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Markers of melanocytic tumours Markers of melanocytic tumours Tomas Seidal, MD, PhD Länssjukhuset i Halmstad Chairman of NordiQC ¾ Basic facts ¾ Antibodies well known to most, most, for many years ¾ Well recognized diagnostic situation ¾ NordiQC experience this far ¾ Discussion Markers of melanocytic tumours ¾ There are several markers, reported to stain positively in melanoma cells and cells of other naevocellular tumours: tumours: z z z z z z z Protein ss-100 Vimentin Microphtalmia transcription factor Tyrosinase HMB 45 Melan A C-kit (CD 117) and many others Markers of melanocytic tumours ¾ Melanocytic tumours are virtually never positive for: z z z z ¾ And very rarely positive for: z z z Markers of melanocytic tumours ¾ In practical immunohistochemistry, immunohistochemistry, however, however, there are only few markers that are used, used, because of their sensitivity and/or specificity and because they are well known and quite easy to use z z z Protein ss-100 Melanoma Specific Antigen, (MSA) HMBHMB-45 Melan A Cytokeratin 7 and 20 Desmin CD 20 Chromogranin Cytokeratin coctails Actin EMA Markers of melanocytic tumours ¾ Protein ss-100 z z z z Dimeric 21kDa protein Two subunits: subunits: alfa and beta May be found in the nucleus, nucleus, the cytoplasm and the cytoplasmic membrane Present in, for instance, instance, glial tissue, tissue, Schwann cells, melanocytes, melanocytes, myoepithelial cells and some glandular epithelium (sweat glands, glands, kidney, kidney, breast, breast, striated muscle, muscle, chondrocytes and FDC 1 Markers of melanocytic tumours ¾ Protein ss-100 continued z Markers of melanocytic tumours ¾ Present in >90 % of • • • • • • • • Protein ss-100 continued z Markers of melanocytic tumours ¾ Protein ss-100 continued z Present in <50 % of • • • Granulosa cell tumours Adenocarcinomas of breas and several others Thus, Thus, ss-100 is sensitive but very unspecific for melanocytic neoplasms. neoplasms. Protein ss-100 may also be of importance in tumour diagnosis not involving melanomas z z z z z Present in junction nevi, nevi, compound nevi (epidermal part, weaker in dermal part), blue nevi, nevi, dysplastic nevi, nevi, Spitz Rhabdomyoma Angiomyolipoma Clear cell sarcoma and some other fairly uncommon neoplasms and other conditions PNET Clear cell sarcomas Rhabdomyosarcomas Chondroid tumours Sweat gland carcinomas Thyroid carcinomas Renal cell carcinoma Serous and endometroid ovaraian tumours Monocytic/ Monocytic/monoblastic leukemias Markers of melanocytic tumours ¾ MelanomaHMB-45 Melanoma-specific antigen (MSA) HMBz z z Markers of melanocytic tumours ¾ MelanomaHMB-45 Melanoma-specific antigen (MSA) HMB- Present in >50<90 % of • • • • • • • • • Astrocytoma, Astrocytoma, glial tumours Benign and malignant Scwannomas, Scwannomas, neurofibromas Granular cell tumours Myoepithelial tumours Polymorphous low grade adenocarcinoma Langerhan’s cell histiocytosis, histiocytosis, xanthogranulomas Chordomas Lipomas, Lipomas, liposarcomas The melanomamelanoma-specific antigen is a poorly characterized oligosaccharide, oligosaccharide, identified by the monoclonal antibody HMBHMB-45 Present in the cytoplasm of activated and immature melanocytes, melanocytes, but not in mature melanocytic cells. Positive in 6060-90 % of melanomas; melanomas; not in spindlespindle-cell/desmoplastic cell/desmoplastic variants Markers of melanocytic tumours ¾ MelanomaHMB-45 Melanoma-specific antigen (MSA) HMBz z z Considerably more specific than s-100 Less sensitive than s-100 May play a role in rare instances of differential diagnosis in nonnon-melanocytic neoplasms 2 Markers of melanocytic tumours ¾ Melan A z z z z Also called MARTMART-1 (Melanocyte (Melanocyte antigen recognized by TT-cells) 2020-22 kDa protein associated with endoplasmatic reticulum and melanosomes Expressed in all normal melanocytes and melanocytic cellcell-lines Also detected in steroidsteroid-producing cells (adrenal (adrenal cortex, Leydig cells, granulosa and theca cells) due to cross reaction since the MARTMART-encoding gene is not detected in these cells Markers of melanocytic tumours ¾ Melan A z z z z Markers of melanocytic tumours ¾ Melan A z z z z z z z Positive in other neoplasms of melanocytic origin, origin, such as : Benign nevi, nevi, Spitz, blue nevi Clear cell sarcoma Melanotic Schwannoma PEComa (perivascular epithelioid cell tumour) Angiomyolipoma SteroidSteroid-producing tumours Markers of melanocytic tumours ¾ Melan A z z z z Markers of melanocytic tumours ¾ Immunohistochemistry using melanocytic markers is of particular value in the diagnosis in cases of: z Cutaneous melanocytic tumours with an unusual appearance • Signet ring cell melanoma • Spindle cell or desmoplastic melanoma z Melanocytic tumours with an unusual localization (and sometimes also an unusual appearance) appearance) • Mucosal • Nasal Expressed in 8080-100 % of melanomas Almost 100 % expression in primary cutaneous and mucosal melanoma Less often and weaker expressed in metastatic lesions Desmoplastic melanomas may be negative Is a highly specific and sensitive marker for melanocytic differentiation More sensitive than HMBHMB-45 Considerably more specific than s-100 Appears to be the most valuable marker for melanoma Markers of melanocytic tumours ¾ Immunohistochemistry using melanocytic markers is of particular value in the diagnosis in cases of: z z z Metastatic lesions with no known primary tumour To confirm metastatic melanoma/ melanoma/melanocytic tumours -sentinel node As a help in the distinction between benign and malignant lesions?? 