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The Internet Journal of Dermatology 2007 : Volume 5 Number 1

Diagnostic dilem m a: HMB-45 and Melan-A negative tum or , can it be still a m elanom a?: MITF(Microphthalm ia-associated tran scription factor)stain m ay confirm the diagnosis

Jeff F. W ang M.D.

Department of Pathology

Creighton University Medical Center

Omaha NE USA

Deba P. Sar ma M.D.

Department of Pathology


Omaha NE USA

Pam ela Ulmer D.O.

Department of Pathology Creighton University Medical Center

Omaha NE USA

C i t a t i o n : J. F. Wang, D. P. Sarma & P. Ulmer : Diagnostic dilemma: HMB-45 and Melan-A negative tumor, can it be still a melanoma?:

MITF (Microphthalmia-associated transcription factor) stain may confirm the diagnosis . The Internet Journal of Dermatology. 2 0 0 7

Volume 5 Number 1

Keywords: Melanoma | HMB-45 | Melan-A | MITF

Abstract

We report a case of dermal malignant melanoma that stained negatively for commonly done immunostains, HMB-45,

and Melan-A. It stained weakly positive for S-100 protein, a less specific marker for melanocytes. The diagnosis was

established by strongly positive immunostaining by MITF ( microphthlmia-associated transcription factor). A brief

review of the MITF and its usefulness in the diagnosis of melanoma are presented.

Source of support

None

Case Report

An 82-year-old male presented with a 1-cm raised dermal nodule on the medial side of the right foot that has been



present for unknown duration. There was no pigmented lesion of the skin. The patient denied any previous history of

melanoma.

The biopsied skin measured 1.8x 1.4 x 1.0cm and showed a well- circumscribed white, firm dermal nodule. The

epidermis was intact.

On microscopic examination, the tumor mass was composed of large dysplastic epithelioid and spindle cells forming

nests and sheets. The cell nests were surrounded by thin bundles of collagen. The tumor cells contained large,

hyperchronic nuclei with prominent red nucleoli. There were many mitotc figures. There was no ulceration or

epidermal invasion by the tumor cells. The lesion extended from papillary to deep dermis (Figures 1, 2).

Figure 1: Malignant melanoma, H&E, 4x

Figure 2: Malignant melanoma, H&E, 20x



Figure 3: Tumor is negative for HMB-45

Figure 4: Tumor is negative for Melan-A

Figure 5: Weakly positive nuclear and cytoplasmic stain of the melanoma cells by S-100 protein



Figure 6: Strongly positive nuclear stain of the melanoma cells by MITF

The tumor was immunostained with HMB-45, Melan-A, and S-100 protein. The tumor cells were completely negative

for HMB-45 and Melan-A and were weakly positive for S-100 protein (Figures 3, 4, 5).

Additional immunostains, such as, tyrosinase, CD 68, and SMA were performed to exclude melanocytic-, histiocytic-

or smooth muscle origin of the tumor; they all stained negatively. Finally, the tumor was immunostained with MITF,

because the light microscopic feature was very suggestive of melanoma. The MITF stain showed a strongly positive

nuclear stain of the tumor cells (Figure 6) confirming the diagnosis of melanoma.

CommentMalignant melanoma is the most serious form of skin cancer. Although it accounts for only 4 percent of all

dermatologic cancers, it is responsible for 80 percent of deaths from skin malignancy. In the clinical practice, one may

rarely find a dermal nodule in the absence of a primary melanocytic lesion. A biopsy of the lesion may show a

neoplasm with histological features of melanoma. Usually, the diagnosis is confirmed by immunostaining with HMB-

45, Melan-A, and S-100 protein, all of which are usually positive in melanocytes. The nodule may represent a primary

melanoma in the dermis or a metastatic nodule from some other sites. If such a tumor does not stain for HMB-45 or

Melan-A, a specific diagnosis of melanoma cannot be made with certainty.

Microphthalmia-associated transcription factor (MITF) is a melanocyte-specific transcription factor that plays a key

role in melanocyte development, survival and differentiation. MITF appears to contribute to melanocyte survival by

increasing the expression of the BCL-2 gene, a key antiapoptotic component. It also regulates the transcription of

silver homologue (SILV) the malanocytic-specific genes

melan-A(MLANA), whose immunohistochemical detection points to the diagnosis of melanoma. Malignant melanocytic

cells appear to have an increased number of MIFT loci. This increase is accompanied by the amplification of the MITF

protein, which subsequently enhances the expression of BCL-2 gene1. King et al

2first reported that the malignant

melanoma cells showed a 100% positive staining for MITF with a nuclear pattern of reactivity. MITF staining was

positive for 76 specimens of melanoma that failed to stain for either HMB-45 or S-100. Additional reports

3

,

4

haveconfirmed that MITF is a very sensitive and specific tumor marker for melanoma cells.

HMB-45 is a widely used immunohistochemical stain for detection of primary as well as metastatic melanoma. This

method uses monoclonal antibodies to a glycoprotein (gp100) that is present in cytoplasmic premelanosomes. In

immunohistochemical assays, this antibody reacts with melanoma cells, junctional nevus cells, and fetal melanocytes.

Melan-A is a differentiation antigen expressed in all melanocytic cytoplasm, and is reported to be positive in most

cases of melanoma. It also stains positively in adrenal cortex, granulosa and theca cells of ovary, and ledig cells. S-100

protein is calcium binding protein, which mostly distributed in the cytoplasm. This antibody recognizes all the S-100

isoforms and stains schwannomas, ependymomas, astrogliomas, and almost all benign and malignant melanomas and

their metastases. S-100 protein is also expressed in the antigen presenting cells such as the Langerhan cells in skin

and interdigitating reticulum cells in the paracortex of lymph nodes.

In our case, the morphology of tumor indicated a malignant melanoma. However, the tumor cells stained negatively

for traditional melanocytic markers, HMB-45 and Melan-A, and weakly positive for S-100. It did, however, show

strong positivity for MITF. Our observation confirms that a stain for MITF, a specific nuclear marker for



melanocytes may be very useful in evaluating biopsies from a suspicious melanoma cases when all other traditional

melanocyte markers are negative. Otherwise an HMB-45 and Melan-A negative tumor could be easily interpreted as

a non-melanocytic tumor.

Corr espondence To

Deba P Sarma, MD

Department of Pathology,


Omaha, NE 68131Tel: 402-449-4951

[[email protected]]

References

1. McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding

HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE. Bcl2 regulation by the melanocyte master regulator

Mitf modulates lineage survival and melanoma cell viability. Cell. 14; 109(6): 707-18, 2002. (s)

2. King R, Weilbaecher KN, MGill G, Cooley E, Mihm M, and Eisher DE. Microphthalmia Transcription Factor, A

sensitive and specific melanocyte marker for melanoma diagnosis. Am J Pathol. 155(3): 731-738, 1999. (s)

3. Yaziji H, Gown AM. Immunohistochemical markers of melanocytic tumors. International Journal of Surgical

Pathology 11(1): 11-15, 2003. (s)

4. Sheffie MV, Yee H, Dorvault CC, Weiaecher KN, Eltoum SA, Siegal GP, Fisher DE, Chhieng DC. Comparison of five

antibodies as markers in the diagnosis of melanoma in cytologic preparations. Am J Clin Pathol. 118(6): 930-936,

2002. (s)

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