Sentinel Node Biopsy for Conjunctival Melanoma; Single Centre Experience and Review of Current Literature.

PURPOSE: To evaluate the role of sentinel lymph node (SLN) biopsy in patients with conjuctival melanoma (CjM). STUDY DESIGN: Retrospective observational cohort study and literature review. SUBJECTS: Slovenian patients with CjM are included in the study. METHODS: Prospectively collected data of CjM patients treated from June 2005 to December 2016 were retrospectively analyzed. MAIN OUTCOME MEASURES: The numbers of SLN biopsy procedures, positive and false positive SLN, and local and regional relapses have been described together with overall survival. RESULTS: From June 2005 until December 2016, 24 patients with CjM were treated. The median follow-up time was 65.3 months. The mean Breslow thickness was 1.5 mm (sd = 1.8 mm), and ulceration was present in 29% of cases. Altogether, 14/24 (58%) SLN biopsy procedures were performed. SLN was positive in 2/14 (14%) cases. The estimated 5-year overall survival (OS) of the group was 72.5%, with a median survival of 151 months (95% CI 77-224). From January 2013 to January 2020, five (5/140, 3%) authors reported results comparable to our study. CONCLUSION: Our results confirm that CjM is a rare disease with approximately 14% of positive SLN. At the moment, there are no firm conclusions regarding who would benefit most from SLN biopsy or whether or not CLND should be offered. Data from literature emphasize the need for consistent and uniform staging and future multicentric studies.

PD-L1 Expression in 65 Conjunctival Melanomas and Its Association with Clinical Outcome.

Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed. PD-L1 expression in IC correlated with a higher pTNM stage and PD-L1 expression in TC with worse disease-specific survival. PD-L1 expression is a potential prognostic biomarker that correlates with poor prognosis in CM patients.

Prognostic factors and survival for malignant conjunctival melanoma and squamous cell carcinoma over four decades.

PURPOSE: To determine the epidemiology and survival of primary conjunctival malignant neoplasms. METHODS: Retrospective analysis of primary malignant conjunctival neoplasms using Surveillance, Epidemiology, and End Results database from 1973 to 2012. RESULTS: Of 1661 cases, the most common neoplasms are squamous cell carcinoma (SCC) at 54.8% and melanoma at 38.8%. Mean diagnostic age for melanoma was 62.1 compared to 65.5 years for SCC (p = 0.002). 52.2% of melanoma are male versus 77.4% of SCC (p < 0.001). For SCC only age (HR: 1.09, 95% CI:1.04-1.14) is a predictor of survival. For melanoma, age (HR: 1.07, 95% CI: 1.05-1.10), male sex (HR: 2.04, 95% CI: 1.16-3.60), T4 tumors (HR: 3.38, 95% CI: 1.17-9.80) and N1 status (HR: 8.69, 95% CI: 2.75-27.42) are all survival predictors. The 5 and 10-year overall survival (OS) estimates are not significantly different between SCC and melanoma, with 70% and 50% respectively for SCC, and 71% and 50% respectively for melanoma. Median survival time is worse for blacks (52 months) compared to whites (118 months) and Asians/Native Americans/Pacific Islanders (145 months), however race was not found to be a significant prognostic factor in multivariate analysis. Five-year survival are similar between decades 1973-1982 (66.2%), 1983-1992 (69.2%), 1993-2002 (71.3%) and 2003-2012 (70.2%). CONCLUSION: Age at diagnosis is a determinant of survival for both conjunctival SCC and melanoma. Male sex, T4 and N1 staging are also important prognostic factors for melanoma. With respect to overall survival, SCC and melanoma did not differ significantly.

Progesterone and estrogen receptors in conjunctival melanoma and nevi.

