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TWEDNESDAY SURGICAL PATHOLOGY

SALIVARY TYPE TUMORS OF THE LUNG

DR. CESAR A. MORAN

2018 NAPA VALLEY PATHOLOGY CONFERENCE WWW.PATHCME.COM || 888.976.9248 Salivary-Gland Type Tumors of the Lung

Cesar A. Moran, MD Professor of Pathology Salivary-Gland type Tumors

• This family of tumors is rare as primary of the lung. Because of the similar histological features as those occurring in the salivary , it is important to obtain a careful clinical history in order to rule out a primary tumor in that location.

Mucoepidermoid

• Clinical features: – Occurs at any age – Some studies suggest higher incidence in men – Usually symptoms of obstruction due to the central location of the tumor – No predilection for any particular lobe or lung segment Gross Features Histological Features

• Low and High grade tumor • Solid epidermoid cellular proliferation admixed with mucous producing cells. – Clear cell - intermediate cells – No keratinization

High Grade

Mucoepidermoid Carcinoma

• The immunohistochemical profile of this tumor is similar to other epithelial tumor in the lung, mainly . Therefore, the diagnosis is more often on morphological basis. Mucoepidermoid Carcinoma

Histochemistry Immunohistochemistry • Mucicarmine + in the • Keratin CAM 5.2 mucous producing cells • Keratin 5/6 • PAS + • P40 • DPAS + • p63 MEC/MAML2 1. Positive more often in low grade tumors.

2. May be more often positive in the tumors of the salivary gland than those in the lung or mediastinum.

3. It may vary from 30 to 90% of cases tested.

4. It is not require to make the diagnosis of MEC.

5. It is not a test needed for treatment options. Mucoepidermoid Carcinoma

• Differential Diagnosis – Adenosquamous carcinoma – Squamous cell carcinoma (in a small biopsy) Adenosquamous Carcinoma Mucoepidermoid Carcinoma

• Conclusions: – The prognosis of these tumors depends on the histological subtype – Low grade tumors appear to be controlled by surgery alone – High grade tumor have a more aggressive behavior. has been used Adenoid Cystic Carcinoma

• Clinical features – Mainly in adult individuals – No gender predilection – In our study, we found a slight predilection for men. – Since it is often a central lesion, patients present with cough, hemoptysis, and shortness of breath. Gross Features Histological Features

• Essentially there are three different growth patterns: – Cylindromatous – Tubular – Solid

Adenoid Cystic Carcinoma

• Immunohistochemical Features: – Myoepithelial proliferation – Keratin, actin, vimentin, and S-100 protein can show positive staining. – More often Myb, CD117, DOG1 have been reported as important stain in this tumor. Adenoid Cystic Carcinoma

• Treatment and Prognosis – Surgical resection in the majority of patients. – Slow-growth tumor – Recurrences are common – Staging at the time of diagnosis is highly important. – Survival at 10 years is less than 50%. Adenoid Cystic Carcinoma

• Differential Diagnosis: – Mixed tumor (in small biopsies) – Carcinoma with amyloid-like stroma – Pleomoprhic

• Clinical Features: – Adult individuals with slight predilection for women – Ages 35-74 – Central or peripheral tumor – Symptoms depend on location Pleomorphic Adenoma • Malignant (ex-pleomorphic adenoma) – Similar features as the benign but with clearly malignant areas – Necrosis, vascular invasion • Benign – Chondromyxoid areas – Glandular component – Solid Myoepithelial proliferation – Plasmacytoid appearance

Pleomorphic Adenoma

• Immunohistochemical Features: – CAM 5.2 + – Broad spectrum keratin + – Smooth muscle actin (HHF-35) + – S-100 protein +/- – GFAP +/- Pleomorphic Adenoma

• Differential Diagnosis: – Mucoepidermoid Carcinoma – Epithelial Myoepithelial Carcinoma – Carcinoma – Blastoma – Carcinosarcoma Pleomorphic Adenoma

• Outcome: – It is an uncommon tumor and its behavior is similar to that observed when these tumors occur in the salivary gland. The majority of these tumors will behave in an indolent fashion. – Those with cellular atypia, mitosis, and infiltrative pattern will follow a more aggressive behavior. Acinic Cell Carcinoma Acinic Cell Carcinoma

• Clinical Features: – The tumor occur at any age – No gender predilection – Central or peripheral tumors – Symptoms will depend on the location Acinic Cell Carcinoma

• Histology – Oncocytic – Cystic (papillocystic) – Acinar • Clear granular cytoplasm • Cellular atypia is rare • Mitosis are infrequent

Electron Microscopy Acinic Cell Carcinoma

• Immunohistochemistry: – The conventional epithelial markers will likely show positive staining. – Amylase, Chymotrypsin may be positive. – SOX10 and DOG1 may also be positive. Acinic Cell Carcinoma

• Differential Diagnosis – Oncocytic – Clear cell (Sugar) tumor – Granular cell tumor Acinic Cell Carcinoma

• Conclusions – It is a rare tumor that behaves like a low grade malignant tumor. Surgical resection appears to be the treatment of choice. Epithelial-Myoepithelial Carcinoma Epithelial-Myoepithelial Ca

