Molecular profiling of a primary cutaneous signet‐ring cell/histiocytoid carcinoma of the eyelid

Abstract

Primary cutaneous signet‐ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next‐generation sequencing. The patient is an 85‐year‐old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histopathologic sections revealed a proliferation of cells with signet‐ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next‐generation sequencing revealed a CDH1 mutation, which is known to confer signet‐ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B, and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets.

Primary Signet Ring Cell/Histiocytoid Carcinoma of the Eyelid: Somatic Mutations in CDH1 and Other Clinically Actionable Mutations Imply Early Use of Targeted Agents

“…Another significant finding is that our case was found to have mutations in targetable kinases, ERBB2 and PIK3CA, similar to the results reported in plasmacytoid urothelial carcinoma [36]. Raghavan et al also described the presence of targetable mutations in NTRK3, CDKN1B, and PIK3CA in their case of primary signet ring cell carcinoma of the eyelid [30]. Alterations in ERBB2(HER2) have been reported in diverse cancers, including breast and gastric cancer.…”

“…The splice site mutation of CDH1 detected in our case has been reported in 27% and 10% of hereditary diffuse gastric cancers and lobular breast cancers, respectively [31], and it constitutes one type of truncating mutations of CDH1, which is the most commonly identified mutations in CDH1. Compared with the recent publication by Raghavan et al, they also discovered a spice site mutation of CDH1 (c.531+1 G>T, VAF 23.3%) [30]. Our case represents the second case of CDH1 mutation reported in the literature.…”

“…Previous studies have demonstrated the possible origin of apocrine/eccrine glands with a variable expression of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Her2-Neu immunohistochemically [2][3][4]24]. However, the genetic alterations of the tumor had not been determined until a recent publication by Raghavan et al, indicated a mutation in the CDH1 gene [30] that has been demonstrated in signet ring cell carcinoma of the stomach, breast lobular carcinoma, and plasmacytoid urothelial carcinoma. In this study, we performed a comprehensive mutational investigation using next-generation sequencing to elucidate the mutational profile of the tumor and expand our current understanding of this rare neoplasm.…”

Current Diagnosis and Treatment Options for Cutaneous Adnexal Neoplasms with Apocrine and Eccrine Differentiation

“…Other DNA mutations were also reported, including abnormalities commonly found in other cancers, such as EGFR (epidermal growth factor receptor), HRAS (HRas Proto-Oncogene, GTPase), TP53, RB1 (retinoblastoma protein), ATM (ATM Serine/Threonine Kinase), and PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) (Table 1 and Figure 3) [18][19][20][21][22][23][24][25]. Similar genetic abnormalities were reported in benign and malignant adnexal tumors, and some mutations were found in multiple adnexal neoplasms [26][27][28]. Tumors are occasionally found in patients with several other genetic and systemic disorders, including Down syndrome or diabetes mellitus, Marfan syndrome, Ehler-Danlos syndrome, sarcoidosis, etc., and alopecia areata for syringoma [29,30].…”

“…In most cases, lesions are considered benign, however a malignant variant is also reported. Several mutations have been identified, including PLAG1 (pleiomorphic adenoma gene 1 protein) or EWSR1 (Ewing sarcoma breakpoint region 1) gene rearrangements, also found in myoepitheliomas, similar to pleomorphic adenomas ( Table 1 ) [ 26 , 27 ].…”