Oral Hedgehog Inhibitor, Vismodegib, for Locally Advanced Periorbital and Orbital Basal Cell Carcinoma: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the efficacy and safety of oral vismodegib (Erivedge; Genentech) in the management of locally advanced orbital and periorbital basal cell carcinoma (BCC). METHODS: A literature search was conducted last in September 2023 in the PubMed database for English language original research that evaluated the effect of oral vismodegib on orbital and periorbital BCC. Sixty articles were identified and 16 met the inclusion criteria. RESULTS: Most studies demonstrated high response rates, with up to 100% of patients responding to the medication in individual studies and initial complete regression occurring in up to 88% of patients. Vismodegib treatment resulted in significant reductions in tumor volume, resulting in globe preservation for most patients. However, in 12% of patients, the response was partial. Recurrences also occurred with substantial frequency, even after an initial complete response. As such, up to 79.4% of patients required surgical intervention, and up to 23% of patients still required exenteration. Use of these agents resulted in reductions in tumor volume that may delay or prevent the need for exenteration in some, but not all, patients. Importantly, molecular analysis of tissue excised after vismodegib therapy revealed persistent tumor in all patients, with frequent accumulation of mutations that may confer resistance to further hedgehog inhibitor therapy. Although most adverse events were rated as level I or II, side effects were common, with up to 100% of patients in studies experiencing at least 1 event. Muscle cramps, alopecia, weight loss, fatigue, and dysgeusia were the most common adverse events, and several patients discontinued therapy because of them. Furthermore, 1 patient died of sepsis that may have resulted from the therapy. CONCLUSIONS: Although level I and II evidence are lacking, most studies indicate a benefit from the use of oral vismodegib to treat orbital and periorbital BCC tumor volume. However, patients should be cautioned about the adverse side effects of treatment and the persistence of tumor cells with mutations that may cause long-term resistance. Use of vismodegib as short-term neoadjuvant therapy may be effective in shrinking tumor volume to reduce surgical morbidity while reducing the frequency and severity of side effects. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Comprehensive analysis of orbital lymphoma in a Turkish cohort: clinical characteristics, histological subtypes, treatment modalities, prognostic factors, and implications for management.

The study analysed the clinical characteristics, treatment approaches, and survival outcomes of 97 consecutive patients with orbital lymphoma (OL) over a 25-year period at. The median age of the patients was 57.6 years, and 59.8% (n = 58) were male. Marginal zone lymphoma constitutes the most prevalent subtype, accounting for 67% of cases, whereas other common subtypes include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, and T-cell lymphomas. Unilateral involvement was observed in the majority of cases (72.3%). Common clinical presentations included mass (30.9%), swelling (26.8%), and epiphora (11.3%). Of the patients, 7.2% received rituximab alone, 14.4% received radiotherapy alone, 48.5% received chemotherapy, 27.8% received radiotherapy plus rituximab, 22.7% received radiotherapy plus chemotherapy, and 5.2% underwent surgery as the first-line treatment. During a median follow-up of 4.3 years, 15.5% of patients experienced relapse or disease progression. The 5-year and 10-year progression-free survival rates were 84.1% and 79.1%, respectively. This study contributes to our understanding of OLs and provides a foundation for further investigations in this field. Male gender, presence of B symptoms, advanced stage, secondary orbital lymphoma, aggressive histological subtype, and elevated serum lactate dehydrogenase levels were associated with poorer (either inferior or worse) progression-free survival.

Investigating the frequency of somatic MYD88 L265P mutation in primary ocular adnexal B cell lymphoma.

