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 isofrom 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 sensitivty 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 particualr cause of concern⁷.

Immunohistochemical expression

Normal and non-neoplastic tissues²:

	positive staining	no staining
skin	melanocytes, macrophages	epidermis, adnexal epithelium, Langerhans cells3
nerve	Schwann cells	perineurium
brain	inflammatory and stromal cells of leptomeninges	glial and neuronal cells
lung	macrophages	epithelium
stomach, colon, gallbladder	muscularis	mucosa
bladder	muscularis	mucosa
prostate	smooth muscle	epithelium
breast	stroma	epithelium
lymph node	histiocytes, dendritic cells, tingible body macrophages3, epithelioid granulomas3, Langhans cells3	majority of lymphocytes, interdigitating reticulum cells3
bone	osteoclasts9	osteoblasts
kidney	rare tubular cells
testis, thyroid, liver, parotid, ovary	none

Benign melanocytic lesions
common acquired naevi	21/215
dysplastic naevi	4/45
blue naevi	16/165, 3/44
Spitz naevi	5/55
cellular blue naevi	7/75, 3/4
pigmented spindle cell naevi	9/95
melanocytic schwannoma	3/3
Malignant melanomas
malignant melanoma in situ	5/55
superficial spreading melanoma	24/245
metastatic melanoma	12/122
lentigo maligna	11/115
nodular melanoma	4/45
desmoplastic melanoma	1/145, 11/204, 7/202, 6/21 (described as "spindle cell and desmoplastic")8
clear cell sarcoma	7/104, 4/42, 10/153
melanotic Schwannoma	3/34
Non-melanocytic skin lesions
dermatofibroma	2/52, 0/203, 4/68
dermatofibrosarcoma	1/52
schwannoma	0/75, 3/52
atypical fibroxanthoma	0/65, 1/104, 2/22
spindle cell squamous cell carcinoma	0/65
basal cell carcinoma	0/65
giant cell tumour	0/25
neurofibroma	0/105, 2/104, 2/52
malignant peripheral nerve sheath tumour	3/52, 0/203, 0/124
palisaded and encapsulated neuroma	0/105
leiomyosarcoma	3/32, 0/103, 0/65
fibrosarcoma	3/52, 0/103
scar tissue	0/104, 3/52
Renal tumours
angiomyolipoma	22/291, 4/42, 2/123
clear cell renal cell carcinoma	0/91
sarcomatoid renal cell carcinoma	1/61
renal leiomyosarcoma	0/21
well differentiated liposarcoma	1/51
undifferentiated renal sarcoma	0/11
Other non-cutaneous tumours
squamous cell carcinoma of head and neck	0/203
adenocarcinoma	breast, ductal 0/103 breast, lobular 0/103 lung 0/42, 0/103 stomach 0/42 colon 0/42 pancreas 1/42 kidney 1/42 endometrium 0/42 ovary 1/122 ovarian & endometrial 0/203 prostate 0/42 total 3/90
adenocarcinoma and squamous cell carcinoma	0/803
poorly differentiated carcinoma	0/203
mesothelioma	0/103
neuroendocrine tumours	carcinoid 0/122 large cell carcinoma 0/42 small cell carcinoma 0/42 Merkel cell carcinoma 0/42 paraganglioma 0/42
germ cell tumours	seminoma 2/42 dysgerminoma 2/42 embryonal carcinoma 0/42 yolk sac tumour 0/42 teratoma 0/122 choriocarcinoma 0/122 implantation site trophoblastic tumour 0/22
haematolymphoid neoplasms	follicular lymphoma 0/42 diffuse large B cell lymphoma 2/42, 0/203 peripheral T cell lymphoma 1/42 CD30+ large cell lymphoma 0/42, 0/43 Burkitt's lymphoma 0/42 LP Hodgkin's 0/42 NS Hodgkin's 1/42 Maltoma 1/42 myeloma 0/42 hairy cell leukaemia 0/42
soft tissue tumours	granular cell tumour 2/42 glomus tumour 0/42 haemangiopericytoma 1/42 solitary fibrous tumour 2/42 Schwannoma 2/42, 1/68 Neurofibroma 1/42 MPNST 1/42, 0/203 epithelioid sarcoma 0/42 synovial sarcoma 0/42, 0/113 lymphangioleiomyomatosis 1/63 leiomyoma 1/28 leiomyosarcoma 9/122, 0/103, 2/68 GIST 1/42 alveolar soft part sarcoma 0/42 fibromatosis 1/42 chordoma 1/42 angiosarcoma 0/42, 0/203 chondrosarcoma 2/42 osteosarcoma 2/82
endocrine tumours	thyroid 0/202 parathyroid 0/42 islet cell tumour 0/42 pituitary tumour 0/42 adrenocortical tumour 0/82, 0/123
paediatric tumours	osteoclastoma 7/73 rhabdomyosarcoma 0/82 Ewing's sarcoma 0/42 desmoplastic small round cell tumour 0/42 lymphoblastic lymphoma 0/42 rhabdoid tumour 0/42 neuroblastoma 0/42 Wilm's tumour 0/42 hepatoblastoma 0/42
others	Leydig cell tumour 0/42 Sertoli-Leydig cell tumour 0/42

Diagnostic utility

Diagnosis of malignant melanoma. This includes the analysis of sentinel lymph nodes; however, care needs to be taken as histiocytes may be immunoreacitve⁷.

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