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.

p63, a recently identified homologue of the p53 gene, is mainly expressed by basal and myoepithelial cells in skin. Others and we have shown the value of p63 in distinguishing primary adnexal tumors from visceral adenocarcinomas metastatic to skin. We now investigate the pattern of p63 expression in metastases from skin adnexal carcinomas and their cognate primaries and evaluate p63 expression in a larger case series of malignant cutaneous adnexal neoplasms. Immunohistochemical analysis for p63 was performed on 13 metastases of adnexal carcinomas and their corresponding primary tumors. Twenty visceral metastatic adenocarcinomas to the skin and 7 primary mucinous carcinomas with cutaneous or visceral origin were compared. The majority (90.9%) of primary adnexal tumors strongly expressed p63 and their metastases labeled similar to their cognate primary tumors. With one exception, primary or metastatic mucinous carcinomas did not express p63. Metastases from two apocrine carcinomas lacked p63 expression. All other cutaneous metastases from internal adenocarcinomas were negative for p63. Analysis of p63 expression may assist in the differential diagnosis of primary adnexal carcinomas versus metastatic visceral adenocarcinomas to the skin. Metastases from adnexal carcinomas generally retain p63 expression similar to their associated primary tumors.

A 44-year-old man was referred for a right chest nodule of 3 months duration. A 'benign' nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.

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Basal cell carcinoma is the most common malignancy in Caucasian individuals. Metastatic basal cell carcinoma is extremely rare (with a rate estimated as 0.03%). Actin has been detected in aggressive forms of basal cell carcinoma, but their expression in metastatic lesions is not known. We compared the expression of actin and actin-related cytoskeletal proteins in relatively less aggressive basal cell carcinoma (nodular), aggressive basal cell carcinoma (infiltrative/morpheaform), and metastatic basal cell carcinoma. We studied 12 cases of nodular basal cell carcinoma, 10 cases of infiltrative basal cell carcinoma, and 10 cases of metastatic basal cell carcinoma with immunohistochemistry for alpha-smooth muscle actin, calponin, myosin, and E-cadherin. Expression was interpreted as positive when at least 5% of the tumor exhibited at least weak expression. Five of the ten patients with metastatic basal cell carcinoma had an antecedent history of radiotherapy. Actin was present in 3 of 12 (25%) of the nodular, all 10 of the infiltrative, and 3 of 10 of the metastatic basal cell carcinomas (Po0.05 for metastatic vs infiltrative and nodular vs infiltrative). Calponin was present in 50% of the nodular, 60% of the infiltrative, and 30% of the metastatic basal cell carcinomas (not statistically significant). Myosin expression was not detected in any of the cases. E-cadherin was present in 75% of the nodular, 70% of the infiltrative, and all of the metastatic basal cell carcinomas (Po0.05 for metastatic vs nodular). Our results suggest that increased actin may contribute to local invasiveness, but it is lost in the metastatic phenotype. History of previous radiotherapy may contribute to development of the metastatic phenotype. Despite this high incidence, metastatic basal cell carcinoma is extremely rare, with most recent studies suggesting that the rate is approximately 0.03%.2 Many of the reported cases have involved recurrent tumors or aggressive histological subtypes. Nearly 85% of all metastasizing basal cell carcinomas involve the head and neck region.3 Metastatic spread is most often to the regional lymph nodes followed in descending order by the lungs, bones, and skin. 4 A review of 170 published cases of metastatic basal cell carcinoma showed a twofold male predilection, an average age of primary onset at 45 years, and a 9-year median interval to metastasis.5 Risk factors for metastatic basal cell carcinoma include persistent tumor for many years, previous radiation and large tumor size with a rate of 1.9% in tumors over 3 cm in diameter, nearly 50% for tumors over 10 cm in diameter, and 100% in tumors 4400 cm 2