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Microphthalmia transcription factor (Mitf)

The microphthalmia (mi) gene encodes a transcription factor, Mitf, a nuclear basic helix–loop–helix leucine zipper protein9, which is essential for the development and survival of melanocytes. The transcription factor regulates the transcription of genes involved in melanin synthesis, including tyrosinase, TRP1 and TRP2. Heterozygous mutation of the mi gene results in Waardenburg syndrome type IIA, a pigmentary disorder with a white forelock and hearing loss. Homozygous mi-deficient mice show complete loss of melanocytes from skin, the choroid of the eye and the stria vascularis of the inner ear: they are deficient in mast cells and develop osteopetrosis. Melanocyte stimulating hormone (a-MSH) stimulates expression of Mitf.

There are at least four isoforms (A, H, B and M). Only isoform M is specific to melanocytes. Antibodies C5 and D5 are immunoreactive with formalin-fixed paraffin-embedded tissues. However, they are not specific to Mitf-M10. D5 appears more sensitive than C5, and a cocktail may show greater sensitivity than either alone6. Immunoreactivity for Mitf is nuclear.

Although most papers indicate that it is a useful melanocytic marker, the diagnostic specificity of Mitf for melanomas has been thrown into question by a study of a large range of normal tissues and neoplasms, showing immunoreactivity in a wide range of tumours2. Reactivity of histiocytes is a particular cause of concern7.

Immunohistochemical expression

Normal and non-neoplastic tissues2:

Diagnostic utility

Diagnosis of malignant melanoma. This includes the analysis of sentinel lymph nodes; however, care needs to be taken as histiocytes may be immunoreactive7.

References

1Zavala-Pompa, A., Folpe, A. L., Jimenez, R. E., Lim, S. D., Cohen, C., Eble, J. N., Amin, M. B. Immunohistochemical study of microphthalmia transcription factor and tyrosinase in angiomyolipoma of the kidney, renal cell carcinoma, and renal and retroperitoneal sarcomas: comparative evaluation with traditional diagnostic markers. Am J Surg Pathol 2001;25:65-70.

2KJ Busam et al. Analysis of microphthalmia transcription factor expression in normal tissues and tumors, and comparison of its expression with S-100 protein, gp100 and tyrosinase in desmoplastic malignant melanoma. Am J Surg Pathol 2001;25:197-204.

3Miettinen 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.

4Koch MB et al. Microphthalmia transcription factor and melanoma cell adhesion molecule expression distinguish desmoplastic spindle cell melanoma from morphologic mimics. Am J Surg Pathol 2001;25:58-64.

5King R et al. Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic and nonmelanocytic tumors. Am J Surg Pathol 2001;25:51-57.

6Xu, 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.

7Busam KJ. Microphthalmia transcription factor: expression is not restricted to melanocytes. Advances in Anatomic Pathology 2002;9:140-144.

8Granter, S.R., Weilbaecher, K.N., Quigley, C., Fletcher, C.D. and Fisher, D.E. Microphthalmia transcription factor: not a sensitive or specific marker for the diagnosis of desmoplastic melanoma and spindle cell (non- desmoplastic) melanoma. Am J Dermatopathol 2001;23:185-9.

9Prasad, M. L., A. A. Jungbluth, et al. (2001). “Expression of melanocytic differentiation markers in malignant melanomas of the oral and sinonasal mucosa.” Am J Surg Pathol 25(6): 782-7.

10Busam KJ, Kucukgol D, Sato E, Frosina D, Teruya-Feldstein J,Jungbluth AA Immunohistochemical Analysis of Novel Monoclonal Antibody PNL2 and Comparison With Other Melanocyte Differentiation Markers. Am J Surg Pathol 2005; 29:400-406

This page last revised 27.12.2002.

©SMUHT/PW Bishop