbestos), anthophyllite, and tremolite. In addition, other materials, like talk and vermiculite, can contain asbestos (Huuskonen, 1990). Asbestos has two main groups, serpentine (chrysotile) and amphibole (other five minerals). Chrysotile is the most common asbestos fibre and 90% of the asbestos production is

associated with it. Amosite and crocidolite have also been used in the asbestos industry. Being a rock, asbestos is resistant to acid, friction, and heat (Toyokuni, 2014, Yang, Testa & Carbone, 2008, Carbone et al., 2012, Gao et al., 2015).

Exposure to crocidolite has been reported to have a high association with

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developing mesothelioma, whereas the association between chrysotile and mesothelioma has only been reported in animal studies (Antman, 1993).

Mesothelial cells have been reported to be 10–100 times more sensitive to amosite cytotoxic effects than normal human squamous and fibroblastic cells (Yang, Testa

& Carbone, 2008).

Approximately 33–50% of all diagnosed MPeM cases have been associated with asbestos exposure and up to 80% of pleural cases (Kaspar, 2015, Boffetta, 2007, Bridda et al., 2007, Teta et al., 2008) The association between MPeM and asbestos exposure was first reported in the 1960s and has been validated several times since (Baratti et al., 2013) Shorter exposure times have been more associated with pleural mesothelioma, whereas long exposure periods have been connected with MPeM (Antman, 1993). A latency period of 15–40 years between exposure and MPeM diagnosis has been reported. This long latency time has been suggested to be explained by the slow progression of damage from asbestos minerals

(Toyokuni, 2014) Compared to malignant pleural mesothelioma, the latency time has been reported to be shorter in MPeM (20 years vs 30–40 years) (Garcia- Fadrique et al., 2017). Compared to the peritoneum, asbestos has been shown to affect the pleura six times more effectively (Gao et al., 2015). No certain level of asbestos exposure has been reported to cause MPeM. However, the risk for MPeM has been reported to increase during more extended periods of exposure. In addition to MPeM, lung cancer, pleural mesothelioma, laryngeal cancer, ovarian cancer, asbestosis, retroperitoneal fibrosis, and pleural plaques have been reported as connected to asbestos exposure (Huuskonen, 1990). However, the association of MPeM and asbestos exposure has been reported to be stronger among men (Spirtas et al., 1994, Sugarbaker, P. H. et al., 2003).

Nowadays, asbestos is forbidden for use in new buildings in Finland, but asbestos can still be found in old buildings. Due to this, renovation and deconstruction of older buildings can cause asbestos exposure if insufficient protection equipment is provided (Huuskonen, 1990, Gao et al., 2015). In addition, asbestos was a common material in the shipping industry, especially in the United States and in Europe during the years 1940–1979, due to its windproof and fireproof characteristics (Yang, Testa & Carbone, 2008). Even today, asbestos is still used as a construction material (Frank, Joshi, 2014). MPeM linked to non-occupational asbestos exposure has also been reported (Vianna, Polan, 1978, Newhouse, Thompson, 1993). The families of asbestos-exposed workers have been reported as having a risk of 1%

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for malignant mesothelioma. Families can be exposed for example, by washing contaminated working clothes. People can also be exposed by living near buildings that contain asbestos as asbestos can spread through the air (Carbone et al., 2012).

The mechanism of asbestos affecting organs is not widely known. Fibres that are swallowed or inhaled make their way to the bowel and the peritoneal cavity (Kaspar, 2015, Mirarabshahii et al., 2012, Elias et al., 2007). These fibres then enter the mesothelial cells through the lymphatic system (Claimon et al., 2015). Three potential mechanisms for damage have been proposed: First, the formation of free oxygen radicals may affect DNA in ways connected to the malignancy process;

The second theory is that local chronic inflammation forms free oxygen radicals;

The third mechanism suggests that asbestos fibres function as chemical-based carcinogen transmitters within affected cells (Mirarabshahii et al., 2012).

2.2.5 Other risk factors

Beyond asbestos, the aetiology of MPeM has been correlated to ionising radiation, such as X-radiation, exposure to MICA-silicate, recurrent peritonitis, chromide oxide, mineral fibres such as erionite, and with Simian virus 40 (SV40), a DNA virus that originates from monkeys. In addition, chronic pancreatitis has been suggested to correlate with MPeM. A genetic risk with an autosomal-dominant pattern has also been suggested (Roushdy-Hammady et al., 2001). Smoking and MPeM have been suspected to correlate negatively. However, it has been suggested that smokers are more likely to die of lung cancer, which removes them from the MPeM risk group (Mirarabshahii et al., 2012, Boffetta, 2007, Conti et al., 2015, Antman, 1993, Yang, Testa & Carbone, 2008, Peterson, Greenberg & Buffler, 1984, Shivapurkar et al., 2000, Baris et al., 1987, Rivera et al., 2008, Mujahed et al., 2021) Finally, MPeM has been connected with a low-vegetable consumption diet

(Schiffman et al., 1988).