• Only a few cases are reported in the literature. Therefore, it is difficult to define its biologic behavior while primary in the lung. It is possible that complete surgical resection be the treatment of choice. E-M Carcinoma Epithelial-Myoepithelial Ca

• Histology – Glandular and tubular proliferation – Distinctive clear cell morphology – Myoepithelial immunophenotype

IHC

A) lung bx, B) glandular pattern, C-E) SMA +; F) S-100 +; G) GFAP focally +, H) CD117 scattered cells + E-M Carcinoma

• Prognosis and Treatment – Unusual cases may involved lymph nodes – Although difficult to determine for these tumors in the lung, their behavior may that of a low grade tumor. – Surgical resection is the treatment of choice. Hyalinizing Clear Cell Carcinoma Hyalinizing Clear Cell

• Unusual tumor as primary lung . • Only a few cases have been reported in the literature. • It is possible that the clinical behavior is similar to those tumors in the salivary glands. • Surgical Resection is the treatment of choice.

Hyalinizing Clear Cell

• IHC • Molecular – Keratin 5/6 – MALM2 negative – P40 – Keratin CAM 5.2 – P63 Hyalinizing Clear Cell

• Differential Diagnosis: – Mucoepidermoid carcinoma – Squamous cell carcinoma

• There are only a few cases reported in the literature. However, before rendering the diagnosis of pulmonary oncocytoma, it is important to rule out other more common primary lung tumors such as Oncocytic Carcinoid tumor. Immunohistochemical and/or E.M. can be helpful Conclusions

• Salivary gland type tumors in the lung represent a small percentage of primary lung tumors. It is highly important to separate them from other more conventional of the lung. • Also important is to obtain a careful clinical history in order to properly rule out the possibility of metastatic disease. WEDNESDAY SURGICAL PATHOLOGY

AN UPDATE ON PANCREATIC NEOPLASMS

DR. ARIEF A. SURIAWINATA

2018 NAPA VALLEY PATHOLOGY CONFERENCE WWW.PATHCME.COM || 888.976.9248 An Update on Pancreas Neoplasms

Arief Suriawinata, M.D.

Professor of Pathology and Laboratory Medicine Geisel School of Medicine at Dartmouth

Department of Pathology and Laboratory Medicine Dartmouth-Hitchcock Medical Center Pancreas - normal

Pancreas - tumors Lines of Differentiation in Pancreatic Neoplasms

Differentiation Special Stain IHC EM Ductal Mucin stain Glycoprotein markers Mucigen (CEA, B72.3, Ca19.9, CA125) granules MUC1, MUC3, MUC4, MUC5AC, CK7 60% loss of SMAD4 Acinar PAS-D, butyrate Enzyme markers Zymogen esterase (trypsin, chymotrypsin, lipase, others) granules, irregular fibrillary granules Neuroendocrine Grimelius stain Neuroendocrine markers Dense core (chromogranin, synaptophysin, CD56) granules Peptide markers (insulin, glucagon, etc.) Pancreas Ductal Adenocarcinoma (PDAC)

Synonyms Tubular adenocarcinoma, infiltrating duct carcinoma

Epidemiology 60-80 y.o. 4th leading death in US (increasing to 2nd by 2030) 50% higher in men than women 5 year survival rate – 7% Etiology Tobacco smoking (3X), chronic pancreatitis (10X), obesity, alcohol, diabetes mellitus Signs & Jaundice, pruritus, back pain, weight loss Symptoms New onset diabetes mellitus in 70% of patients Late symptoms: liver metastasis, duodenal invasion (gastric outlet obstruction), peritoneal cavity involvement (ascites) Tests Serum tumor markers (CA19-9, CEA) CT (best method) – mass, “double duct sign”, vascular invasion assessment EUS – heterogenous mass, lymph node assessment, FNA biopsy Localization Head of pancreas (60-70%), body (5-15%), tail (10-15%) Recent Developments on PDAC

• EUS – FNA has become an established method in the initial diagnosis of pancreatic tumors • Cytopathology evaluation • Neoadjuvant chemoradiation has been widely administered • Resectable and nonresectable PDAC • 2 tier grading system on precursor lesions • PanIN, IPMN, MCN • AJCC Cancer Staging Manual, 8th edition PDAC Treatment

• Complete surgical resection remains the only potentially curative option • Median overall survival of 28 months after resection and adjuvant • Borderline resectable or locally advanced disease may have margin negative resection after neoadjuvant chemotherapy • Similar overall survival with resectable disease • Neoadjuvant chemoradiation • reduces micrometastases • increases likelihood of complete resection and survival Treatment and Median Survival

Gillen et al. PLoS 2010 • Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response PDAC Precursors

• Pancreatic intraepithelial neoplasia • Intraductal papillary mucinous neoplasm • Mucinous cystic neoplasm • 2 tier system for all precursor lesions – low grade & high grade • PanIN • IPMN • MCN • PanIN of any grade in pancreas with invasive carcinoma does not have prognostic implications • Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs • "Intraductal spread of invasive carcinoma" (aka, "colonization") is invasive carcinoma invading back into and extending along the ductal system, may morphologically mimic high-grade PanIN • High grade PanIN needs to reported, but no need to report low grade PanIN Molecular Alterations in Pancreatic Ductal Lesions