BACKGROUND: Ocular adnexal B cell lymphoma is the most common orbital malignancy in adults. Large chromosomal translocations and alterations in cell-signaling pathways were frequently reported in lymphomas. Among the altered pathways, perturbations of NFκB signaling play a significant role in lymphomagenesis. Specifically, the MYD88 L265P mutation, an activator of NFκB signaling, is extensively studied in intraocular lymphoma but not at other sites. Therefore, this study aims to screen the MYD88 L265P mutation in Ocular adnexal B cell lymphoma tumors and assess its clinical significance. METHODS AND RESULTS: Our study of twenty Ocular adnexal B cell lymphoma tumor samples by Allele-Specific Polymerase Chain Reaction identified two samples positive for the MYD88 L265P mutation. Subsequent Sanger sequencing confirmed the presence of the heterozygous mutation in those two samples tested positive in Allele-Specific Polymerase Chain Reaction. A comprehensive review of MYD88 L265P mutation in Ocular adnexal B cell lymphoma revealed variable frequencies, ranging from 0 to 36%. The clinical, pathological, and prognostic features showed no differences between patients with and without the MYD88 L265P mutation. CONCLUSION: The present study indicates that the MYD88 L265P mutation is relatively infrequent in our cohort, underscoring the need for further validation in additional cohorts.

Fully automated segmentation and volumetric measurement of ocular adnexal lymphoma by deep learning-based self-configuring nnU-net on multi-sequence MRI: a multi-center study.

PURPOSE: To evaluate nnU-net's performance in automatically segmenting and volumetrically measuring ocular adnexal lymphoma (OAL) on multi-sequence MRI. METHODS: We collected T1-weighted (T1), T2-weighted and T1-weighted contrast-enhanced images with/without fat saturation (T2_FS/T2_nFS, T1c_FS/T1c_nFS) of OAL from four institutions. Two radiologists manually annotated lesions as the ground truth using ITK-SNAP. A deep learning framework, nnU-net, was developed and trained using two models. Model 1 was trained on T1, T2, and T1c, while Model 2 was trained exclusively on T1 and T2. A 5-fold cross-validation was utilized in the training process. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), sensitivity, and positive prediction value (PPV). Volumetric assessment was performed using Bland-Altman plots and Lin's concordance correlation coefficient (CCC). RESULTS: A total of 147 patients from one center were selected as training set and 33 patients from three centers were regarded as test set. For both Model 1 and 2, nnU-net demonstrated outstanding segmentation performance on T2_FS with DSC of 0.80-0.82, PPV of 84.5-86.1%, and sensitivity of 77.6-81.2%, respectively. Model 2 failed to detect 19 cases of T1c, whereas the DSC, PPV, and sensitivity for T1_nFS were 0.59, 91.2%, and 51.4%, respectively. Bland-Altman plots revealed minor tumor volume differences with 0.22-1.24 cm3 between nnU-net prediction and ground truth on T2_FS. The CCC were 0.96 and 0.93 in Model 1 and 2 for T2_FS images, respectively. CONCLUSION: The nnU-net offered excellent performance in automated segmentation and volumetric assessment in MRI of OAL, particularly on T2_FS images.

Assessment of prognostic factors in patients with primary ocular adnexal lymphoma when considering competing risk elements.

BACKGROUND: Accurate prognostic factors for primary ocular adnexal lymphoma (POAL) are scarce. Survival models and prognostic factors derived without considering competing risk factors suffer from major statistical errors. This study aimed to accurately assess prognostic factors in POAL patients using competing risk models, and compare this to the traditional COX proportional hazards model. METHODS: This retrospective study utilised data from the Surveillance, Epidemiology, and End Results (SEER) program 2010-2015 and included patients with B-cell POAL. The cumulative incidence function and Gray's test for cause-specific survival were calculated as univariate analysis. The competing risk models were a Fine-Gray subdistribution hazard model and a cause-specific model, and a traditional COX model was employed as a multivariate analysis. RESULTS: This study enrolled 846 eligible patients with POAL: 60 patients (7.09%) died from POAL and 123 patients (14.54%) died from other causes. Multivariate competing risk models indicated that age, laterality, histology subtype, the 7th edition of American Joint Committee on Cancer stage T, and radiotherapy were independent predictors for cause-specific survival of patients with POAL. There was high consistency between the two competing risk models. The COX model made several misestimations on the statistical significance and hazard ratios of prognostic factors. CONCLUSIONS: This study established competing risk models as a method to assess POAL prognostic factors, which was more accurate than traditional methods that do not consider competing risk elements.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

MRI-Based Radiomics Nomogram for Preoperative Differentiation Between Ocular Adnexal Lymphoma and Idiopathic Orbital Inflammation.