BACKGROUND: Since it has been observed that melanocytic lesions can alter their appearance during pregnancy, we analyzed whether hormone receptors are expressed in conjunctival nevi as well as conjunctival melanoma. We further analyzed whether the number of estrogen (ER) or progesterone receptors (PR) might be associated with the disease course in conjunctival melanoma. METHODS: Twenty-seven paraffin-embedded samples of conjunctival nevi and 27 conjunctival melanoma specimens were examined using immunohistological analysis with antibodies against PR and ER. The percentage of stained cells were analyzed, taking into account patient gender and age. Out of the melanoma group, all patients with complete data for tumor thickness, tumor localization, age at diagnosis, gender, and follow-up including recurrence, metastasis and tumor-related death were included in the second part of the study (n = 15), where hormone receptor rates were associated with tumor outcome, regarding recurrences, metastasis or death. Written consent was received from all included patients. RESULTS: Both nevi and melanomas showed high rates of PR- and ER-positive cells. In Nevi, 64 ± 25 % of cells stained positive for PR and 35 ± 34 % for ER. In melanoma specimens, 68 ± 30 % showed PR and 44 ± 34 % ER expression. Differences between men and women in expression rates were not statistically significant. Out of 15 melanoma patients (nine female, six male), 53 % (five women and three men) experienced 1-4 recurrences, and four patients developed metastases. The median estimated survival time was 12.2 years. A multivariate survival model taking into account known risk factors for prognosis in conjunctival melanoma confirmed tumor location to be an important predictive factor for outcome (p = 0.05). The rate of PR or ER did not show a statistically significant correlation with the disease course in our cohort. CONCLUSIONS: We observed that conjunctival melanocytic lesions express hormone receptors, which could explain why these tumors can alter their appearance under hormonal changes. Regarding the prognosis of conjunctival melanoma, no statistically significant correlation between hormone receptor expression and event-free survival was found in this analysis.

Clinical features and prognosis of conjunctival melanoma in Japanese patients.

PURPOSE: To evaluate the clinical features and prognosis of conjunctival melanoma in Japanese patients. STUDY DESIGN: Retrospective observational case series. METHODS: Twenty patients (8 men and 12 women) diagnosed with conjunctival melanoma at a singlehospital between 2003 and 2017 were analyzed. Data on clinical presentation, sex, age, the affected eye, tumor location, tumor origin, tumor stage according to the American Joint Committee on Cancer staging system (eighth edition), treatment, outcomes, local recurrence, metastasis, and survival were extracted from the patients' medical records and reviewed. RESULTS: The mean age at diagnosis was 64.2 ± 14.8 years. Tumor locations at the first examination included the bulbar conjunctiva (n = 19), plica (n = 13), and fornix (n = 12). The tumor stage was T1 in 5 cases (25%), T2 in 12 cases (60%), T3 in 3 cases (15%), and T4 in none. The mean follow-up duration was 91.7 ± 46.0 months. The local recurrence rates at 1, 5, and 10 years were 5.0%, 18.8%, and 31.5%, respectively, whilst the metastasis rates were 5.0%, 25.6%, and 32.4%, respectively. Four of the 6 patients who experienced metastasis died; duration from metastasis to death was 17.5 months (range, 7-25). The 5-year survival rate for conjunctival melanoma was 78.8%. Tumor thickness was significantly associated with survival duration on univariate Cox regression analyses. CONCLUSION: The mortality rate for conjunctival melanoma in the Japanese population was lower and higher than that reported in the Chinese and United States populations, respectively. Tumor thickness was a prognostic factor for survival in patients with conjunctival melanoma.

Ocular adnexal lymphoma - a retrospective study and review of the literature.

