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* Context.--Ophthalmic pathology is a discipline that relies heavily on a knowledge of clinical ophthalmology. The diagnosis of ocular and periocular lesions can be challenging because some lesions and diseases are unique to this region, whereas others may demonstrate site-specific differences from nonocular counterparts. Because of these challenges, ocular and periocular biopsies are frequently referred to specialized ophthalmic pathology centers for second-opinion diagnoses. Objective.--To analyze the referral patterns, diagnostic challenges, and diagnostic discrepancies for second-opinion referrals at a dedicated ophthalmic pathology laboratory with an emphasis on lesions of special interest in ophthalmic pathology. Data Sources.--Data sources included the pathology records of all slides and blocks received in consultation at the referral eye pathology center between December 1, 2015, and December 1, 2022, the personal experience of senior authors, and published peer-reviewed literature. Conclusions.--Corneal, intraocular, and conjunctival biopsies are the most common types of cases received in consultation without the referring pathologist's diagnosis, likely reflecting diagnostic challenges. Degenerative intraocular processes occasionally raise concern for a neoplasm. Conjunctival melanocytic lesions are the most common conjunctival biopsies referred for second-opinion diagnosis and require careful tissue sampling and clinical-pathologic correlation. Careful clinical-pathologic correlation, a high level of suspicion, and adequate sampling also are required for the accurate diagnosis of periocular sebaceous carcinoma. The diagnostic discrepancies involving uveal, retinal, conjunctival, eyelid, and temporal artery biopsies are most likely to adversely influence patient management and possible outcome. Such specimens may benefit from referral to specialized ophthalmic pathology laboratories. (Arch Pathol Lab Med. 2024;148:1279-1291; doi: 10.5858/arpa.2022-0507-RA), Histopathologic diagnosis of ocular and periocular lesions can be challenging. Ophthalmic pathology is a discipline that relies heavily on a knowledge of clinical ophthalmology and ocular anatomy and histology. Some [...]

ObjectiveTo analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication.DesignRetrospective case-control study.SubjectsPatients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea.MethodsTargeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features.Main outcome measuresPresence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence.ResultsHotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized.ConclusionsIn this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.

Granular cell nevus is a rare benign variant of melanocytic nevus, which can be mistaken for malignant melanoma because of the morphologic and immunohistochemical overlap between the 2 lesions. (1-3) [...], * Context.--Granular cell change in melanocytic nevus is underrepresented in the literature with only 4 well-documented cases, 1 described in the conjunctiva. Unfamiliarity with the clinical and pathologic features of these lesions contributes to the diagnostic difficulty. Objective.--To delineate the clinical and histopathologic features of conjunctival nevi with granular cell change. Design.--In a retrospective observational case series, the medical records of all patients with conjunctival nevi and granular cell change diagnosed between December 2016 and October 2018 were reviewed. Data collected included age, sex, clinical presentation, pathologic findings, and follow-up. Results.--Twelve patients, 6 males and 6 females, with a median age of 14 years (range, 8-82 years) were identified. The nevus manifested as a pigmented, well-circumscribed nodule (7 of 9; 78%) or patch (2 of 9; 22%) in the bulbar and limbal conjunctiva (7 of 9; 78%) or in the plica semilunaris/caruncle (2 of 9; 22%). Cysts were noted in 7 of 9 lesions (78%). Features prompting surgical excision included atypical pigmentation (8 of 9; 89%), growth (7 of 9; 78%), and atypical vascularity (4 of 9; 44%). Microscopically, all lesions comprised a conventional melanocytic nevus with focal granular cell change and immunoreactivity for Melan-A, SOX10, and HMB-45, with Ki-67 proliferative index of less than 2%. Of the 9 lesions with follow-up information, there were no recurrences over mean follow-up of 11.2 months (range, 1-23 months). Conclusions.--Granular cell change in melanocytic nevi is an underrecognized finding that can simulate melanoma clinically and histopathologically. Young age at diagnosis, lack of associated conjunctival melanosis, bulbar location, cysts, and the absence of mitotic figures with a low Ki-67 proliferative index are helpful clinical and pathologic diagnostic clues. (Arch Pathol Lab Med. 2020;144:457-465; doi: 10.5858/arpa.2019-0053-OA)

Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing α-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.