BACKGROUND: Ocular adnexal lymphoma (OAL) and idiopathic orbital inflammation (IOI) are malignant and benign lesions for which radiotherapy and corticosteroids are indicated, but similar clinical manifestations make their differentiation difficult. PURPOSE: To develop and validate an MRI-based radiomics nomogram for individual diagnosis of OAL vs. IOI. STUDY TYPE: Retrospective. POPULATION: A total of 103 patients (46.6% female) with mean age of 56.4 ± 16.3 years having OAL (n = 58) or IOI (n = 45) were divided into an independent training (n = 82) and a testing dataset (n = 21). FIELD STRENGTH/SEQUENCE: A 3-T, precontrast T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and postcontrast T1WI (T1 + C). ASSESSMENT: Radiomics features were extracted and selected from segmented tumors and peritumoral regions in MRI before-and-after filtering. These features, alone or combined with clinical characteristics, were used to construct a radiomics or joint signature to differentiate OAL from IOI, respectively. A joint nomogram was built to show the impact of the radiomics signature and clinical characteristics on individual risk of developing OAL. STATISTICAL TESTS: Area under the curve (AUC) and accuracy (ACC) were used for performance evaluation. Mann-Whitney U and Chi-square tests were used to analyze continuous and categorical variables. Decision curve analysis, kappa statistics, DeLong and Hosmer-Lemeshow tests were also conducted. P < 0.05 was considered statistically significant. RESULTS: The joint signature achieved an AUC of 0.833 (95% confidence interval [CI]: 0.806-0.870), slightly better than the radiomics signature with an AUC of 0.806 (95% CI: 0.767-0.838) (P = 0.778). The joint and radiomics signatures were comparable to experienced radiologists referencing to clinical characteristics (ACC = 0.810 vs. 0.796-0.806, P > 0.05) or not (AUC = 0.806 vs. 0.753-0.791, P > 0.05), respectively. The joint nomogram gained more net benefits than the radiomics nomogram, despite both showing good calibration and discriminatory efficiency (P > 0.05). DATA CONCLUSION: The developed radiomics-based analysis might help to improve the diagnostic performance and reveal the association between radiomics features and individual risk of developing OAL. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 3.

Adnexal squamous cell carcinoma: incidence of eyelid margin involvement.

PURPOSE: We aimed to perform a review of facial and periorbital squamous cell carcinoma (SCC) cases to assess the relative incidence of eyelid margin involvement. METHODS: This is a retrospective review of all patients with biopsy-proven SCC who were evaluated at a single oculoplastic surgery practice from 2007 to 2019. The charts were reviewed for the anatomical location of the malignancy, and those involving the eyelid were further divided into marginal and non-marginal lesions. Statistical analysis was performed using a one proportion z-test. RESULTS: A total of 76 patients with a diagnosis of biopsy-proven periorbital and facial SCC were identified, 67 involved the ocular adnexa. Thirty-nine (58.2%) patients had lesions located on the eyelid. Of these, 33 (84.6% p < 0.0001, 95% CI 69.45-94.13) had lesions located at the margin, six of the 39 lesions were non-marginal. The remaining lesions were present within the brow (n = 10, 14.9%), medial canthus (n = 10, 14.9%), palpebral conjunctiva (n = 1, 1.5%), or orbit (n = 1, 1.5%). In six patients (8.9%) lesions involved multiple anatomic subunits. CONCLUSION: We present our investigation of the incidence of SCC of the marginal vs. non-marginal eyelid, revealing a statistically significant increased involvement of the eyelid margin. Future investigations are necessary to further elucidate the vulnerability of the eyelid margin to the development of SCC in particular in regards to the role of the unique genetic expression profile of eyelash follicular stem cells.