2.2.6 Diagnostics 2.2.6.1 Symptoms

Due to the atypical way of extension and its wide extent of spread within the peritoneum, the symptoms of MPeM can be nonspecific and may occur in many ways, which makes MPeM hard to diagnose. The most common symptom of

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MPeM is ascites and subsequently, increased abdominal girth (Kaya et al., 2014) Ascites is reported to be found in 60-100% of diagnosed MPeM patients (Kebapci et al., 2003, Ros et al., 1991). A case report describing mucinous ascites has also been published (Field et al., 2018). Other symptoms include common malignancy- related symptoms such as abdominal pain, weight loss, dyspnoea, night-time sweating, asthenia, cachexia, high fever, diarrhoea, vomiting, and subcutaneous abdominal resistances. Thrombocytosis and anaemia have also been associated with MPeM (Mohamed, Sugarbaker, 2002, Sugarbaker, 2017, Manzini et al., 2010, de Pangher Manzini, 2005, Chen et al., 2011). Additionally, cases of bowel

obstruction and perforation, as well as incidental discovery during laparoscopy, have been reported (Salemis et al., 2007, Sethna, Sugarbaker, 2005, Sugarbaker, P.

H. et al., 2000) Due to nonspecific symptoms, diagnosis of MPeM is often delayed (Chua, Yan & Morris, 2009, Acherman et al., 2003) In 8% of the cases, the diagnosis is made incidentally, during abdominal surgery or imaging (Boussios et al., 2018).

Even though MPeM usually occurs diffusely within the peritoneal cavity, a localised variant of malignant mesothelioma has been reported (Levy et al., 2008,

Sugarbaker, P. H., Jelinek, 2020, D'Abbicco et al., 2012, Feldman et al., 2003).

Localised MPeM seldom spreads extra-abdominally and often presents as abdominal pain or a palpable mass within the abdomen.

2.2.6.2 Imaging

Computed tomography (CT) provides X-ray pictures in three dimensions, consisting of narrow slices. (Ambrose, Hounsfield, 1973). CT of the chest,

abdomen, and pelvis is considered the first-line imaging modality of choice when diagnosing MPeM (Garcia-Fadrique et al., 2017) The sensitivity and specificity of CT in the diagnosis of MPeM have not been reported. In CT images with intravenous (IV) contrast, MPeM often is identified by expansive distribution within the abdominal cavity, as a heterogeneous and solid tumour cake with irregular margins (Busch et al., 2002).

In CT images, common findings include ascites, peritoneal thickening, omental caking, diaphragmatic involvement, small bowel involvement, and cystic or solid masses (Ros et al., 1991, Reuter et al., 1983, Kebapci et al., 2003, Park et al., 2008, Chandramohan et al., 2017, Takeshima et al., 2008). CT has been reported to have significant prognostic value when selecting patients for comprehensive treatment (Yan, Haveric, Carmignani, Chang et al., 2005).

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Favourable findings have been reported to include minimal soft tissue masses with ascites, the normal anatomy of small bowel and mesentery, and the absence of lymph node metastases. The absence of ascites, tumours larger than 5 cm involving the lesser omentum, subpyloric space, or jejunal regions, nodular thickening, and hydroureter have been considered as unfavourable findings (Greenbaum, Alexander, 2020, Sugarbaker, P. H. et al., 2016, Sugarbaker, P. H., 2018). CT images are an applicable tool in assessing treatment, though there are no absolute CT findings that would prove the inoperability of the tumour.

Magnetic resonance imaging (MRI) or positron emission tomography (PET) can be utilised in the diagnosis of MPeM. MRI imaging is based on the magnetisation of hydrogen protons (Lauterbur, 1989). Currently, the role of PET in the diagnosis of MPeM is unclear (Broeckx, Pauwels, 2018, Deraco, Marcello et al., 2008). The utility of MRI in the diagnosis of MPeM is not well defined (Low, Barone, 2012). Studies concerning the role of ultrasound in the imaging and diagnosis of MPeM are scarce.

2.2.6.3 Diagnosis and staging

Diagnosing MPeM is difficult. It has been suggested that information regarding previous asbestos exposure eases the diagnosis (Boffetta, 2007). Even though ascites is the most common symptom, ascitic fluid assessment may not be confirmatory in MPeM since MPeM cells often seem like normal cells with mesothelial hyperplasia (Zha et al., 2015, Taskin et al., 2012, Sugarbaker, 2017).

