Search

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 [...], * 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)

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.

To the Editor.--Our group previously described in this journal an under-recognized conjunctival nevus termed granular cell nevus (GCN) or a nevus with granular cell change (combined nevocellular and GCN) (1) [...]

PURPOSE: To characterize demographic, clinical, and histopathologic features of ocular adnexal lymphoma (OAL) at a single institution. METHODS: Retrospective review of all patients with pathologic diagnosis of OAL between 2015 and 2020. RESULTS: There were 133 patients with OAL, with a median age of 65 years (range 23-97) and a slight female predominance (male: female = 1:1.46), (n = 79, 59%). The majority of tumors were non-Hodgkin B-cell lymphomas (n = 131, 99%), most frequently Extranodal Marginal Zone B-Cell Lymphoma (EMZL, n = 93, 70%), followed by follicular lymphoma (n = 21, 16%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7, 5%), diffuse large B-cell lymphoma (n = 5, 4%), and mantle cell lymphoma (n = 5, 4%). The most frequently involved sites included the orbit (n = 85, 64%) and conjunctiva (n = 43, 32%). Information was available on oncologic staging in 78 (59%), treatment in 82 (62%), and follow-up in 75 (56%) patients. By the Ann-Arbor classification system, patients were classified as IE (54/78, 69%), IIE (9/78, 12%), IIIE (6/78, 8%), and IVE (9/78, 12%). The most common treatments included external beam radiotherapy (standard and ultra-low-dose) (48/82, 59%), biologics (22/82, 27%), and surgical excision with cryotherapy (14/82, 17%) (some patients had >1 therapy). Median follow-up time was 24 months (range 0-221 months). Recurrence was observed in 13% (10/75) with a median time to recurrence of 60 months (95% confidence interval 47-73 months). Excision with cryotherapy as a sole treatment modality was associated with earlier recurrence (P = 0.003). CONCLUSION: In this largest single-center study of OAL, we found that most OAL were Ann-Arbor Stage IE EMZL, occurring in older patients with a female predominance. Early recurrence was noted in tumors treated with excision and cryotherapy alone. [ABSTRACT FROM AUTHOR]

Retinoblastoma, the most common primary malignant intraocular tumor of childhood, is a major therapeutic success story in developed countries. Adjuvant chemotherapy is one of the factors responsible for remarkably improved [...], * Context.--Certain histopathologic risk factors in enucleated eyes are important indicators for adjuvant chemotherapy in patients with retinoblastoma. Objectives.--To determine the frequency of histopathologic risk factors in a large series of retinoblastomas treated by enucleation on file in the pathology laboratory of a large American eye hospital, assess the relationship between tumor differentiation and age at enucleation, and investigate the frequency of photoreceptor differentiation and the role of retinoma/retinocytoma as retinoblastoma precursor. Design.--Retrospective histopathologic review of 387 eyes with retinoblastoma treated by enucleation including 297 with no prior treatment. Results.--Fifty-five of 297 untreated eyes (18.5%) had high-risk features. Retrolaminar optic nerve invasion was present in 31 (10.4%), and 24 (8.1%) had massive uveal invasion (defined as >3 mm in diameter). Of the high-risk eyes, 70.9% had iris neovascularization and 60% had neovascular glaucoma. There was a statistically significant inverse relationship between age at enucleation and the degree of tumor differentiation, evidenced by the presence of rosettes. Tumors in older children tended to be poorly differentiated, while rosettes were often numerous in the tumors of younger infants. In all, 20.4% of tumors contained foci of photoreceptor differentiation, which localized in the base of a predominantly endophytic tumor in about one-fourth. Lack of correlation between photoreceptor differentiation and age at enucleation is consistent with early or prenatal malignant transformation. Both preceding observations provide evidence for the hypothetical role of retinoma as a retinoblastoma precursor. Conclusions.--Slightly less than 1 in 5 infants with retinoblastoma treated by enucleation at a large American eye hospital would require adjuvant chemotherapy on the basis of existing high-risk histopathologic features. Retinoblastomas become progressively less differentiated with time and may be spawned by precursor retinomas. (Arch Pathol Lab Med. 2009;133:1203-1209)