Granulomatosis with polyangiitis-associated sclerokeratitis in a case of ocular adnexal B-cell lymphoma.

We describe the first reported case of granulomatosis polyangiitis (GPA)-associated sclerokeratitis in a patient with treated ocular adnexal lymphoma (OAL). The patient presented with pain and decreased vision in the left eye over several weeks. Past medical history was significant for recent bilateral relapsing OAL that was treated successfully with radiotherapy. Examination of the eyes revealed sectoral scleritis and peripheral ulcerative keratitis. Magnetic resonance imaging (MRI) of the orbits excluded recurrence of OAL and serum antineutrophil cytoplasmic autoantibody (ANCA) titres confirmed the diagnosis of GPA. Disease was poorly responsive to systemic steroids, azathioprine and rituximab. Ultimately, resolution was achieved with successive subconjunctival dexamethasone and subconjunctival triamcinolone injections. This case highlights the need to consider ocular inflammation in patients with a history of malignant hemopathies.

Long-term follow-up and health-related quality of life among cancer survivors with stage IEA orbital-type lymphoma after external photon-beam radiotherapy: Results from a longitudinal study.

We assessed the long-term outcomes and treatment-related adverse effects of patients with Stage I, "orbital-type" lymphomas that were uniformly treated with photons. All consecutive patients diagnosed with low-grade, Ann Arbor Stage IEA orbital lymphoma treated between 1999 and 2020 at our department were retrospectively reviewed. We excluded patients with exclusive conjunctival involvement, typically treated with en face electrons. In order to quantify radiotherapy related side effects we applied the CTCAE criteria, analyzed changes in visual acuity, quantified dry eye symptoms by use of the Ocular Surface Disease Index (OSDI) score and applied the EORTC QLQ-C30 questionnaire for quality of life (QoL) assessment. In total 66 eyes of 62 patients were irradiated with a median dose of 30.6 Gy. The median follow-up was 43.5 months. The predominant histological subtype were MALT lymphomas. No local failure occurred in this cohort. Of nine outfield relapses, six solely occurred in the contralateral eye. The 5- and 10- years distant progression free survival rates (PFS) were 81.4% and 63.5%. The 5- and 10-years overall survival rates were 85.1% and 71.9% without any tumor related death. Of the acute toxicities none was higher than CTCAE grade 1. The predominant late toxicities were dry eyes (21.2%) of CTCAE Grade <2 and radiation induced cataracts (19.7%). During long-term follow up the average visual acuity did not deteriorate. The global QoL was worst before treatment and improved significantly after 24 months (p = 0.007). External beam radiotherapy of "orbital-type" lymphomas with photons is an effective and gentle treatment option with excellent local control rates. From the high control rates the trend to use slightly lower total doses of 24-27 Gy with conventional fractionation is supported. As non-coplanar radiotherapy techniques improved and total doses can slightly be reduced, the current status of radiotherapy as first line therapy is provided.

Investigation of epidemiological characteristics and development of a nomogram to predict survival in primary ocular adnexal lymphoma.

BACKGROUND: Studies on the epidemiology and prognosis of primary ocular adnexal lymphoma (POAL) are scarce for its low occurrence. The goal of our research was to assess the epidemiologic characteristics, prognostic variables and survival of POAL patients. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to collect data on patients identified with POAL from 1975 to 2011 and the incidence rate of POAL from 1975 to 2017. To discover independent predictive markers for overall survival (OS) and disease-specific survival (DSS), multivariable Cox regression analysis was utilised. The independent prognostic factors found by multivariate Cox regression analysis were used to generate a nomogram. RESULTS: A total of 2839 patients were diagnosed with POAL, with an average age of 64.1 years. The total incidence of POAL was 2.51/1000000 (according to the overall adjustment of the 2000 American standard) from 1975 to 2017, and the annual percentage change (APC) was 2.47 (95% confidence interval 1.64-3.32, p < 0.05), showing a sharp upward trend. After multivariate Cox regression analysis, age, gender, year of diagnosis, marital status, primary site, laterality, pathological type and treatment strategy were evaluated as independent prognostic factors of OS or DSS (p < 0.05). A nomogram was constructed to forecast the DSS of 1, 3, 5 and 10 years. The concordance index (C-index) and the calibration plots demonstrated the robustness and accuracy of the nomogram. CONCLUSIONS: Although POAL is sporadic, the incidence has generally increased in the past 36 years. In recent years, survival rates have risen, and radiotherapy can render better OS and DSS. The nomogram specially made for POAL is robust and precise in predicting the DSS of 1, 3, 5 and 10 years.

