Endocrine Mucin-Producing Sweat Gland Carcinoma: Emerging Evidence of Multicentric Cutaneous Origin and Occasional Concurrence With Analogous Breast Tumors.

INTRODUCTION: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade carcinoma with predilection for the eyelid. It is analogous to solid papillary carcinoma of the breast with both expressing neuroendocrine markers and the potential to progress to invasive mucinous carcinoma (IMC). Although over 80 cases of EMPSGC have been reported, few multicentric cases have been described in the literature. In this article, we report 9 cases of EMPSGC including 3 with multicentric disease. METHODS: A computerized search was performed for EMPSGC and IMC of the eyelid from January 2000 to February 2021. Records were reviewed for age, sex, tumor location, and clinical impression. RESULTS: Eight EMPSGC (7 associated with IMC) and 1 IMC of the eyelid were identified. Lesions were slightly more common in men (55%) than women. The mean age of presentation was 76 years (range, 59-98 years). Lesions ranged from 2.5 to 12 mm. Three cases had multicentric synchronous lesions on the skin. Histologically, these were well-circumscribed dermal tumors with solid or partially cystic nodules. Tested tumors expressed at least 1 neuroendocrine marker and were positive for CK7, ER/PR, 1 or more of GCDFP-15, mammaglobin, and GATA-3. One case had an associated IMC of the breast, and another case was associated with an intraductal papilloma of the breast in a man. There was no evidence of metastasis. CONCLUSION: EMPSGC is a low-grade adnexal neoplasm, commonly affecting the eyelid of the elderly. Lesions often progress to IMC, metastases being exceptionally rare. EMPSGC can be bilateral and multicentric. Concurrence with breast neoplasms has been observed and deserves investigation.

Epithelioid Fibrous Histiocytoma With Chondroblastoma-Like Features: A Report of a Rare Entity and Discussion of Related Diagnostic Challenges.

ABSTRACT: Epithelioid fibrous histiocytoma (EFH) is an uncommon benign skin lesion. It is distinct from FH by virtue of its recurrent anaplastic lymphoma kinase (ALK) gene rearrangements and immunohistochemical expression of ALK protein. It often poses a challenge in interpretation. Clinically, it is characterized by a flesh-colored papule/nodule on an extremity of a young to middle-aged individual. Microscopically, it is represented by a circumscribed dermal papule/nodule composed of sheets of plump epithelioid cells, forming whorled aggregates around numerous intralesional vessels. Immunohistochemistry, notably ALK positivity and relevant negative stains, serves to distinguish EFH from its morphological mimics. Rare examples of chondroblastoma-like EFH and EFH with osseous metaplasia are recorded in the literature. Our case is of a 58-year-old man who attended an oculoplastic surgeon because of an exophytic cutaneous nodule on the right upper eyelid. The lesion was excised. Microscopically, it displayed morphological and immunohistochemical features of EFH. Of interest, discrete foci of chondro-osseous change, including chondroblastoma-like pericellular calcification, osteoid formation, and osteoclast-like giant cells, were noted throughout the lesion. A diagnosis of EFH with chondroblastoma-like features was made. Of interest, the changes observed in this EFH serve to link the previously reported examples of pure chondroblastoma-like EFH and EFH with osseous metaplasia. This morphological variant of EFH adds to the existing diagnostic challenge presented by these lesions, particularly in the distinction from other calcifying tumors of the skin.

Bilateral HPV Positive Squamous Cell Carcinoma In Situ of Conjunctiva.

A 45 year-old woman presented with blurred vision and irritation of the left eye. Clinical examination revealed a superior palpebral conjunctival lesion consistent with a diagnosis of papilloma. She was lost to follow up despite repeated attempts to schedule a biopsy, and presented again after an extended period with bilateral disease. Subsequent biopsy confirmed bilateral squamous cell carcinoma in situ which was human papilloma virus-16 positive by molecular testing. She declined further treatment; during the subsequent year, the lesions extended across the bulbar conjunctiva bilaterally.

Oncocytic lesions of the ocular adnexa: A review of the histopathology with a brief discussion of the pathogenesis.

