Primary Signet Ring Cell/Histiocytoid Carcinoma of the Eyelid: Clinicopathologic Analysis with Evaluation of the E-Cadherin/β-Catenin Complex and Associated Genetic Alterations

Abstract

Signet Ring Cell (SRC)/Histiocytoid carcinoma of the eyelid is a rare neoplasm that shares histological and immunohistochemical similarities with diffuse gastric cancer and breast lobular carcinoma. The CDH1 gene, which encodes the E-cadherin protein, is the best known gene associated with these tumors. The structural and functional integrity of E-cadherin is regulated by interconnecting molecular pathways which might participate in the development of this disease. Hence, we analyzed the protein expression in key genes in E-cadherin-related pathways associated with primary SRC/Histiocytoid carcinoma of the eyelid. SRC/Histiocytoid carcinoma diagnosed in the eyelid/orbit at MD Anderson Cancer Center from 1990 to 2016 were evaluated. Clinicopathologic findings were studied to confirm the primary site of origin. Immunohistochemical studies for the expression of E-cadherin, β-catenin, c-Myc, Cyclin D1, Src, and p53 were analyzed. Next generation sequencing for the detection of somatic mutations was performed on each tumor with matched normal tissue, examining 50 cancer-related genes. Four primary SRC/Histiocytoid carcinomas of the eyelid were diagnosed in four male patients aged 40-82 years. Immunohistochemically, two tumors with loss of E-cadherin expression had weak β-catenin and low cytoplasmic staining for Src while the other two cases with intact E-cadherin showed strong β-catenin expression and high cytoplasmic expression for Src. Cyclin D1 was focally positive in three cases. Somatic mutations in CDH1, PIK3CA, and TP53 genes were detected in two cases. Our results suggest an abnormality in the convergence of E-cadherin/β-catenin pathways which may promote tumorigenesis by inducing expression of oncogenes such as Cyclin D1 and C-Myc. Mutations in CDH1, PIK3CA, and TP53 genes could induce E-cadherin dysfunction which takes part in the development and progression of this malignancy.

Cutaneous Squamous Cell Carcinoma with Signet-Ring Cell Component and CDX2 Expression in a Patient Treated with PD-1 Inhibitor: A Case Report of a Common Tumor with Unusual Differentiation

“…Fedeles et al [ 7 ] described two cases of panfollicular carcinoma which displayed an aberrant nuclear and cytoplasmic expression of beta-catenin in tumor cells. Our findings are similar to those previously described in primary SRC/histiocytoid carcinoma of the eyelid in which an incomplete, heterogenous cytoplasmic/membranous staining was noted in more than 10% but less than 90% of tumor cells [ 8 ].…”

“…Normal beta-catenin expression is characterized by a homogeneous membranous staining along the intercellular junctions of the epidermis while a mutant protein is expressed in the nucleus [ 7 ]. An abnormal staining for beta-catenin has been reported in cutaneous carcinomas including SRC/histiocytoid carcinoma of the eyelid, BCC, and matrical carcinomas, among others [ 7 , 8 ]. Fedeles et al [ 7 ] described two cases of panfollicular carcinoma which displayed an aberrant nuclear and cytoplasmic expression of beta-catenin in tumor cells.…”

Signet-Ring Cell/Histiocytoid Carcinoma: Report of Two Cases and Systematic Review of the Literature on the Epidemiology, Clinical Characteristics, and Pathological and Molecular Findings

“…We performed a systematic review of studies reporting SRCHC cases using PubMed (methods described in detail in Annex , Supplemental Digital Content 1 , http://links.lww.com/AJDP/A138). Forty-eight publications were included in the review 1,4–50 (see Figure , Supplemental Digital Content 1 , http://links.lww.com/AJDP/A136). The 48 publications covered 78 cases of SRCHC.…”