Nowadays, ascites fluid assessment is not recommended and a definite diagnosis can be made only via tissue biopsy (Husain et al., 2013, Claimon et al., 2015).

A laparoscopic peritoneal biopsy is considered the gold standard for MPeM diagnosis and is required for definitive diagnosis (Zha et al., 2015). However, the extent of the disease might be underestimated when performing laparoscopy (Greenbaum, Alexander, 2020). Therefore, video-assisted thoracic surgery (VATS) is recommended when assessing the extent of disease in patients with pleural effusion (Kim, Bhagwandin & Labow, 2017).

To date, no official staging or grading system for MPeM has been accepted universally. TNM staging is not well suited for MPeM due to a rare rate of distal metastases and MPeM’s tendency to present widely throughout the abdominal

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cavity. However, several staging systems have been proposed (Jacquet,

Sugarbaker, 1996, Jacquet, Sugarbaker, 1996, Yan et al., 2011, Schaub et al., 2013, Magge et al., 2014). The radiological PCI is a score created for radiographic assessment in peritoneal carcinomatosis. PCI can be measured either radiologically from CT or MRI images or clinically during laparotomy. PCI is assessed by dividing the peritoneum into 13 abdominal regions and evaluate the tumour size and distribution by scoring each region with 0-3 points: zero points for no identifiable disease, one point for lesions 0.5 cm or smaller, two points for lesions 0.5 cm-5 cm and three points for lesions larger than 5 cm. The total PCI score can vary between 0 and 39 (Jacquet, Sugarbaker, 1996, Jacquet, Sugarbaker, 1996) Different abdominal regions of PCI are presented in Table 1.

PCI can also be measured clinically during surgery. In earlier literature, CT has been shown to underestimate the intraoperative PCI (Chua et al., 2011, Low, Barone & Lucero, 2015). In a study by Lee et al in 2020, wherein radiological and intraoperative PCI were compared in a multi-centre study of the US HIPEC Collaborative in 2000–2017, CT PCI did have a significant correlation with

intraoperative PCI in peritoneal mesothelioma (p=0.665). In colorectal carcinoma, invasive appendiceal carcinoma, and non-invasive appendiceal carcinoma, significant correlations were also found (Lee, R. M. et al., 2020).

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Figure 3. Abdominal regions 0-8 are used in the Peritoneal Cancer Index (Jacquet, Sugarbaker, 1996).

Figure 4. Abdominal regions 9-12 are used in the Peritoneal Cancer Index (Jacquet, Sugarbaker, 1996).

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Table 1. Peritoneal cancer index (Deraco et al., 2008).

Region number Abdominal region Score

0 Central 0-3

1 Right upper 0-3

2 Epigastrium 0.3

3 Left upper 0-3

4 Left flank 0-3

5 Left lower 0-3

6 Pelvis 0-3

7 Right lower 0-3

8 Right flank 0-3

9 Upper jejunum 0-3

10 Lower jejunum 0-3

11 Upper ileum 0-3

12 Lower ileum 0-3

Total 0-39

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2.2.6.4 Tumour markers

Histopathological diagnosis of MPeM remains challenging, as MPeM remains unknown to most pathologists (Husain et al., 2013, Patel et al., 2007). Earlier, the diagnosis was even more difficult when made cytologically via ascites fluid, as ascites fluid contains few malignant cells (Enomoto et al., 2019). Nowadays, the diagnosis is made immunohistochemically, as described earlier.

Common gastrointestinal tumour markers are utilised in the diagnosis of MPeM as negative markers, such as carcinoembryonic antigen (CEA) (King et al., 2006, Taskin et al., 2012, Elias et al., 2007, Husain et al., 2013). CA-125, when measuring the peritoneal irritation, has shown to present at a normal level after MPeM treatment, whereas it would have been elevated prior to treatment. It thus connects with disease progression after treatment (Baratti et al., 2007).

Previous papers have suggested that, in the diagnosis of MPeM, two

mesothelioma biomarkers and two carcinoma biomarkers should be examined (Boussios et al., 2018, Lee, M., Alexander & Burke, 2013) Nevertheless, due to a large variety of different biomarkers, the diagnosis should be confirmed using a solid tissue sample (Attanoos et al., 2001).

