consensus report

Wien Klin Wochenschr (2016) 128:611–617DOI 10.1007/s00508-016-1080-z

Management ofmalignant pleuralmesothelioma – part 1:epidemiology, diagnosis, and staging

Consensus of the AustrianMesothelioma Interest Group (AMIG)

Christian Geltner · Peter Errhalt · Bernhard Baumgartner · Gerhard Ambrosch · Barbara Machan ·Josef Eckmayr · Thomas Klikovits · Mir Alireza Hoda · Helmut Popper · Walter Klepetko · Austrian MesotheliomaInterest Group (AMIG)

Received: 5 February 2016 / Accepted: 8 June 2016 / Published online: 12 September 2016© The Author(s) 2016. This article is available at SpringerLink with Open Access.

Summary Malignant pleural mesothelioma is a raremalignant disease that in the majority of cases is as-sociated with asbestos exposure. The incidence in Eu-rope is about 20 per million inhabitants and it is in-creasing worldwide. Initial symptoms are shortness ofbreath, pleural effusion, cough, and chest pain. Thetypical growth pattern is along the pleural surface;however, infiltration of the lung and/or mediastinaland chest wall structures can occur in a more ad-vanced stage. Ultimately, distant metastases outsidethe chest can result. Several histological subtypes ofpleural mesothelioma exist, which must be differenti-ated from either benign diseases or metastases in thepleural space by other tumor entities. This differen-tial diagnosis can be very difficult and a large panel of

All authors contribute on behalf of the AustrianMesothelioma Interest Group (AMIG).

Prim. Dr. C. Geltner, MSc, MBA (�)Department of Pulmonology, Klinikum Klagenfurt,Feschnigstraße 11, Klagenfurt, Austriachristian@geltner.at

P. ErrhaltDepartment of Pulmonology, University Clinic Krems,Krems, Austria

B. BaumgartnerDepartment of Pulmonology, LandeskrankenhausVöklabruck, Vöklabruck, Austria

G. AmbroschDepartment of Pulmonology, Landeskrankenhaus GrazSüdwest, Graz, Austria

B. MachanRehabilitation Center Tobelbad, AllgemeineUnfallversicherungsanstalt, Tobelbad, Austria

immunohistochemical markers is required to estab-lish the exact diagnosis. The standard procedure forconfirming the disease and obtaining sufficient tis-sue for the diagnosis is videothoracoscopy. Full thick-ness biopsies are required, while transthoracic needlepuncture of pleural fluid or tissue is considered to beinsufficient for a cytological diagnosis. Complete anddetailed staging is mandatory for categorization of thedisease as well as for therapeutic decision making.

Keywords Malignant pleural mesothelioma · Epi-demiology · Staging · Pathology · Diagnosis

J. EckmayrDepartment of Pulmonology, Landeskrankenhaus Wels,Wels, Austria

Prim. Dr. C. Geltner, MSc, MBA · T. Klikovits · M. A. Hoda ·W. KlepetkoDivision of Thoracic Surgery, Department of Surgery,Comprehensive Cancer Center, Medical University Vienna,Währinger Gürtel 18–20, 1090 Vienna, Austria

H. PopperDepartment of Pathology, Medical University Graz, Graz,Austria

Austrian Mesothelioma Interest Group (AMIG)Division of Thoracic Surgery, Department of Surgery,Comprehensive Cancer Center, Medical University Vienna,Waehringer Guertel 18–20, 1090 Vienna, Austria

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Epidemiology

Asbestos exposure is the main risk factor for the devel-opment of malignant pleural mesothelioma (MPM)[1]. Asbestos comprises silicate minerals with verythin fibers: chrysotile, crocidolite as serpentines,amosite, anthophyllite, tremolite, and actinolite fromthe amphibole group [2]. Chrysotile is biologicallyactive and detectable in the lungs for a shorter time.Chrysotile, amosite, and crocidolite were mined andused in ship and railway construction as well as infire protection engineering. The first evidence oftheir high carcinogenic potential was found in the UKand South Africa as early as the 1960s [3]. Amositeand crocidolite seem to have a higher carcinogenicitythan the other types of asbestos [2]. Asbestos expo-sure is typically labor-dependent and is recognizedas an occupational disease. More recently, a shifthas been observed from asbestos-removal workersto professionals involved in post-construction work,e. g., electricians, plumbers, or heat protection tech-nicians. This is paralleled by a profession-dependentgender distribution, as more than 80% of affectedindividuals are men [4].

“Environmental” occurrence of mesothelioma hasbeen found in people growing up in the vicinity ofnatural asbestos resources (Turkey, Corsica, Cyprus)or in areas where asbestos was used for the whiteningof house walls. The load in rooms built with asbestos-containing materials was initially seen as hazardous.The actual resulting asbestos dose is, however, ex-tremely low and carcinogenic levels are not detectable[5].

