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Biomarkers Distinguish Pleural Diseases
- 1. HISTOLOGY, CYTOLOGY AND BIOMARKERS OF PLEURAL DISEASES Rex Michael C. Santiago, MD, DPSP Thoracic Pathology Affiliations : - St. Luke’s Medical Center – QC and GC - Lung Center of the Philippines - St. Frances Cabrini Medical Center
- 2. Thickened pleura Case 1 : 66 year old male with pleural effusion.
- 4. DIAGNOSIS : - METASTATIC ADENOCARCINOMA.
- 6. TTF-1
- 7. Calretinin
- 8. CK 7
- 9. CEA - negative TTF-1 - negative Calretinin - positive CK7 - Positive The proliferation is more likely mesothelial rather than epithelial in origin.
- 12. Is the proliferation benign or malignant?
- 13. Neoplastic and Non-neoplastic lesions of the pleura Non-neoplastic Inflammatory conditions Pleuritis Pneumothorax Reactive and atypical mesothelial hyperplasia Other non-neoplastic lesions of the pleura Parietal pleural plaques Rounded atelectasis Amyloidosis Atypical mesothelial hyperplasia Marchevsky AM, 2018
- 15. Neoplastic Diffuse malignant mesothelioma Epithelioid Sarcomatoid Biphasic Carcinomas Primary Metastatic (Lung, ovarian, gastric, pancreatic, colonic, others) Lymphoid malignancies Mesenchymal tumors Neoplastic and Non-neoplastic lesions of the pleura Marchevsky AM, 2018
- 16. Table of contents I. Histology of the pleura II. Distinction of benign from malignant lesions of the pleura III. Cytology of serous membrane effusions
- 17. Table of contents I. Histology of the pleura II. Distinction of benign from malignant lesions of the pleura III. Cytology of serous membrane effusions
- 18. Histology of the pleura. Lung parenchyma Visceral pleura
- 19. Histology of the pleura. Parietal pleura Chest wall Adipose tissue Skeletal muscle
- 20. Table of contents I. Histology of the pleura II. Distinction of benign from malignant lesions of the pleura III. Cytology of serous membrane effusions
- 21. Is the lesion epithelial or mesothelial?
- 24. - No specific panel of antibodies recommended (depends on antibody clone and laboratory experience) - Antibodies chosen should have a sensitivity and specificity of at least 80% - TWO MESOTHELIAL AND TWO EPITHELIAL MARKERS
- 26. If the lesion is epithelial…
- 28. If the lesion is epithelial…
- 29. If the lesion is epithelial… TTF-1
- 30. No guidelineShould-testMust-test EGFR, ALK, ROS1 ERBB2, MET, BRAF, KRAS, RET NTRK, FGFR, others
- 31. NSCLC Adenocarcinoma/ NSCLC, NOS Molecular – EGFR, BRAF FISH – ALK, ROS1 IHC – ALK, PD-L1 Squamous cell carcinoma PD-L1 TTF-1, Napsin A, Mucin Stain P40, p63, CK 5/6
- 32. If the lesion is mesothelial… Calretinin WT-1 D2-40 TTF-1 mCEA
- 33. Is the lesion benign or malignant?
- 34. WHO, 2015
- 37. Features of benign mesothelial proliferations – zonation. Fibrin Acute and organizing pleuritis
- 38. Features of benign mesothelial proliferations – perpendicular capillaries. Pleural surface
- 39. Features of benign mesothelial proliferations – zonation. Pleural surface
- 40. The utility of cytokeratin (AE1/AE3).
- 41. The utility of cytokeratin (AE1/AE3). WT-1
- 42. The utility of cytokeratin (AE1/AE3). WT-1
- 44. Features of malignant mesothelial proliferations – nodules.