2.2.6.5 Differential diagnosis

Unfortunately, there are no absolute immunohistochemical or molecular markers that could differentiate benign proliferative conditions from diffuse MPeM. In addition, differentiating sarcomatoid MPeM from sarcomatoid carcinoma is difficult. Before the time of immunohistochemical markers, MPeM could easily be misdiagnosed as metastatic adenocarcinoma from ovaries, lungs, or breast, due to reactive mesothelium and inflamed proliferative tissue (Taskin et al., 2012, Kaspar, 2015, Carbone et al., 2012, Boffetta, 2007, Mirarabshahii et al., 2012) Nevertheless, the lack of infiltrative extent and a primary site arouses suspicion of MPeM

(Deraco et al., 2008).

In previous literature, case reports of MPeM being misdiagnosed as ischaemic colitis, incisional hernia, a palpable mass within the abdomen, or an inguinal hernia, have been published (Mitsuka et al., 2010, Chakravartty et al., 2012, Hong et al., 2016, Kobayashi et al., 2020).

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2.2.7 Treatment 2.2.7.1 Background

Despite treatment, MPeM is often fatal due to resistance to chemotherapy and radiation. Literature and randomised controlled trials concerning the treatment of MPeM is scarce (Garcia-Carbonero, Paz-Ares, 2006). However, during the last years, genetic and molecular information regarding MPeM has increased, which has led to a more profound understanding of future treatment opportunities.

2.2.7.2 Chemotherapy

Most MPeM patients die within five years after diagnosis. However, during recent years, survival has increased by treating MPeM patients with the combination of CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) (Yan et al., 2009).

Unfortunately, most MPeM patients receive only palliative treatment or systemic chemotherapy, even though many would benefit from more invasive treatment options (Sugarbaker, 2018).

In 1983, Antman et al described the treatment of MPeM for the first time (Antman et al., 1983). Twenty-three MPeM patients and their treatment were studied, revealing that 14/18 patients received doxorubicin and had measurable disease.

Four of these patients had partial response to treatment, one patient responded completely to treatment, and one patient did not respond at all.

The response of MPeM to systemic treatment has been reported to be low and the effect on the outcome remains to be weak (Malgras et al., 2018). The combination of cisplatin or pemetrexed and doxorubicin has been reported to be the most efficient chemotherapeutic regimen for the treatment of MPeM (Garcia-

Carbonero, Paz-Ares, 2006, Sugarbaker, 2017, Berghmans et al., 2002). Systemic chemotherapy has been reported to give MPeM patients palliative benefit, but not to improve survival and is recommended as a treatment modality for inoperable patients and those with biphasic or sarcomatoid MPeM or with poor overall status (Lainakis et al., 2011, Boussios et al., 2018, Witkamp et al., 2001). Nowadays, the recommended standard chemotherapy used in MPeM is a combination of pemetrexed 500 mg/m² and cisplatin 75 mg/m² for six cycles or more (Turner, Varghese & Alexander, 2011) In MPeM, second-line chemotherapy is not usually used, due to its insignificant benefit (Carteni et al., 2009) Sequential chemotherapy

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(SIC) may be given either systemically or intraperitoneally, either right after operative treatment or later than that (Verma et al., 2018).

2.2.7.3 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal

chemotherapy (HIPEC) or early postoperative chemotherapy (EPIC) is considered the standard of care in MPeM (Turaga, Deraco & Alexander, 2017, Greenbaum, Alexander, 2020, Sugarbaker, 2018). It was introduced in 1995 (Sugarbaker, P. H., 1995). CRS aims to remove all visible macroscopic tumour tissue, whereas, in HIPEC, hyperthermic chemotherapeutic agents are given to the patient intraperitoneally. CRS combined with HIPEC is suitable and recommended for patients with a tumour that can be operated on and who can tolerate the surgical procedure (Haque et al., 2018). It has been estimated that surgeons require approximately 140 cases to achieve expertise in CRS+HIPEC (Lemoine et al., 2019).

In HIPEC, chemotherapeutic agents are usually heated to 40–42 degrees and perfusion lasts for 90 minutes (Yan et al., 2007, Chua, Yan & Morris, 2009, Feldman et al., 2003).

In CRS, all visible macroscopic tumour tissue is extirpated. The remaining tumour tissue can be described by the completeness of cytoreduction (CC score), which is associated with the prognosis after surgery (Broeckx, Pauwels, 2018) CRS is considered successful if with a postprocedural CC score of 0 or 1. In a study by Aydin et al in 2015, different characteristics of MPeM patients were compared, finding out CC score was the most significant factor in long-term overall survival of MPeM patients (Aydin et al., 2015).

Sugarbaker et al. have reported that findings, such as sarcomatoid subtype, 5 cm or larger tumour masses on the surface of the small bowel or directly facing the mesentery of the small bowel, or segmental obstruction of the small bowel, predict a poor prognosis for complete cytoreduction (Sugarbaker, P. H., 2004). In a report by Sugarbaker in 2018, an algorithm for management of MPeM patients suggested CRS+HIPEC for patients with epithelial MPeM only. Biphasic or

sarcomatoid subtypes were suggested to be treated with systemic chemotherapy (Sugarbaker, 2018).

