Iris freckle: a distinct entity.

PURPOSE: To report distinctive clinical and imaging features of iris freckles to differentiate them from iris nevi. DESIGN: Retrospective observational study. SUBJECTS: 53 patients (277 freckles) with incidental iris freckles and 102 patients (104 nevi) with iris nevi that are either clinically stable or pathologically confirmed. METHODS: Patient data were collected from the Department of Ophthalmic Oncology, Cleveland Clinic, Cole Eye Institute database (2012-2023). Lesion characteristics were recorded from slit-lamp examination descriptions and review of colour photographs. Ancillary imaging features observed using anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) were assessed in patients (where available). MAIN OUTCOME MEASURES: Comparison of clinical and imaging features of iris freckles and iris nevi. RESULTS: A total of 277 iris freckles and 104 iris nevi were analysed. Iris freckles were more frequently bilateral (17%; nevi 0%) and multiple (69%; nevi 2%) and located centrally (89%; nevi 17%) compared with iris nevi (p<0.001). The median freckle largest basal diameter and thickness were 0.8 mm (nevi; 2.1 mm, p<0.001) and 0.04 mm (nevi 1.0 mm, p<0.001), respectively. All iris freckles had irregular margins without any secondary effects compared with iris nevi. Iris freckles appeared flat without effacement of iris folds compared with iris nevi on AS-OCT (p<0.001). Iris freckles were not detectable by UBM. Heat map revealed that freckles demonstrated several features with uniform or near uniform values, whereas nevi demonstrated more variability in values across features. CONCLUSIONS: Iris freckles exhibit specific clinical and imaging features reflective of their characteristic histological composition that support their classification as a distinct entity within the spectrum of iris pigmented lesions.

MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma.

Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan-Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19-93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT-sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45-2.95; p < 0.0001) and males (1.51; 95% CI, 1.14-2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01-1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.

Uveal melanoma in African Americans: Diagnostic challenges.

Uveal melanoma (UM) is uncommon in African Americans. Owing to its rarity, UM may not be suspected in African Americans leading to delayed diagnosis. In addition, socioeconomic factors may also play a role in delayed diagnosis. Clinical and ultrasonographic features may be atypical due to racial pigmentation, necessitating diagnostic fine needle aspiration biopsy. Herein, we report an illustrative case series of 12 African Americans with UM highlighting clinical features and diagnostic challenges.

Secondary somatic glioblastoma arising from a mature ovarian cystic teratoma in a patient with underlying Li-Fraumeni syndrome.

•First report of a secondary somatic glioblastoma arising from MCT-MT in a patient with underlying Li-Fraumeni syndrome.•The rarity of glioblastoma arising from MCT-MT warrants investigation for underlying genetic predisposition.•Glioblastomas arising from MCT-MT appear to exhibit wild type IDH gene status.•Advanced-stage glioblastoma arising from MCT-MT exhibits aggressive behavior and requires adjuvant therapy.•Optimal adjuvant therapy regimen for glioblastoma arising from MCT-MT remains unknown.

Rathke's cleft cyst presenting with recurrent aseptic meningitis and inflammatory apoplexy: illustrative case.

BACKGROUND: Rathke's cleft cyst (RCC) is a benign sellar/suprasellar lesion often discovered incidentally. Rarely, symptomatic cases can present with headache and may exhibit concomitant aseptic meningitis or apoplexy. The authors describe a patient with an RCC presenting with recurring episodes of aseptic meningitis and ultimately inflammatory-type apoplexy. OBSERVATIONS: A 30-year-old female presented with three episodes of intractable headaches over 2 months. Each episode's clinical picture was consistent with meningitis though cerebrospinal fluid cultures, and viral tests remained negative. Imaging demonstrated a sellar lesion, initially thought to be coincidental. On the third presentation, there was rapid interval growth of the lesion, adjacent cerebritis, and new endocrinopathy. Resection was then performed via an endoscopic endonasal approach. Pathology showed an RCC with acute and chronic inflammation and no evidence of hemorrhage. Cultures were negative for organisms. The patient received several weeks of antibiotic treatment with the resolution of all symptoms and no recurrence. LESSONS: Recurrent aseptic meningitis with apoplexy-like symptoms is a rare presentation of RCC. The authors propose the term inflammatory apoplexy to describe such a presentation without evidence of abscess, necrosis, or hemorrhage. The mechanism is unclear although may be due to intermittent microleakage of cyst contents into the subarachnoid space.

Metastatic gastric carcinoma to the eyelids masquerading as a chalazion: A case report.