- 45. Features of malignant mesothelial proliferations : Cytokeratin Calretinin D2-40 mCEA Ber-EP4 TTF-1
- 46. Features of malignant mesothelial proliferations :
- 47. Features of malignant mesothelial proliferations :
- 48. Features of malignant mesothelial proliferations – invasion of adjacent structures (adipose tissue, lung, diaphragm, etc.). Cytokeratin
- 49. Features of malignant mesothelial proliferations – fat invasion. Calretinin
- 50. Features of malignant mesothelial proliferations – fat invasion. Calretinin
- 51. Features of malignant mesothelial proliferations – fat invasion. CK 5/6
- 52. Features of malignant mesothelial proliferations – lung invasion.
- 53. Features of malignant mesothelial proliferations – lung invasion.
- 54. Features of malignant mesothelial proliferations – lung invasion. Calretinin
- 56. Atypical mesothelial proliferation : Cytokeratin
- 57. Atypical mesothelial proliferation : Zonation
- 58. Atypical mesothelial proliferation : Zonation
- 59. Atypical mesothelial proliferation : Haphazard proliferation
- 60. Atypical mesothelial proliferation – haphazard proliferation but no definite invasion.
- 62. Reactive versus neoplastic? Immunohistochemical stain Reactive Mesothelioma Desmin Positive Mostly negative EMA Negative Positive IMP3 Negative Positive GLUT1 Negative Positive P53 Negative Positive
- 64. BRCA-1 Associated Protein (BAP-1) Marchevsky AM, 2018
- 65. BRCA-1 Associated Protein (BAP-1) Marchevsky AM, 2018 - Loss of expression : - None in benign cases - Approximately 70% in epithelioid MM - Approximately 15% in sarcomatoid MM
- 66. Loss of p16/CDKN2A Marchevsky AM, 2018 - Loss of expression : - None in benign cases - Approximately 60-70% in epithelioid and biphasic MM - 100% in sarcomatoid MM
- 67. Patterns of Epithelioid Mesothelioma Tubular Papillary Trabecular Tubulo-papillary Solid
- 68. Rare patterns of Epithelioid MM Marchevsky AM, 2018 Micropapillary Transitional Adenomatoid Deciduoid
- 70. Sarcomatoid Mesothelioma Immunohistochemical stain results Sarcomatoid Mesothelioma Sarcomatoid (Pleomorphic Carcinoma) Sarcoma (Synovial Sarcoma) Cytokeratin Positive, may be diffuse or focal Positive, may be diffuse of focal Positive, usually focal TTF-1 Negative May be positive if with adenocarcinoma component (diffuse or focal) or negative Negative P40 Negative; may be focal May be positive if with squamous cell carcinoma component (diffuse or focal) or negative Negative Calretinin Positive (usually focal) or negative Negative Negative D2-40 Positive (usually focal) or negative Negative Negative WT-1 Positive (usually focal) or negative Negative Negative CK 5/6 Positive (usually focal) or negative May be positive if with squamous cell carcinoma component (diffuse or focal) Negative
- 71. Sarcomatoid Mesothelioma Immunohistochemical stain results Sarcomatoid Mesothelioma Sarcomatoid (Pleomorphic Carcinoma) Sarcoma (Synovial Sarcoma Cytokeratin Positive, may be diffuse or focal Positive, may be diffuse of focal Positive, usually focal TTF-1 Negative May be positive if with adenocarcinoma component (diffuse or focal) or negative Negative P40 Negative; may be focal May be positive if with squamous cell carcinoma component (diffuse or focal) or negative Negative Calretinin Positive (usually focal) or negative Negative Negative D2-40 Positive (usually focal) or negative Negative Negative WT-1 Positive (usually focal) or negative Negative Negative CK 5/6 Positive (usually focal) or negative May be positive if with squamous cell carcinoma component (diffuse or focal) Negative
- 72. Sarcomatoid Mesothelioma Immunohistochemical stain results Sarcomatoid Mesothelioma Sarcomatoid (Pleomorphic Carcinoma) Sarcoma (Synovial Sarcoma Cytokeratin Positive, may be diffuse or focal Positive, may be diffuse of focal Positive, usually focal TTF-1 Negative May be positive if with adenocarcinoma component (diffuse or focal) or negative Negative P40 Negative; may be focal May be positive if with squamous cell carcinoma component (diffuse or focal) or negative Negative Calretinin Positive (usually focal) or negative Negative Negative D2-40 Positive (usually focal) or negative Negative Negative WT-1 Positive (usually focal) or negative Negative Negative CK 5/6 Positive (usually focal) or negative May be positive if with squamous cell carcinoma component (diffuse or focal) Negative Differential Diagnosis with Sarcomatoid Mesothelioma : - Sarcoma (synovial sarcoma) : test for translocation (SS18-SSX1). - Pleomorphic carcinoma : Difficult differential diagnosis if differentiation markers are negative/ only CK is positive. Need to correlate with clinical and imaging findings.