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In 2018, Naffouje et al compared different treatment modalities for MPeM and their effect on overall survival. They found out that chemotherapy after surgery, either combined with CRS or given as neoadjuvant treatment, increased the short- term survival at one year. However, the survival rate did not increase beyond this one-year point (Naffouje, Tulla & Salti, 2018).

When considering CRS+HIPEC, patient selection is important. CRS+HIPEC is often offered to patients with characteristics, such as female gender, age below 60 years, PCI favourable for successful CRS, epithelial subtype of MPeM, and absence of preoperative thrombocytosis (Li, Alexander, 2018, Yan et al., 2009, Kaya et al., 2014, Greenbaum, Alexander, 2020, Li, Y. C. et al., 2017, Sugarbaker, 2018). A biphasic and sarcomatoid subtype, age over 60 years, preoperative

thrombocytosis, deep tissue invasion, severe renal, hepatic, or cardiac dysfunction, extra-abdominal spread, or para-aortic metastases are usually contraindications for CRS+HIPEC (Li et al., 2017, Witkamp et al., 2001, Sugarbaker et al., 2016) Often, laparoscopy is needed to evaluate disease extent and the likelihood of CRS+HIPEC success in a patient (Laterza et al., 2009).

The perioperative mortality of CRS+HIPEC has been reported to range from 1.9–

6.0% in experienced centres delivering HIPEC (Magge et al., 2014, Yan et al., 2007, Cao, S. et al., 2015). Complications, such as pulmonary embolism, prolonged bleeding, and venous thromboembolism, have been reported to occur in up to 15–

56% of patients undergoing CRS+HIPEC (Alyami et al., 2018, Cao et al., 2015).

Proliferation biomarker Ki-67 has also been reported to determine survival after CRS+HIPEC: patients with Ki-67 9% or less had a median survival of 86.6 months, and patients with Ki-67 more than 9% had a median survival of 10.3 months (Kusamura et al., 2016).

In a study by Yan et al in 2009, early postoperative chemotherapy (EPIC) did not affect survival (Yan et al., 2009). However, in a meta-analysis by Helm et al in 2015, EPIC reported to potentially increase survival (Helm et al., 2015).

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Table 2. Determination of Completeness of Cytoreduction score.

CC score

CC0 No visible residual tumour

CC1 Tumour tissue <2,5 mm

CC2 Tumour tissue <2,5 mm and <2,5 cm

CC3 Tumour tissue >2,5 cm

HIPEC, also called Heated Intraoperative Intraperitoneal Chemotherapy (HIIC) or Intraperitoneal Hyperthermic Chemoperfusion (IPHC), is performed to address non-visible, microscopic residual tumour tissue. The duration of HIPEC is 90 minutes. Chemotherapeutic agents are heated to 40–42 Celsius degrees. Often cisplatin combined with doxorubicin is used (Greenbaum, Alexander, 2020). The RENAPE study in France compared different chemotherapeutic agents used in CRS+HIPEC, concluding that survival was improved when two agents were used when compared with that with the use of a single agent. However, no significant difference was found when comparing different chemotherapeutic agents (cisplatin, cisplatin combined with doxorubicin, mitomycin C, oxaliplatin, or oxaliplatin combined with irinotecan) (Malgras et al., 2018) Chemotherapeutic agents are made hyperthermic to impair DNA repair, denature proteins, induce heat-shock proteins, induce apoptosis, inhibit angiogenesis, and to deliver direct cytotoxic effects to malignant cells (Witkamp et al., 2001) Nevertheless, cisplatin used in HIPEC has been reported to associate with longer postoperative survival than mitomycin C (p=0.22) (Blackham, Levine, 2012) The effectiveness of HIPEC relies on the CC score. Chemotherapeutic agents have been reported to penetrate only up to a depth of 3 mm (Turner, Varghese & Alexander, 2011, Dedrick et al., 1978).

Both open and closed HIPEC techniques have been described in the literature. The open technique is also known as the coliseum technique, wherein HIPEC is given through an open peritoneal cavity, with a plastic sheet covering the abdominal wall (Witkamp et al., 2001). In the closed technique, the skin is closed and

chemotherapeutic agents are delivered via perfusion to the abdomen. No

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significant differences have been found when comparing these techniques (Sugarbaker, 2018). The open technique is commonly used in Finland.

