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Microphthalmia means small eyes. In mammals the failure of expression of a transcription factor, MITF (microphthalmia-associated transcription factor), in the pigmented retina prevents this structure from fully differentiating. This in turn causes a malformation of the choroid fissure of the eye, resulting in the drainage of vitreous humor fluid. Without this fluid, the eye fails to enlarge, thus the name microphthalmia. more...

Mac Ardle disease
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The gene encoding the microphthalmia-associated transcription factor (Mitf) is a member of the basic helix-loophelix-leucine zipper (bHLH-ZIP) family. Waardenburg syndrome type 2 (WS type 2)in humans is also a type of microphthalmia syndrome. Mutation in MITF gene are thought to be responsible for this syndrome. The human MITF gene is homologous to the mouse MITF gene (aka mouse mi or microphthalmia gene); mouse with mutations in this gene are hypopigmented in their fur. The identification of the genetics of WS type 2 owes a lot to observations of phenotypes of MITF mutant mice.


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Malignant Melanoma With a Rhabdoid Phenotype: Histologic, Immunohistochemical, and Ultrastructural Study of a Case and Review of the Literature
From Archives of Pathology & Laboratory Medicine, 6/1/04 by Abbott, Jared J

* Malignant melanoma is known to display tremendous histologic diversity. One rare variant is the rhabdoid phenotype, so called because of the appearance of cells resembling rhabdomyoblasts seen in malignant rhabdoid tumors of the kidney. We present the histologic, immunohistochemical, and ultrastructural features of a malignant melanoma composed entirely of rhabdoid cells. A 62-year-old man presented with a 6.5-cm lung mass. Although presumed to be a metastatic lesion, extensive workup failed to reveal a primary tumor site. Histologic sections showed a mass composed entirely of polygonal neoplastic cells with prominent nucleoli and large hyaline cytoplasmic inclusions. The tumor cells were strongly immunoreactive with S100 protein, vimentin, and CD56, and were focally reactive with Mart-1. Tumor cells were negative for MelanA, tyrosinase, HMB-45, AE1/AE3, cytokeratin (CK) 7, CK8/ 18, CK20, CK903, CAM 5.2, epithelial membrane antigen, smooth muscle actin, desmin, leukocyte common antigen, Bcl-2, CD3, CD20, CD30, CD138, [kappa] and [lambda] light chains, CD68, CD34, factor VIII, synaptophysin, and glial fibrillary acidic protein. Electron microscopy showed cytoplasmic whorls of intermediate filaments containing entrapped rough endoplasmic reticulum, mitochondria, and lipid. Recognition of this rare variant of malignant melanoma is important in the evaluation of tumors with rhabdoid morphology.

(Arch Pathol Lab Med. 2004;128:686-688)

Malignant melanoma is known to display tremendous histologic diversity.1 Rare cases of malignant melanoma with a rhabdoid phenotype have been reported, so called because of the appearance of cells resembling the rhabdomyoblasts seen in malignant rhabdoid tumors of the kidney.2-7 Rhabdoid features in melanoma are seen primarily in metastatic lesions, similar to the signet ring and myxoid phenotypes.3-5,8,9 The largest study to date reported 31 cases of metastatic malignant melanomas with rhabdoid phenotype from 29 patients.3 Rhabdoid cells were the predominant neoplastic cells in 15 cases and comprised less than 25% of the tumor in the remaining cases. To our knowledge, only 4 cases of primary malignant melanoma of the skin with rhabdoid features have been reported in the literature to date.2,6

We present the histologie, immunohistochemical, and ultrastructural features of a malignant melanoma composed entirely of rhabdoid cells. To our knowledge, our case is the seventh rhabdoid malignant melanoma with documented ultrastructural features to be described in the literature.3,4,7 Recognition of this variant of malignant melanoma is important in the evaluation of tumors with rhabdoid morphology.


A 62-year-old man without pulmonary or constitutional symptoms was found to have a lung mass in his right upper lobe on routine chest radiograph during his admission for hypertension. Subsequent lobectomy revealed a 6.5-cm solitary tumor within the lung parenchyma that did not involve the pleura; the tumor was most consistent with a metastasis. Fourteen hilar and peribronchial lymph nodes were free of tumor. Skin examination showed only 2 nevi on his face (present since birth) and no lesions under his nails or on the soles of his feet. Computed tomography of chest, abdomen, and pelvis failed to reveal a possible primary tumor.