Mucinous Papillary Atypical CIS Invasive Metaplasia Hyperplasia Hyperplasia Carcinoma

PanIN 1A PanIN 1B PanIN 2 PanIN 3

High grade Low grade PanIN PanIN K-ras 35% 45% 65% 85% 90% p53 0% 0% <5% 20% 55% HER-2/neu 82% 86% 92% 100% 69% p16 24% 19% 55% 71% 95% SMAD4/DPC4 0% 0% 0% 31% 55%

Wilentz et al., Cancer Res 60: 2002 Basturk et al., Am J Surg Pathol 2015 Hereditary Pancreatic Carcinoma

 Heritable factors involved in 10%

 Familial pancreatic carcinoma  At least two first degree relatives with PDAC and not associated with other known hereditary syndromes

 PDAC-associated hereditary syndromes:  Peutz-Jeghers syndrome (STK11/LKB)  Hereditary pancreatitis [PRSS1 (cationic trypsinogen), SPINK1]  Familial atypical multiple mole melanoma syndrome [CDKN2A (p16- Leiden deletion)]

 Lynch syndrome (hMSH2; hMLH1)  Familial adenomatous polyposis  Hereditary breast-ovarian cancer syndrome (BRCA2)  Ataxia telangiectasia Pancreatic Carcinoma Screening

• High risk individuals • Familial pancreatic carcinoma • Hereditary pancreatitis • Peutz Jeghers syndrome • Chronic pancreatitis • Identification of precursor lesions and early resectable PDAC • Cancer of the Pancreas Screening-5 CAPS5)Study (CAPS5) https://clinicaltrials.gov/ct2/show/study/NCT0 2000089 • Pancreatic fluid mutations & circulating pancreatic epithelial cells Acinar Ductal Metaplasia & Atypical Flat Lesions

• Alternative pathway – KRAS mutation • Metaplasia – dysplasia – cancer sequence • Seen in individuals with familial

Basturk, et al. Am J Surg Pathol 2015

Intraductal Papillary Mucinous Neoplasms

. Definition: “Grossly and radiographically visible (>1cm) epithelial tumor arising from the main pancreatic duct or duct branches, causing dilatation and mucin production” . Often lack invasive carcinoma . 30% of surgically resected IPMNs harbor invasive carcinoma . 5 year survival is better than PDAC . IPMN alone 30-50% . IPMN + invasive ca = 70-90%

STK11/L Genetic Features K-ras p53 DPC4 p16 GNAS RNF43 KB11

Ductal adenocarcinoma >95% 50-70% 40-60% 95% 5% 5% 5%

IPMN 13-100% 0-50% 5% 0-20% 32% 50-79% 23-36% Intraductal Papillary Mucinous Neoplasm

Synonyms Mucinous duct ectasia, duct ectatic mucinous /carcinoma, mucin producing tumor, villous adenoma, papillary adenoma/carcinoma

Epidemiology 3% of pancreatic exocrine and 20% of cystic neoplasms 50-90 y.o., 8.7% in individuals >80 y.o, incidence is increasing (incidental, asymptomatic), male = female Etiology Cigarette smoking, Peutz-Jeghers syndrome, FAP, family history of pancreatic carcinoma, McCune-Albright syndrome Signs and Nonspecific abdominal pain, chronic pancreatitis, weight loss, new onset symptoms diabetes mellitus, jaundice Clinical findings CA19-9 and CEA elevated in cases with invasive carcinoma Endoscopy – mucin extrusion from ampulla of Vater Radiology – ectasia and cystic dilatation of pancreatic duct Localization Predominantly in head of pancreas; localized, multicentric or diffusely involving the entire pancreas ductal system, extending to ampulla or common bile duct IPMN Classification

Old, WHO 2000, AFIP Fascicle 4th New 2-tier system WHO 2010 terms series terms Baltimore Consensus 2015

Intraductal papillary mucinous IPMN with low-grade adenoma, IPMN with low dysplasia grade dysplasia IPMN low grade IPMN, borderline; IPMN with IPMN with intermediate- moderate dysplasia grade dysplasia

Intraductal papillary mucinous carcinoma (in situ); intraductal IPMN with high-grade IPMN high grade papillary mucinous carcinoma, dysplasia noninvasive IPMN, ….grade, with an associated invasive Intraductal papillary mucinous IPMN with an associated carcinoma carcinoma, invasive invasive carcinoma Invasive carcinoma with an associated IPMN H&E MUC1 MUC2 MUC5AC MUC6 CDX2

Gastric foveolar - - + - -

Intestinal type - + + + +

Pancreatobiliary + - + - -

Oncocytic focal+ focal+ + + - Tubulopapillary + - - + - IPMN – Carcinogenesis Pathway

GNAS

KRAS

Source: Katabi & Klimstra 2008 Tan, Basturk, Klimstra, 2015 IPMN - Main vs. Branch Ducts • 70% involve main duct, 30% confined to branch ducts • Branch duct type (Terris, et al) • Younger patients & low risk of progression • Main duct type: 20% CIS, 37% invasive carcinoma • Branch duct type: 15% CIS, 0% invasive carcinoma • 5 year risk of progression(Levy, et al) • MD 63% vs BD 15% Prognosis & Treatment