BACKGROUND: To review the characteristics of all Slovenian patients with ocular adnexal lymphoma (OAL) in the period of 24 years with the aim of evaluating demographic data, lymphoma location and type, disease stage, treatment modality, local control rate and survival rate. PATIENTS AND METHODS: All patients with histologically diagnosed OAL in the main tertiary centre of Slovenia, Eye Hospital, University Medical Centre Ljubljana, who were treated at Institute of Oncology Ljubljana were included in the study. Patients' data were collected from October 1995 through April 2019. RESULTS: Seventy-four patients were included in the study having a median age of 68 years at diagnosis. The majority of lymphomas were of B-cell origin (98.6%). The most frequent type was the extranodal marginal zone B-cell lymphoma (MALT) (71.6%). Orbital lymphomas were diagnosed in 56 cases (75.7%) and conjunctival in 18 cases (24.3%). Ocular manifestation was the first sign of the disease in 78.4% of patients and in 67.6% of patients ocular adnexa were the only disease location. Fifty-one patients (68.9%) were treated with radiotherapy, 7 patients (9.4%) with systemic treatment, 5 patients (6.8%) with combined radiotherapy and systemic treatment and in 11 patients, biopsy and active surveillance strategy was applied (14.9%). Local control of the disease was achieved in 96.6% of treated patients. Median overall survival of the whole study group has not been reached yet. Five-year overall survival rate was 80.1% (95% CI 68.1% - 88.5%) and 5-year lymphoma specific survival rate was 87.2% (95% CI 83.2%-91.2%). CONCLUSIONS: OALs comprise a group of heterogeneous diseases with variable outcomes depending predominately on the patient's age and lymphoma type, with low grade lymphomas carrying good prognosis even in elderly patients.

Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system.

PURPOSE: To assess distribution, correlations, and prognostic effect of tumor (T), node (N), and metastasis (M) staging on relapse and survival. DESIGN: Retrospective clinical review. PARTICIPANTS: Sixty-three patients diagnosed with primary ocular adnexal lymphoma (OAL) between January 1986 and November 2011. METHODS: Complete ocular examination and systemic evaluation were performed. Patients were staged according to the American Joint Committee on Cancer (AJCC) seventh edition tumor-node-metastasis (TNM) clinical staging system for OAL and followed every 6 to 12 months (median follow-up, 27.9 months). MAIN OUTCOME MEASURES: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site and overall survival. RESULTS: There were 40 men (63.5%). The median age was 65 years (range, 24-85 years). The affected site was the conjunctiva in 27 patients (42.9%), orbit in 38 patients (60.3%), and eyelid in 3 patients (4.8%). The histologic subtype was extranodal marginal zone lymphoma (EMZL) in 51 patients (81.0%). A total of 14 patients (23.3%) had T1, 42 patients (70.0%) had T2, 1 patient (1.7%) had T3, and 3 patients (5.0%) had T4 disease. A total of 48 patients (82.8%) had N0 disease, and 10 patients (17.2%) had N1-4 disease. M stage was M0 in 47 patients (81.0%) and M1 in 11 patients (19.0%). With advanced T stage, there was an increase in both N1-4 (P = 0.045) and M1 disease (P = 0.041). M1 disease was greater among patients with N1-4 disease compared with N0 stage (50.0% vs. 12.5%, P = 0.003). Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died. In Cox analysis, relapse was not associated with T stage (hazard ratio [HR], 1.14 per 1 level increase, P = 0.71), N stage (HR, 1.47; P = 0.51 N1-4 vs. N0), or M stage (HR, 1.22; P = 0.76 M1 vs. M0). T stage was not associated with survival (HR, 0.86; P = 0.81), whereas N1-4 had marginally worse survival than N0 (HR, 5.35; P = 0.07), and M1 had worse survival than M0 (HR, 9.27; P = 0.008). CONCLUSIONS: The TNM staging system for primary OAL is useful for precise characterization of extent of local disease. Although T stage does not predict relapse or survival, N1-4 and M1 stages indicated less favorable survival. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes.