Fig. 1 IncidenceofMPM incomparison toAustria [25]

3.40

3.20

2.85

2.50

2.08

2.00

1.84

1.76

1.50

1.40

1.40

1.40

1.23

1.11

1.07

1.00

0.90

0.82

0.60

00..00 00..55 11..00 11..55 22..00 22..55 33..00 33..55 44..00

UK

Australia

Netherlands

New Zealand

Malta

Belgium

Croa�a

Denmark

Finland

Cyprus

Germany

Norway

Israel

Sweden

South Africa

Austria

Iceland

Ireland

Poland

Furthermore, there is an increasing incidence ofnonoccupational asbestos disease among housewivesand family members of asbestos workers as well asa high environmental impact in the vicinity of miningand processing facilities [6, 7].

There is a clear correlation between the amountof asbestos exposure and the incidence of MPM. Themean latency period between exposure to asbestosand the onset of symptoms is up to 40 years, and 99%of cases show a latency of more than 15 years [8].

The occurrence of MPM is independent of otherasbestos-associated diseases such as classic asbesto-sis of the lung (interstitial lung disease with fibrosis)and benign pleural plaques. Although pleural plaquesare also associated with asbestos exposure, studiesfrom Australia could not find any connection betweenplaques and an increased incidence of MPM [9].

The incidence of MPM varies between 7 per millioninhabitants in Japan and 40 per million in Australia.In Europe, the average incidence is 20 per million in-habitants. The frequency is highly dependent on theamount of asbestos removal, asbestos import, and in-dustrialization. In Europe, peak incidence is to be ex-pected between 2015 and 2020 due to the long latencyperiod [10].

By contrast, the incidence of mesothelioma with-out asbestos contact is extremely low (<1: 1 million).Other potential cofactors for the development ofmesothelioma besides asbestos are synthetic materi-als (ceramics, nanoparticles), ionizing radiation, andSV-40 virus infections [11].

The impact of cigarette smoke as well as numerousother fibrous materials such as glass fibers and min-eral glass wool is, however, excluded. Genetic factors

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may play a role, since both familial clustering and en-demic accumulation in populations with high naturalexposure are known in Turkey [5, 12].

In Austria, there have been 276 cases of MPM ap-proved by the AUVA (Allgemeine Unfallversicherungs-anstalt – General accident insurance company) as be-ing caused occupationally within the last 5 years. Ofthese, 53 were approved in 2014 only. In contrastto this, ten asbestos-related MPM cases were docu-mented in 1995 and 41 in 2005. However, there isstill uncertainty about the number of MPM cases notbeing reported to the AUVA. A comparison of the in-cidence of MPM worldwide and in Austria is depictedin Fig. 1.

Screening

In the current European Society of Thoracic Surgery(ESTS)/European Respiratory Society (ERS) guidelines

Fig. 2 Computer tomog-raphyof patientwithmalig-nantpleuralmesotheliomashowingcircular involve-mentofthevosceraandpari-etal pleura, pericardiumandmediastinum. Pulmonarywindow (left) andmediasti-nalwindow (right)

Fig. 3 Video-assisted tho-racoscopic viewofMPMmainlyon theparietal pleura(a,b), forcepsbiopsy (c), andtalcpleurodesis (d)

no general screening methods are recommended[13]. This is based on the low sensitivity of evenadvanced imaging techniques such as low-dose com-puted tomography (CT) in screening of asbestos work-ers.

Circulating biomarkers, such as osteopontin, meso-thelin-related peptides, and soluble mesothelin-re-lated peptide (SMRP) [14], and fibulin-3 [15] havealso been evaluated in MPM extensively. However,none of them are considered to be a reliable screen-ing tool, since false-positive results are too frequent[16].

Diagnosis

Clinical symptoms

Specific symptoms of MPM are dyspnea, cough, andchest pain on initial examination. Shortness of breath

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Chest CT

VATS

MPM confirmed

Unfit for surgery

Candidate for surgery

Oncological/ Pallia�ve

treatment

Medias�nal LNs nega�ve

PET/CT

Staging of medias�nal LN

Induc�on treatment

Restaging PET/CT

Response: Surgery

No Response

Medias�nal LNs posi�ve

Fig. 4 Proposedstaging algorithm forMPMpatients inAustria

Table 1 Histological specificationofmalignantpleuralmesothelioma [23]

Epithelioid Sarcomatoid Biphasic mixed

– Tubulopapillary– Acinar– Glandular– Adenomatoid– Solid epithelioid patterns– Small cell– Oat cell

