c-Kit expression in spindle cell melanoma--a diagnostic pitfall in anorectal biopsy.
|Article Type:||Letter to the editor|
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: August, 2009 Source Volume: 133 Source Issue: 8|
To the Editor.--Although the constant expression of c-Kit protein
is perhaps the best defining feature of gastrointestinal tumors (GISTs),
(1) c-Kit is also positive in other tumors, including spindle cell
melanoma, which could represent--when used as a single marker as in the
case herein presented--a major diagnostic pitfall.
A 66-year-old woman presented with anal pain and discomfort, which was initially thought to be related to hemorrhoids. Clinical examination revealed a 4 to 5 cm anal tumor, located in the upper anterior wall, with an extension to the recto-vaginal septum. Microscopic examination of the biopsy specimen showed a spindle cell tumor (Figure 1, A) with an elongated hyperchromatic nuclei (Figure 1, B) and numerous mitotic figures (15/10 high-power fields). Tumor cells were positive on immunohistochemistry with c-Kit (CD117) and negative for cytokeratin. The diagnosis of anorectal GIST was made, and the patient was referred to our hospital for surgery.
Repeated immunohistochemical study from the original biopsy demonstrated that beside intermediate cytoplasmic c-Kit expression (Figure 2, A), tumor cells were strongly and diffusely positive for S100 protein and HMB-45 (Figure 2, B). They were negative for CD34, smooth muscle actin, and desmin. The diagnosis of spindle cell melanoma was made, and abdominoperineal resection with vaginal excision was performed.
Microscopic examination of the surgical specimen revealed malignant spindle cell tumors, with numerous nuclear atypia and, as with the original biopsy, pigmentation was not present. Immunohistochemical study revealed the same immunophenotype as described above. There was no lymph node metastasis, and all surgical margins were free of disease.
The patient received no further therapy, and she is still alive and well after 18 months of follow-up, without evidence of recurrence or metastasis.
c-Kit, also known as CD117, is a transmembrane receptor for a growth factor, termed stem cell factor and has an internal tyrosine component. (1) It is involved in the development and maintenance of erythrocytes, mast cells, melanocytes, germ cells, and interstitial cells of Cajal. (1) The consistent expression of c-Kit protein is perhaps the best defining feature of GISTs and is seen in approximately 95% of tumors. (1) c-Kit is also positive in other tumors: angiosarcoma, Ewing sarcoma, extramedullary myeloid tumors, seminoma, a few carcinomas, and melanoma, (2) which could represent, as in our case, a major diagnostic pitfall. c-Kit protein is expressed in normal melanocytes, melanocytic nevi, in situ melanomas, and invasive radial growth phase melanomas. c-Kit expression decreases with melanoma progression: 55% of metastatic melanomas in Shen and colleagues' series (3) lacked expression of c-Kit versus 100% expression in dysplastic nevi and 96% in malignant melanomas.
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In their series of 17 cases of primary anorectal melanoma, Chute et al (4) found c-Kit expression in 12 of 16, including 5 of 6 cases with spindle cell morphology. Staining for c-Kit was intermediate in distribution, weakly positive in the epithelioid tumor cells, and strongly and diffusely positive in the lymphoma-like tumor cells.
Owing to its rarity, and histological variability, misdiagnosis of anorectal melanoma as lymphoma, carcinoma, or sarcoma is not uncommon (10%-15% of anaplastic tumor biopsies in the experience of Gatter KC et al (5)). The confusion is more understandable in a small biopsy, and particularly for an amelanotic tumor, as was our case.
The 5-year survival rate for anorectal melanomas has been reported as less than 20% (4); GISTs have a better prognosis, with long latency, sometimes up to 10 years, between surgery and recurrences and metastases. (6) Both can benefit from treatment with imatinib, whereas none of the small number of patients with melanoma (3, selected from 40 cases) responded to the treatment with imatinib, (7) and only 1 of 21 patients, whose metastatic melanomas expressed at least 1 protein tyrosine kinase in phase II trial, responded to this drug. (8)
MARIE-THERESE PELLE, MD
Department of Pathology
YANN PARC, MD, PhD
Department of Surgery
NAJAT MOURRA, MD, PhD
Department of Pathology
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(2.) Dow N, Giblen G, Sobin LH, Miettinen M. Gastrointestinal stromal tumors: differential diagnosis. Semin Diagn Pathol. 2006;23:111-119.
(3.) Shen SS, Zhang PS, Eton O, Prieto VG. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol. 2003; 30:539-547.
(4.) Chute DJ, Cousar JB, Mills SE. Anorectal malignant melanoma: morphologic and immunohistochem ical features. Am J Clin Pathol. 2006;126:93-100.
(5.) Gatter KC, Ralfkaier E, Skinner J, et al. An immunocytochemical study of malignant melanoma and its differential diagnosis from other malignant tumours. J Clin Pathol. 1985;38:1353-1357.
(6.) Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol. 2001;25:1 121-1 133.
(7.) Alexis JB, Martinez AE, LutzkyJ. An immunohistochemical evaluation of c-Kit (CD117) expression in malignant melanoma, and results of imatininb mesylate (Gleevec) therapy in three patients. Melanoma Res. 2005;15:283-285.
(8.) Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99:734-740.
The authors have no relevant financial interest in the products or companies described in this article.
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