PURPOSE: The aim of this study was to evaluate conjunctival melanoma outcomes based on American Joint Committee on Cancer classification. The study design constituted a nonrandomized interventional case series. METHODS: This was a retrospective chart review comprising 343 participants, and the main outcome measures were melanoma local recurrence, lymph node metastasis, distant metastasis, and death. RESULTS: On the basis of the American Joint Committee on Cancer classification (seventh edition), conjunctival melanoma was classified as T1 (196 [57%]), T2 (110 [32%]), T3 (37 [11%]), and T4 (0). The mean tumor basal diameter increased with tumor staging with 8.5 mm for T1, 12.7 mm for T2 (p = 0.0003), and 16 mm for T3 (p < 0.0001). The melanoma arose from primary acquired melanosis (T1 = 71%; T2 = 84%; T3 = 81%), preexisting nevus (T1 = 8%; T2 = 5%; T3 = 3%), or de novo (T1 = 21%; T2 = 12%; T3 = 16%). Outcomes at 5 years (Kaplan-Meier) revealed melanoma local recurrence/new tumor in 44% T1, 78% T2 (p < 0.0001), and 76% T3 (P=0.0044); regional lymph node metastasis in 17% T1, 52% T2 (p < 0.0001), and 49% T3 (p = 0.0092); melanoma-related distant metastasis in 11% T1, 35% T2 (p < 0.0001), and 42% T3 (p = 0.0018); and melanoma-related death in 5% T1, 20% T2 (p = 0.0655), and 23% T3 (p = 0.0526). Based on American Joint Committee on Cancer classification, factors predictive of melanoma recurrence included T2 stage (p < 0.0001), and T3 stage (p = 0.0061). After adjusting for tumor origin, factors predictive of regional lymph node metastasis, melanoma-related distant metastasis, and melanoma-related death included melanoma arising de novo (p < 0.0001; p < 0.0001; p < 0.0001), T2 stage (p < 0.0001; p < 0.0001; p = 0.007), and T3 stage (p = 0.005; p = 0.0014; p = 0.0342). CONCLUSION: The American Joint Committee on Cancer staging predicts prognosis of conjunctival melanoma. Melanoma classified as T2 and T3 (compared with T1) showed significantly higher rates of local recurrence, regional lymph node metastasis, distant metastasis, and death.

[Clinical findings and prognosis of 11 cases of conjunctival malignant melanoma].

PURPOSE: To describe the clinical findings and prognosis of conjunctival malignant melanomas. SUBJECTS: We investigated the clinical findings and prognosis of 11 cases of conjunctival malignant melanomas diagnosed and treated at Tokyo Medical University Hospital. RESULTS: The mean age at presentation was 62.3 years, male/female ratio was 6/5. Cases arose from primary acquired melanosis (PAM) in 45% of the patients, from conjunctival nevus in 9%, from both conjunctival nevus and PAM in 27% and de novo in 18%. In all cases local resection was performed with either adjuvant cryotherapy, or similar methods for diagnosis and treatment. Postoperative local recurrence was detected in 45% of the patients. According to the Kaplan-Meier survival curve, local recurrence at 2 years is 38%. Total surgical excision of the tumor was performed for recurrent lesions. Three cases were treated with systemic chemotherapy following surgical excision for metastasis. CONCLUSION: A combination of surgical excision with adjuvant therapy has been used for the treatment of conjunctival melanoma. A more effective therapeutic strategy is required because of the high rate of recurrence and metastasis seen in this study.

Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases.

PURPOSE: To evaluate prognostic factors based on origin of conjunctival melanoma. DESIGN: Interventional case series. PARTICIPANTS: Three hundred eighty-two consecutive patients. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Melanoma-related metastasis and death. RESULTS: The melanoma arose from primary acquired melanosis (PAM; n = 284; 74%), from pre-existing nevus (n = 26; 7%), and de novo (n = 72; 19%). The mean tumor base was 11 mm for melanoma arising from PAM, 6 mm for melanoma arising from nevus, and 10 mm for those arising de novo. At 5 years (10 years), melanoma metastasis occurred in 19% (25%) in melanoma arising from PAM (P = 0.003), 10% (26%) in melanoma from nevus (P = 0.193), and 35% (49%) in those de novo. Factors predictive of metastasis by multivariable analysis included tumor origin de novo (P = 0.001), palpebral location (P<0.001), nodular tumor (P = 0.005), and orbital invasion (P = 0.022). At 5 years (10 years), melanoma-related death occurred in 5% (9%) in melanoma arising from PAM (P<0.001), 0% (9%) in melanoma arising from nevus (P<0.057), and 17% (35%) in those arising de novo. Factors predictive of death by multivariable analysis included tumor origin de novo (P<0.001), fornix location (P = 0.04), and nodular tumor (P = 0.001). CONCLUSIONS: Melanoma arising de novo carries a higher risk of melanoma-related metastasis and death compared with those cases arising from PAM or nevus.