Clinical characteristics and outcomes of ocular adnexal mantle cell lymphoma.

PURPOSE: To compare characteristics of initial ocular adnexal (OA) mantle cell lymphoma (MCL) and initial systemic MCL. METHODS: Retrospective, comparative case series. Patients treated for MCL at Mayo Clinic from 1/1/1990 to 11/30/2020. MCL was classified as initial OA if first site was OA or initial systemic if first site was elsewhere with progression or recurrence to the OA region. OUTCOME MEASURES: Features, treatment, and survival. RESULTS: There were 50 patients with MCL, 23 initial OA and 27 initial systemic. Patients with initial OA MCL had more conjunctival (52% vs. 19%, p = .017) involvement and less frequently received chemotherapy plus autologous stem cell transplant (ASCT) (9% vs. 33%, p = .046) as initial treatment. Complete remission was achieved in 41 (91% vs. 74%, p = .152) patients. Five-year disease-specific survival was similar in initial OA and initial systemic MCL (92% vs. 83%, p = .187). Subanalysis of patients with initial OA MCL revealed 9 (39%) patients developed tumor recurrence, with mean time to recurrence of 28 months. Comparison (no recurrence vs. recurrence) of initial OA MCL patients revealed those with no recurrence had shorter mean final follow-up (3.3 vs. 9.8 years, p = .005) and more frequent initial treatment with rituximab-based chemotherapy plus ASCT (43% vs. 0%, p = .048). Recurrence had no effect on the 5-year age-adjusted risk of death from lymphoma (HR 2.17, 95% CI 0.55-9.09, p = .266). CONCLUSIONS: Initial OA and initial systemic MCL patients differ in presentation and management but have similar survival.

Double-hit and triple-hit high-grade B-cell lymphoma of the ocular adnexa.

High-grade B-cell lymphoma (HGBL) with c-MYC and BCL2 and/or BCL6 rearrangements, also known as a double-hit and triple-hit lymphoma, is an aggressive non-Hodgkin lymphoma affecting older adults. After formal recognition of this entity in the 2017 revision of the World Health Organization Classification of lymphoid neoplasms, only two well-documented cases of triple-hit lymphoma of the orbit appear in the literature. Herein, we describe a 70-year-old man with progressive diplopia, ophthalmoplegia, and rapidly enlarging temporal mass. Biopsy revealed a tumor morphologically consistent with HGBL, coexpressing CD20, CD10, BCL6, BCL2, and c-MYC on immunohistochemical analysis. Fluorescence in-situ hybridization showed rearrangements in c-MYC and BCL-2 genes, confirming double-hit HGBL. Systemic workup revealed Ann Arbor stage IV disease. This report reviews the existing literature on ocular adnexal double-hit and triple-hit lymphoma and provides an update on the diagnostic ancillary studies, prognostic implications, and latest management for this aggressive hematolymphoid malignancy.

Clinical analysis of ocular adnexal mucosa-associated lymphoid tissue lymphoma with IgG4-related ophthalmic disease.

