Melanoma

Immunohistochemistry

Typically positive for:

S-100. Positive in 95% of melanomas. Usually negative in signet-ring cell and rhabdoid melanomas. Usually positive in desmoplastic malignant melanomas.

NKIC3. Slightly more specific than S-100 but stains many non-melanocytic tumours.

HMB-45 Stains between 90% and 100% of primary melanomas, 80% or recurrent and metastatic melanomas and a lower proportion of spindle cell melanomas. Stains only minority of cases of desmoplastic malignant melanomas.

Melan-A. Rarely stains desmoplastic malignant melanomas.

Anti-tyrosinase. Sensitivity and specificity not yet adequately assessed, but appears to be less sensitive than S-100 and more sensitive than HMB-45². Stains only minority of cases of desmoplastic malignant melanomas.

PNL2: a initial report shows it is of similar sensitivity to other marker.s

MAGE expression by melanocytic cells appears to be restricted to malignant melanoma, with negativity in nevi^6,7. MAGE-1 is less sensitive than are S-100, tyrosinase, Melan-A and HMB-45¹⁰: its has been claimed that expression shows an inverse relationship with expression of HMB-45 in non-desmoplastic melanomas and may therefore be useful in S-100 positive / HMB-45 negative tumours⁵; others have not reproduced this¹⁰. Its sensitivity in desmoplastic melanoma is lower. MAGE-3 has a low sensitivity of 25%⁶ to 40%⁷.

Vimentin: least useful; stains a wide variety of tumours

NSE: least useful; stains a wide variety of tumours.

CD117 tends to stain the in-situ component strongly, with loss of staining in deep dermal and nodular components⁴.

MDA-7 (melanoma differentiation associated gene 7) is a newly-described putative tumour suppressor gene sharing homology with IL-10. Its protein product can be detected by immunohistochemistry. It is highly expressed in normal melanocytes and benign nevi. Some initial studies show loss in thick melanomas. This has not been confirmed, but it is downregulated in metastatic melanoma. Its usefulness remains to be elucidated⁸.

Studies of conventional metastatic malignant melanomas gave the following comparison between melanoma markers:

	S-100	HMB-45	Tyrosinase	Melan A	Mitf	MAGE-1
negative	4% (12/266)1	14% (36/266)1	7% (19/266)1	12% (33/266)1	12% (31/266)1
<10% of tumour cells	2% (2/266)1	20% (52/266)1	3% (8/266)1	10% (26/266)1	3% (9/266)1
10% to 30% of tumour cells	4% (10/266)1	11% (30/266)1	7% (18/266)1	17% (445/266)1	15% (39/266)1
>30% of tumour cells	90% (240/266)1	55% (148/266)1	82% (221/226)1	61% (163/266)1	70% (187/266)1
strongly positive	52/5610	39/5610		42/5610		15/5610

Studies have been made of the value of the other markers in those melanomas which are negative for HMB-45

Melanoma markers have been compared in a series of vaginal, ovarian and sinonasal melanomas

Melan-A (clone A103) and MART-1 (clone M2-7C10) appear to be superior to either S-100 or HMB-45 for the diagnosis of micrometastases in sentienl lymph nodes³. However, a cocktail of HMB-45, Tyrosinase and Melan A / Mart-1 may optimise sensitivity, equal to that of S-100 but with superior specificity, particularly for the assessment of sentinel lymph nodes⁹.

Desmoplastic melanomas pose a particular diagnostic problem.

Aberrant immunophenotypes:

Cytokeratins. Most frequently positive with Cam5.2, in up to 10% of melanomas.

CEA. Usually seen with polyclonal antibodies.

EMA. Unusual in conventional melanomas, but has been reported in 43% of desmoplastic malignant melanomas.

Desmin. Rarely positive.

SMA. Very rare in conventional melanomas and non-desmoplastic spindle cell melanomas, but is commonly seen in desmoplastic malignant melanomas

NFP. Rarely positive.