Figure 5. A HIPEC procedure is performed in Helsinki University Hospital on a MPeM patient. The blue catheters (2 cranially, 2 caudally) are measuring the temperature in the abdominal cavity, while the heated chemotherapeutic agents are circulated using 6 abdominal drains (3 on each side of the patient). Picture provided by Monika Carpelan-Holmström.

In 2011, Pressurised intraperitoneal aerosol chemotherapy (PIPAC) was introduced for treating peritoneal metastases and MPeM. In PIPAC, aerosolised

chemotherapeutic agents are delivered to the closed abdominal cavity via trocars.

Few studies concerning PIPAC in the treatment of MPeM have been published;

however, it has been reported to be a feasible treatment option for end-stage MPeM (Alyami et al., 2019, Giger-Pabst et al., 2018). A randomised controlled study comparing the use of PIPAC and systemic chemotherapy as first-line treatment of MPeM has been initiated, with the results being awaited (Sgarbura et al., 2019).

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2.2.7.4 Radiation therapy

The role of radiation therapy in the treatment of MPeM remains unclear (Munkholm-Larsen, Cao & Yan, 2009). Radiation therapy has not been noted to increase survival but can be more effective when combined with CRS and HIPEC (Blackham, Levine, 2012, Hesdorffer et al., 2008). Due to generally wide peritoneal spread, targeted radiation therapy is difficult to perform. The whole abdominal cavity cannot be radiated and therefore, radiation therapy can be potentially considered to treat single tumour nodules.

In earlier literature, inoperable patients were suggested to be treated by the combination of chemotherapy, radiation therapy, and immunotherapy (Cao et al., 2015). Studies concerning only radiation as treatment in MPeM are scarce. The same goes for studies on radiation doses used in the treatment of MPeM.

2.2.7.5 Immunological treatment

Recently, more interest has been shown towards immunological factors in MPeM (Greenbaum, Alexander, 2020). Mutations in BRCA-associated protein 1 (BAP1) have been reported to occur in pleural mesothelioma among 27–67% of MPeM patients (Singhi et al., 2016, Carbone et al., 2019). Germline BAP1 mutations have been connected to malignancies, such as mesothelioma (pleural and peritoneal), renal cell carcinoma, uveal and cutaneous melanomas, and other cancers (Pilarski et al., 1993). In MPeM, BAP1 expression loss has been found in 57% of the patients (Singhi et al., 2016) The loss of BAP1 expression has been reported to increase the risk of malignancy, and in MPeM, to connect with the more inflammatory tumour microenvironment (Shrestha et al., 2019, Ladanyi, Sanchez Vega & Zauderer, 2019, Yu et al., 2014). MPeM patients with rather than without BAP1 mutations have improved survival (Pastorino et al., 2018, Leblay et al., 2017).

In 2018, Kittaneh et al recommended that mesothelioma patients aged 50 years or younger and that patients with multiple family members with BAP1 associated cancers, such as mesothelioma, renal cell carcinoma, or melanoma, should be tested for BAP1 mutations (Kittaneh, Berkelhammer, 2018)

The connection between mesothelioma and Programmed death ligand 1 (PD-L1) has also been studied. However, the usage of Anti-PD-1 immunotherapy among MPeM patients has not been studied (Cornelissen et al., 2012, Dong, Sun & Zhang,

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2017) In a study by Brosseau et al in 2019, among patients with pleural mesothelioma, PD-L1 expression was reported to be higher in biphasic and sarcomatoid subtypes than in the epithelial subtype (Brosseau et al., 2019) Contrary to pleural mesothelioma, anaplastic lymphoma kinase (ALK)

rearrangement has been shown to present in 3% of MPeM patients, giving hope that, in the future, a group of MPeM patients could receive benefit from ALK inhibitors (Hung et al., 2018).

Erlotinib and gefitinib are tyrosine kinase inhibitors that act by affecting the epidermal growth factor (EGFR). In mesothelioma, no activity of these enzymes was found (Stahel et al., 2015, Kalra, N. et al., 2012). Nintedanib, which is an angiokinase inhibitor acting towards vascular endothelial growth factor (VEGF) receptors, and bevacizumab, which is a humanised anti-VEGF antibody, have been reported to be connected to increased overall survival in malignant pleural

mesothelioma, when combined with cisplatin and pemetrexed, in both phase II (Grosso et al., 2017) and phase III (Zalcman et al., 2016) trials. However, these results were applied only to pleural mesothelioma, not MPeM.

2.2.8 Prognosis

MPeM has a poor prognosis. The median survival time after diagnosis has been reported to be around one year, and a survival time of over five years is rare. The USA Surveillance, Epidemiology and End Results (SEER) registry has reported the median survival after diagnosis of MPeM to be 10 months, and five-year survival of 16%. However, longer survival times have also been reported (Surveillance,

Epidemiology, and End Results (SEER) Program).

