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, 6/218

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