Outcomes in 15 patients with conjunctival melanoma treated with adjuvant topical mitomycin C: complications and recurrences.

PURPOSE: To report the long-term complications and rate of local recurrence in a cohort of patients with histopathologically confirmed conjunctival melanoma (CM) treated with adjuvant topical mitomycin C (MMC). DESIGN: Retrospective, nonrandomized interventional study. PARTICIPANTS: Fifteen patients with histopathologically confirmed diagnosis of CM treated with topical MMC. METHODS: We identified all patients with histopathologically confirmed diagnosis of CM treated with topical MMC between January 1999 and March 2010. Data extracted from the patients' medical records included demographic, clinical, and histopathologic findings; treatments; long-term complications (>6 months) of MMC therapy; recurrent and metastatic disease; and mortality. MAIN OUTCOME MEASURES: Prevalence of long-term complications of MMC and development of recurrent disease were assessed. RESULTS: Fifteen patients (12 female) received topical MMC a median of 2.8 months (0.37-110.9 months) after the diagnosis of CM. Median age at diagnosis was 62 years (29-82 years), and median length of follow-up was 23.8 months (2.2-130.8 months). Most common complications included injection (n=13), tearing (n=10), irritation (n=9), pain (n=9), and limbal stem cell deficiency with keratopathy (n=4). Twelve patients (80%) experienced at least 1 long-term complication, with failure of resolution of symptoms in 7 of these patients. Local recurrence was associated with longer delay to MMC initiation (2 ±8.0 vs. 30.8 ±11 months, P=0.06). Three patients developed metastases. Recurrence was associated with metastatic disease (P=0.001). Exenteration was required in 2 patients, 1 of whom developed metastatic disease and died. CONCLUSIONS: Careful consideration should be given to the use of adjuvant MMC for the treatment of residual intraepithelial disease after the diagnosis of CM given the risk of potential long-term ocular surface toxicities.

Electron beam radiation for conjunctival squamous carcinoma.

PURPOSE: To describe the authors' technique and preliminary results using electron beam radiation as rescue therapy for recalcitrant squamous cell carcinoma of the conjunctiva and cornea. METHODS: A retrospective review comprised of an interventional case series of patients with pathologically confirmed diagnosis of squamous cell carcinoma of the conjunctiva and cornea, who had failed multiple standard treatments and underwent electron beam radiation therapy. Outcomes, radiation-related complications, and adverse effects were documented. Mortality and local control rates were calculated by the Kaplan-Meier survival probability method. RESULTS: Eight patients met the inclusion criteria; of these, 6 (75%) were men and 2 (25%) were women, with ages ranging from 38 to 65 years (mean 50 years). One tumor (12.5%) was classified as T2N0M0, 6 (75%) were classified as T3N0M0, and one (12.5%) was classified as T4N0M0. Follow up from electron beam radiation therapy ranged from 3 to 72 months (mean 30.25 months). The most common side effect was erythema and edema of the eyelids with diffuse transient eyelash loss, seen in all patients. Tumor local control and regression after electron beam radiation therapy were noted in 6 patients (75%); recurrence was noted in 2. There was neither metastatic spread nor tumor-related deaths. CONCLUSIONS: The authors report a small case series where local tumor control was achieved with electron beam radiation therapy for recalcitrant squamous cell carcinoma of the conjunctiva and cornea. This approach may be considered for patients who fail conventional therapy.

Conjunctival melanoma treatment outcomes in 288 patients: a multicentre international data-sharing study.

BACKGROUND: To relate conjunctival melanoma characteristics to local control. METHODS: Retrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. RESULTS: 288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2-8.9%), 19.3% (14.4-25.5%) and 36.9% (26.5-49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence. CONCLUSION: This multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.

