Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type

Abstract

The role of immunohistochemistry in the assessment of KIT status in melanomas, especially acral lentiginous/mucosal, is not well established. Although the reported prevalence of KIT mutations in acral lentiginous/ mucosal melanomas is relatively low, detection of mutations in KIT can have profound therapeutic implications. We evaluated the efficacy of immunohistochemistry to predict mutations in KIT. One hundred seventy-three tumors, comprising primary and metastatic melanomas (141 acral lentiginous/mucosal, 5 nodular, 4 lentigo maligna, 3 superficial spreading, 2 uveal, 1 melanoma of soft parts, 8 metastases from unclassified primaries, and 9 metastases from unknown primaries) were studied. Immunohistochemical expression of KIT using an anti-CD117 antibody and KIT mutational analysis by gene sequencing of exons 11, 13, and 17 were performed. Eighty-one percent of acral lentiginous/mucosal melanomas, primary and metastatic, showed KIT expression by at least 5% of the tumor cells. The overall frequency of activating KIT gene mutations in acral lentiginous/ mucosal melanomas was 15% (14 out of 91 cases), being the L576P mutation in exon 11 the most frequently detected (4 of 14 cases). Cases showing less than 10% positive tumor cells were negative for KIT mutations. Eighty-two percent (12 of 14) of cases positive for KIT mutation showed KIT expression in more than 50% of the cells. An association between immunohistochemical expression of KIT and mutation status was found (P= 0.007). Immunohistochemical expression of KIT in less than 10% of the cells of the invasive component of acral lentiginous/mucosal melanomas appears to be a strong negative predictor of KIT mutation and therefore can potentially be used to triage cases for additional KIT genotyping.

Genetic aberrations in primary esophageal melanomas: molecular analysis of c-KIT, PDGFR, KRAS, NRAS and BRAF in a series of 10 cases

“…12 However, a recent publication showed a significant correlation between immunohistochemical c-Kit staining and c-KIT mutation status in acral-lentiginous or mucosal-type melanomas. 15 In our study, both cases with c-Kit mutations had a high c-Kit immunohistochemical expression, which is consistent with the findings of this paper.…”

“…For immunohistochemical analysis, paraffin sections were immunostained on an automated immunostainer (Benchmark, Ventana Medical Systems, Tucson, AZ, USA) using the polyclonal rabbit antibodies anti-CD117 (anti-human CKIT A 4502, Dako, Glostrup, Denmark) and anti-PDGFR-A (anti-human PDGFR-A 3164, Cell Signaling Technologies, Beverly, MA, USA). The immunohistochemical protein expression was evaluated semiquantitatively based on the intensity of membranous or membranous and cytoplasmic staining ( þ 1, þ 2, þ 3) and the percentage of positive tumor cells (o5%, 5-50%, 50-95% and 495%) according to TorresCabala et al 15 …”

KIT mutations in ocular melanoma: frequency and anatomic distribution

“…[6][7][8][9]14,15 Most of these reported mutations are predicted to be sensitive to tyrosine kinase inhibitors. Indeed, clinical studies using imatinib in melanoma patients with confirmed KIT-activating mutations have yielded promising results.…”

“…Acral, mucosal, and chronic sun damaged skin melanomas have been shown to harbor KIT mutations while non-chronic sun damaged skin melanomas generally do not since they are often characterized by BRAF or NRAS mutations. [7][8][9]14,15 The frequency of KIT-activating mutations in specific melanoma subtypes is relatively low with reports of 15% for acral, 19% for mucosal, and 17% for chronic sun damaged skin melanomas. 15,16 Ocular melanoma, although a rare melanoma subtype, does account for the majority of all intraocular malignancies.…”

“…[7][8][9]14,15 The frequency of KIT-activating mutations in specific melanoma subtypes is relatively low with reports of 15% for acral, 19% for mucosal, and 17% for chronic sun damaged skin melanomas. 15,16 Ocular melanoma, although a rare melanoma subtype, does account for the majority of all intraocular malignancies. Arising from melanocytes of the choroid, iris, ciliary body, and conjunctiva, ocular melanomas have been reported to express KIT (CD117) at frequencies between 63 and 91%.…”