• Presence and size of invasive component - Mural nodules - Solid masses - Large tumor size - Dilated main pancreatic duct - wall thickening - Increase serum CA19-9 • Complete surgical resection is curative for IPMN • Partial pancreatectomy - Extent - Status of margin – frozen section difficulties - Risk of local recurrence – skip nature - Surveillance • 2 tier system for all precursor lesions • PanIN • IPMN • MCN • Clinical significance of dysplasia at resection margin of IPMN lacking invasive carcinoma remains to be determined • Increased risk of recurrence after prolonged follow up • Further resection recommended on high grade dysplasia at margin • “Incipient IPMN” are lesions 0.5-1.0cm with intestinal or oncocytic papillae or GNAS mutations (intestinal or gastric type) • “Simple mucinous cyst” are > 1 cm with gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma Intraductal Oncocytic Papillary Neoplasm

• Synonym: IPMN, oncocytic type • Form large cystic lesion with friable papillary growths in large pancreatic ducts • Distinctive feature: - oncocytic cytoplasm (mitochondria) - eccentric nucleoli - intraepithelial lumina, often containing mucin, producing cribriform architecture • Difference from conventional IPMNs: MUC6 +, HepPar1 +, lack of KRAS mutation Intraductal Tubulopapillary Neoplasm

• Synonym: Intraductal tubular neoplasm • Definition: Grossly visible intraductal lesion composed of tubule-forming epithelial neoplasm with high grade dysplasia and ductal differentiation without overt production of mucin • 3% of IPMN’s • Solid, nodular masses in dilated pancreatic ducts, no mucin • 40% ITPN’s harbor invasive carcinoma, usually localized Mucinous Cystic Neoplasm (MCN)

• Definition: Cyst forming epithelial neoplasm that commonly does not communicate with the pancreatic ductal system, lined by mucin-producing and with associated ovarian-type subepithelial stroma • Almost exclusively in women, 40-50 y.o. • Patients with MCNs with associated invasive carcinoma are 5-10 years older • >95% in body and tail of pancreas • Incidental finding, less likely to present with pancreatitis, jaundice or new onset diabetes mellitus Mucinous Cystic Neoplasm

• Noninvasive tumor: CK 7,8,18, 19, CA19-9, EMA, CEA, MUC5AC, MUC2 (goblet cells), KRAS mutation • Invasive tumor: MUC1, loss of SMAD4, alterations of p16 and p53 • Similar molecular alterations to PanIN Mucinous Cystic Neoplasm Grading

New 2-tier system Old terms WHO 2010 Baltimore Consensus 2015

MCN with low-grade dysplasia MCN low grade Mucinous cystic tumor, MCN with intermediate- borderline grade dysplasia Mucinous MCN with high-grade MCN high grade dysplasia MCN, …grade, with an Mucinous MCN with an associated associated invasive carcinoma cystadenocarcinoma, invasive carcinoma Invasive carcinoma associated invasive with MCN Pancreatic Neurondocrine Neoplasms

• Non-syndromic (non-functioning), but IHC + - alpha-cell/glucagon producing NET - beta-cell/insulin producing NET - G-cell/gastrin-producing NET

• Syndromic (functioning) – “..oma” - - - - - VIPoma Pancreatic Neuroendocrine Neoplasms Criteria for Malignancy

• Traditional Criteria • Metastases • Gross invasion • Vascular invasion • Correlation with clinical syndromes • Predictors of aggressive behavior • Mitotic rate • Ki-67 index • Invasion • Necrosis • Poorly Differentiated Neuroendocrine Carcinoma Pancreatic Neuroendocrine Neoplasm Grading

WHO 2010 WHO 2017

Well differentiated Well differentiated neuroendocrine tumor (PanNET)

Neuroendocrine tumor (PanNET) G1 Neuroendocrine tumor (PanNET) G1 (<2 mitoses/10hpf and/or =<2% Ki67 index) (<2 mitoses/10hpf and/or <3% Ki67 index)

Neuroendocrine tumor (PanNET) G2 Neuroendocrine tumor (PanNET) G2 (2-20 mitoses/10hpf and/or 3-20% Ki67 index) (2-20 mitoses/10hpf and/or 3-20% Ki67 index)

Neuroendocrine tumor (PanNET) G3 (>20 mitoses/10hpf or >20% Ki67 index)

Poorly differentiated neuroendocrine carcinoma Poorly differentiated neuroendocrine carcinoma (PanNEC) (PanNEC) Neuroendocrine carcinoma (PanNEC) G3 Neuroendocrine carcinoma (PanNEC) G3 (>20 mitoses/10hpf or >20% Ki67 index) (>20 mitoses/10hpf or >20% Ki67 index) Small cell type Large cell type Mixed neuroendocrine-non-neuroendocrine Mixed adeno-neuroendocrine carcinoma (MANEC) neoplasm (MINEN) Pancreatic Neuroendocrine Tumor (PanNET)