3 Melanoma in rectal mucosa Metastatic melanoma in duodenum S-100 CK Melan Metastatic melanoma in duodenum Metastatic melanoma in duodenum Protein s-100 Melan A Melanoma in nasal mucosa Melanoma in the anal mucosa S-100 Melan A 4 Melanoma in the anal mucosa Malignant melanoma in the maxillary sinus EMA EMA CK S-100 Melan A S-100 Melan A Metastatic melanoma in the jejunal wall The NordiQC experience ¾ Run 7, 2003 ¾ 63 labs submitted s-100 stainings ¾ 66 labs submitted MSA stainings ¾ 35 labs submitted Melan A stainings The NordiQC experience ¾ MultiMulti-tissue block, z z z z z ss-100 staining Malignant melanoma of the bowel Brain tissue Malignant melanoma of the testis Appendix Blue nevus The NordiQC experience ¾ Criteria for the ss-100 staining as optimal: z z Strong and distinct nuclear and cytoplasmic staining reaction in the tumour cells of malignant melanoma and the nevus Glial cells, Schwann cells, fat cells, reticulom cells including epidermal Langerhan’s cells should also be demonstrated. demonstrated. 5 The NordiQC experience ¾ Results of the assessment of ss-100 stainings z z z z Optimal 19 (30%) Good 26 (41%) Borderline 10 (16%) Poor 8 (13%) The NordiQC experience ¾ S-100 staining ¾ What characterized the submitted protocols when the staining results were optimal or good? z z z Polyclonal ab Z0311 Sufficient concentration of the ab Sufficient prepre-treatment (HIER or enzymatic) enzymatic) The NordiQC experience The NordiQC experience, experience, ss-100 ¾ MultiMulti-tissue block, z z z Normal appendix z z MSA staining Malignant melanoma of the bowel Granulosa cell tumour Malignant melanoma of the testis Adrenal gland Blue nevus Normal app, HM The NordiQC experience ¾ Criteria for the MSA staining as optimal: z z Strong and distinct cytoplasmic staining reaction in the tumour cells of malignant melanoma and the nevus No staining reaction seen in other cells. The NordiQC experience ¾ Results of the assessment of MSA stainings z z z z Optimal 30 (45%) Good 19 (29%) Borderline 13 (20%) Poor 4 (6%) 6 The NordiQC experience ¾ ¾ MSA staining What characterized the submitted protocols when the staining results were optimal or good? z z z Sufficient concentration of the ab Sufficient prepre-treatment (HIER or enzymatic) enzymatic) The use of a nonnon-biotin based detection system or efficient biotin blocking The NordiQC experience ¾ MultiMulti-tissue block, z z z z z The NordiQC experience ¾ Criteria for assessing the Melan A staining as optimal: z z z Strong and distinct cytoplasmic staining reaction in the normal melanocytes, melanocytes, the tumour cells of malignant melanoma and the nevus If mAb was used, used, a distinct staining of the granulosa cell tumour and adrenal cortex cells should be seen No staining reaction seen in other cells. The NordiQC experience ¾ ¾ Melan A staining Malignant melanoma of the bowel Granulosa cell tumour Malignant melanoma of the testis Adrenal gland Blue nevus The NordiQC experience ¾ Results of the assessment of Melan A stainings (35! labs submitting stainings) stainings) z z z z Optimal 14(40%) Good 10 (29%) Borderline 8 (23%) Poor 3 (8%) The NordiQC experience Melan A Melan A staining What characterized the submitted protocols when the staining results were optimal or good? z z z The use of HIER in TrisTris-EDTA pH 9, when using mAb A103 Sufficient prepre-treatment (HIER or enzymatic) enzymatic) Sufficient concentration of the mAb A B C A.Blue nevus B. Malignant melanoma C. Malignant melanoma D. Granulosa cell tumour E Adrenal cortex D E 7 Suggestions/conclusions I Benign nevus, Mel A ¾ The antibody panel för melanocytic differentation should contain What can be suggested or concluded? z z z Suggestions/conclusions II ¾ The antibody panel för melanocytic differentation may also contain z Microphtalmia transcription factor • A nuclear marker • Expressed in desmoplastic variants z When appropriate • Vimentin • Ki 67 always positive in melanoma may contribute in some cases Protein ss-100 Melan A for its sensitivity for its specificity In fact: sfact: a tumour cell population that is s100+/Mel A+ is very likely to be melanocytic Suggestions/conclusions III ¾ The NordiQC experience clearly indicates that improvements are needed and that external quality control is very important in immunohistochemistry to achieve and maintain high standards in routine diagnostic work Thanks for listening 8