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

Abstract

Primary signet ring cell/histiocytoid carcinoma of the eyelid is a rare ocular malignancy and its diagnosis is often delayed. This neoplasm presents as an insidious, diffusely infiltrative mass in the periocular area that later infiltrates the orbit. An exenteration is usually indicated; however, nearly one-third of patients develop local recurrence or metastasis. Morphologically, it resembles signet ring cell carcinoma of the stomach and breast, raising the possibility of mutations in CDH1, the gene encoding E-cadherin. To determine whether primary signet ring cell/histiocytoid carcinoma harbors the CDH1 mutation or other actionable mutations, we analyzed the tumor tissue via next-generation sequencing. We identified only one case of primary signet ring cell carcinoma of the eyelid with adequate DNA quality for sequencing from the pathological archive during the period 2000 to 2020. A comprehensive evaluation including histopathology, immunohistochemistry, and next-generation sequencing assay was performed on tumor tissue. Immunohistochemically, the tumor exhibited E-cadherin membranous staining with the aberrant cytoplasmic staining of β-catenin. Using next-generation sequencing, we demonstrated the mutation in the CDH1 gene. In addition, other clinically actionable mutations including ERBB2 and PIK3CA were also detected. The alterations in other actionable genes indicate a need for larger studies to evaluate the pathogenesis and potential therapies for primary signet ring cell/histiocytoid carcinoma of the eyelid.

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

“…Due to the long-term potential to recur and metastasize, regular follow-up and examination of the patient are recommended [ 19 , 80 , 92 ]. Only a few adnexal malignancies show a favorable prognosis, and no cases of recurrent or metastatic disease were reported [ 183 , 189 , 193 , 195 ].…”

“…Due to the long-term potential to recur and metastasize, regular follow-up and examination of the patient are recommended [19,80,92]. Only a few adnexal malignancies show a favorable prognosis, and no cases of recurrent or metastatic disease were reported [183,189,193,195]. [151,[154][155][156]321] A: 45-70 [151] Squamoid eccrine ductal carcinoma R ND [162,322] ND [161,162,322] Syringocystadenocarcinoma papilliferum R LD [170,172] LD [170][171][172] Secretory carcinoma R ND [183] ND [183] Cribriform carcinoma R ND [189,190,193] ND [189,193] Signet-ring cell/histiocytoid carcinoma R NA, A-conventional and targeted therapy (HER2 inhibitors, tamoxifen, anti-androgen) [23,197,199,204] NA, A [24,197,199,203,204] Hidrocystoma/cystadenoma R ND ND In a recent single-institution experience report, the median overall survival (OS) was 158 months (95% CI, .…”

“…Immunohistochemically, the tumor is usually positive for AE1/AE3, CAM5.2, CK5/6, CK7, CD117, MNF116, and BerEp4, and variably positive for EMA, CEA, p53, S100 protein, and estrogen receptor [ 192 , 193 , 194 ]. Stains such as GCDFP-15, ER, PR, CK20, CDX-2 (caudal type homeobox 2 protein), PSA (prostate-specific antigen), and PAX-8 (paired box gene 8) may help support metastasis diagnosis to distinguish them from primary cutaneous lesions; forasmuch, lesions with the cribriform pattern are seen in other organs [ 190 , 195 ]. Differential diagnosis also includes tubular adenoma, which can be distinguished by a myoepithelial layer around the tumor nests [ 189 ].…”

“…There has been no metastases report with singular cases of recurrent disease treated by reoperation because of incomplete primary resection ( Table 2 ). Due to the low number of reported cases and uncertain ability to form metastases, long-term follow-up is recommended [ 189 , 193 , 195 ].…”

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.…”