Elsevier

Human Pathology

Volume 43, Issue 6, June 2012, Pages 801-807
Human Pathology

Original contribution
c-kit gene mutation and CD117 expression in human anorectal melanomas

https://doi.org/10.1016/j.humpath.2011.08.005Get rights and content

Summary

c-kit and BRAF mutations play an important role during the pathogenesis of melanoma. The subtypes of melanomas arising from different parts of the body have variable c-kit or BRAF mutation frequencies. Few studies in the literature have examined c-kit and BRAF mutation status in melanomas that occur in the anus and rectum. In this study, we analyzed 40 cases of anorectal melanoma for c-kit and BRAF mutations by DNA sequencing using paraffin-embedded tissues. c-kit Mutations were detected in exons 9, 11, 13, and 17. CD117 expression in tumor cells was analyzed by immunohistochemistry. Our study showed that a c-kit mutation was found in 7 of the 40 cases of anorectal melanoma. CD117 expression was detected in 16 of the 40 cases, and 3 of these 16 cases also had c-kit mutations. Mutations in BRAF were also identified in 2 patients. These results indicate that a subset of anorectal melanomas have activating c-kit mutations, which suggests that kinase inhibitors such as imatinib may be used to treat this subset of melanoma patients. In addition, our results show that c-kit mutations do not correlate with CD117 expression.

Introduction

Primary malignant melanoma of the anus and rectum is a rare and highly lethal neoplasm. Mucosal melanomas account for approximately 1.2% of all melanomas, and anorectal melanomas account for fewer than 25% of all mucosal melanomas [1]. This form of melanoma is clinically aggressive with an extremely poor prognosis. There is no effective treatment option for patients who develop metastatic disease [2]. Even with aggressive surgical resection, more than 80% of patients die of distant metastatic disease within 5 years [3]. Although a variety of chemotherapies have been used to treat patients with metastatic melanoma, the disease control rate is still disappointing.

Molecular research into the pathogenesis of melanoma has provided a new perspective for treatment because of the discovery of a number of somatic mutations. It has been suggested that anorectal mucosal melanoma has a different etiology from cutaneous melanoma [4]. Melanomas arising from skin intermittently exposed to the sun, which represent a major group of cutaneous melanomas, have frequent BRAF mutations, particularly the BRAF V600E mutation. However, melanomas developing on body sites with little ultraviolet exposure, such as acral or mucosal melanomas, have a very low incidence of BRAF mutations, but they often harbor activating mutations in c-kit [5], [6], [7], [8]. c-kit is a member of the type III trans-membrane receptor tyrosine kinase family [9]. The dysregulation of c-kit is thought to play a causative role in several neoplasms, including acute myelogenous leukemia, germ cell tumors, and gastrointestinal stromal cell tumors (GISTs) [10]. A recent study showed that imatinib, a c-kit inhibitor, significantly prolongs the lifespan of patients with metastatic melanoma harboring c-kit mutations [11]. It is increasingly important to examine the c-kit mutation status in melanoma. Because the c-kit and BRAF mutation status in anorectal melanoma has not been well studied, we analyzed c-kit and BRAF mutations in 40 cases of anorectal melanomas.

Section snippets

Patient selection and sample preparation

Forty patients with anorectal melanoma, treated at Fudan University Shanghai Cancer Center from 1992 to 2010, were involved in the study. The samples were collected from 35 primary melanomas, 1 lymph node metastasis, 1 abdominal wall metastasis, and 3 local recurrences tumors. The study was approved by the Ethical Committee for Clinical Research at the Fudan University Shanghai Cancer Center.

DNA extraction

Tumor-rich areas were scraped from 5-μm unstained serial sections after confirmation by hematoxylin and

Clinicopathologic characteristics

Among the 40 patients, there were 18 males and 22 females. Ages ranged from 37 to 79 years, with a mean age of 59.2 years. The median age was 58 years. All of the diagnoses of anorectal melanoma previously made by 2 experienced pathologists were confirmed by histology and immunohistochemical analysis with melanocytic markers according to standard protocols, including S-100 protein, HMB-45, and MART-1.

About the primary lesions of the 40 patients, 21 were found in the anus, 15 in the rectum, and

Discussion

Surgery is the primary treatment for anorectal melanoma. However, 29% of patients are not candidates for surgery at the time of initial diagnosis owing to distant metastases. Even with surgical resection, more than 80% of patients die from distant metastatic disease within 5 years [3]. Adjuvant treatments for melanoma include chemotherapy, immunotherapy, and radiation therapy. However, these treatments are ineffective in general. No effective treatment options exist for patients who develop

Acknowledgment

We thank Mr Xu Cai and Mr Yongming Lu in the Department of Pathology of our hospital for technical support.

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    This study was supported in part by the Key Basic Research Project of the Science and Technology Commission of Shanghai Municipality (08411961800).

    1

    These authors have contributed equally to this publication.

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