1

©2018 MFMER | 3793435-1

Mesothelial Proliferations: Challenges and Ancillary Testing

©MFMER | 3793435-2

Presenter:

Anja Roden, M.D.Professor of Laboratory Medicine and PathologyDivision of Anatomic Pathology

Department of Laboratory Medicine and Pathology Mayo Clinic, Rochester, Minnesota

2

©MFMER | 3793435-3

Disclosures• No disclosures

©MFMER | 3793435-4

Outline• Introduction• Spectrum of mesothelial disease• Distinction mesothelioma ↔ carcinoma, sarcoma• Distinction reactive ↔ malignant mesothelial proliferation• Take home message

3

©MFMER | 3793435-5

IntroductionMalignant Mesothelioma1

• Aggressive neoplasm of mesothelial differentiation• Pleura (parietal, visceral, mediastinal, diaphragmatic),

pericardium, peritoneum• Epithelioid, biphasic, sarcomatoid subtypes• Poor survival - 12-27 months (epithelioid)

- 8-21 months (biphasic)- 4-18 months (sarcomatoid)

(data from pleural mesothelioma)

©MFMER | 3793435-6

IntroductionMalignant Pleural Mesothelioma1-4

• Strongly associated with remote asbestos exposure (latency 20 - >40 years)

• Rarely in young patients (mantle radiation, family history of breast cancer, BAP1 germline mutation)

• Presentation - Unilateral pleural effusion +/- thickening- Occasional single pleural-based mass

• Pleural plaques - sign of asbestos exposure ≠ MPM

4

©MFMER | 3793435-7

Behavior Mesothelial Proliferation

BenignReactive mesothelial proliferationMulticystic mesotheliomaAdenomatoid tumor

Indeterminate Well differentiated papillary mesotheliomaAtypical mesothelial proliferation

MalignantMalignant mesothelioma in situMalignant mesotheliomaDiffuse intrapulmonary malignant meso

©MFMER | 3793435-8

Case• 92-yo male• Asbestos exposure while

in Navy as young man• 5 months ago -

“lung cancer”

5

©MFMER | 3793435-9

©MFMER | 3793435-10

6

©MFMER | 3793435-11

Epithelioid Sarcomatoid (50%)

©MFMER | 3793435-12

• Morphologic overlap

• Patterns of meso: Solid, acinar (glandular), tubulopapillary, microcystic (adenomatoid), clear cell, deciduoid, small cell

• Psammoma bodies – not specific

• Cytoplasmic mucin might occur

Malignant Mesothelioma ↔ Carcinoma

7

©MFMER | 3793435-13

Malignant Mesothelioma ↔ Carcinoma5

• Keratin+

• No IHC marker specific for malignant mesothelioma

→ ≥ 2 carcinoma markers & 2 markers of mesothelial differentiation

• Markers based on differential diagnosis

©MFMER | 3793435-14

IHC Markers

Malignant Mesothelioma Non-small Cell CarcinomaWT-1CalretininPodoplanin (D2-40)CK5; CK5/6GATA3 (if diffuse, sarcomatoid MM)

pCEATTF-1, Napsin AMOC31, BerEP4B72.3P40Claudin 4 (adenoCa)PAX8 (Gyn, RCC, Thyroid)

Keratin (AE1/AE3, CAM5.2, CK7)

8

©MFMER | 3793435-15

CalretininAE1/AE3

CK5

Neg: WT-1, TTF-1, pCEA

Malignant mesothelioma, biphasic type

©MFMER | 3793435-16

Reactive ↔ Malignant Mesothelial ProliferationDiagnosis → different treatments and prognosis

Reactive Meso. Prolif. Malignant MesotheliomaInfectionPneumoniaPneumothoraxTraumaFluid overload