Oncocytic lesions may be metaplastic, hyperplastic, or neoplastic and occur in a variety of tissues, including those of the ocular adnexa. Oncocytes are enlarged epithelial cells with abundant eosinophilic granules in the cytoplasm, which represent large mitochondria with distorted cristae. The causes of oncocytic lesions remain uncertain, although in some sites such as the lacrimal sac, chronic inflammation may be a factor. Oncocytic neoplasms in all adnexal sites are generally benign (oncocytoma/oncocytic adenoma) and oncocytic adenocarcinomas are uncommon. Research into oncocytic neoplasms, particularly of the kidney and thyroid, has shed some light on the complicated genomic and metabolic changes that are associated with mitochondrial dysfunction in such neoplasms. The major driver event is mutation of mitochondrial DNA-encoding subunits of complex I in the respiratory chain. The subsequent metabolic events may promote tumorigenesis and inhibit malignant transformation. This review discusses the histopathology and histogenesis of two examples of oncocytoma in the ocular adnexa and presents a simplified synopsis of the genomic and metabolic changes that are significant in the pathogenesis of these neoplasms.

Basal cell carcinosarcoma of the eyelid with osteosarcomatous transformation.

A carcinosarcoma is a neoplasm with malignant epithelial and mesenchymal components. It is thought to arise by mesenchymal transformation of the epithelial elements. The cutaneous form of carcinosarcoma is rare and is associated with sun exposure; most cases arise in the head and neck. The epithelial component may be a basal cell carcinoma, a squamous cell carcinoma, or an adnexal carcinoma. The mesenchymal component may be an osteosarcoma, a pleomorphic undifferentiated sarcoma, or another type of sarcoma. Only a few cases of cutaneous carcinosarcoma have been described in the periocular skin. We present a case of basal cell carcinosarcoma with osteosarcoma and pleomorphic undifferentiated sarcoma arising in the lower eyelid of an elderly man.

Orbital metastasis: clinical features, management and outcome.

PURPOSE: To review the clinical features, treatment, outcome and survival of metastatic tumors of the orbit. MATERIALS AND METHODS: Retrospective, non-comparative, chart review of 80 patients with orbital metastasis treated in four tertiary orbital centres in Australia. RESULTS: The study included 80 patients of which, 44 were male with a mean age of 60 years. Orbital involvement commonly presented late in a multisystemic disease; however, the orbit was the first presentation in 15% of the cases. Diplopia (48%), pain (42%), and visual loss (30%) were the commonest symptoms at presentation; whereas proptosis (63%), strabismus (62%), and visual loss (41%) were the most frequent clinical signs. Computed tomography commonly showed a solid enhancing mass (42 cases) located within the orbital fat (43%), or enlarging an extraocular muscle (28%). Breast carcinoma (29%), melanoma (20%), and prostatic cancer (13%) were the most frequent histological types. Treatment was often multi-disciplinary and modalities included radiotherapy, chemotherapy, hormone therapy, surgery, and immunotherapy. Survival was limited to 1.5 years after diagnosis independent of the histological type, with 29% of patients alive after 17 months follow-up. CONCLUSIONS: A high index of suspicion and appropriate intervention with histological diagnosis can help in the management and quality of life in patients with metastatic orbital disease. Overall survival is limited and we encountered statistical limitations proving differences in the survival based on the sub-type of primary tumour involved. Metastatic orbital melanoma presented a higher incidence when compared with previous studies, probably due to the increase frequency of skin found in the Australian population.

NUT carcinoma of the sinonasal tract infiltrating the orbit in a man with birdshot chorioretinitis.

A 48-year-old man with a history of birdshot chorioretinitis presented with blurry vision, retro-bulbar pain and sinusitis. Though visual acuity was unaffected, he had left optic disc oedema and mild restriction of left eye abduction. His symptoms progressed quickly, with diplopia in primary gaze, epistaxis from his left nostril, and a left relative afferent pupillary defect (RAPD). On computed tomography, there was a mass in the nasal cavity that extended through the left cribriform plate and lamina papyracea and posteriorly into the optic canal. Pathological examination of biopsy specimens revealed sheets of undifferentiated cells with extensive areas of necrosis and islands of squamous differentiation. The tumour cells expressed monokeratin, p63, CD34, and p16. Molecular testing indicated rearrangement of the NUTM1 (15q14) locus and fusion of the NUTM1 and BRD4 (19p13.12) loci, confirming the diagnosis of NUT carcinoma of the sinonasal tract. This is the first reported case of NUT carcinoma in a patient with birdshot chorioretinitis. The onset of chorioretinitis may have been the earliest sign of the effects of the BRD4-NUTM1 fusion protein, resulting in expression of HLA-A29. There is evidence that bromodomain and extra terminal (BET) family proteins play a role in inflammatory marker expression.