PURPOSE: To analyse the incidence and characteristics of ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD), and to compare with IgG4-negative OAML. METHODS: We enrolled 130 patients with pathology-confirmed OAML at a single tertiary medical centre. Patients were divided into IgG4-positive and IgG4-negative groups based on the pathologic criteria for IgG4-ROD. The data were reviewed and compared between the groups. RESULTS: IgG4-positive OAML was identified in 5.4% (7/130) of OAML and 13.5% (7/52) of non-conjunctival OAML. IgG4-positive group had a higher incidence of involvement of the lacrimal gland (7/7 vs. 18/123, p = .001), extraocular muscles (3/7 vs. 10/123, p = .022) and infraorbital nerve (2/7 vs. 0/123, p < .001), and had a lower incidence of involvement of the conjunctiva (0/7 vs. 84/123; p < .001) than IgG4-negative group. IgG4-positive group had higher T and N categories of the American Joint Committee on Cancer classification (T1:T2:T3:T4 ratio of 0:6:0:1 vs. 78:32:8:5, p < .001; and ≥N1 ratio of 2/7 vs. 7/123, p = .021). There were no differences in the response rate to initial treatment (5/6 vs. 39/41, p = .343) or the relapse rate (1/6 vs. 5/41, p = 1.000) between the groups. CONCLUSION: IgG4-positive OAML showed clinical features similar to IgG4-ROD, such as predominant disease involvement of the lacrimal gland, extraocular muscles, infraorbital nerve and lymph nodes, but not the conjunctiva. However, treatment outcomes were favourable with or without background IgG4-ROD. Physicians should be aware that IgG4-ROD might undergo a malignant transformation and that thorough treatment and surveillance of IgG4-ROD are important.

The diagnostic value of 123I-IMP SPECT in ocular adnexal lymphoma.

BACKGROUND: N-isopropyl- (123I) p-iodoamphetamine (123I-IMP) is specifically accumulated in primary central nervous system lymphoma (PCNSL) during single-photon emission tomography (SPECT) and contributes to its diagnostic imaging. However, whether 123I-IMP is accumulated in ocular adnexal lymphoma (OAL), one of the malignant intraorbital tumors, remains unclear. This study aimed to evaluate the diagnostic value of 123I-IMP SPECT in OAL. METHODS: Between August 2005 and June 2020, 26 patients with intraorbital tumors underwent neurosurgery at the tertiary care center. Of these, 15 patients who underwent 123I-IMPSPECT before surgery were retrospectively examined. The region of interest was set in the cerebellum ipsilateral to the intraorbital tumor on 123I-IMP SPECT, and the tumor-to-cerebellum ratio (T/C ratio) was calculated using the following formula: T/C ratio = [accumulation of tumor (count/pixel)]/[accumulation of ipsilateral normal cerebellar hemisphere (count/pixel)]. RESULTS: Six patients were included in the OAL group, who were pathologically diagnosed with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), diffuse large B-cell lymphoma (DLBCL), and plasmacytoma. The T/C ratio in the OAL group was statistically higher than that in the non-OAL group (p < 0.01). The optimal cutoff values for both groups were between 0.76 and < 0.93. The sensitivity and specificity were 1.00, respectively. CONCLUSIONS: 123I-IMP SPECT is useful as one of the examinations in the differential diagnoses of OAL, because it showed a significantly higher accumulation in OAL group than in non-OAL group.

High-risk human papillomavirus and ZEB1 in ocular adnexal sebaceous carcinoma.

BACKGROUND: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. METHODS: A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. RESULTS: High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size. CONCLUSION: As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.

NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas.

Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.

Ocular adnexal manifestations of neuroendocrine neoplasms: a case report and a major review.