• Well differentiated NEN - low, intermediate or high grade • Minimal to moderate atypia • Typical organoid patterns, lacking necrosis • General neuroendocrine markers + • Associated with hormonal syndrome/functioning tumor Pancreatic Neuroendocrine Carcinoma (PanNEC)

• Poorly differentiated high grade NEN • Highly atypical small cells or intermediate to large cells • General neuroendocrine markers + • Exocrine markers - • Rarely associated with hormonal syndromes • TNM classification follows PDAC WD G3 PanNETs vs PD G3 PanNECs

WD G3 PanNETs PD G3 PanNECs MEN1, DAX, ATRX mutations P53, RB1, KRAS mutations IHC loss of DAXX or ATRX IHC loss of RB

Recognizable as NETs Small cell or large cell type

Often evolve from a recognizable No lower grade component lower grade component (1 or 2)

No upper limit given, but usually Must have ki67 index >20%, no lower ki67<40 to 55%, mitotic count limit given but usually >55% <20/10hpf Plasmacytoid morphology, smooth Pleomorphism, nuclear molding, nuclear contour, round nuclei necrosis • Plasmacytoid morphology • Smooth nuclear contour • Abundant cytoplasm • Apoptosis • Nuclear tangles Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MINEN)

• Mixed neoplasm with components of a nonendocrine carcinoma (mostly ductal adenocarcinoma or acinar cell carcinoma) combined with a neuroendocrine neoplasm

• Usually both components are high grade malignant carcinomas (G3), but ocasionally one of the two or both components may belong to the G1/G2 category

• Each component comprises >30% of the tumor Pancreatic Endocrine Neoplasms Associated Conditions

• Multiple Endocrine Neoplasia I

• von Hippel-Lindau Syndrome

• Tuberous Sclerosis

• Pheochromocytoma

• Cushing’s Syndrome Solid-Pseudopapillary Tumor

 2-3% of pancreatic tumors  Tumor of young females  F:M = 9.5:1; Mean age = 30.3 yrs  Symptoms usually related to presence of mass  Detected during pregnancy, after trauma, incidentally

 Low grade malignant neoplasm  Metastases in 15%  Long survival after metastases  Uncertain histogenesis  Monomorphic epithelial cells with solid and pseudopapillary structures Solid-Pseudopapillary Tumor: Molecular Features

 APC / β-catenin pathway upregulation (95%)

 β-catenin mutations

 Overexpression of cyclin D1

 Upregulation of genes required in Notch, Hedgehog, and androgen receptor signaling pathways

 E-cadherin expression changes from a membranous to intracytoplasmic localization

 No abnormalities in “ genes”

 K-ras

 p53

 DPC4 Solid Pseudopapillary Tumor: Staining Profile Stain % Positive Trypsin 0 Chymotrypsin 0 Lipase 0 Chromogranin 0 Synaptophysin 30 Neuron Specific Enolase 80 CD56 95 Mucicarmine 0 CEA 5 Keratin 30 Vimentin 100 α-1-antitrypsin 84 CD10 100 Beta catenin 97 Progesterone receptor 90 Acinar Cell Carcinoma Clinical Features

 1-2% of pancreatic tumors

 Male predominance, mean age = 61

 Non-specific presenting symptoms

 Jaundice rare

 Lipase hypersecretion syndrome Acinar Cell Carcinoma Genetic Features

Al-Hader A et al, World J Gastroenterol 2017 • BRAF fusion in 24% acinar tumors, including pure and mixed types • BRAF partners: • SND1 (50%) • HERPUD1 (18%) • Potential for targeted therapy to inhibit MAPK pathway activity Treatment • Aggressive surgical resection • 5-year survival on resected patients 72% • Resection for metastases • No defined treatment guidelines for cure • May be chemoresponsive to agents that have activity against pancreatic and colorectal carcinomas • Targeted therapy • MMR deficient – PD-1 receptor blocker • SND1 -BRAF fusion – MEK inhibitor • JAK -1 mutation – JAK-1 & 2 inhibitor WEDNESDAY SURGICAL PATHOLOGY

PLEURAL MESOTHEMLIOMA

CESAR A. MORAN

2018 NAPA VALLEY PATHOLOGY CONFERENCE WWW.PATHCME.COM || 888.976.9248 Malignant Mesothelioma : an overview

Cesar A. Moran, MD Malignant Mesothelioma

• First described by Wagner in 1870. However, the terminology was controversial and terms such as “Endothelioma” were used to designate this tumor. Malignant Mesothelioma

• DuBray and Rosson in 1920 introduced the term “mesothelioma” after their observation that these tumors arose from the surface of parietal pleura. Malignant Mesothelioma

• Klemperer and Rabin in 1931, described important features for these tumors, most of them currently used in modern surgical pathology – The localized tumor connected to the pleura was usually benign – Malignant mesothelioma was usually diffuse – High histological variability Malignant Mesothelioma

• Weiss in 1953 suggested that asbestos exposure was responsible for the induction of malignant mesothelioma.