Female gender, good state of health, and epithelial histological subtype have been reported to be factors associated with better prognosis in MPeM. Better prognosis among females has been suggested as caused by asbestos exposure being more common among males. Additionally, one suggestion was that the epithelial subtype is more common among female patients, with no significant association with asbestos exposure (Mirarabshahii et al., 2012, Sugarbaker et al., 2006, Zha et al., 2015, van der Bij et al., 2012).

With a careful patient selection, CRS combined with HIPEC has reached a median survival rate of up to 34–100 months(Helm et al., 2015, Esquivel et al., 2007, Baratti

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et al., 2012, Miura et al., 2014). Many single-centre studies and multi-centre studies concerning the treatment of MPeM have been published, reporting a median survival of 30-92 months among patients treated with CRS and HIPEC (Helm et al., 2015, Passot et al., 2016, Feldman et al., 2003, Brigand et al., 2006, Loggie et al., 2001). In 2009, Yan et al published a 29-centre study of MPeM patients treated with CRS+HIPEC, reporting a median survival of 53 months and long-term survival of 81% at one year, 60% at three years, and 47% at five years after diagnosis (Yan et al., 2009). Patients with more symptoms such as abdominal distension or pain, and patients with solid tumour masses in the abdominal cavity, achieved a worse overall survival (Llanos, Sugarbaker, 2017), which also accentuates the significance of patient selection prior to treatment attempts.

Systemic chemotherapy is recommended for patients with sarcomatoid or biphasic MPeM and epithelial inoperable patients (Chicago Consensus Working Group, 2020). No survival benefit from neoadjuvant chemotherapy has been reported (Deraco, M. et al., 2013, Kepenekian et al., 2016).

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3 AIMS OF THE STUDY

I Clarify the incidence and epidemiology of malignant peritoneal mesothelioma in Finland.

II Identify and compare the effectiveness of different treatment modalities given to malignant peritoneal mesothelioma patients diagnosed in Finland.

III Evaluate the prognostic value of radiological Peritoneal Cancer Index and other radiological features in MPeM patients.

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4 SUBJECTS AND METHODS

4.1 STUDY DESIGNS

All patients diagnosed with MPeM in Finland from 1 January 2000 to 31 December 2012 were identified through the Finnish Cancer Registry (FCR).

All patients diagnosed with MPeM in Finland during the study period formed the study population in study I.

In Study II, we excluded patients who had not been treated at all.

In Study III, abdominal CT and MRI images were obtained from hospitals where patients had been diagnosed or treated. The patient group in Study III was formed from patients who had radiological scans available.

4.2 DATA

The Finnish Cancer Registry (FCR) has maintained a registry since 1953, including all cancers diagnosed in Finland. The coverage of solid tumours by FCR has been reported to be as high as 99% (Teppo, Pukkala & Lehtonen, 1994). Information concerning the time of diagnosis, histological subtype, and date of death was gathered from the cancer notifications, laboratory notifications, and death

certifications from FCR. In addition, the survival status was gathered from Statistics Finland (SF) and information concerning occupational diseases and asbestos exposure was collected from the Workers’ Compensation Center (WCC). Additional information concerning symptoms, diagnosis, and treatment, was collected from the respective patient medical records from hospitals where the patients had been diagnosed and treated.

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Figure 6. Flowchart of 94 patients in studies I, II, and III.

In study I, which clarified the epidemiology of MPeM, we collected basic

characteristics of the patients, such as date of birth, gender, profession at the time of diagnosis, histological subtype, diagnosing method, way of treatment,

profession, date, cause of death according to the diagnosis in the 10th version of the International Statistical Classification of Diseases and Related Health Problems (ICD10), and potential or confirmed occupational disease and confirmed asbestos exposure. After went through patient medical records, four patients were

excluded from the study due to a primary tumour other than MPeM. The final study group included 90 patients. In Study I, patient survival status was verified by February 2013. Patient professions were divided into six categories: technical and household workers, science and art workers, commercial workers, agriculture and forestry workers, traffic workers, social and health workers, and clerical workers.

In Study II, which clarified different treatment modalities in MPeM, we excluded those patients from the Study I patient group who did not receive cancer-aimed treatment. Those patients received only palliative treatment or did not receive any kind of treatment at all. The final study group included 50 patients. We clarified patient treatment status from their medical records, obtained from the health institutions where respective patients had been diagnosed and treated. The information concerning treatment included first-line chemotherapeutic agents

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used, performed surgical procedures, and total radiation doses are given. Patient survival status was verified in May 2018.

