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.

We report a case of a 74-year-old gentleman who presented with floaters and decreased vision in the right eye after cataract surgery. His past medical history was significant for metastatic renal cell carcinoma (mRCC) to bone, lung and abdomen which was presumed stable for the last two years while on the tyrosine kinase inhibitor (TKI), pazopanib. Clinical examination revealed significant vitritis with a distinctive clumping of cells on the pre-retinal surface and posterior hyaloid face. Magnetic resonance imaging of the brain revealed new lesions suspicious for metastases. A diagnostic vitrectomy was performed to determine the nature of the vitritis and clear the visual axis. Cytopathologic evaluation of the vitreous demonstrated clusters of malignant cells that were positive for AE1/AE3 and PAX-8, and negative for the CD20, CD3, RCC, SOX-10 and S-100 immunohistochemical markers. The overall findings favored a metastatic RCC to the vitreous. Choroidal and retinal metastases from mRCC have been previously reported; however, vitreous involvement by mRCC with no evidence of retinal or choroidal mass has not been described. New treatments of mRCC include TKIs which target vascular endothelial growth factor receptors (VEGFRs). Herein, we analyze the factors that could have precipitated this unusual metastasis to the vitreous.

A 52-year-old Hispanic woman with a history of metastatic thyroid carcinoma presented with left eye degeneration and a choroidal mass without evidence of orbital disease on neuroimaging. She underwent enucleation for a blind, painful eye. Histopathology demonstrated choroidal metastasis of thyroid carcinoma with a well-circumscribed episcleral nodule, consistent with extraocular tumor extension. The interdisciplinary team recommended expectant management. Three months later, she developed periorbital edema and discomfort with poor ocular prosthesis fit. Neuroimaging revealed a mass in the anophthalmic socket that proved to be thyroid carcinoma. The patient subsequently underwent exenteration for pain control and local tumor burden reduction. At 12-month follow-up, there was no evidence of residual orbital disease, and she remains in remission. While the orbit involvement likely represents direct extraocular extension, a discrete orbital metastasis remains a possibility. In either scenario, this is the only known case of anaplastic thyroid carcinoma metastatic to the choroid then orbit.

Signet-ring cell squamous cell carcinoma (SRCSCC) is an uncommon variant of cutaneous SCC that has been reported in the head and neck region. Herein, we present a case of a 56-year-old female with a cutaneous SCC that recurred after surgical excision, during treatment with cemiplimab (a programmed death receptor-1 (PD-1) inhibitor). Histologically, the recurrent SCC revealed a second component characterized by the presence of signet-ring-like cells (SRLCs). Immunohistochemical studies demonstrated that the tumor cells were positive for P63, CK5/6, CDX2, and P53 while negative for P16, CK7, CK20, and CD68 stains. An abnormal expression of B-catenin was also observed in the tumor. To our knowledge, SRCSCC developing during treatment with an immune checkpoint inhibitor has not been documented in the literature. Our findings suggest a form of acquired SCC cell resistance to immunotherapy that might involve CDX2-related pathways.