Treatment of metastatic malignant melanoma with recombinant interferon alpha 2

Fifty-nine patients with metastatic malignant melanoma were entered into a phase II trial of recombinant alpha-2 interferon given in a dosage of 10 million IU/M2 subcutaneously three times per week for one year. Forty-five of these were evaluable for response. Of five evaluable patients with ocular primaries, none responded to interferon treatment. Four of 40 patients (10%) with cutaneous primaries achieved complete remission, and 6 further patients (15%) had partial remissions for a combined response rate of 25%. Two patients remain in complete remission 15+ and 32+ months after starting treatment. Responses were limited to subcutaneous, lymph node and lung metastases. The treatment schedule was well tolerated with the majority of patients receiving more than 70% of their predicted doses. Flu-like symptoms were the most common side effect. No evidence of cumulative toxicity was seen. We conclude that interferon is an active agent in metastatic malignant melanoma of cutaneous origin and that further trials are indicated.     

CEA immunoreactivity in metastatic malignant melanoma.

Immunohistochemical techniques may aid in the diagnosis of poorly differentiated metastatic tumors. Anti-carcinoembryonic antigen (CEA) antibodies have been used in the identification of epithelial neoplasms. However, recent unpublished data report CEA reactivity in malignant melanoma and melanoma cell lines. We studied 28 cases of known metastatic malignant melanoma with an antibody panel for CEA (polyclonal and monoclonal), AE1:3, S-100, and HMB-45. Reactivity for CEA (polyclonal) was seen in 15 of 28 (53%) cases: nine exhibited strong diffuse positivity, five moderate focal positivity, and one globular cytoplasmic staining. Focal reactivity for cytokeratin (AE1:3) was seen in three of 28 cases. HMB-45 staining was present in 23 of 28 (82%, including strong positivity in the cytokeratin-reactive cases). Staining for S-100 protein was strong in all cases. No staining was seen for CEA (monoclonal). CEA immunoreactivity is seen in a significant number of metastatic malignant melanoma cases. This may be due to CEA expression by tumor cells, or crossreactivity of the polyclonal antibody with substances such as nonspecific crossreacting antigen (NCA) that share antigenic sites with CEA. These findings emphasize the need for care in interpreting immunohistochemical results. Immunohistochemical evaluation of CEA should not be made alone, but only as part of a diagnostic antibody panel.     

Spontaneous regression of metastatic malignant melanoma in 2 sibs with xeroderma pigmentosum.

The clinical and pathology findings in 2 sibs with xeroderma pigmentosum (XDP), complicated by metastatic malignant melanoma which underwent spontaneous regression, are described. The pathology of one of these patients showed features of possible spontaneous regression, namely foamy histiocytes, capillary proliferation, and a chronic inflammatory infiltrate which was devoid of malignant cells, suggesting the possibility that an immunological mechanism was at work. It was of interest that a recent review of 27 cases of spontaneous regression of metastatic melanoma since 1900 contained a patient with XDP. Adding our 2 cases, at least 10% of the spontaneous regressions of metastatic melanoma occurred in patients with XDP. This unusual association raised the question that the genotype for XDP may possibly foster control of metastatic malignant melanoma in some as yet unknown way.     

Cytodiagnosis of amelanotic metastatic malignant melanoma: An immunocytochemical study

Malignant melanomas are known to present diverse patterns and this can result in considerable difficulties for an interpretation of malignancy type from cytohistologic material. Such difficulties are further compounded, if melanin pigment cannot be demonstrated by conventional histochemical stains; unfortunately many cases do exhibit this feature, especially in its metastases. This study was designed to review cases of amelanotic metastatic malignant melanomas in a variety of cytologic samples which were received from 40 patients with a known history of malignant melanoma. Cytomorphologically, the cases were classified as classical, carcinoma-like, spindle cell type, lymphoma-like, and undifferentiated type (Table I). While in 36 of the cases, the diagnosis of metastases from a melanoma was confirmed based on an immunopositivity to a variety of melanoma markers (Table III), in four of the cases, the immunostaining indicated metastases from another primary source, which was subsequently found. Based on our study, we are of the opinion that an immunologic characterization is useful to conclusively diagnose the majority of cases of metastatic amelanotic malignant melanomas. Furthermore, we feel that a reliance on a single melanoma marker is not justified, and a panel of antibodies should be used to distinguish a metastatic amelanotic malignant melanoma from other metastatic neoplasms. Diagn. Cytopathol. 16:238–241, 1997. © 1997 Wiley-Liss, Inc.     