PURPOSE: To describe a patient with orbital neuroendocrine neoplasm (NEN)/carcinoid tumor and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported ocular adnexal (OA) NENs. METHODS: A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of OA NENs. RESULTS: Final analysis yielded 94 patients with OA NENs, 50 females (53%) and 44 (47%) males with an average age of 63 years (range 14-86). Of 91 patients with known information, the most common presenting signs were proptosis (56/91, 61%) and visual disturbances (42/91, 47%), induced by a mass most commonly associated with an extraocular muscle (49/63, 78%). The majority of tumors (88/94, 94%) were metastases, most commonly from the gastrointestinal tract (52/88, 59%). OA NEN metastasis presented following detection of primary tumor in 73/94 (78%) patients (median time to metastasis 36 months, range 0-288 months) and as an initial manifestation of disease in 15/94 (16%) patients (median time to primary detection 18 months, range 1-108 months). Systemic work-up included extra-OA NEN biopsy (37/54, 69%), multimodal imaging (42/54, 78%), and other laboratory studies (32/54, 59%). Resection with or without adjuvant chemotherapy, radiotherapy, and biologics was the most common intervention for OA NENs (36/82, 44%). Of 67 patients with available follow-up, the median survival was 108 months (95% CI 55-161 months) and the absolute 5-year survival rate was 68%. CONCLUSIONS: OA NENs are almost exclusively metastases and can precede detection of primary tumor by many months, requiring appropriate diagnostic work-up.

Effects of radiation therapy on the meibomian glands and dry eye in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Radiation therapy (RT) is the treatment of choice in patients with low-grade ocular adenexal mucosa-associated lymphoid tissue lymphoma (OAML) and many of them experience post-RT dry eye with varying severity. The purpose of the present study was to investigate ocular effects of RT on meibomian glands and dry eye by directly visualizing structural changes. Secondly, we focused on the comparison of two groups of patients according to tumor location and radiation technique. METHODS: Sixty-four eyes with OAML of conjunctiva, orbit, lacrimal gland, or lacrimal sac were grouped into conjunctival lymphoma and "orbital-type" lymphoma (i.e., orbit, lacrimal gland, and lacrimal sac). Subjects were investigated for morphological changes in meibomian glands by meiboscore grading system. Radiation technique was examined and Ocular Surface Disease Index (OSDI) questionnaire, Schirmer's test, tear film break-up time (TBUT), slit lamp examination of corneal surface and lid margin abnormality were conducted before and after RT. RESULTS: The increase in meiboscore was statistically significant over time after RT in both groups (P < 0.001). The extent of increase in meiboscore was significantly greater in the "orbital-type" lymphoma group than in the conjunctival lymphoma group (P < 0.001). The changes in OSDI, TBUT, corneal fluorescein staining score and lid margin abnormality score after RT were significantly different across two groups (P = 0.042, 0.001, 0.035 and 0.001, respectively). Schirmer's value decreased after RT in both groups. Dry eye symptoms were most severe right after RT in both groups, but a gradual resolution was noted in most patients with conjunctival lymphoma, whereas symptoms persisted in "orbital-type" lymphoma patients. The OSDI score and corneal fluorescein staining score were positively correlated with meiboscore in "orbital-type" patients at post-RT 6 months (r = 0.43, P = 0.04; r = 0.39, P = 0.03, respectively). CONCLUSIONS: Patients with OAML had different degrees of morphological changes in meibomian glands according to tumor location and radiation technique. "Orbital-type" lymphoma patients are more likely to experience severe injury to meibomian glands, which eventually leads to persistent dry eye. Patients with "orbital-type" lymphoma should be well informed of post-RT damage on meibomian glands and persistent dry eye.

Cancers of the eye.

Ocular cancers are unique among the diseases of the eye, threatening both vision and life. In most cases, the diagnosis can be made utilizing a careful clinical history and specialized ocular examination. Eye cancer diagnosis relies heavily on imaging techniques such as high-frequency ultrasound, fluorescein angiography, anterior and posterior segment optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI). Once the diagnosis is established, treatment decisions depend on the tumor's location, size, local extension, patterns of growth, and secondary complications. Treatment options include observation, local resection, chemotherapy (topical, intravenous, intra-arterial, or intravitreal), and radiation (ophthalmic plaque or external beam). Enucleation or exenteration is only employed if these eye- and vision-sparing treatments are not possible. The core of this comprehensive review is a consecutive series of the most common ocular tumor of each structure of the eye, anterior to posterior, including basal cell carcinoma of the eyelid, squamous conjunctival neoplasia, choroidal melanoma, retinoblastoma, ocular adnexal lymphoma, and metastatic orbital tumors.