Prognostic factors for relapse and survival among patients with ocular adnexal lymphoma: validation of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM classification.

BACKGROUND/AIMS: To validate the prognostic performance of the American Joint Committee on Cancer (AJCC) eighth edition classification for ocular adnexal lymphoma (OAL). METHODS: We performed a retrospective review of 140 consecutive patients treated for primary OAL between March 2010 and September 2017. Associations between T/N/M categories at presentation and disease-related outcomes, including relapse, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Seventy-nine women and 61 men (median age, 52 (range 20-84) years; median follow-up, 57 (range 7-131) months) were included. Histological subtypes included mucosa-associated lymphoid tissue lymphoma (92.1%, n=129), diffuse large B-cell lymphoma (5.0%, n=7), follicular lymphoma (1.4%, n=2) and mantle cell lymphoma (1.4%, n=2). Patients with ≥T2 disease had significantly higher risks of overall relapse (unadjusted HR)=4.32, p=0.016), decreased PFS (uHR=5.19, p=0.004) and decreased OS (uHR=9.21, p=0.047). Patients with ≥N1 disease had significantly higher risks of overall relapse (uHR=9.17, p<0.001) and decreased PFS (uHR=9.24, p<0.001). M1 disease was significantly associated with higher risks of overall relapse (uHR=3.62, p=0.036), decreased PFS (uHR=5.13, p=0.001) and decreased OS (uHR=9.24, p=0.013). On considering TNM categories as continuous data, the uHRs for per level increase in T, N and M categories were 1.77, 1.83 and 2.30 for overall relapse and 1.72, 1.87 and 2.78 for decreased PFS, respectively (p<0.05 for each comparison). CONCLUSION: The T, N and M categories of the AJCC eighth edition classification have prognostic value for relapse and survival among patients with primary OAL. Particularly, nodal/metastatic involvement at presentation indicated less favourable outcome.

Greater Tumor Thickness, Ulceration, and Positive Sentinel Lymph Node Are Associated With Worse Prognosis in Patients With Conjunctival Melanoma: Implications for Future AJCC Classifications.

Identifying tumor characteristics that correlate with metastasis and survival in patients with conjunctival melanoma can potentially lead to better outcomes through a better selection of patients for adjuvant treatments including potentially life-saving new melanoma therapy. The objective of this study was to validate the conjunctival melanoma staging criteria in the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th edition) and explore the prognostic importance of tumor thickness, histologic ulceration, and sentinel lymph node biopsy (SLNB) findings in patients with conjunctival melanoma. This is a case series of 88 consecutive patients with conjunctival melanoma. Clinicopathologic characteristics were analyzed. Associations between pathologic characteristics and outcomes were studied using Kaplan-Meier survival analysis. Local recurrence, lymph node metastasis, distant metastasis, and disease-specific survival (DSS) were the main outcome measures. The study included 56 women and 32 men; the median age was 62 years. At presentation, 41 patients had T1 disease, 23 had T2 disease, 23 had T3, and 1 had T4 disease. Sixty-six patients had invasive conjunctival melanoma (median thickness, 1.56 mm), 17 had conjunctival melanoma in situ, and in 5 patients, tumor thickness could not be determined. Overall, 22 patients had ulceration. In total, 31 patients underwent SLNB, and 4 had a positive sentinel lymph node (SLN). The median follow-up time was 46.6 months. Overall, 12 patients had nodal metastasis at presentation or during follow-up, 19 patients had distant metastasis at last follow-up, and 14 patients died of the disease. Tumor thickness and ulceration were associated with increased risks of nodal metastasis, distant metastasis, and death from the disease. Overall, greater clinical T category at presentation was associated with increased risks of distant metastasis and disease-related death; however, the risks of distant metastasis and disease-related death did not differ between T1 (bulbar) and T2 (nonbulbar) tumors or between T2c,d (caruncular) and T1-T2a,b (noncaruncular) tumors. In patients who underwent SLNB, a positive SLN was associated with worse distant metastasis free survival and DSS. Consideration should be given to adding ulceration and emphasizing tumor thickness as the main determinants of pathologic T category for conjunctival melanoma in future AJCC classifications. The significant association between a positive SLN and worse DSS highlights the importance of SLNB for prognosis in patients with conjunctival melanoma and selecting high-risk patients for adjuvant drug treatment.