Classification of CEA-related positivity in primary and metastatic malignant melanoma

Using a panel of antibodies to carcinoembryonic antigen (CEA), in paraffin-processed biopsy material patchy, predominantly membranous positivity was seen on tumour cells in 70 per cent of cases of superficial spreading melanoma, 60 per cent of nodular melanomas, and 75 per cent of secondary deposits studied with unabsorbed polyclonal anti-CEA only. No staining was seen using monoclonal anti-CEAs. Localization of CEA to the cell membrane was confirmed with confocal microscopy. Immunoblotting of fresh frozen material detected CEA of around 180 kD in both primary and metastatic melanomas migrating with an apparent molecular weight of between 150 and 200 kD, indicating variable glycosylation of the protein. Recognition of an adhesive role for CEA with roles in immunolocalization and immunotherapy emphasizes the importance of more precise classification of CEA-related positivity in human tumours.     

Fine-needle aspiration biopsy of metastatic malignant melanoma resembling a malignant peripheral nerve sheath tumor

We report a case of metastatic malignant melanoma resembling a malignant peripheral sheath tumor, which posed a significant diagnostic challenge. The patient is a 76-year-old male, who presented in the emergency room with bilateral chest pain exacerbated by inspiration. The pain was present for 3 week and was not exacerbated by physical exercise. The diagnostic workup revealed bilateral parenchymal pulmonary infiltrates. The CT-scan guided fine-needle aspiration and the core biopsies of the largest pulmonary lesion revealed high-grade spindle cell neoplasm with individual cell apoptosis and necrosis. The immunohistochemical profile on the cell block showed that the cells are positive for Vimentin. The S-100 stain showed only focal positivity. The immunohistochemical stains for HMB45, Melan A, pancytokeratin, and smooth muscle actin were negative. Five years ago the patient was diagnosed with melanoma on the back with Clark level of IV. The melanoma was excised with clear margins and sentinel lymph nodes were negative. Careful examination of patient's previous slides revealed an area of spindle cell melanoma adjacent to a nodular type melanoma. Based on the patient's previous history, current clinico-pathologic presentation and immunohistochemical profile, the diagnosis of metastatic malignant melanoma resembling peripheral nerve sheath tumor was favored over the diagnosis of metastatic malignant spindle cell neoplasm of unknown primary site, which by itself is very rare clinical scenario.     

A case of metastatic malignant melanoma masquerading as disseminated mammary carcinoma

A 42-year-old woman presented with widespread secondaries and a mammary mass. A provisional diagnosis of metastatic breast carcinoma was made. Histological evaluation of the mammary tumour including immunohistochemical studies suggested the diagnosis of metastatic malignant melanoma, which was later confirmed.     

Kba.62 and S100 protein expression in cytologic samples of metastatic malignant melanoma

