Mesothelioma: diagnostic challenges from a pathological perspective Naseema Vorajee August 2016 Naseema.vorajee@nhls.ac.za
Pleural diseases (whether neoplastic, reactive or infective) may have similar clinical, radiographic and gross features Common features include pleuritic chest pain, a pleuralbased mass or pleural thickening and pleural effusion Treatment and prognoses of these diverse pleural diseases vary greatly and therefore the correct diagnosis is critical for the patient.
Main challenges 1. Mesothelioma vs reactive pleural reactions***** 2. Mesothelioma vs other primary and metastatic neoplasms 3. Immunohistochemistry: Lack of specific and sensitive IHC markers and specific challenges with sarcomatoid mesothelioma Diagnosing a malignant mesothelioma can be most challenging for the pathologist
Challenge Mesothelioma vs reactive pleural reactions*****
INVASION Proliferations on the surface: may be benign or malignant unequivocal invasion into lung or chest wall (fat and skeletal muscle ) = most diagnostic feature of malignant mesothelioma vs reactive fake fat phenomenon (Churg 2011 )
LINEAR ARRAYS Epithelioid mesothelioma vs 1. Mesothelial hyperplasia 2. Entrapped mesothelial cells and mesothelial inclusions
CYTOLOGICAL ATYPIA Sarcomatoid mesothlioma vs Chronic fibrous pleuritis Important features of a reactive pleuritis: 1. Zonation = decreasing cellularity with increasing amounts of collagen as you progress from surface to the base of the pleura 2. Capillaries arranged perpendicular to the surface 3. Active inflammation
Confounding factor: Open versus closed pleural biopsy and small specimen size (Attanoos and Gibbs 2008) Diagnosis of malignant mesothelioma was attained in 75% of biopsies measuring > 10 mm in size but only 8% when the biopsy < 10 mm 2010 guidelines from the ERS & ESTS: Thoracoscopy is the preferred technique extensive inspection of the pleura multiple and large biopsies that include subpleural tissue to assess invasion
Desmoplastic mesothelioma vs pleural plaque vs diffuse pleural fibrosis
This is a biopsy from a lesion in the head of the femur from a metastatic desmoplastic mn mesothelioma Patient had a an initial diagnosis a few months earlier of a fibrous pleuritis
Challenge Mesothelioma vs reactive pleural reactions***** Mesothelioma vs other primary and metastatic neoplasms Confounder Marked variation in histological patterns of mesothelioma lack of adequate clinical and radiologic information pleural based mass, diffuse pleural thickening with involvement of interlobar fissures Pseudomesotheliomatous carcinoma (Attanoos and Gibbs 2003)
Diffuse malignant mesothelioma 1. Epithelioid (50-60%) 2. Sarcomatoid (incl Desmoplastic) (25-35%) 3. Biphasic (mixed) (10-20%)
Epithelioid mesothelioma ACINAR type : Lung and other Adenoca Unusual variants: Deciduoid type CLEAR CELL type: Renal cell ca, Clear cell lung/ ovarian ca, Squamous ca SMALL CELL type: SCLC, Lobular breast ca, SRCT, Lymphoma, Melanoma Adenomatoid type
Sarcomatoid Mesothelioma Benign and intermediate mn potential spindle cell tumours of the Pleura: Schwannomas, Calcifying fibrous tumours Solitary fibrous tumours (SFT) Inflammatory myofibroblasatic tumours Malignant Primary and metastatic pleural tumours: Mn SFT Mn peripheral nerve sheet tumour Leiomyosarcoma Angiosarcoma
BIPHASIC MESOTHELIOMA Tumour with both epithelioid and sarcomatoid components; each component occupying approximately 10% of an adequate biopsy sample. Main DDX: Sarcomatoid ca Synovial sarcoma
Challenge 1. Mesothelioma vs reactive pleural reactions***** 2. Mesothelioma vs other primary and metastatic neoplasms 3. Immunohistochemistry: Lack of specific and sensitive IHC markers and specific challenges with sarcomatoid mesothelioma
IHC to differentiate mesothelioma from metastatic carcinoma and sarcoma NO IHC marker that is 100% specific / sensitive for mesothelioma Mesothelioma Calretinin WT1 CK5/6 Cam 5.2 Thrombo modulin mesothelin D240 Adenocarcinoma CEA Ber EP4 B72.3 MOC31 CD15 TTF1 Thrombomodulin (D240) and calretinin: highly sensitive but low specificity for DMM (Carbone et al 2016) Calretinin + in 6% adenoca and 23% Squamous ca D240 + in 77% Squamous ca Calretinin also + in sex cord stromal txs, synovial sarcoma, adrenal gland txs and D240 + in urothelial txs WT1: most specific marker for epithelioid mesothelioma but lacks sensitivity
Role of Cytology in diagnosing mesothelioma Published sensitivity of cytologic diagnosis of mesothelioma ranges between 32% and 76% high false-negative rate Sarcomatoid mesos do not shed Most useful cytologic feature of epithelioid mesothelioma: = numerous, large (>50 cells) balls of cells with berrylike external contours
IHC to differentiate benign from malignant mesothelial cells
Electron microscopy
P16 FISH
More recently published Usefulness of adding BRCA1 associated protein 1 (BAP1) IHC stain to the panel Differentiate reactive mesothelial cells from malignant mesothelioma and mesothelioma from Non Small Cell Lung Carcinoma BRCA1 associated protein 1 (BAP1) genetic mutations recently discovered in familial and sporadic cases of Mn mesothelioma (Carbone 2003, 2016) Loss of nuclear signalling is regarded as positive Caveat: only 63% of malignant mesothelioma show the BAP1 mutation
Features not useful in making the diagnosis: 1. History of asbestos exposure 2. Simian virus 40
In a NUTSHELL Malignant mesothelioma is a rare tumor that has a grave prognosis and invariably has medicolegal implications Unequivocal invasion into lung or chest wall is the single most reliable diagnostic feature of mesothelioma Caution exercised on being definitive on a small, poorly orientated biopsy and a biopsy with active inflammation Cytology has several limitations Sarcomatoid mesotheliomas have their own set of diagnostic dilemmas There is no Golden IHC stain; a PANEL of IHC stains is always required
References Aliya N.Husain, Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2012 Update of the Consensus Statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med Vol 137, May 2013 Andrew Churg et al, The Fake Fat Phenomenon in Organizing Pleuritis: A Source of Confusion With Desmoplastic Malignant Mesotheliomas. Am J Surg Pathol 2011;35:1823 1829 Michel Carbone et al, Positive nuclear BAP1 immunostaining helps differentiate nonsmall cell lung carcinomas from malignant mesothelioma. www.impactjournals.com/oncotarget/ Oncotarget, Advance Publicatns 2016 R L Attanoos & A R Gibbs, Pseudomesotheliomatous carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff. Histopathology 2003, 43, 444 452 R L Attanoos & A R Gibbs, The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma. Histopathology 2008, 53, 340 344 Joseph R Testa et al, Germline BAP1 mutations predispose to malignant mesothelioma. Nature genetics; published online 28 August 2011