– Weiss A. Medizinische 1953 Malignant Mesothelioma

• Wagner et al in 1960 described cases of mesothelioma in residents of Northwest Cape Providence of South Africa and reported strong association of asbestos exposure and malignant mesothelioma. – In two cases no history of asbestos exposure was obtained. Malignant Mesothelioma

• In the past, it was a tumor of more unusual occurrence, 0.1 - 0.01% of autopsies. • Currently, there are about 2000 new cases diagnosed in the USA each year. • The frequency of asbestos exposure varies depending on the population studied. Malignant Mesothelioma

• Rare tumor • Occurs in any age group • More frequent in the 6th and 7th decade of life • 50 - 80% associated with asbestos fibers Malignant Mesothelioma

• Clinical Features – Chest pain – Shortness of breath – Weight loss Radiological Features Radiological Features Pathologic Staging

• TNM system – T1-T4 = it will depend on the surgical procedure performed (Extrapleural peumonectomy, decortication, biopsy) – N1-N3 (ipsilateral, contralateral,hilar, mediastinal) – M1 = Distant metastasis

Gross Features

• Diffuse pleural thickening • White-tan tumor • May be infiltrating into intralobar pulmonary septum Malignant Mesothelioma

• Histological Patterns – Epithelioid – Sarcomatoid – Biphasic – Unsual forms Malignant Mesothelioma

• Epithelioid type: – Epithelioid – Tubulopapillary – Glandular – Myxoid – Clear cell – Deciduoid – Lipid rich Malignant Mesothelioma

• Malignant Mesothelioma In situ – Is diagnosable only when invasion is demonstrable in the same specimen, in a follow-up biopsy, or at autopsy – It should be considered proven only when unequivocal invasion is identified in a different area of the pleura – this Dx should not be made in patients not expose to asbestos. Malignant Mesothelioma Malignant Mesothelioma Epithelioid Mesothelioma Tubulopapillary Mucinous Glandular Myxoid Clear Cell Ancillary Studies • PAS w and w/o diastase • Mucicarmine • Keratin broad spectrum • Keratin 5/6 • Calretinin • D2-40 • Carcinomatous epitopes – CEA, CD-15, B72.3, TTF-1 Keratins Calretinin Am J Surg Pathol 2003; 27 (8): 1031. Conclusions:

From a practical viewpoint, a panel of four markers usually allows for the distinction between epithelioid mesothelioma and Adenocarcinoma - Calretinin and Keratin 5/6 -- CEA, MOC-31 Electron Microscopy What about asbestos bodies ?? Is it always possible ?? Malignant Mesothelioma

• Treatment: – Decortication – Extrapulmonary Pneumonectomy Variants & Mimickers Malignant Mesothelioma

• Differential Diagnosis – Pleuritis – Reactive Mesothelial Hyperplasia Pleuritis

• Acute or chronic • Collagen vascular • Pleural effusion disease • Thoracic pain • Trauma • Infections • Drug reactions Pleuritis

• Histological Features – Fibrin – Granulation tissue – Inflammatory reaction – Cellular atypia - mitotic figures Pleuritis Pleuritis Pleuritis

• Can immunohistochemistry help in differentiating Mesothelioma from Pleuritis? Atypical Mesothelial Hyperplasia

• AMH • Mesothelioma – No evidence of – Infiltration into infiltration into adjacent tissue, I.e., adjacent tissue adipose tissue – Lack of increase – Cellular atypia mitotic activity or – Mitotic activity cellular atypia – Inflammatory infiltrate • fibrin AMH vr Mesothelioma Immunohistochemistry in AMH

• Keratin + • Calretinin + • Keratin 5/6 +/- • CEA, B72.3, CD15, TTF-1 negative Sarcomatoid Mesothelioma

• The tumor should have more than 50% of this histology • Represents approximately 10% of malignant mesotheliomas • Similar clinical and radiological features as those previously described for epithelioid mesotheliomas Sarcomatoid Mesothelioma

• Histological variants: – Fibrosarcoma or MFH-like – Desmoplastic Sarcomatoid Mesothelioma Sarcomatoid Mesothelioma MFH-Like MFH-Like Desmoplastic Mesothelioma

• Diagnostic Criteria: – Invasion of chest wall or lung – Foci of bland necrosis – Frankly sarcomatoid foci – Distant metastases (very rare) Desmoplastic Mesothelioma Desmoplastic Mesothelioma Sarcomatoid Mesothelioma

• The most important differential diagnosis is with either a metastasis or a primary sarcoma of the pleura and more importantly with fibrous pleuresy. Fibrous Pleuresy Fibrous Pleuresy Sarcomatoid Mesothelioma

• Immunohistochemical Features – It has very little value – Namely to rule out other sarcomas – Broad spectrum Keratin is helpful, mainly in identifying invasion into adjacent tissue – Cannot help in distinguishing it from fibrous pleuresy Fibrous Pleuresy vr Mesothelioma • FP • Mesothelioma – Increased cellularity – No zonation under effusion, more – Bland appearance fibrotic away from – Capillaries “ ” effusion zonation inconspicuous – Atypical cells – Stromal invasion – Capillaries – Sarcomatoid foci perpendicular to pleural surface – Bland Necrosis – Organizing pleuritis Sarcomatoid Mesothelioma

• Treatment – In some medical centers, the diagnosis of Sarcomatoid mesothelioma is not follow by surgical treatment – Extrapleural pneumonectomy is being performed more frequently Mesotheliomas

