mart-1-antigen and Lymphangioleiomyomatosis

Melan-A/MART-1 is a recently identified new melanocytic differentiation marker, which is recognized as an antigen on melanoma cells by cytotoxic T-lymphocytes. It is of interest for clinicians as potential immunotherapeutic target and it is relevant for pathologists as a novel diagnostic marker, since two antibodies (A103 and M2-7C10) have become available to study Melan-A/MART-1 expression on archival material. Both antibodies are useful in the differential diagnosis of melanocytic tumors, especially metastatic tumors, since they are more sensitive than HMB-45. Both antibodies are also of diagnostic value in the recognition of perivascular epithelioid cell tumors (angiomyolipoma, lymphangioleiomyomatosis, and clear cell tumor). Since A103 has the unique property of staining many steroid hormone producing cells, this antibody is also of value for the recognition of tumors derived from these cells, such as adrenocortical carcinomas. Both antibodies are likely to be included in the routine diagnostic armamentarium of many immunohistochemical laboratories in the near future.

Topics: Adrenal Cortex Neoplasms; Angiomyolipoma; Antibodies, Monoclonal; Antigens, Differentiation; Antigens, Neoplasm; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Lymphangioleiomyomatosis; Lymphatic Metastasis; Male; MART-1 Antigen; Melanocytes; Melanoma; Neoplasm Proteins; Ovarian Neoplasms; Skin Neoplasms; Testicular Neoplasms

The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8(+) lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8(+) T cells in functional assays. Responder T cells selectively clustered and secreted interferon-gamma in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.

Topics: Antigens, Neoplasm; Cell Separation; Cytotoxicity, Immunologic; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; gp100 Melanoma Antigen; Humans; Immunohistochemistry; Immunotherapy; Intramolecular Oxidoreductases; Lymphangioleiomyomatosis; Lymphocytes, Tumor-Infiltrating; MART-1 Antigen; Melanoma; Membrane Glycoproteins; Microscopy, Electron, Transmission; Neoplasm Proteins; Oxidoreductases; Skin Neoplasms; T-Lymphocytes, Cytotoxic

The antibody to the melanoma antigen recognized by T cells (anti-MART-1, clone M2-7C10) is a newly described antibody to a transmembrane protein previously detected only in normal skin melanocytes, retinal tissue, and malignant melanoma (MM). This antibody is the basis for ongoing immunotherapy protocols at the National Institutes of Health/National Cancer Institute. HMB-45, an antibody directed against a premelanosome glycoprotein, although used predominantly for the diagnosis of MM, has shown consistent staining in angiomyolipoma (AML), lymphangiomyoma/lymphangiomyomatosis (LAM), and clear cell sugar tumor (CCST), a group of tumors proposed to be related on the basis of their common perivascular epithelioid cells, which exhibit various degrees of smooth muscle differentiation, melanogenesis, and intracytoplasmic membrane bound granules. To compare the immunoreactive patterns of anti-MART-1 with those of HMB-45, we performed avidin-biotin immunoperoxidase testing on nonmelanocytic neoplasms (AMLs, LAMs, CCSTs) known to express HMB-45. Microwave pretreatment was necessary for anti-MART-1 staining on paraffin-embedded material. Our results showed that all of the 10 cases of AML were immunoreactive for both anti-MART-1 and HMB-45; that all of the 4 cases of LAM were positive for HMB-45, with 1 of the 4 reacting with anti-MART-1; and that 3 of the 4 cases of CCST expressed HMB-45, whereas 1 of the 4 was positive for anti-MART-1. Our findings lent additional support to previous studies that proposed a relationship between AML, LAM, and CCST. Anti-MART-1 and HMB-45 share similar specificities for these nonmelanocytic tumors, but the former seems to be a less sensitive marker for these lesions. In similar circumstances, anti-MART-1 and HMB-45 are potentially useful clinical markers.

Topics: Adenocarcinoma, Clear Cell; Angiomyolipoma; Antigens, Neoplasm; Humans; Immunoenzyme Techniques; Lymphangioleiomyomatosis; MART-1 Antigen; Melanoma-Specific Antigens; Neoplasm Proteins; T-Lymphocytes; Tumor Cells, Cultured