Four-micrometer-thick sections were cut from paraffin blocks and stained with hematoxylin-eosin and Fontana-Masson stains. Additional paraffin sections of selected blocks were obtained for immunohistochemical studies, which were performed on an automated immunostainer (Biotek System, Ventana Medical Systems, Inc, Tucson, Ariz) with the use of standard avidin-biotin peroxidase complex technique and heat-induced epitope retrieval. The following primary antibodies were used: S100 protein (1: 1200; Dako Corporation, Carpinteria, Calif), Mart-1 (M2-7C10, 1: 100; Signet Laboratory, Dedham, Mass), Melan-A (A103, 1:50; Dako), tyrosinase (T311, 1:50; Vector/Novocastra, Burlingame, Calif), HMB-45 (1:100; Dako), AE1/AE3 (1:50; Zymed Laboratories, South San Francisco, Calif), cytokeratin (CK) 7 (1:40; Dako), CK20 (1:80; Dako), CK8/18 (35[beta]11,1:160; Dako), CK903 (34[beta]E12, 1:100; Dako), CAM 5.2 (1:4; Becton Dickinson, Mountain View, Calif), epithelial membrane antigen (E29, 1:200; Dako), smooth muscle actin (IA4, 1:400; Dako), desmin (D33, 1:50; Dako), CD56 (123C3, 1:20; Monosan, San Francisco, Calif), leukocyte common antigen (CD45, 1:40; Signet), Bcl-2 (124, 1:20; Dako), CDS (1:200; Dako), CD20 (L26, 1:40; Signet), CD30 (BerH2, 1:20; Dako), [kappa] light chain (1:300; Signet), [lambda] light chain (1:350; Signet), CD34 (QBEnd 10, 1:40; Dako), factor VIII (1:1000; Dako), CD68 (Dako), glial fibrillary acidic protein (1:5600; Dako), synaptophysin (1:100; Dako), and vimentin (1:200; Dako).

For electron microscopic study, tissue was postfixed in 3% glutaraldehyde, and thin sections were stained with lead citrate and uranyl citrate. all grids were examined with a Hitachi 7500 electron microscope.


Histologie Findings

Histologie sections showed a mass well demarcated from the adjacent pulmonary parenchyma. The tumor was comprised entirely of rhabdoid cells, that is, polygonal and discohesive neoplastic cells with eccentric nuclei, single prominent nucleoli, and large hyaline cytoplasmic inclusions (Figure, A). An in situ component was not observed in the adjacent bronchi. A Fontana-Masson stain demonstrated no evidence of melanin pigment.

Immunohistochemical Findings

The neoplastic cells exhibited strong and diffuse immunoreactivity for S100 protein (Figure, B), vimentin (with paranuclear accentuation) (Figure, C), and CD56. They were focally positive for Mart-1. The tumor cells were negative for Melan-A, tyrosinase, HMB-45, AE1/ AE3, CK7, CK20, CK8/18, CK903, CAM 5.2, epithelial membrane antigen, smooth muscle actin, desmin, leukocyte common antigen, Bcl-2, CD3, CD20, CD30, CDl 38, [kappa] and lambda light chains, CD68, CD34, factor VIII, synaptophysin, and glial fibrillary acidic protein.

Ultrastructural Findings

The nuclei of tumor cells were prominent and contained a large nucleolus. The majority of the tumor cells had a cytoplasmic paranuclear whorl of intermediate filaments containing entrapped rough endoplasmic reticulum, mitochondria, and lipid (Figure, D). Melanosomes, basal lamina, primitive cell junctions, tonofilaments, microtubules, and contractile filaments were not identified. Occasional neurosecretory granules were noted.


Rhabdoid features are defined by morphologic characteristics, such as eccentric nuclei, large nucleoli, and abundant cytoplasm containing hyaline filamentous inclusions. First described in a pediatrie renal neoplasm as a rhabdomyosarcomatous variant of Wilms tumor, malignant rhabdoid tumor was later recognized as a separate entity.10 Subsequent studies revealed the presence of rhabdoid cells in many other tumors at various sites, which cast doubt on a distinctive characterization of rhabdoid tumors.2,11 Indeed, many now believe that rhabdoid features represent a common dedifferentiated end point for a variety of neoplasms, and they may be regarded as a phenotype.12

The immunoprofile of our case is similar to that of previously reported cases of malignant melanoma with rhabdoid phenotype, that is, positive for S100 protein but negative for other melanocytic markers, such as HMB-45, Melan-A, Mart-1, tyrosinase, and microphthalmia transcription factor.3,6,7,13 Chang et al3 observed that melanomas with rhabdoid features tend to lose their immunoreactivity to HMB-45 and, to a lesser degree, S100 protein. Borek et al6 reported that all 3 of their cases were positive for S100 protein but negative for HMB-45. On the contrary, Laskin et al7 described a possible case of malignant melanoma with rhabdoid features that did not stain with either S100 protein or HMB-45. The reason for this variability in immunostaining has been attributed to the "dedifferentiated" state of the rhabdoid phenotype.6

The ultrastructural features of extrarenal rhabdoid tumors, including our case and 2 reported cases of rhabdoid malignant melanomas, are generally similar to those of the renal counterpart (ie, whorls of paranuclear intermediate filaments with entrapped organelles).4,7,11,14 However, in a series by Chang et al,3 ultrastructural studies of 4 cases showed that the rhabdoid appearance resulted from collections of mitochondria and dilated rough endoplasmic reticulum containing microtubular arrays. In addition, premelanosomes were identified in these cases.3

Although extensive workup failed to demonstrate a primary melanoma, especially of the eye and internal organs, this case most likely represents a metastatic lesion for the following reasons: (1) there is no bronchial connection and an in situ component was not seen; (2) the marked pleomorphism favors a metastasis; and (3) primary pulmonary malignant melanoma with rhabdoid features has not been reported.