• Other types of Mesotheliomas include: – Biphasic (Epithelioid - Sarcomatoid) – Chondroid differentiation – Osteosarcomatous differentiation – Lymphohistiocytic Biphasic Mesotheliomas Chondroid Differentiation Osteosarcomatous Differentiation Lymphohistiocytic Is there a role for Molecular Biology • FISH analysis for p16 (CDKN2A probe): – Homozygous Deletion • Very helpful in establishing a diagnosis • Not all mesotheliomas will have the deletion (30- 50%). – Heterozygous

Adenocarcinoma Pseudomesotheliomatous Adenocarcinoma • Harwood in 1976 reported a form of peripheral carcinoma of lung characterized by diffuse neoplastic involvement of pleura • Clinically, radiologically, grossly and histologically similar to pleural mesothelioma • Later named Pseudomesotheliomatous Adenocarcinoma Pseudomesotheliomatous Ca Pseudomesotheliomatous Ca Ancillary Studies Carcinomatous Epitopes

CEA Leu M1 Carcinomatous Epitopes

B72.3 Ber-Ep4 Mesothelioma vr AdenoCa

• Mesothelioma • Adenocarcinoma – Poor prognosis – Poor prognosis – Chemotherapy – Chemotherapy – Extrapulmonary – Survival about 18 pneumonectomy months – Survival about 12 months Questions WEDNESDAY SURGICAL PATHOLOGY

TBA

KONSTANTINOS LINOS

2018 NAPA VALLEY PATHOLOGY CONFERENCE WWW.PATHCME.COM || 888.976.9248 WEDNESDAY SURGICAL PATHOLOGY

THYMOMA: AN UPDATE

DR. CESAR A. MORAN

2018 NAPA VALLEY PATHOLOGY CONFERENCE WWW.PATHCME.COM || 888.976.9248 : An Update

Cesar A. Moran, MD Thymoma

• The most common epithelial tumor of the anterior mediastinum. However, the tumor in general practice is rare. • The classification of these tumors over the years has been controversial. • Numerous nomenclatures or schemas have been postulated without general agreement. Thymoma

– Important Issues – Classification – Sampling – Staging Classifications

• …no attempt is made in this fascicle to give special name to any particular variant. – Dr. Clastleman 1955 Rosai J, Levine GD: Tumors of the Thymus AFIP Fascicle 13, 2nd. Series, 1976. ….”A review of cases of thymoma in preparation for this fascicle strengthened our previous belief that once the term thymoma is restricted to the tumor of epithelial thymic cells, all further subdivisions are artificial. We have found that all the morphologic criteria that have been used for this purpose, such as the shape of the nucleus, the relative number of lymphocytes, etc, exhibit such a continuous range within as to prevent any rigid separation based on these criteria”……

Rosai J, Levine GD: Tumors of the Thymus AFIP Fascicle 13, 2nd. Series, 1976. Bernatz et al (Mayo Clinic) 1961

• Lymphocyte-rich thymoma • Mixed (lymphoepithelial) thymoma • Epithelial-rich thymoma • Spindle cell thymoma Survival Curves by Histology and Status of Capsular Integrity (Bernatz et al; Surg Clin NA, 1973) Levine & Rosai Classification

• Thymoma, encapsulated (benign)

• Thymoma, invasive (malignant): - Malignant thymoma type-I - Malignant thymoma type II (thymic carcinoma)

• Levine GD, Rosai J; Hum Pathol, 1976. Marino and Muller-Hermelink (1985) “Histogenetic” Classification

• Cortical thymoma

• Medullary thymoma

• Mixed thymoma Progress in Surgical Pathology, Vol.10: 167-189, 1989.

“Using specific mAbs, specific immunophenotypes of the different histological tumor types cannot be defined. Therefore, presence or absence of reactivity with one of these mAbs does not allow a clear immunohistochemical differentiation between the different tumor types. Furthermore, the immunophenotype of the epithelial neoplastic cells cannot be strictly correlated to the immunophenotype of different epithelial cells in the normal thymus” (pp.177-178). Circa 1990….

• Lymphocyte-rich • Polygonal cell thymoma • Lymphoepithelial • Differentiated thymoma • Spindle cell • Undifferentiated • Epithelial-rich thymoma • Invasive thymoma • Cortical thymoma • Malignant thymoma • Predominantly cortical type-I • Organoid thymoma • Malignant thymoma • Medullary thymoma type-II • Well-differentiated • Thymic carcinoma thymic carcinoma WHO Panel, 1999

• Juan Rosai - Chairman • Boris Elsner • Frantisek Havlicek • Tseng-tong Kuo • Cesar Moran • Kiyoshi Mukai • H.K. Muller-Hermelink • Giorgio Palestro • Robert Rouse • Mark Wick ...”the terminology chosen here is a non-committal one based on a combination of letters and numbers. It is not proposed as a new classification, but mainly to facilitate comparison among the many terms and classification schemes that have been offered over the years”…