Purpose: To describe an unusual case of metastatic gastric adenocarcinoma involving the eyelids and anterior orbit. Observations: An 82-year-old female with prior diagnosis of locally metastatic gastric adenocarcinoma developed eyelid edema. Initial ophthalmic assessment suggested presence of a chalazion that did not resolve with medical management. A few weeks after initial evaluation, the eyelid and facial edema worsened. Eyelid skin biopsy showed only inflammatory changes, but inflammatory work up was unrevealing and there was poor response to steroid therapy. Orbitotomy with biopsy ultimately revealed involvement of eyelid skin by a signet ring cell metastatic gastric carcinoma. Conclusions and importance: Eyelid and orbital metastasis from gastric adenocarcinoma may present mainly with inflammatory signs and symptoms masquerading as a chalazion. This case highlights the spectrum of presentation of this rare periocular metastasis.

EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status.

BACKGROUND: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. METHODS: In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (n = 40 patients, 20 with EGFR amplification). RESULTS: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. CONCLUSION: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Primary acquired melanosis/melanoma: utility of conjunctival map biopsy.

AIM: To assess the role of map biopsy in patients with conjunctival primary acquired melanosis (PAM)/melanoma. METHODS: Retrospective case series of 400 conjunctival biopsy samples of 51 unique patients in a tertiary referral centre. RESULTS: Each patient underwent one diagnostic biopsy and several additional map biopsies (range 2-7) providing a total of 400 samples for the analysis (55 diagnostic biopsies, 345 map biopsies). The median age was 63 years old (range 20-88) with women representing 67% of the cases. Histopathological findings were graded as negative for melanosis/normal (grade 0), melanosis without atypia (grade 1), melanosis with mild atypia (grade 2), melanosis with severe atypia (grade 3) or invasive melanoma (grade 4). Clinicopathologic concordance was observed in the majority of the map biopsies (313, 91%) (positive: clinical+/path+ (57,17%), negative: clinical-/path- (256, 74%)). Three discordant samples (clinical-/path+) represented PAM sine pigmento. The histopathological spectrum of atypia was absent (40, 73%) or limited (11, 20%) in the majority of cases with tendency to cluster as low-grade or high-grade atypia. Map biopsy led to the identification of six patients (11%) with severe atypia, requiring topical mitomycin (MMC). Similarly, in 29 cases, periodic observation without topical MMC was recommended. One case of invasive melanoma transformation occurred in the MMC-treated group. CONCLUSIONS: Map biopsy enhances overall assessment of the anatomic and pathologic extent, impacting use of adjuvant topical chemotherapy. In absence of map biopsy, it would be impossible to diagnose PAM sine pigmento. Additional corroborative work is needed to validate our observations.

Germ Line BAP1 Mutation in Patients with Uveal Melanoma and Renal Cell Carcinoma.

Uveal melanoma (UM) and renal cell carcinoma (RCC) can occur sporadically and as a manifestation of BAP1 tumor predisposition syndrome. We aimed to understand the prevalence of germ line BAP1 pathogenic variants in patients with UM and RCC. We reviewed patients managed at Cleveland Clinic between November 2003 and November 2019 who were diagnosed with UM and RCC. Charts were reviewed for demographic and cancer-related characteristics. RCC samples were tested for BAP1 protein expression using immunohistochemical (IHC) staining, and testing for germ line BAP1 pathogenic variants was performed as part of routine clinical care. Thirteen patients were included in the study. The average age at diagnosis of UM was 61.3 years. Seven patients underwent fine-needle aspiration biopsy for prognostic testing of UM (low risk =5, high risk =2). Twelve patients were treated with plaque radiation therapy, and 3 patients developed metastatic disease requiring systemic therapy. The median time to diagnosis of RCC from time of diagnosis of UM was 0 months. RCC samples were available for 7 patients for BAP1 IHC staining (intact =6, loss =1). All patients underwent nephrectomy (total = 3, partial = 8, unknown =2), and 1 received systemic therapy for metastatic RCC. Six patients underwent germ line BAP1 genetic testing. Of these, 1 patient was heterozygous for a pathogenic variant of BAP1 gene: c.1781-1782delGG, p.Gly594Valfs*48. The overall prevalence of germ line BAP1 pathogenic variants in our study was high (1/6; 17%; 95% CI 0-46%). Patients with UM and RCC should be referred for genetic counseling to discuss genetic testing.

Ocular surface squamous neoplasia: outcomes following primary excision with 2 mm margin and cryotherapy.