Differential diagnosis: metastatic carcinomas andother epithelioid tumors

Mimic malignant mesenchymal tumors: leiomyosar-coma synovial sarcomaDesmoplastic mesothelioma bland tumor cellsDifferential diagnosis: sarcomatoid carcinoma andother sarcomas

Combination of all epithelioid and sarcomatoidfeaturesDifferential diagnosis: Synovial sarcoma, othermixed or biphasic tumors

Fig. 5 Examplesofmalignantpleuralmesothelioma (MPM): epithelioidMPMa), biphasicMPM (b), andsarcomatoidMPM(c).(KindlyprovidedbyDr. LukaBrcic,DepartmentofPathology,MedicalUniversityGraz)

is often initially caused by a pleural effusion and laterby extensive restriction due to pleural and pulmonarytumor masses in the thoracic cavity. Patients describechest pain as diffuse, sometimes radiating into theshoulders, arms, or abdomen. Tumor ingrowth intothe neural structures of the brachial plexus and theintercostal or paravertebral structures can also causeneuropathic pain. Weight loss is a symptom of moreadvanced disease.

Typically, MPM occurs initially unilaterally. The tu-mor can, however, spread to the other pleural cavity orinto the peritoneum in the further course of disease.Compared with lung cancer, distant metastases in theextrathoracic lymph nodes or in other parenchymalorgans are usually rare, although they do occur in veryadvanced stages [17].

Diagnostic procedures

The typical finding on chest X-rays of patients withMPM is pleural effusion or pleural thickening, which,however, is not specific. CT scan (Fig. 2) is more help-ful, but it still does not allow a definitive diagnosis tobe made since its sensitivity reaches only 40%, and inmost cases it does not distinguish between benign andmalignant processes. The same holds true for positronemission tomography (PET)-CT where no clear stan-dardized uptake value (SUV) level is considered sug-gestive for MPM and false-positive results can occur inother processes such as tuberculosis, parapneumoniceffusions, and uremia [18].

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Fig. 6 FDGPET-CT im-ages: malignantpleuralmesotheliomaof the rightpleural cavity (variousslidesofPET/CT fusion imaging).Varoius slidesofCT/PETfusion imaging showingpleural tumor apical right(top left), involving the vis-ceral andparietal pleura inthepleura costodiaphrag-matic area (bottom leftandright) and thepericardium(top right)

Table 2 Clinical approachandpretherapeutic evaluationaccording toERS/ESTS recommendations [13]

Investigation at presentation (all patients)

Demographics Gender, age, asbestos exposure

Clinical history Performance status symptoms

Physical examination Body weight

Radiology Chest radiograph

Blood tests –

Investigations for diagnosis and staging

Biopsy of tumor, histological confir-mation

– Thoracoscopy– Thoracocentesis– Needle aspiration

Radiology – CT scan– Brain MRI or CT– Bone scan as required

Pulmonary function tests –

CT computer tomography,MRI magnetic resonance imaging

Puncture of the pleural effusion that is usuallypresent and cytological examination of the fluid isalso not conclusive, especially since the differentialdiagnosis with pleural metastases of other tumorssuch as bronchial or breast cancer (e. g., adenocar-cinomas) cannot be made in most cases. Also themacroscopic aspect of MPM is so variable that simplethoracoscopy does not confirm the diagnosis.

For these reasons, the precise diagnosis of MPMrequires a histopathological confirmation and thora-coscopy remains the standard procedure for obtain-ing tissue and performing macroscopic staging of thepleural tumor spread at the same time (Fig. 3). Tho-racoscopy can be performed with the patient underlocal anesthesia or as video thoracoscopy via a sur-gical approach. This allows one to combine the di-agnostic procedure with the initial therapeutic step oftalc pleurodesis (Fig. 3). Only in exceptional situations

should a CT- or ultrasound-guided fine needle biopsybe performed, which, however, has a a clearly lowersensitivity.

The typical diagnostic algorithm applied in mostcenters around the world is displayed in Fig. 4.

Histopathology

MPM derives from the pleural stem cell, which ex-hibits epithelioid and sarcomatoid growing patternsat the same time. Depending on which componentis predominant, three histological types of MPM canbe distinguished: epithelioid (50–70%), sarcomatoid(7–20%), and a mixed or biphasic form (20–35%; Ta-ble 1 and Fig. 5).

The pathological diagnosis and differential diagno-sis of MPM can be very challenging. In a French study,the initial diagnosis of MPM was revised as false pos-itive in 13% of cases [19]. This can be explained inpart by the fact that MPM can present in very het-erogeneous forms on the one hand and must be dis-tinguished from benign processes and other tumors,especially metastases of various tumor entities, on theother hand. Such a differential diagnosis can be par-ticularly difficult sincemesothelioma-like features canalso be found in some lymphomas, thymomas, andcarcinomas, etc.