J. Rosai – WHO Histological Typing of Tumors of the Thymus Springer-Verlag, 1999; pp.3-4.

WHO Schema for the Classification of Thymoma, 1999

• Type A: thymomas composed of spindle cells • Type B: thymomas composed of round cells* • Type AB: mixture of the above • Type C: cytologically malignant thymoma

*B 1-2-3: refers to the progressive loss of the lymphocytic component Comparison of WHO Schema with Traditional and Muller-Hermelink

WHO Traditional (Bernatz) Histogenetic (M-H)

A Spindle cell Medullary

AB ----- Mixed

B1 Lymphocytic Organoid/Cortical

B2 Lymphoepithelial Cortical

B3 Epithelial Well-differentiated thymic carcinoma C Thymic carcinoma Other thymic carcinomas

Issues with WHO Schema, 1999 • Only two classifications were considered out of more than 8 existing schemas. • Sampling was never discussed. • As the schema is presented, it appears that thymomas are homogenous tumors. • Because it was never intended as a “classification system” there was no need of validation and reproducibility. Bernatz: cell shape & proportion of lymphocytes 1961 PROGRESS WHO: cell shape & Levine & Rosai: proportion of lymphocytes benign vs. 1999 malignant 1976 Muller-Hermelink: Histogenesis 1985 A study of 630 cases showed that a cutoff of 5 sections of tumor provided a significant difference in sub-typing thymomas, contrary to the use of only biopsy material. AJCP 2000; 114:760.

Classification of Thymic Epithelial Neoplasms- WHO 2004

• Thymoma type A • Thymoma type AB • Thymoma type B (1-2-3) • Metaplastic thymoma • Micronodular thymoma • Sclerosing thymoma • Microscopic thymoma • Thymic carcinoma WHO Grading of Malignancy

• Type A: benign • Type AB: benign • Type B1: low-grade malignancy (10 yr. survival >90%) • Type B2: “greater degree of malignancy” • Type B3: (in advanced stages) poor prognosis equivalent to thymic carcinoma Chen G, Marx A, Wen C, Yong J, Puppe B, Stroebel P, Mueller-Hermelink HK: New WHO Histologic Classification Predicts Prognosis of Thymic Epithelial Tumors. A Clinico- Pathologic Study of 200 Tumors from China. Cancer 95:420-429, 2002. Chalabreysse et al; Am J Surg Pathol 26:1605-1611, 2002. “In this study of 218 patients, survival curves for WHO types A, AB, B1 and B2 showed great overlap without any significant differences. Further simplification of both the WHO and traditional classifications into only 3 subgroups led to classes with good discriminatory power in respect to survival. In addition, very good inter-observer agreement was found in the simplified classification” …”In comparison with the carcinoma group, the other subtypes showed nearly identical prognosis for survival. We therefore introduced 3 subgroups. By this simplification, subgroups with distinct survival could be identified. Therefore, our results are in favor of classifications that permit accurate allocation of these neoplasms to simple and reproducible diagnostic categories, as proposed by Suster & Moran…”

Rieker RJ et al. Histologic Classification of Thymic Epithelial Tumors: Comparison of Established Classification Schemes. Int. J. Cancer 98:900-906, 2002. Suster & Moran, Am J Clin Pathol Vol.111: 826-833, 1999. Survival Curves in 218 Thymoma Patients Utilizing a 3-Tiered System Rieker et al, Int J Cancer, 2002. WHO Grading of Malignancy

• Type A: benign • Type AB: benign • Type B1: low-grade malignancy (10 yr. survival >90%) • Type B2: “greater degree of malignancy” • Type B3: (in advanced stages) poor prognosis equivalent to thymic carcinoma 41 cases out of 230 invasive thymomas (18%). Only cases with 5 or more sections of tumor were included. AJCP 2010; 134:793.

Sub-typing of Thymomas

AJCP 2012; 137:444 SUB-TYPING Only 47% of thymomas can be subtype using WHO. More than 50% are mixed types, making the use of the WHO schema impractical. Moran et al AJCP 2012; 137:444.

Staging

• There are at least 5 different approaches for the staging of thymomas: – The French approach – Berg’s approach – Masaoka’s original – Two modifications of the Masaoka’s Staging Masaoka’s Staging Solution

New Proposed Staging

AJCP 2012; 137:451. Proposed Staging System • Stage 0 – Encapsulated tumors • Stage I – Invasion limited to the thymus • Stage II – A: Pleura/lung/I.V; B:pericardium; C: great vessels • Stage III – A: diaphragm (drop metastasis); B: Below diaphragm or neck invasion • Moran CA, Walsh G, Suster S, Kaiser L: AJCP 2012; 137:451. Stage 0

Stage I

Stage II-A

Stage II-B

Stage II-C

Stage III-A

Just Published Final Thought

• The largest series of resected thymomas up to now. • Pathologists from 11 countries including the USA. • We stratified 1470 cases using the Suster-Moran histological classification and the Moran staging system.

Conclusions

• Staging remains the most important parameter to determine outcome in patients with thymoma. • Sub-grouping thymic epithelial tumors into three categories – Thymoma – Atypical Thymoma – Thymic Carcinoma, appears to be the most reproducible way to classify these tumors. • All thymomas are potentially aggressive tumors regardless of the histology that they may display.