MLA

(Melan-A)
Characteristics

Melan-A is a melanocyte differentiation antigen, recognized by autologous cytotoxic T lymphocytes. Melan-A is also called MART-1 (melanoma antigen recognized by T cells). The Melan-A/MART-1 gene encodes this protein, 20-22 kDa, associated with endoplasmic reticulum and melanosomes. The function of the protein is unknown. Melan-A is expressed in all normal melanocytes and melanocyte cell lines. Using the monoclonal antibody A-103, staining is also seen in steroid hormone producing cells: adrenal cortex, granulosa and theca cells of the ovary and Leydig cells of the testis. This is due to cross reaction (as the Melan-A gene is not detected in these cells).

Neoplasms

Melan A is expressed in 80-100% of malignant melanomas, including all primary cutaneous malignant melanomas and mucosal melanomas. In metastastic melanomas the staining may be patchy and somewhat less often positive than in the corresponding primary tumours. In desmoplastic melanoma the staining reaction is frequently patchy or negative. Cutaneous naevi (intradermal, compound, junctional) are Melan-A positive as are Spitz naevus, blue naevus etc. Melan-A is also demonstrated in other tumours of melanocytic origin or differentiation (i.e., melanosome producing), such as clear cell sarcoma, melanotic neurofibroma, melanotic schwannoma and other melanotic neural crest derived tumours, as well as in so-called PEComas (perivascular epitheloid cell tumour) derived from modified smooth muscle cells in the so-called tuberous sclerosis complex: angiomyolipoma, lymphangioleiomyoma(-tosis), and pulmonary sugar tumour. Using the antibody A-103, staining is furthermore seen in steroid hormone producing tumours: adrenocortical adenoma and carcinoma , sex cord-stromal tumour of the ovary and Leydig cell tumour of the testis.

Application

Together with Microphtalmia transcription factor, Melan-A is one of the most valuable melanoma markers. In several studies, Melan-A has shown to be a more sensitive marker of melanocytic differentiation than e.g., Melanosoma Antigen and Tyrosinase, particularly regarding spindle cell and desmoplastic malignant melanomas. Melan-A is a more specific marker than S-100 protein. Melan-A should therefore be included in a standard melanoma panel. Melan-A is useful in confirming melanocytic differentiation of primary cutaneous tumours, differentiating these from neurothekeoma and benign fibrous histiocytoma. It is, however, of little help in differentiating melanocytic tumours with Schwannian differentiation from peripheral nerve sheath tumours. Melan-A is useful for the identification of PEComas (together with alpha smooth muscle actin). Using antibody A-103, Melan-A should also be included in panels for the diagnosis of e.g., clear cell tumours (for the identification of adrenal cortical tumours) and non-epithelial ovarian tumours.

Controls

Adrenal gland is a recommendable positive tissue control for MLA when using the mAb clone A103. A moderate to strong granular cytoplasmic staining reaction must be seen in virtually all epithelial cells throughout the adrenal cortex. However, this reaction pattern can only be applied when a non-biotin based detection system is used, as adrenal cortical cells are rich on endogenous biotin and a false positive staining reaction will thus mimic the specific reaction and eliminate the potential as a reliable positive control. For the rest of the MLA clones (without cross reactivity towards steroid producing cells) normal skin and melanomas with low MLA expression must be used as positive controls. In normal skin, virtually all melanocytes should show a strong positive reaction in the cytoplasm and weak to moderate reaction in the melanocytic dendrites in most melanocytes. Kidney is recommended as negative tissue control. No staining should be seen in the epithelial cells of tubules. Scattered epithelial cells may show a granular staining reaction caused by lipofuscin. 

Selected references

Busam KJ. The use and application of special techniques in assessing melanocytic tumours. Pathology. 2004 Oct;36(5): 462-9. Busam KJ. Cutaneous desmoplastic melanoma. Adv Anat Pathol. 2005 Mar;12(2):92-102. Chen Y-T, et al. Serological analysis of Melan-A (Mart-1), a melanocyte specific protein homogenously expressed in human melanomas. Proc Natl Acad Sci USA 1996;93:5915-5919. Coulie PG, et al. A new gene coding for a differentiation antigen recognised by autologous cytotoxic T lymphocytes on HLA-A2 melanomas. J Exp Med 1994;180:35-42. Jungbluth AA, et al. An anti melan-A monoclonal antibody for the detection of malignant melanoma in paraffin embedded tissues. Am J Surg Pathol 1998;22:595-602. Kawakami Y, et al. Cloning the gene coding for shared human melanoma antigen recognised by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 1994;91:3515-3519. Miettinen M, Fernandez M, Franssila K, Gatalica Z, Lasota J, Sarlomo-Rikala M. Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol. 2001 Feb;25(2):205-11. Orosz, Z. Melan-A/Mart-1 expression in various melanocytic lesions and in non-melanocytic soft tissue tumours. Histopathology 1999,34:517-525. Stewart CJ, Nandini CL, Richmond JA. Value of A103 (melan-A) immunostaining in the differential diagnosis of ovarian sex cord stromal tumours. J Clin Pathol. 2000 Mar;53(3):206-11.

09.12.14 - HH/MV/LE