Full-thickness biopsies are required to separate in-vasive from noninvasive growth patterns and a panelof numerous immunohistochemical markers is re-quired for the differentiation of epithelioid MPMfrom adenocarcinoma [13].

Staging

Both CT and PET-CT (Fig. 6), however, are useful forthe further staging.

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Table 3 TNMstagingofmalignantpleuralmesothelioma [24]

T0 No evidence of primary tumor

T1 Tumor limited to the ipsilateral parietal pleura with or without mediastinal pleura and with or without diaphragmatic pleural involvement

T1a No involvement of the visceral pleura

T1b Tumor also involving the visceral pleura

T2 Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:– Involvement of the diaphragmatic muscle– Extension of tumor from the visceral pleura into the underlying pulmonary parenchyma

T3 Locally advanced but potentially resectable tumor; tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, andvisceral pleura) with at least one of the following:– Involvement of the endothoracic fascia– Extension into the mediastinal fat– Solitary, completely resectable focus of tumor extending into the soft tissue of the chest wall– Nontransmural involvement of the pericardium

T4 Locally advanced, technically unresectable tumor; tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and vis-ceral pleura) with at least one of the following:– Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction– Direct diaphragmatic extension of the tumor to the peritoneum– Direct extension of the tumor to the contralateral pleura– Direct extension of the tumor to a mediastinal organ– Direct extension of the tumor into the spine– Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium

Regional lymph nodes (N)

NX Regional lymph node(s) cannot be assessed

N0 No regional lymph node metastases

N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph node

N2 Metastases in the subcarinal or in the ipsilateral mediastinal lymph node, including the ipsilateral internal mammary and peridiaphragmatic nodes

N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral, or contralateral supraclavicular lymph nodes

Distant metastases (M)

M0 No distant metastasis

M1 Distant metastasis

Table 4 UICC–IMIGstaging [24]

UICC staging (7th edition)

Stage IA T1a N0 M0

Stage IB T1b N0 M0

Stage II T2 N0 M0

Stage III T1, T2T1, T2T3

N1N2N0, N1, N2

M0M0M0

Stage IV T4T1–4T1–4

N0–3N3N0–3

M0M0M1

For all patients, the following assessments for stag-ing and further treatment are required: After initialimaging with CT scan and confirmation of diseasevia video-assisted thoracic surgery (VATS), a poten-tial candidate for surgical treatment should undergoPET-CT scanning to rule out distant metastasis and in-volvement of the abdomen and the mediastinal lymphnodes. To rule out the latter, histological confirma-tion has to be made either by endobronchial/endo-esophageal ultrasonography and transbronchial nee-dle aspiration (EBUS/EUS-TBNA) or mediastinoscopyor VATS according to the lymph node station involve-ment and the involved side.

If nodes are negative, patients can proceed to in-duction treatment and should be re-staged with CTor PET-CT. In some cases of unclear involvement of

adjacent structures (e. g., chest wall), magnetic reso-nance imaging (MRI) can be added in order to judgethe resectability.

The investigations shown in Table 2 were recom-mended by many consensus groups.

The most recent available and widely used TNM-based stating system was developed by the Interna-tional Mesothelioma Interest Group (IMIG) and wasalso approved by the Union for International CancerControl (UICC; Tables 3 and 4).

A possible staging algorithm for MPM patients isdisplayed in Fig. 4.

Prognosis

The prognosis for MPM depends on the patient’sage, gender, tumor stage, and geographic region [20].Other factors such as weight loss and performancestatus are important for the prognosis as in othertumor entities as well as quality of life and symp-tom scores. Epithelioid MPM has a better overallprognosis than non-epithelioid histological subtypes.Low hemoglobin levels, high platelet levels, and highserum lactat dehydrogenase (LDH) are prognosticallyunfavorable characteristics [21]. Numerous new lab-oratory markers are in evaluation, but no validateddata on their prognostic value are available yet [22].

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Funding The publication has not been funded by any phar-maceutical company.

Open access funding provided by Medical University of Vi-enna.

Conflict of interest C. Geltner, P. Errhalt, B. Baumgartner,G. Ambrosch, B. Machan, J. Eckmayr, T. Klikovits, M.A. Hoda,H. Popper, and W. Klepetko declare that they have no com-peting interests.

Open Access This article is distributed under the terms ofthe Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which per-mits unrestricted use, distribution, and reproduction in anymedium, provided you give appropriate credit to the origi-nal author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made.

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