Original contributionc-kit gene mutation and CD117 expression in human anorectal melanomas☆
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.
References (29)
- et al.
KIT as a therapeutic target in melanoma
J Invest Dermatol
(2010) - et al.
Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders
Hum Pathol
(1998) - et al.
BRAF mutations distinguish anorectal from cutaneous melanoma at the molecular level
Gastroenterology
(2004) - et al.
The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society
Cancer
(1998) - et al.
Major response to imatinib mesylate in KIT-mutated melanoma
J Clin Oncol
(2008) - et al.
Anorectal melanoma
Clin Colon Rectal Surg
(2009) - et al.
Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas
Br J Cancer
(2008) - et al.
Somatic activation of KIT in distinct subtypes of melanoma
J Clin Oncol
(2006) - et al.
L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition
Int J Cancer
(2007) - et al.
c-Kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma
Virchows Arch
(2008)
Genetic subgrouping of melanoma reveals new opportunities for targeted therapy
Cancer Res
Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders
Curr Cancer Drug Targets
Large-scale analysis of KIT aberrations in Chinese patients with melanoma
Clin Cancer Res
Anorectal melanoma. A rare and highly malignant tumor entity of the anal canal
Pathologe
Cited by (39)
Research progress in advanced melanoma
2017, Cancer LettersCitation Excerpt :These mutations mainly exist in skin melanoma but are rarely found in mucosal melanoma. Exon 15 is the most frequently mutated site in the BRAF gene, with the V600E and V600K mutations being the most common although other rare types include V600R, V600D, G596R, D594N, L597R, and K601E [10–12]. KIT gene: KIT maps to chromosome 4q11-12 and encodes the KIT protein (namely, CD117), which is a tyrosine kinase receptor important for regulating the cell cycle in normal melanocytes.
Identification of recurrent mutational events in anorectal melanoma
2017, Modern PathologyUpdate on primary mucosal melanoma
2014, Journal of the American Academy of DermatologyCharacterization of KIT mutation in melanoma
2014, Dermatologica SinicaTargeted therapy in melanoma: The era of personalized medicine
2014, Diagnostic HistopathologyCitation Excerpt :There is some correlation between the mutation profile and clinicopathologic features of melanoma (Table 1). Mutation frequency differs by anatomic site, with KIT mutations found more often in acral and mucosal locations8 and BRAF mutations found in fewer than 20% of acral melanoma.5 Nail apparatus melanomas share a mutational profile similar to acral sites.9
- ☆
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.