Eye muscle antibodies and subtype of thyroid-associated ophthalmopathy.

The eye changes associated with Graves' hyperthyroidism can be classified into two subtypes, congestive ophthalmopathy (CO), in which inflammatory changes in the periorbital tissues predominate, and ocular myopathy (OM), in which eye muscle damage is the main feature. Antibodies against the flavoprotein (Fp) subunit of succinate dehydrogenase (SDH), the 64-kd protein, and G2s, a thyroid and eye muscle shared protein of unknown function, are good markers of eye muscle cell damage in patients with OM. Another antigen associated with ophthalmopathy is the flavine adenine nucleotide (FAD) cofactor of several mitochondrial enzymes, including SDH. We tested for serum antibodies against purified human recombinant Fp, FAD, and a G2s fusion protein, in patients with thyroid-associated ophthalmopathy (TAO) and control patients and subjects, in enzyme-linked immunosorbent assay. Antibodies against Fp were detected in 32% of patients with TAO, 30% with Graves' hyperthyroidism (GH), 16% with Hashimoto's thyroiditis (HT), in 14% of patients with multi-nodular goiter (MNG), and in 6% of normal subjects. Antibodies against FAD were found in 24%, 30%, 24%, and 14%, respectively, of these patients and in 12% of the normals, while antibodies against G2s were detected in 50% of patients with TAO, 40% with GH, 40% with HT, in 29% of patients with MNG, and in 7% of normals. We also tested for antibodies against SDH, FAD, and G2s in 12 patients with GH who developed CO (6 patients) or OM (6 patients) after treatment with antithyroid drugs. Of the 6 patients who developed OM, antibodies against SDH preceded the onset of eye disease in 4 and coincided with it in 2, antibodies against G2s preceded eye muscle disease in 5 and coincided with it in 1 patient while antibodies against FAD preceded the development of OM in 5 patients. Of the 6 patients who developed CO, antibodies against SDH were detected in only one patient and borderline levels were demonstrated in 1, while anti-FAD and anti-G2s each preceded the onset of eye signs in 6 patients. Positive sera from another group of patients with TAO, and a second group of normal subjects, were tested at increasing serum dilutions. Sera from the two groups showed similar dilution patterns, except for a few patients with TAO in whom increasing dilutions was associated with increased, then decreased, antibody levels. In this experiment the prevalences of the two antibodies were much greater in patients with TAO namely, 67% for anti-Fp and 89% for anti-G2s, while the prevalences in the normals were 11% and 22%, respectively. The reason for this apparent discrepancy is not clear but may reflect subject and assay differences. Because Fp is found within the mitochondrial membrane it is likely that the corresponding antibodies are produced after eye muscle necrosis, and do not play a role in its pathogenesis. The primary reaction in the eye muscle may be T-cell autoimmunity against G2s, although this has not been proven. The mechanism for the production of antibodies against G2s, FAD, and Fp in subjects who do not have ophthalmopathy is unclear. The significance of such antibodies in control subjects is presently being addressed in our laboratory.

Orofacial granulomatosis presenting as bilateral eyelid swelling.

Orofacial granulomatosis (OFG) is an uncommon but increasingly recognized disease of unknown etiology. The typical presentation is chronic swelling of the perioral soft tissue, but eyelid edema can be the sole manifestation. Terminology of this disease can be confusing as it may also be referred to as granulomatous cheilitis and a monosymptomatic presentation of Melkersson-Rosenthal syndrome (MRS). Crohn's disease and sarcoidosis should also be considered in the differential as the histopathology can be similar. Corticosteroids are the mainstay of treatment but can lack efficacy. Atypical presentations and the possibility of systemic disease involvement can further challenge the management. We describe an unusual case in which OFG manifests solely as chronic eyelid swelling. This 69-year old Asian female patient had a delayed diagnosis that responded well to intralesional corticosteroid injection with surgical skin reduction. In addition to describing this unusual presentation of OFG, we review the relevant literature and evaluate the current terminology used to describe this entity.