Oncologic and visual outcomes after postoperative proton therapy of localized conjunctival melanomas.

INTRODUCTION: conjunctival melanomas have high local relapse rates. Oncologic and visual outcomes can be improved with proton therapy and no-touch surgery. MATERIAL AND METHODS: a monocentric retrospective study of consecutive patients treated with surgery and proton therapy for conjunctival melanoma was conducted. Proton therapy was performed to a total dose of 45 Grays physical dose delivered in eight fractions over two weeks. RESULTS: Ninety-two patients were included. The mean age was 63-year-old. 65.2% of patients had primary acquired melanosis. The mean tumor thickness and diameter was 2.5 mm and 7.0 mm respectively. The clinical stage was T1 in 71.6% of cases, with a quadrangular involvement of more than 90° in 69% of cases. Conjunctival melanomas were of epithelioid cell-type in 40% of cases. Mean follow-up was 4.7 years. Five-year local failure rate was 33.2%. Of 25 local recurrences, 14 were marginal/out-of-field, 4 in-field, others were undetermined. First surgery at expert center resulted in 24.3% of local failure at 5 years versus 38.7% if performed elsewhere (p = 0.41). Salvage exenteration was performed in 13 patients. Tumor stage and quadrangular involvement were significant factors for local failure. Five-year progression-free survival and cause-specific death rates were 61.5 and 3.6%. Stage and epithelioid type were associated with poorer progression-free survival. Trophic toxicity occurred in 22.9% of patients and was treated locally, with grafts in 7 patients. Glaucoma and cataract occurred in 13 and 22 patients respectively. Prognostic factors for visual deterioration were age, tumor extent (multifocality, quadrangular involvement > 180°) and cryotherapy. CONCLUSIONS: 5-year local failure rate after postoperative proton therapy for conjunctival melanoma was of 33.2%. Radiation-induced complications were overall manageable.

Loss of pRB in Conjunctival Squamous Cell Carcinoma: A Predictor of Poor Prognosis.

Conjunctival squamous cell carcinoma (SCC) is the most common tumor of conjunctival epithelium. It is associated with risk of permanent visual impairment and has the capability to recur, metastasize, and cause death. Deregulation of cell cycle control has been reported in a number of malignancies. The aim of the present study was to assess expression of G1/S cell cycle regulatory proteins [retinoblastoma protein (pRb)/P16/cyclin D1] in conjunctival SCC. Forty-four prospective cases of conjunctival SCC from a tertiary eye care referral center in northern India were included in this study. American Joint Committee on Cancer (AJCC) staging was performed and patients were followed up for 46±3.2 months. pRb loss was seen in 87% and overexpression of p16 and cyclin D1 in 36% and 66%, respectively. Kaplan-Meier analysis revealed reduced disease-free survival in patients with pRb loss (P=0.006). On univariate analysis, pRb loss (P=0.02), orbital invasion (P=0.03), and AJCC stage ≥T3 (P=0.03) emerged as significant high-risk features. On multivariate analysis pRb loss emerged as the most significant poor prognostic indicator in conjunctival SCC cases. Our findings suggest pRb loss to be a useful indicator of aggressive behavior and is recommended for identifying high-risk conjunctival SCC patients.

Prognostic significance of histopathology of primary conjunctival melanoma in Caucasians.

