Apocrine-Eccrine Carcinomas: Molecular and Immunohistochemical Analyses

Apocrine-eccrine carcinomas are rare and associated with poor prognosis. Currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. However, studies on genetic alterations and EGFR and Her2 status of apocrine-eccrine carcinomas are few in number. In addition, hormonal studies have not been comprehensive and performed only on certain subsets of apocrine-eccrine carcinomas. To investigate whether apocrine-eccrine carcinomas express hormonal receptors or possess activation of oncogenic pathways that can be targeted by available chemotherapeutic agent we performed immunohistochemistry for AR, PR, ER, EGFR, and HER2 expression; fluorescence in situ hybridization (FISH) for EGFR and ERBB2 gene amplification; and molecular analyses for recurrent mutations in 15 cancer genes including AKT-1, EGFR, PIK3CA, and TP53 on 54 cases of apocrine-eccrine carcinomas. They include 10 apocrine carcinomas, 7 eccrine carcinomas, 9 aggressive digital papillary adenocarcinomas, 10 hidradenocarcinomas, 11 porocarcinomas, 1 adenoid cystic carcinoma, 4 malignant chondroid syringomas, 1 malignant spiradenoma, and 1 malignant cylindroma. AR, ER, PR, EGFR and HER2 expression was seen in 36% (19/53), 27% (14/51), 16% (8/51), 85% (44/52) and 12% (6/52), respectively. Polysomy or trisomy of EGFR was detected by FISH in 30% (14/46). Mutations of AKT-1, PIK3CA, and TP53 were detected in 1, 3, and 7 cases, respectively (11/47, 23%). Additional investigation regarding the potential treatment of rare cases of apocrine-eccrine carcinomas with PI3K/Akt/mTOR pathway inhibitors, currently in clinical testing, may be of clinical interest

Apocrine-Eccrine Carcinomas: Molecular and Immunohistochemical Analyses

<div><p>Apocrine-eccrine carcinomas are rare and associated with poor prognosis. Currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. However, studies on genetic alterations and EGFR and Her2 status of apocrine-eccrine carcinomas are few in number. In addition, hormonal studies have not been comprehensive and performed only on certain subsets of apocrine-eccrine carcinomas. To investigate whether apocrine-eccrine carcinomas express hormonal receptors or possess activation of oncogenic pathways that can be targeted by available chemotherapeutic agent we performed immunohistochemistry for AR, PR, ER, EGFR, and HER2 expression; fluorescence <em>in situ</em> hybridization (FISH) for <em>EGFR</em> and <em>ERBB2</em> gene amplification; and molecular analyses for recurrent mutations in 15 cancer genes including <em>AKT-1</em>, <em>EGFR, PIK3CA</em>, and <em>TP53</em> on 54 cases of apocrine-eccrine carcinomas. They include 10 apocrine carcinomas, 7 eccrine carcinomas, 9 aggressive digital papillary adenocarcinomas, 10 hidradenocarcinomas, 11 porocarcinomas, 1 adenoid cystic carcinoma, 4 malignant chondroid syringomas, 1 malignant spiradenoma, and 1 malignant cylindroma. AR, ER, PR, EGFR and HER2 expression was seen in 36% (19/53), 27% (14/51), 16% (8/51), 85% (44/52) and 12% (6/52), respectively. Polysomy or trisomy of EGFR was detected by FISH in 30% (14/46). Mutations of <em>AKT-1</em>, <em>PIK3CA</em>, and <em>TP53</em> were detected in 1, 3, and 7 cases, respectively (11/47, 23%). Additional investigation regarding the potential treatment of rare cases of apocrine-eccrine carcinomas with PI3K/Akt/mTOR pathway inhibitors, currently in clinical testing, may be of clinical interest.</p> </div

Hidradenocarcinoma.

<p>(A) Cribriform necrosis and clear cell change are seen in a hidradenocarcinoma (X40). (B) Strong membranous expression of EGFR was noted (X200). (C) However, fluorescence <i>in situ</i> hybridization revealed only balanced polysomy of chromosome 7 and <i>EGFR</i> gene (X1000).</p

Summary of <i>TP53</i> mutations in apocrine-eccrine carcinomas [15]–[19].

<p>Summary of <i>TP53</i> mutations in apocrine-eccrine carcinomas <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047290#pone.0047290-Biernat1" target="_blank">[15]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047290#pone.0047290-Takata2" target="_blank">[19]</a>.</p

Mutational profiling of apocrine-eccrine carcinoma using SNaPshot® genotyping.

<p>The top panel shows genotypic data obtained with normal male genomic DNA (Promega, Madison, WI, USA) and the lower panel illustrates mutation detection in tumor DNA derived from formalin-fixed paraffin-embedded specimens.</p

Kaplan-Meier plot of metastasis-free survival time by <i>EGFR</i> FISH results (N = 34).

<p>The plot shows the distribution of time from diagnosis to metastasis for patients with (n = 12) and without (n = 22) polysomy/trisomy for EGFR, for whom follow-up information is available (N = 34). Patients who did not have metastases are censored (indicated by vertical mark) at the time of the most recent follow-up information.</p

Clinical data of the fifteen patients with apocrine-eccrine carcinomas and metastatic disease.

<p>F: female, M: male, R: right, L: left, ADPA: aggressive digital papillary adenocarcinoma, LN: lymph node.</p

Apocrine carcinoma.

<p>(A) Cribriform architecture, polygonal neoplastic cells and eosinophilic cytoplasm are characteristic features of apocrine carcinoma (X200). (B) Strong and diffuse nuclear staining for androgen receptor is noted (X200).</p