PURPOSE: To assess margins and the rate of local recurrence of ocular surface squamous neoplasia after excision with a 2 mm margin and cryotherapy at a single ophthalmic oncology center. OUTCOME MEASURES: (1) Conjunctival margin were assessed as positive, negative, or indeterminate margins. (2) Feasibility of repair without a graft. (3) Local recurrence. METHODS: Retrospective chart review of histologically proven conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma cases that underwent excision with a 2 mm margin and cryotherapy. RESULTS: Eighty cases met inclusion criteria for the quantitative analysis. The margin was positive in six cases (7.5%), four of which were treated with post-op topical immunotherapy/chemotherapy. Of the six positive margin cases, there was one recurrence which occurred in the patient who did not receive post-op topical adjuvant therapy, however resolved after starting topical treatment. Conjunctival repair without use of a graft was feasible in 74 (93%) cases with a mean basal diameter of 6.4 mm. Total number of local recurrence was seen in three cases (4%), which were successfully treated with adjuvant topical treatment (one positive margin case, one indeterminate margin case) or repeat resection followed by episcleral plaque brachytherapy (one negative margin case). CONCLUSION: Excision with 2 mm margin of OSSN is not associated with high rates of positive surgical margins. Even those with positive margins, when treated with adjuvant topical therapy did not develop recurrence. While achieving low rates of local recurrence, the conjunctiva is conserved, thereby minimizing the need for amniotic membrane or free conjunctival grafts for conjunctival repair.

VITREOUS SEEDING OF CHOROIDAL MELANOMA.

PURPOSE: To report a case of vitreous seeding in a medium-sized choroidal melanoma and review the literature. METHODS: Observational case report and review of literature for pathogenesis, role of vitreous biopsy, and treatment outcomes. RESULTS: A case of 57-year-old man diagnosed with vitreous seeding in the left eye 1 year after episcleral brachytherapy for medium-sized choroidal melanoma. The patient was initially diagnosed to have subretinal and vitreous hemorrhage due to rupture of a retinal artery macroaneurysm for which focal laser and intravitreal antivascular endothelial growth factor injections were administered. Over the next 9 months, the vitreous hemorrhage cleared and choroidal melanoma with retinal invasion became evident. One year after brachytherapy, the primary tumor regressed with resolution of surrounding subretinal fluid and hemorrhage. However, gradual decline in the visual acuity from 20/50 to 20/500 with increase of pigmented debris over the retinal surface and in the vitreous cavity was noted. A vitreous biopsy confirmed the presence of viable melanoma cells (epithelioid type), and the eye was enucleated. Histopathology showed microscopic persistence of primary tumor with diffuse vitreous seeding. CONCLUSION: Vitreous seeding of choroidal melanoma poses a diagnostic and management challenge.

Conjunctival Melanoma Angiotropic Microsatellitosis: A Mechanism of Local Extravascular Migratory Metastasis.

PURPOSE: To report a case of local metastasis of conjunctival melanoma, which may occur via extravascular migratory metastasis (EVMM), and discuss its clinical relevance in conjunctival melanoma tumor staging and possible management implications. METHODS: Retrospective chart review of a single clinical case with clinicopathologic correlation. RESULTS: A 65-year-old male referred due to local recurrence of conjunctival melanoma at the caruncle was successfully treated after two excisional procedures with negative sentinel lymph node biopsies. Forty-eight months after initial presentation, the patient developed a nodular lesion representing local recurrence in the ipsilateral upper tarsal conjunctiva, distant from the primary tumor site. Histopathology showed nodules in the substantia propria in the absence of primary acquired melanosis. The tumor cells were found along the extravascular surface without intralymphatic or intravascular tumor cells consistent with local metastasis. One possible mechanism is angiotropic microsatellitosis leading to local EVMM. Additional neck CT imaging showed no lymphadenopathy. CONCLUSION: EVMM via angiotropic microsatellitosis is another possible mechanism of noncontiguous local recurrence of conjunctival melanoma. Angiotropic microsatellitosis may represent a high-risk finding possibly related to increased melanoma-related mortality.

Large B-cell lymphoma of the uvea: Histopathologic variants and clinicopathologic correlation.