Most-no specific treatment > chemo > trimodality treatment

Potentially medicolegal action

9

©MFMER | 3793435-17

• Invasion (adipose tissue, lung, skeletal muscle) (keratin)• Tumefactive growth• Haphazard growth of neoplastic spindle cells (keratin)• Loss of BAP1 and/or mTAP expression• Homozygous deletion of CDKN2A (p16) and/or NF2• Insufficient specificity and therefore not useful: GLUT-1,

p53, desmin, EMA, IMP3, EZH2

Malignant (vs Reactive) Mesothelial Proliferation6-8

©MFMER | 3793435-18

77 yo male, recurrent right pleural effusion→ Excision right parietal pleura

10

©MFMER | 3793435-19

©MFMER | 3793435-20

AE1/AE3

11

©MFMER | 3793435-21

Calretinin WT-1

GATA3 BAP1Malignant mesothelioma,

sarcomatoid type

Neg: MOC31, BerEP4

©MFMER | 3793435-22

FISH for CDKN2A/D9Z1

Courtesy of Dr. William R. SukovMayo Clinic Rochester

12

©MFMER | 3793435-23

• 61 yo male• RUL and RLL

consolidation• COPD, bullae• S/P left

pneumothorax• → VATS-Bx of

pleura

©MFMER | 3793435-24

13

©MFMER | 3793435-25

WT-1 BAP1

Reactive mesothelial proliferation

©MFMER | 3793435-26

Malignant Mesothelioma Sensitivity(%)

Specificity(%)

Loss of nuclear BAP1 Epithelioid MMSarcomatoid MM

27 – 6756 – 81

0 – 63100

Loss of cytoplasmic mTAPEpithelioid MM Sarcomatoid MM

3780

100

Homozygous CDKN2A deletionEpithelioid MMSarcomatoid MM

58 - 9248 - 78

67 - 100100

14

©MFMER | 3793435-27

Malignant Mesothelioma Sensitivity(%)

Specificity(%)

Loss of BAP1 and/or mTAPSarcomatoid MM

76 - 9090 100

Loss of BAP1 and/or homozygous CDKN2A deletion

Epithelioid MMSarcomatoid MM

58 - 92

9267 - 100

100

©MFMER | 3793435-28

• Helpful in distinction reactive ↔ malignant mesothelial proliferation

• Applicable in cytology preparations (cell block)• Preserved expression does not exclude malignant meso• Loss of expression – not specific to malignant meso, can

be seen in other malignancies

BAP1 & mTAP ExpressionHomozygous CDKN2A Deletion

15

©MFMER | 3793435-29

• Distinction malignant mesothelioma ↔ carcinoma / sarcoma → Panel of immunostains (≥ 2 carcinoma markers,

2 markers of mesothelial proliferation)

• Distinction reactive ↔ malignant mesothelial proliferation→ Morphology +/- immunostains, FISH

Take Home Message

©MFMER | 3793435-30

References1. Kim R, Sterman D, Haas A. Malignant mesothelioma: has anything changed?

Semin Respir Crit Care Med. 2019; 40(03):347-602. Fels Elliott D, Jones K. Diagnosis of mesothelioma. Surg Pathol Clin.

2020;13(1):73‐893. Abratt R, Vorobiof D, White N. Asbestos and mesothelioma in South Africa. Lung

Cancer. 2004;45 Suppl 1:S3‐S64. Viero M, Bueno R, Chirieac L. Clinicopatholigic and genetic characteristics of

young patients with pleural diffuse malignant mesothelioma. Mod Path. 2018; 31:122-131.

5. Husain A, Colby T, Ordóñez N, et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the international mesothelioma interest group. Arch Pathol Lab Med. 2018 Jan;142(1):89-108

16

©MFMER | 3793435-31

References6. Cigognetti M, Lonardi S, Fisogni S, et al. BAP1 (BRCA1-associated protein 1) is a

highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol. 2015;28(8):1043‐1057

7. Sheffield B, Hwang H, Lee A, et al. BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations. Am J Surg Pathol. 2015;39(7):977‐982

8. Berg K, Dacic S, Miller C, et al. Utility of methylthioadenosine phosphorylase compared with BAP1 immunohistochemistry, and CDKN2A and NF2 fluorescence in situ hybridization in separating reactive mesothelial proliferations from epithelioid malignant mesotheliomas. Arch Pathol Lab Med. 2018;142(12):1549‐1553

©MFMER | 3793435-32

THANK YOU