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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., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The present study prospectively evaluated outcome, pathologic findings, and compliance in orbital retinoblastoma patients (International Retinoblastoma Staging System [IRSS] stage III)., Design: Prospective study and case series., Participants: Twenty-eight consecutive IRSS stage III retinoblastoma patients were enrolled prospectively in the study after ethics committee approval and written informed consent., Methods: Planned therapy for patients included treatment with a uniform protocol consisting of neoadjuvant chemotherapy followed by enucleation, adjuvant radiotherapy, and chemotherapy. Prospective computerized data entry and telephone contact were undertaken to improve compliance, a major issue in treatment of orbital retinoblastoma., Main Outcome Measures: Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis. The difference between groups was analyzed using the log-rank test., Results: Median follow-up was 14.75 months (range, 2.23-26.3 months). The OS for all patients was 40.4% and the EFS was 33.33% at a follow-up of 26.3 months. The median EFS and OS were 10.37 months and 15.73 months, respectively. At baseline, bilateral retinoblastoma predicted inferior EFS (P = 0.0006) and OS (P = 0.0081). Twenty-two of 28 patients underwent enucleation, and viable tumor was present in 21 of 22 enucleated specimens (95%). Neoadjuvant chemotherapy prevented orbital exenterations. Presence of tumor in the cut end of the optic nerve significantly correlated with inferior EFS (P = 0.012) and OS (P = 0.0098). Central nervous system metastasis was the most common site of relapse and death. The overall rate of compliance with treatment was 67.8% (19/28), which was twice the compliance rate at the authors' center before initiation of the present study., Conclusions: There is a paucity of information in the literature on outcomes and pathologic findings after neoadjuvant chemotherapy in IRSS stage III retinoblastoma treated with a uniform treatment protocol, and as far as the authors are aware, there has been no prospective study. Neoadjuvant chemotherapy was able to avoid exenteration in all operated patients; however, residual viable tumor was present in 95% of enucleated specimens. Bilaterality and tumor in the optic nerve cut end after neoadjuvant chemotherapy were associated with inferior outcome. Compliance could be improved with computerized data entry and regular telephone contact., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the risk for systemic lymphoma (SL) in the patients with orbital lymphoproliferative tumor (OLT)., Design: Observational, retrospective case series., Participants: One hundred sixty consecutive cases with OLT., Methods: Clinical features and treatment method were collected retrospectively. Data from 106 patients without systemic disease at presentation were analyzed for their impact on the main outcome measure using univariate and multivariate regression models., Main Outcome Measure: Occurrence of SL diagnosed based on the 6 monthly systemic evaluation., Results: Of 106 patients with OLT alone, SL subsequently developed in 16% of patients and 84% patients remained free of SL. Of 17 patients in whom SL developed subsequently, 29% had marginal zone, B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT), 24% had small lymphocytic lymphoma (SLL), 24% had atypical lymphoid hyperplasia (ALH), 6% each had mantle cell, follicular, and diffuse large B-cell lymphoma (DLCL). In these 17 patients, systemic disease appeared after a mean interval of 152 months, and the involved systemic sites were abdominal lymph nodes (LN) in 44% patients, pelvic LN in 40%, and head and neck LN in 31%. Of 17 patients, 53% had the same SL classification with orbital tumor and 47% had a different SL classification. Among 8 patients with different systemic and orbital lymphoma classifications, systemic SLL developed in 4 patients with orbital ALH and in 2 patients with MALT. Two patients with orbital SLL manifested systemic DLCL. Using Kaplan-Meier estimates of 106 OLT patients without systemic involvement, SL developed in 14% at 3 years, in 17% at 5 years, and in 33% at 10 years. Using Kaplan-Meier estimates of 24 patients with bilateral OLT alone, SL developed in 18% at 3 years, in 29% at 5 years, and in 72% at 10 years. In 82 patients with unilateral OLT alone, SL developed in 12% at 3, 5, and 10 years. Multivariate analysis showed that bilateral involvement at presentation was the only significant factor predictive of SL., Conclusions: In patients with OLT alone at presentation, SL eventually developed in 33% by 10 years in this retrospective case series. Classification of SL can be the same or different from OLT. Development of SL is significantly associated with bilateral involvement.