PURPOSE: To assess histopathologic prognostic factors relative to clinical ones in predicting local recurrence and survival after primary conjunctival melanoma (CM). METHODS: 85 patients with CM were identified in Finland between 1967 and 2000, and 70 primary tumors were available for histopathologic study. Time to first recurrence and melanoma-related mortality were analyzed. RESULTS: Absence of epithelioid cells (P=0.033), smaller mean diameter of the ten largest nucleoli (P=0.041) and increasing mitotic count (P=0.042) were associated with shorter time to recurrence. The mean diameter of the ten largest nucleoli, the number of tumor-infiltrating lymphocytes and macrophages, extravascular matrix loops and networks, and microvascular density were unassociated with recurrence. Nonlimbal location (P=0.001), recurrence (P<0.001), and increasing tumor thickness (P=0.007) were associated with mortality. By multivariate Cox regression, a model including recurrence and tumor location fitted best with mortality data. CONCLUSIONS: Histopathological factors are not consistently associated with survival in CM. Tumor location, thickness, and recurrence are predictors of mortality from CM.

Screening for conjunctival melanoma metastasis: literature review.

Local tumour control in conjunctival melanoma has improved in recent years. However the tumour-related death rate of these patients is still 14% at 5 years up to 33% at 15 years. With the introduction of sentinel node biopsies for conjunctival melanomas with a poor prognosis and screening for locoregional and distant metasases prognosis might be improved.

Conjunctival Melanoma in Chinese Patients: Local Recurrence, Metastasis, Mortality, and Comparisons With Caucasian Patients.

Purpose: To evaluate the prognosis in Chinese patients with conjunctival melanoma and determine its predictors. Further, to explore the racial differences in clinical characteristics and outcomes between Chinese and Caucasian patients. Methods: This cohort study included 57 eyes of 57 consecutive patients with pathologically verified conjunctival melanoma between 1996 and 2016. Medical records were reviewed for factors associated with the local recurrence, metastasis, and tumor-related mortality. All eligible patients were followed up for these three outcome measures. The demographic data, clinical characteristics, and outcomes were compared between Chinese and Caucasian patients. Results: The mean follow-up period was 52.2 ± 49.4 months. Among the total 57 patients, 29 (51%) patients experienced local recurrence. The 1-, 5-, and 10-year recurrence rate was 31.0%, 59.7%, and 66.4%, respectively. Treatment complications detected in the follow-up included dry eye (32, 56.1%), irregular eyelid margin (25, 43.9%), eyelid retraction (18, 31.6%), blepharoptosis (9, 15.8%), mixed pigmentation of the tarsus reconstructed by mucosal membrane graft, corneal opacities (6, 10.5%), and symblepharon (2, 3.5%). Twenty (35%) patients developed metastasis. The 1-, 5-, and 10-year metastasis rate was 16.7%, 38.7%, and 50.9%, respectively. Fourteen (25%) patients died of conjunctival melanoma, with a median survival time of 24 months. The 1-, 5-, and 10-year tumor-related mortality was 3.8%, 30.5%, and 37.4%, respectively. Tumor hemorrhage is an independent risk factor for tumor-related death (hazard ratio [HR]: 18.81, P = 0.01) and metastasis (HR: 4.57, P = 0.02). Significant differences were noted between Chinese and Caucasians patients from America, Germany, and England in demographics, clinical characteristics, and outcomes. Compared to Caucasians, Chinese patients tended to have more male cases (P < 0.01) and to be younger (P = 0.03). At initial presentation, more Chinese patients had de novo tumor origin (P < 0.01), epithelioid cell type (P < 0.01), nonbulbar tumor location (P < 0.01), greater basal diameter (P = 0.04), multifocal tumor (P < 0.01), feeder vessels (P < 0.01), eyelid (P < 0.01) and orbit involvement (P < 0.01), and advanced T stages (P < 0.01). Over a similar follow-up period with Caucasians patients (52.2 vs. 52 months, P = 0.97), a significantly larger proportion of Chinese patients exhibited eyelid invasion (P = 0.04) and orbital invasion (P < 0.01) at follow-up, local recurrence (P < 0.01), metastasis (P < 0.01), and tumor-related death (P < 0.01). Conclusions: Conjunctival melanoma is a rare malignancy with great potential for mortality in Chinese. Special attention should be paid to patients with tumor hemorrhage. Compared to Caucasians, Chinese patients exhibit more aggressive clinical signs with compromised prognosis.