In Study III, which studied the radiological assessment of MPeM, CT, and MRI images were collected for all patients in the Study I group when available. CT or MRI was available in 53 of the patients. All of the images were re-analysed by an experienced board-certified abdominal radiologist (EL). The radiologist was blinded to the individual patient radiology reports and clinical details but was aware of an MPeM diagnosis. The radiologist assessed the PCI score and checked the images for pleural effusion, regional and distant lymph nodes, extra-

abdominal organ metastases, and ascites. Lymph nodes were considered

malignant if with a radiological short axis of 10 mm or more. Pleural effusion was not considered as an extra-abdominal spread, whereas pleural thickening was considered as metastatic. We divided the patients into a low PCI group (PCI 0–19) and a high PCI group (PCI 20–39). Patient survival status was verified in May 2018.

4.3 ETHICS

Studies I, II, and III were all population-based, retrospective studies. None of the patients were contacted during the study. All the data was gathered from registries and medical records as mentioned earlier. Medical records were

gathered while preserving patient privacy. All studies were approved by the Heart and Lung Center of Helsinki University Hospital (31,22.03.2013), the National Institute of Health and Welfare (THL/989/5.05.00/2013), SF (TK-53-862-13), and by the Ethical Committee of Helsinki and Uusimaa Hospital District (HUS)

(418/13/03/02/15).

4.4 STATISTICAL ANALYSES

For all studies, data were collected and analysed using IBM SPSS Statistics versions 24 and 25 for Mac (SPSS Inc, Cary, NC< USA). Figures and tables were formed using IBM SPSS Statistics, Microsoft Excel (Microsoft, Redmond, WA, USA), and Microsoft Word (Microsoft, Redmond, WA, USA). In all studies, variables were compared with each other using Fisher’s exact test and Pearson’s chi-square test. Survival

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statistics were calculated by cox regression proportional hazard analysis. A p-value

< 0.05 was considered significant. In Study II, the correlation was calculated by Pearson’s Correlation coefficient. All statistical analyses were reviewed by a biostatistician working at The University of Eastern Finland. In Study III, all images were viewed using Agfa IMPAX (Agfa-gevaert, Mortsel, Belgium). The radiological PCI score was assessed as described earlier (Jacquet, Sugarbaker, 1996, Jacquet, Sugarbaker, 1996).

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5 RESULTS

5.1 EPIDEMIOLOGY (STUDY I)

Malignant peritoneal mesothelioma (MPeM) was diagnosed in 90 patients (56 male, 34 female) during the years 2000-2012 in Finland. The median annual incidence was four new cases per year (range 1–17) and, with a population of 5.5 million in Finland, (Worldometer - Finland Population, 2020) corresponded to 0.74 cases per million per year. The mean annual incidence was 6.9 cases per year (male 4.31, female 2.62). The patient median age at diagnosis was 67.5 years (male 66 years, range 37–92, female 72.5 years, range 24–88). Figure 7 shows new MPeM cases annually during the years 2000–2012 in Finland. Figure 8 shows MPeM patient age at diagnosis. Table 3 shows basic characteristic information about the patients.

In 60/90 (66.7%) of patients, MPeM was diagnosed via histological specimen during laparotomy, laparoscopy, or ultrasound-guided thick needle biopsy. As many as 23/90 (25.6%) of patients were not diagnosed until the autopsy and 6/90 (6.7%) of cases were diagnosed after metastasis. One patient (1.1%) was reported to be diagnosed clinically, with a histological analysis made to confirm the diagnosis.

Patients were treated with chemotherapy (37/90, 41.1%), surgically (14/90, 15.6%), or with radiation therapy (14/90, 15.6%).

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Figure 7. New MPeM cases in Finland during the years 2000-2012 among men, women and in total.

Figure 8. MPeM patient age at diagnosis. Range and median presented.

0 5 10 15 20

2 0 0 0 2 0 0 1 2 0 0 2 2 0 0 3 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2

Male Female Total

Malignant Peritoneal Mesothelioma in Finland : Epidemiology, treatment, prognosis and diagnostics

SILJA SALO

Malignant Peritoneal Mesothelioma in

Finland

Dissertations in Health Sciences

MALIGNANT PERITONEAL MESOTHELIOMA IN FINLAND

Silja Salo

MALIGNANT PERITONEAL MESOTHELIOMA IN FINLAND

ABSTRACT

TIIVISTELMÄ

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

2.1 PERITONEUM

2.2 PERITONEAL MESOTHELIOMA

3 AIMS OF THE STUDY

4 SUBJECTS AND METHODS

4.1 STUDY DESIGNS

4.2 DATA

4.3 ETHICS

4.4 STATISTICAL ANALYSES

5 RESULTS

5.1 EPIDEMIOLOGY (STUDY I)