- 76. Table of contents I. Histology of the pleura II. Distinction of benign from malignant lesions of the pleura III. Cytology of serous membrane effusions
- 84. CalretininCEA
- 85. Epithelial or mesothelial? Do IHC’s (at least two mesothelial and two epithelial markers) Mesothelial Benign vs. malignant? Check features to differentiate. Benign Atypical mesothelial proliferation Correlate with clinical and imaging findings. May test for BAP- 1 loss by IHC and homozygous deletion by p16 FISH. Malignant Mesothelioma Epithelial Markers for differentiation (TTF-1, p40, GATA3, Pax-8, etc.) Summarized approach for cases with a thickened pleura and/ or an atypical proliferation within the pleura.
- 86. Table of contents I. Histology of the pleura II. Distinction of benign from malignant lesions of the pleura III. Cytology of serous membrane effusions IV. Updates and biomarkers V. Selected interesting cases
- 87. Case 1 : 66 year old male with pleural effusion.
- 88. The proliferation of mesothelial cells is not organized. Calretinin
- 89. CK 7
- 90. The CK7 stain shows haphazard arrangement of mesothelial cells.
- 91. However, there is no definitive evidence of tissue invasion. TTF-1 Pneumocytes • Thickened pleura • Haphazard proliferation of mesothelial cells • No definitive evidence of invasion of other structures. Atypical Mesothelial Proliferation
- 92. Case 2 : 42 year old, female with pleural thickening • Clinical history : – With prior diagnosis of “peritoneal mesothelioma” s/p tumor debulking and partial omentectomy in 2007 – s/p chemotherapy (2007-2008)
- 96. Cytokeratin
- 98. Calretinin WT-1 Ber-EP4 Moc-31 Immunohistochemical stain Result CK Positive Calretinin Positive WT-1 Positive Moc-31 Rare cells positive CD68 Negative Ber-EP4 Negative TTF-1 Negative Pax-8 Negative ER Negative PR Negative
- 99. Diagnosis : • Right pleural thickening : – ATYPICAL MESOTHELIAL PROLIFERATION. COMMENTS : - Immunohistochemical stains support mesothelial origin of the cells. However, no evidence of invasion into adjacent tissue (lung parenchyma or fat), which precludes a definitive diagnosis of malignant mesothelioma. - Suggest BAP1 immunohistochemistry and homozygous deletion of p16 FISH. - NO LOSS of expression of BAP1 by immunohistochemistry. - NO HOMOZYGOUS DELETION of p16 gene by FISH.
- 100. REFERENCES : 1. Marchevsky AM, Husain AN, & Galateau-Salle F. Practical Pathology of Serous Membranes (2018). Cambridge University Press : United Kingdom 2. Husain AN et al. Guidelines for Pathologic Diagnosis of Malignant Mesothelioma (2018). Arch Pathol Lab Med, Vol 142 3. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Eds.): WHO Classification of Tumours of Lung, Pleura, Thymus and Heart (4th edition). IARC: Lyon 2015 4. Churg A & Galateau-Salle F. The Separation of Benign and Malignant Mesothelial Proliferations. Arch Pathol Lab Med. 2012; 136 : 1217-1226