Immunohistochemical classification of lung carcinomas and mesotheliomas. Prof. Mogens Vyberg NordiQC Institute of Pathology Aalborg, Denmark

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1 Immunohistochemical classification of lung carcinomas and mesotheliomas Prof. Mogens Vyberg NordiQC Institute of Pathology Aalborg, Denmark

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5 Endobronchial ultrasound guided transbronchial needle biopsy

6 Transthoracic Needle Biopsy

7 Lung carcinomas vs. epithelioid malignant mesothelioma TTF-1 NapA p40 CK5 Calr Pod WT1 Vim Ep- CAM Cld4 Lung adenocarcinoma Lung squamous cell carcinoma Epithelioid mal. mesothelioma 80 * 80? 0 ** 5? 10 f 10 f 20? * w 10 f ? ? f 0 Panou V, Vyberg M, et al. Cancer Treat Rev Jun;41(6): ~ % positivity *Clone SPT24 ** p63: 5% f: focal, w: weak?: insuff. data

8 Lung markers TTF-1 Napsin p63/p40 (CK5) Squamous cell carcinoma: Risk of hemorrhage due to bevacizumab (Avastin)

9 Thyroid transcription factor-1 Thyroid gland: regulating thyroglobulin, thyroperoxidase and thyrotropin receptor Lung: regulating surfactant proteins and Clara cell secretory protein Thyroid follicles and C-cells Histiocytes Lung pneumocytes II and Clara cells Brain Pituitary Parathyroid Normal lung

10 TTF-1 Run 39/2013: 227 labs Optimal: 51% Insufficient: 29%

11 SPT24 8G7G3/1 1:100 Lung adenocarcinoma

12 Matoso et al, AIMM 2010,18: Thyroid transcription factor-1 % pos.: Lung adenocarcinoma SPT24 8G7G3/1 - large cell carcinoma small cell carcinoma carcinoid squamous cell carcinoma 15 0 Non-lung small cell carcinoma 20-40? Thyroid carc. (non-anaplastic) Non-lung carcinomas Non-lung carcinoids ~ 0 ~ 0

13 TTF-1 pos. neoplasms outside lung Neuroendocrine neoplasms Small cell carcinoma ~40% GI tract,prostate, bladder, liver, uterine cervix, breast Large cell neuroendocrine carcinoma prostate, uterine cervix Neuroendocrine tumor/ carcinoid: GI tract Merkel cell carcinoma of skin Non-neuroendocrine adenocarcinomas Gastric, Colorectal, Breast, Primar peritoneal, Endocervical, Endometrial, Ovarian, Nasopharyngeal papillary Others Synovial sarcoma Melanoma Brain tumors

14 TTF-1 Run 39/2013: 227 labs Optimal: 51% Insufficient: 29%

15 Lung squamous cell carcinoma SPT24, SP141 Lung adenocarcinomas 8G7G3/1, MX011

16 Lung adenocarcinoma / TTF1-intermediate expressor SPT24 SP141 EP1584Y MX011 (8G7G3/1)

17 Lung squamous cell carcinoma SPT24 SP141 EP1584Y CK5 MX011 (8G7G3/1) p40

18 Lung squamous cell carcinoma / TTF-1 pos! SPT24 SP141 EP1584Y MX011 (8G7G3/1)

19 Napsin A Aspartic proteinase Type II pneumocytes Proximal and convoluted renal tubules (Pancreatic acini and ducts)

20 Napsin A Aspartic proteinase Type II pneumocytes Proximal and convoluted renal tubules (Pancreatic acini and ducts)

21 Napsin A: lung adenocarcinoma ~ 80%

22 Napsin A: Lung squamous carcinoma 0 30%

23 Napsin A: Renal cell carcinoma 0 70%

24 Napsin Run 39/2013: 104 labs 30% optimal 42% insufficient

25 49 Liver adenocarcinoma of unknown primary CK20

26 49 Liver adenocarcinoma of unknown primary: Lung TTF Napsin A

27 p63 / p40 Nuclear proteins - transcription factors Belongs to the p53 gene family Plays a critical role in the growth and development of many epithelia Confined to squamous epithelia urothelium basal cells/myoepithelial cells - lung, breast, sweat glands, salivary glands, and prostate

