Sclerosing Signet Ring Cell Carcinoma of the Lacrimal Gland: A Potentially New Primary Entity

Abstract

An 88-year-old man presented with diplopia, limitation of extraocular movements, and a firm palpable mass in the superolateral orbit. Biopsy revealed a sclerosing signet ring cell carcinoma with histopathologic features mimicking those of a primary signet ring cell (histiocytoid) carcinoma of the eyelid of eccrine or apocrine gland origin, a metastasis from an invasive lobular breast carcinoma or a metastatic diffuse-type gastric carcinoma. An extensive panel of immunohistochemical stains and molecular genetic analyses unequivocally failed to establish a precise diagnosis. Electron microscopy demonstrated features of a primary lacrimal gland lesion with intracytoplasmic lumens and zymogen granules typical of lacrimal secretory pyramidal cells. A thorough initial systemic work-up failed to reveal a primary visceral malignancy. Fifteen months of follow-up have failed to detect the emergence of another primary malignancy. To the best of our knowledge, a tumor with the morphology of the current lesion has not been previously described in the major or accessory lacrimal glands.

Keywords: Electron microscopy; Immunohistochemistry; Lacrimal gland; Metastatic carcinoma; Mucus-producing carcinoma; Orbit; Scirrhous carcinoma; Sclerosing; Signet ring carcinoma.

Fig. 1

Clinicopathologic features of pri­mary lacrimal gland signet ring carcinoma. a An 88-year-old man developed ocular irritation and diplopia over 6 months. The right orbit was full due to a superolateral palpable, firm mass that had narrowed the inter-palpebral fissure, shallowed the orbital-palpebral upper eyelid sulcus, and displaced the globe downwards. b An axial computed tomogram displays a lateral soft tissue density (arrow) molded to the globe. c A coronel tomogram better delineates the extent of the mass (arrows). There is no adjacent bone destruction and the sinuses and nasal passageways are clear except for some antral mucosal thickening. d A sagittal tomogram demonstrates tracking of tumor posteriorly along the surface of the superior rectus muscle (arrow). e Microscopically the tumor is dominated by marked fibrosis with a pseudoinflammatory dispersal of widely separated individual cells. In this field there is a focus of hypercellularity (arrow). f The round tumor cells adopt a single file columnated growth pattern (arrow; e, f hematoxylin and eosin, 100× and 400× respectively).

Fig. 2

Higher power microscopic evaluation of tumor cells including special stains. a A non-desmoplastic region of the orbital fat contains a disorganized cluster of atypical, polygonal, dyscohesive tumor cells with intermingled lymphocytes (arrow). b The Alcian blue stain reveals many positive cells, which have an intracellular mucus content delimited by a large cytoplasmic vacuole (arrows). The inset represents the Gomori methenamine silver stain of positive mucus vacuoles (arrow), which had displaced the nuclei (crossed arrow). These are referred to as a signet ring cells. c The mucicarmine stain also manifests an affinity for staining the large mucus vacuoles (arrow). d The phosphotungstic acid hematoxylin stain highlights a fine cytoplasmic, blue-staining granularity in the cytoplasm. e The Masson trichrome stain brings out the red staining property of the cytoplasmic granules (arrows). f Cytokeratin 7 is uniformly positive in the tumor cells and reinforces the impression of a single file cellular disposition (a, hemotoxylin and eosin, 400×; b, alcian blue, 600×, insert, gomori methenamine silver, 600×; c, mucicarmine 600×; d, PTAH, 600×; e, Masson trichrome, 600×; f, cytokeratin 7, 100×; immunoperoxidase reaction, diaminobenzidine chromogen, hematoxylin counterstain).

Fig. 3

Positive immunohistochemical results for select biomarkers. a GATA 3, typically present in breast carcinoma, is positive in scattered tumor cells (400×). b GCDFP-15 exhibits moderate to intense positivity in the tumor cells (200×). c Androgen receptors were detected in a majority of the tumor cells' nuclei (400×). d Ki 67 demonstrates nuclear positivity with a proliferation index of approximately 10% of cells in a DNA replicative phase (immunoperoxidase reacts on all 200×).

Fig. 4

Ultrastructural findings in tumor cells. a An overview of a typical tumor cell. There is a large intracytoplasmic lumen (L) with inwardly projecting villi creating a signet ring character. The cytoplasm is endowed with numerous large electron-dense secretory (zymogen) granules. (N, nucleus). b An intracytoplasmic lumen (L) with villi (V) is present near the cytoplasmic limiting membrane, which displays its own cell surface villi. Myriad small vesicles are oriented around the intracytoplasmic lumen prior to discharging their mucoid contents into it. The arrows indicate nearby zymogen granules. c A collection of small vesicles (V) of mucus, is interposed between the nucleus (N) with its prominent nucleolus (NL) and the cell's plasmalemma below. The vesicles are derived from the Golgi zone represented by the variably dilated membranous profiles. d Higher power evaluation of the mucus inclusions reveals that they possess a flocculofibrillar content similar to that seen in goblet cells. (transmission electron micrographs, ultrathin sections stained with osmium tetroxide: (a, 3,400×; b, 14,000×; c, 9,100×; d, 11,000×).