GFAP. Has been seen in desmoplastic malignant melanomas.

VS38.

CD68.

Factor XIIIa may be positive in desmoplastic malignant melanomas.

Differential diagnosis

Benign tumours

benign fibrous histiocytoma

reticulohistiocytoma
xanthoma
cellular neurothekeoma

neurofibroma
Schwannoma

leiomyoma

fibromatosis

Carcinoma

squamous cell carcinoma
adenocarcinoma
signet ring cell carcinoma
extramammary Paget's disease
sebaceous carcinoma
large-cell undifferentiated carcinoma
clear-cell carcinoma
small cell carcinoma
metaplastic carcinoma with bone and cartilage formation

Neuroendocrine tumours

Merkel cell carcinoma

paraganglioma

olfactory neuroblastoma

Sarcomas

fibrosarcoma

leiomyosarcoma

malignant fibrous histiocytoma
atypical fibroxanthoma

myxofibroma
malignant peripheral nerve sheath tumour

synovial sarcoma

rhabdomyosarcoma
epithelioid sarcoma

epithelioid angiosarcoma
Kaposi's sarcoma

interdigitating dendritic cell tumour

haemangiopericytoma
liposarcoma

myxoid
pleomorphic

alveolar soft part sarcoma

extraskeletal Ewing's sarcoma / peripheral neuroectodermal tumour
osteosarcoma
chondrosarcoma

gastrointestinal autonomic neuronal tumour (plexosarcoma)

Malignant lymphomas

anaplastic large-cell Ki-1 lymphoma

Germ cell tumours

References

Banerjee SS, Harris M. Morphological and immunohistophenotypic variations in malignant melanoma. Histopathology 2000. 36: 387-402.

¹Miettinen M et al. Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol 2001;25:205-211.

²Clarkson KS et al. The usefulness of tyrosinase in the immunohistochemical assessment of melanocytic lesions: a comparison of the novel T311 antibody (anti-tyrosinase) with S-100, HMB-45 and A103 (anti-melan-A). J Clin Pathol 2001;54:196-200.

³Shidham, V. B., Qi, D. Y., Acker, S., et al. Evaluation of micrometastases in sentinel lymph nodes of cutaneous melanoma: higher diagnostic accuracy with Melan-A and MART-1 compared with S-100 protein and HMB-45. Am J Surg Pathol 2001;25:1039-1046.

⁴Gibson, P. C., Cooper, K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 2002;9:65-69.

⁵Xu, X., Chu, A. Y., Pasha, T. L., Elder, D. E., Zhang, P. J. Immunoprofile of MITF, tyrosinase, melan-A, and MAGE-1 in HMB45- negative melanomas. Am J Surg Pathol 2002;26:82-87.

⁶Hofbauer, G. F., Schaefer, C., Noppen, C., Boni, R., Kamarashev, J., Nestle, F. O., Spagnoli, G. C., Dummer, R. MAGE-3 immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. Am J Pathol 1997;151:1549-1553.

⁷Busam, K. J., Iversen, K., Berwick, M., Spagnoli, G. C., Old, L. J., Jungbluth, A. A. Immunoreactivity with the anti-MAGE antibody 57B in malignant melanoma: frequency of expression and correlation with prognostic parameters. Mod Pathol 2000;13:459-465.

⁸Volk AL, Siegal GP. MDA-7: a novel prognostic marker. Advances in Anatomic Pathology 2002;9323.xxxxxxxxxxx

⁹Cook, M. G., M. A. Green, et al. (2003). "The development of optimal pathological assessment of sentinel lymph nodes for melanoma." J Pathol 200(3): 314-9.

¹⁰Gajjar, N. A., A. J. Cochran, et al. (2004). "Is MAGE-1 Expression in Metastatic Malignant Melanomas Really Helpful?" Am J Surg Pathol 28(7): 883-8.

This page last revised 17.3.2005.