The differential diagnosis of a tumor with a rhabdoid phenotype is wide and can be excluded through a broad panel of immunohistochemical stains. Rhabdoid tumors are often positive for vimentin, glial fibrillary acidic protein, desmin, actin, and AE1/AE3.2,12,15 Moreover, S100 protein expression has not been observed in renal rhabdoid tumors.11 Malignant peripheral nerve sheath tumor, especially the epithelioid variant, is positive for epithelial membrane antigen and synaptophysin, and is only focally positive for S100 protein.16 Plasmacytoma or plasmablastic lymphoma and anaplastic large cell lymphoma would be positive for CD138 and CD30, respectively. Rhabdoid morphology has been described in carcinoma; however, the lack of expression of both high- and low-molecular-weight cytokeratins excludes an epithelial neoplasm, as well as epithelioid mesothelioma. Rhabdomyosarcoma would express muscle markers, such as desmin and myoglobin.

The rhabdoid phenotype in malignant melanoma occurs rarely and has been reported infrequently. The prognostic significance of the rhabdoid phenotype in melanoma is unknown, probably because those with metastatic melanoma already face a poor prognosis.


1. Banerjee SS, Harris M. Morphological and immunophenotypic variations in malignant melanoma. Histopathotogy. 2000:36:387-402.

2. Parham DM, Weeks DA, Beckwith |B. The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. Am J Surg Pathol. 1994:18:1010-1029.

3. Chang ES, Wick MR, Swanson PE, Dehner LP. Metastatic melanoma with rhabdoid features. Am J CUn Pathol. 1994:102:426-431.

4. Bittesini L, Dei Tos AP, Fletcher CDM. Metastatic malignant melanoma showing a rhabdoid phenotype: further evidence of a non-specific histological pattern. Histopathology. 1992;20:167-170.

5. Slagel DD, Raab SS, Silverman JF. Fine needle aspiration biopsy of metastatic malignant melanoma with "rhabdoid" features. Acta Cytol. 1997;41:1426-1430.

6. Borek BT, McKee PH, Freeman JA, Maguire B, Brander WL, Calonje E. Primary malignant melanoma with rhabdoid features: a histologie and immunocytochemical study of three cases. AmJ Dermatopathol. 1998:20:123-127.

7. Laskin WB, Knittel DR, Frame JN. S-100 protein and HMB-45 negative "rhabdoid" malignant melanoma: a totally dedifferentiated malignant melanoma? Am J Clin Pathol. 1995:103:772-773.

8. Eckert F, Baricevic B, Landthaler M, Schmid U. Metastatic signet-ring cell melanoma in a patient with an unknown primary tumor: histologie, immunohistochemical and ultrastructural findings. ] Am Acad Dermatol. 1992:26:870-875.

9. Bhuta S, Mirra JM, Cochran AJ. Myxoid malignant melanoma: a previously undescribed histologie pattern noted in metastatic lesions and a report of four cases. Am J Surg Pathol. 1986:10:203-211.

10. Weeks DA, Beckwith JB, Mierau CW, Luckey DW. Rhabdoid tumor of kidney: a report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol. 1989:13:439-458.

11. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol. 1995;12:233-248.

12. Weeks DA, Beckwith JB, Mierau CW. Rhabdoid tumor: an entity or a phenotype? Arch Pathol Lab Med 1989;! 13:113-114.

13. Miettinen M, Fernandez M, Franssila K, Catalica Z, Lasota J, SarlomoRikala M. Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol. 2001;25:205-211.

14. Haas JE, Palmer NF, Weinberg AC, Beckwith JB. Ultrastructure of malignant rhabdoid tumor of the kidney: a distinctive renal tumor of children. Hum Pathol. 1981:12:646-657.

15. Fanburg-Smith JC, Hengge M, Hengge UR, Smith JS Jr, Miettinen M. Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immunohistochemical study of 18 cases. Ann Diagn Pathol. 1998:2:351-362.

16. Morgan MB, Stevens L, Patterson J, Tannenbaum M. Cutaneous epithelioid malignant nerve sheath tumor with rhabdoid features: a histologie, immunohistochemical, and ultrastructural study of three cases. J Cutan Pathol. 2000;27:529-534.

Jared J. Abbott, MD, PhD; Robin H. Amirkhan, MD; Mai P. Hoang, MD

Accepted for publication January 28, 2004.

From the Departments of Pathology, University of Texas Southwestern Medical Center, Dallas (Drs Abbott, Amirkhan, and Hoang), and Veterans Affairs North Texas Health Care System, Dallas (Dr Amirkhan).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Mai P. Hoang, MD, Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9073 (e-mail:

Copyright College of American Pathologists Jun 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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