28 Adenocarc. Squamous cell carc.

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30 Lung cancer panel Adenocarcinoma TTF1 +/- -(+) Napsin +/- -(+) Squamous cell carcinoma CK5 -(+) +(-) p63/p40 -(+) / - +(-) PAS/AB +/- -(+)

31 p63 TTF1 Adeno CK5/6 AB/PAS

32 P63/p40 TTF1 Squamous CK5 (5/6) AB/PAS

33 Tonsil p63/p40 p40 p40 p63 p63

34 Squamous cell carcinoma Diffuse large B-cell lymphoma p40 p40 p63 p63

35 p40 Run 44/2015: 124 labs Optimal prostate squamous cell carc. Insufficient

36 ALK expression in lung adenocarcinoma 3-6% of lung adenocarcinoma reveal a driver mutation, a chromosome 2 inversion (inv(2) (p21p23)) causing an ALK-EML4 gene fusion, which gives rise to the oncogen ALK-EML4 fusion protein. A kinase inhibitor, crizotinib (Xalkori, Pfizer), is approved for treatment of ALK mutated cases. ALK can be demonstrated with IHC, FISH and PCR

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38 ALK (lu) Run 45/2015: 177 labs Optimal ALCL Lung adenocarc. Insufficient

39 ALK (lu) Run 45/2015: 177 labs

40 Malignant mesothelioma

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42 Asbestos consumption in Denmark Metric tons År 42

43 Mesothelioma incidens i North Jutland: 5/ fold incrase in 4 decades ( ) and increasing MM tilfælde År Panou V, Meristoudis C, Røe OD. 26 th European Pathology Congress, London

44 Mesothelial markers Calretinin Podoplanin WT1 Vimentin CA125 CK5

45 Calretinin Calcium-binding protein related to S-100 proteins Neurons Mesothelial cells Steroid producing cells adrenal cortical cells testicular Leydig and Sertoli cells ovarian theca interna cells and surface epithelium Neuroendocrine cells Breast glands...

46 Calretinin Mesothelium Appendix

47 Calretinin Ep. malignant mesotheliomas + (>50% nuclear) Steroid producing tumours +/- adrenal cortical tumour testicular Leydig and Sertoli cell tumour ovarian thecal tumours Adenocarcinomas -(+)...

48 Malignant mesothelioma Malignant mesothelioma Calretinin in neoplasms

49 Adrenal gland Granulosa cell tumour Calretinin

50 Calretinin Run 33/2011: 180 labs Optimal adrenal gland mesothelioma Insufficient

51 Calretinin Adenocarcinoma Optimal False positive

52 Podoplanin Lymphatic endothelium Fibroblasts, osteocytes Smooth and striated muscle cells Myoepithelial cells, Cajal cells Basal squamous epithelial cells Gastric crypt c., prostatic basal c. Immature Sertoli c. and gonocytes Renal glomerular podocytes Mesothelium (reactive) Follicular dendritic cells (controls) Some lymphocytes Glial/Schwann cells

53 Podoplanin Lymphatic endothelium Fibroblasts, osteocytes Smooth and striated muscle cells Myoepithelial cells, Cajal cells Basal squamous epithelial cells Gastric crypt c., prostatic basal c. Immature Sertoli c. and gonocytes Renal glomerular podocytes Mesothelium (reactive) Follicular dendritic cells (controls) Some lymphocytes Glial/Schwann cells

54 Podoplanin Mesothelioma Many other tumours but rarely adenocarcinomas

55 Podoplanin Run 36/2012: 102 labs Optimal tonsil mesothelioma Insufficient

56 Pleural biopsy malignant mesothelioma

57 Pleural biopsy malignant mesothelioma Cytokeratin 7 + Cytokeratin 5 Calretinin Podoplanin Normal mesothelium

58 Immunohistochemical classification of lung carcinomas and mesotheliomas Prof. Mogens Vyberg NordiQC Institute of Pathology Aalborg, Denmark