Melanocytoma is a deeply pigmented variant of melanocytic nevus that classically occurs in the optic disk, sometimes with contiguous involvement of the adjacent retina or choroid. Historically, this tumor was often confused with malignant melanoma both clinically and histopathologically. Today, however, it is generally recognized by its typical clinical features that differ from most melanomas and erroneous enucleation is rarely done. Histopathologically, melanocytoma is composed of intensely pigmented round to oval nevus cells with benign features. Although traditionally believed to be a relatively stationary lesion, it is now known to exhibit minor enlargement in 10--15% of cases and can cause minor visual loss by a variety of mechanisms. In rare instance, it can induce severe visual loss due to spontaneous necrosis of the lesion or compressive optic neuropathy. More importantly, it can exhibit malignant transformation into melanoma in 1--2% of cases. Ophthalmologists should be familiar with melanocytoma of the optic disk and affected patients should be followed periodically. [ABSTRACT FROM AUTHOR]

Primary conjunctival rhabdomyosarcoma (RMS) is a rare entity that can present with or without papillomatous features. A 5-year-old Asian boy was referred for a rapidly growing conjunctival tumor in the superior fornix of the left eye. Surgical excision yielded a 28 mm multilobulated papillomatous specimen that exhibited histopathologic and immunohistochemical features consistent with embryonal (botryoid) RMS. Molecular analysis revealed the absence of the PAX3/FOXO1 fusion gene, indicating favorable prognosis. After surgery, he was promptly treated with systemic chemotherapy and proton beam radiotherapy. [ABSTRACT FROM AUTHOR]

A small, but unique subgroup of retinoblastoma has been identified with no detectable mutation in the retinoblastoma gene ( RB1) and with high levels of MYCN gene amplification. This manuscript investigated alternate pathways of inactivating pRb, the encoded protein in these tumors. We analyzed the mutation status of the RB1 gene and MYCN copy number in a series of 245 unilateral retinoblastomas, and the phosphorylation status of pRb in a subset of five tumors using immunohistochemistry. There were 203 tumors with two mutations in RB1 ( RB1−/−, 83%), 29 with one ( RB1+/−, 12%) and 13 with no detectable mutations ( RB1+/+, 5%). Eighteen tumors carried MYCN amplification between 29 and 110 copies: 12 had two ( RB1−/−) or one RB1 ( RB1+/−) mutations, while six had no mutations ( RB1+/+). Immunohistochemical staining of tumor sections with antibodies against pRb and phosphorylated Rb (ppRb) displayed high levels of pRb and ppRb in both RB1+/+ and RB1+/− tumors with MYCN amplification compared to no expression of these proteins in a classic RB1−/−, MYCN-low tumor. These results establish that high MYCN amplification can be present in retinoblastoma with or without coding sequence mutations in the RB1 gene. The functional state of pRb is inferred to be inactive due to phosphorylation of pRb in the MYCN-amplified retinoblastoma without coding sequence mutations. This makes inactivation of RB1 by gene mutation or its protein product, pRb, by protein phosphorylation, a necessary condition for initiating retinoblastoma tumorigenesis, independent of MYCN amplification. [ABSTRACT FROM AUTHOR]

An 8-year-old girl was referred for an amelanotic iris tumor believed to have enlarged slightly over 3 months, suspicious for juvenile xanthogranuloma (JXG). The affected right eye had a lightly pigmented, vascular iris mass measuring 6 mm in basal dimension and 2 mm in thickness. There were no feeder vessels, seeding, inflammatory cells, or cutaneous abnormalities. Diagnostic fine needle aspiration biopsy (FNAB) was performed, revealing spindle B melanoma cells that were immunoreactive for melanocytic markers HMB45 and Melan-A. Complete tumor resection by basal sector iridectomy was performed. Histopathology confirmed spindle B melanoma. At 14-years follow up, there has been no recurrence or metastasis and visual acuity remains 20/25. Iris melanoma can develop in children and clinically resemble nodular JXG. [ABSTRACT FROM AUTHOR]