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.

Figure 1

Strong and diffuse cytoplasmic expression of KIT by immunohistochemistry in a mucosal melanoma case harboring a L576P mutation in KIT (case no. 162). Notice the cell membrane reinforcement (a, H&E, × 20; b, immunohistochemical stain, × 20; inset, sequence analysis of exon 11 of the KIT gene showing a point mutation in codon 576, resulting in the substitution of leucine by proline).

Figure 2

A case of acral-lentiginous melanoma showing strong and diffuse expression of KIT in the in situ component but absence of immunohistochemical staining in the invasive component. This case was found to be negative for mutations in KIT. (a, × H&E, 10; b, immunohistochemical stain, × 10).

Figure 3

Mucosal melanoma (case no. 20), positive for the D816V KIT mutation. The primary tumor (a and b) shows a strong diffuse immunohistochemical expression of KIT in both in situ and invasive components. A lymph node metastasis (c and d) is also diffusely positive for KIT. (a, c, H&E, × 10; b, d, immunohistochemical stain, × 10; inset, sequence analysis of exon 17 of the KIT gene showing a mutation in codon 816 which resulted in the substitution of aspartic acid by valine).