The diagnosis of melanoma can be challenging, especially in metastatic lesions, due to the ability of melanoma cells to morphologically mimic carcinoma, sarcoma and even lymphoma cells. Moreover, melanomas can exhibit negative immunostaining for the melanoma markers HMB‐45 and MART‐1/Melan‐A, often used in the diagnosis of this tumor. KBA.62 is a recently described antibody that reacts with benign and malignant melanocytic proliferations. In this study, we report our experience with KBA.62 and S100 protein immunostaining in the diagnosis of metastatic melanoma on fine‐needle aspiration and effusion samples. We reviewed 60 cytology samples from 58 patients with metastatic melanoma. Our results showed that KBA.62 stained 75% of the cases and S100 protein 87% of the cases. KBA.62 and S100 protein stained the majority of metastatic melanomas that were negative for HMB‐45 and MART‐1; KBA.62 stained 73% of the cases and S100 protein 73% of the cases. The majority (85%) of the cases negative for HMB‐45 and MART‐1 were positive for KBA.62 and/or S100 protein. Additionally, we also observed that KBA.62 staining was positive in the majority of epithelioid and spindle cell type melanoma cells. In conclusion, the performances of KBA.62 and S100 protein were similar and both markers are useful in the diagnosis of metastatic melanoma in cytology material, especially when the tumor cells lack expression of HMB‐45 and MART‐1. Diagn. Cytopathol. 2013;41:847‐851. © 2013 Wiley Periodicals, Inc.     

Cytogenetic findings in a human malignant melanoma metastatic to the brain

Cytogenetic analysis by G-banding of direct and preparations of a malignant melanoma metastatic to the brain in vitro showed a pseudodiploid modal chromosome number, including five marker chromosomes, one of which was an i(6p). These results agree with those recently reported about the preferential involvement of chromosome #6 in malignant melanoma.     

Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response.

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.     

Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma.

Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg/m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-alpha) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%). When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (alpha chain) and high affinity receptor (alpha + beta) expression. In contrast, intermediate affinity p75 (beta chain) expression was decreased significantly (P < or = 0.0001) in MMM patients. During treatment, we found a dramatic increase of beta chain as well as high affinity (alpha + beta) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of beta chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of beta chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early beta chain expression is correlated with the clinical response to chemoimmunotherapy.     

Follow up of soluble IL-2 receptor level in metastatic malignant melanoma patients treated by chemoimmunotherapy.

Immunological parameters following chemoimmunotherapy combination were studied in 31 patients with metastatic malignant melanoma. They received Cisplatin (100 mg/m2) on day 1 and 28, recombinant IL-2 (rIL-2; Eurocetus) in continuous infusion from day 3 to 6, 17 to 21, 31 to 34 and 45 to 49. Interferon-alpha (IFN-alpha; Roche) was given subcutaneously three times weekly. No significant change in CD4/CD8 ratio at onset or during treatment was observed between responder (n = 19) and non-responder (n = 12) patients. Regarding the IL-2 receptor (IL-2R) study, the percentage of cells expressing Tac (p55) receptor did not change either for healthy volunteers (n = 20) and patients before any therapy, or between responder and non-responder patients. Concerning serum soluble IL-2R shedding before therapy, we observed a significant increase (P = 0.001) in patients (79 +/- 40 pM) compared with healthy donors (30 +/- 15 pM), but no significant variation was seen between responder and non-responder patients. In contrast, during the treatment, the soluble IL-2R level increased in both groups but, interestingly, a significant difference was found between responder and non-responder patients from day 7 (P < 0.05) to day 21 (P < or = 0.01), suggesting that the cells from non-responder may be slower in becoming stimulated. This finding is the most striking point of our study and suggests that sIL-2R might be an early predictive factor of the clinical response as obtained by logistic regression (P = 0.0063). Therefore patients with a serum soluble IL-2R level greater than 250 pM at day 21 have a 12-fold more chance of undergoing a clinical response.     

Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1

We developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.     

Malignant melanoma metastatic to a meningioma.

The case presented is that of a 63 year old man with a metastasis to an intracranial meningioma from a malignant melanoma. Although the phenomenon of tumor to tumor metastasis to a meningioma has been previously reported, this is the first case in the literature to date, in which the primary tumor is a malignant melanoma. The criteria for the diagnosis of tumor-to-tumor metastasis and possible reasons for the frequency of metastasis to meningiomas are briefly reviewed.     

Human malignant melanoma cell lines.

A series of 10 cell lines established from human malignant melanomas is described. The morphology varied but, in general, was epithelioid. Five produced visible melanin in culture but others produced melanin precursors. All lines were aneuploid and each had a distinctive human karyotype. One line appeared not to have the same sex as the patient but its karyotype was distinct from that of other lines.