Twenty-eight patients were identified with large B-cell lymphoma of the uvea. Uveal involvement was iris (1 case), ciliary body (1 case), or choroidal in 14 cases. Panuveal involvement was observed in 12 cases. The clinical presentation could be categorized into uveitis (8), intraocular mass (9), neovascular glaucoma (4), and vascular disorders (4). The majority (21 cases, 77%) were diagnosed at autopsy (11) or after enucleation (10). Only 7 were diagnosed with conservative techniques. Histopathologically, 3 distinct subgroups of large B-cell lymphoma could be identified: 15 were characterized as diffuse large B-cell lymphoma, 11 as intravascular large B-cell lymphoma, and 2 as plasmablastic lymphoma. All cases had a poor prognosis, with a median survival of 14 months. Most cases (19, 67%) represented secondary uveal involvement with widespread systemic lymphoma at ophthalmic presentation. Six cases were treated with radiotherapy, most of these diagnosed before the 1990s (4). Subsequent cases (9) received systemic or local chemotherapy and adjunct radiotherapy, depending on the organs affected. Two cases were treated only with enucleation, and systemic treatment was not specified in 13 cases. Large B-cell lymphoma can rarely involve the uvea. The presenting features are nonspecific, often leading to enucleation. Effective therapy is not known. In all 3 variants, the aggressive nature and widespread involvement at ophthalmic presentation is associated with short survival.

Epstein-Barr virus-associated primary central nervous system lymphoma in a patient with diffuse cutaneous systemic sclerosis on long-term mycophenolate mofetil.

BACKGROUND: Epstein Barr virus (EBV)-associated primary central nervous system lymphoma (ePCNSL) is increasingly recognized in immunocompromised subjects, including patients receiving systemic immunosuppressive therapy. Here, we report the first case of primary CNS lymphoma associated with EBV in a patient with diffuse cutaneous systemic sclerosis (dcSSc) receiving long-term mycophenolate mofetil (MMF). CASE REPORT: A 51-year-old female with dcSSc had been on MMF 2 grams daily, which was initiated for a rapidly rising modified Rodnan skin score (mRSS), severe pruritus, and progressive joint contractures. She had an impressive response to this therapy with a significant decrease in her mRSS. Her condition remained stable for the next five years, after which she developed worsening headaches for 2-3 weeks, associated with dizziness, gait instability, and left homonymous hemianopia. MRI scan of the brain revealed a solitary 2.4cm peripherally enhancing right parietal lobe mass. Excised tissue from the right parietal lobe mass showed EBV-associated diffuse large B cell lymphoma. She received four cycles of chemotherapy (high dose methotrexate and rituximab). Currently, her condition is being monitored. Her left homonymous hemianopia persists. CONCLUSION: Because of a favorable toxicity profile, MMF is increasingly being used as long-term immunomodulatory therapy for a wide variety of autoimmune disorders. Nevertheless, patients on long-term MMF should still undergo regular CNS surveillance, not only for opportunistic infections but also for opportunistic malignancies such as PCNSL. Progressive focal or non-focal neurological deficits should always raise the alarm. Prompt evaluation and management can prevent irreversible neurological sequelae.

What Every Neuropathologist Needs to Know: Update on cIMPACT-NOW.

World Health Organization (WHO) central nervous system tumor classification represents the primary source of updates on diagnostic classes, grades, and criteria. However, recent and ongoing advances in molecular pathogenesis warrant more rapid integration into clinical practice between WHO updates. To accomplish this, the consortium to inform molecular and practical approaches to CNS tumor taxonomy-not official WHO (cIMPACT-NOW) was established in 2016. Since then, cIMPACT-NOW has convened 3 separate working committees to address classification and grading questions and challenges. This review covers the progress that these working committees have made on their specific topics.

Ocular Adnexal Amyloidosis: A Mass Spectrometric Analysis.

PURPOSE: Ocular adnexal amyloidosis (OAA) may represent localized manifestation of an underlying systemic process. Accurate identification of the amyloid fibrils can guide the systemic evaluation and treatment. The aim of this study was to characterize subtypes of OAA using immunohistochemistry and mass spectrometric analysis and to correlate with ocular involvement and systemic association. DESIGN: Retrospective case series. METHODS: Review of patients with OAA subtyped by immunohistochemistry and mass spectrometric analysis at the Cleveland Clinic from June 1995 to June 2017. RESULTS: While immunohistochemistry identified AL amyloid protein in 67% (4/6) of specimens tested, mass spectrometry identified AL amyloid protein in all specimens (10/10). AL lambda was identified in 5 (50%) samples, kappa in 3 (30%), and both kappa and lambda light chains in 2 (20%). The 5 cases of conjunctival amyloidosis were either AL lambda only (3 cases) or both lambda and kappa (2 cases). There were 3 cases that had associated systemic involvement. Two of these had eyelid skin involvement and AL kappa amyloidosis and the other patient had uveal involvement and AL lambda amyloidosis. CONCLUSIONS: Primary amyloidosis-AL is the most common form diagnosed by mass spectrometric analysis in patients with OAA. Immunohistochemistry is ineffective in the characterization of the amyloid deposits in a significant number of cases. Evaluation to exclude systemic involvement or associated underlying lymphoproliferative disorder is warranted.