Purpose: To evaluate the clinical features, treatment, and prognosis in patients with metastatic retinoblastoma., Design: Retrospective interventional case series., Participants: Eighteen consecutive patients with metastatic retinoblastoma who were diagnosed and managed at the Oncology Service of Ankara University, Turkey, between January 1999 and January 2005., Methods: All patients underwent magnetic resonance imaging (MRI) of the orbit and brain, lumbar puncture, bone marrow aspiration, and bone scintigraphy for metastatic evaluation. Histopathologic confirmation of retinoblastoma via enucleation, exenteration, or orbital biopsy was obtained in each patient. The status of extraocular spread (optic nerve, extrascleral extension, or both) was assessed based on histopathologic or MRI results. Systemic treatment for metastatic retinoblastoma consisted of chemotherapy and radiotherapy (craniospinal, orbital, or both), if necessary., Main Outcome Measures: Status of extraocular spread, site of metastasis, and survival from metastatic retinoblastoma., Results: At presentation, the mean patient age was 45 months (range, 13-86). Ten patients had unilateral retinoblastoma, 7 had bilateral retinoblastoma, and 1 had trilateral retinoblastoma. All patients with metastatic retinoblastoma had histopathologic or MRI evidence of unilateral extraocular disease characterized by optic nerve involvement, extrascleral extension, or both. Nine of 18 patients experienced central nervous system (CNS) involvement, 5 patients had distant and CNS metastasis, and 4 patients had distant metastasis only. Fourteen patients underwent craniospinal irradiation and 12 had orbital irradiation. At a mean follow-up of 24 months (range, 4-62), all patients with CNS and concurrent distant and CNS metastasis were deceased. Four patients who had distant metastasis only were alive at a follow-up ranging from 9 to 62 months., Conclusions: The prognosis for metastatic retinoblastoma is dismal and the presence of CNS involvement may portend an even worse outcome.

Purpose: To report the outcome of oral chlorambucil as a single treatment in patients with orbital mucosa-associated lymphoid tissue (MALT) lymphoma., Design: Retrospective nonrandomized clinical study., Participants: Thirty-three patients with isolated orbital MALT lymphoma., Methods: Medical records of all patients with histology-verified orbital MALT lymphoma treated with oral chlorambucil at the Royal Melbourne Hospital were reviewed., Main Outcome Measures: Complete clinical response, partial response, local relapse, systemic extension (distant relapse), and survival., Results: Thirty-three patients (19 female; mean age, 69 years) participated in the study. Patients received an average of 4 courses of oral chlorambucil with a mean total dose of 600 mg. The lacrimal gland was the most frequent site of occurrence (24%), followed by the conjunctiva, eyelid, and superior orbit. Orbital mass, swelling, and diplopia were common presenting signs. Complete response was noted in 26 patients (79%). In 2 of the patients with complete clinical response, mild residual thickening was noted on follow-up orbital imaging studies. Four patients (12%) showed disease recurrence or relapse. Mean follow-up time was 32 (+/-20) months (range, 8 months-6 years; median, 26 months). None of the patients developed granulocytopenia secondary to chemotherapy, and none suffered significant nausea or vomiting. One patient with malignant transformation died 12 months after diagnosis and initial treatment., Conclusions: Systemic chemotherapy with chlorambucil is a reasonable option in patients with orbital MALT lymphoma. It is associated with minimal to no side effects. Additionally, it may be well tolerated by elderly patients and also may treat subclinical disease elsewhere.

Purpose: To review the clinical, radiological, and histopathologic features in 8 patients with natural killer/T-cell lymphoma (NKTL) involving the orbit and/or ocular adnexa, and to describe the responses of these patients to various treatment regimens., Design: Retrospective observational case series., Participants: Eight patients (5 male, 3 female) with NKTL involving the orbit and/or ocular adnexa were identified from 1999 through 2005. The mean age at presentation was 45 years (range, 26-65)., Methods: We retrospectively identified patients with NKTL of the ocular adnexa treated in the authors' medical centers from 1999 through 2004 using computerized diagnostic index retrieval. The clinical records and radiologic studies were analyzed to define modes of presentation and progression, response to therapy, and areas of anatomic involvement. Histopathologic findings, including the presence of CD3, CD56, and Epstein-Barr virus-encoded mRNA in each patient, were reviewed., Main Outcome Measurements: Time of survival from presentation to last known follow-up and tumor-related death., Results: Four of the 8 patients (50%) with NKTL involving the orbit or ocular adnexa had systemic involvement at presentation. Five of the 8 patients (62.5%) had concurrent sinonasal involvement, whereas 3 (37.5%) had orbital involvement alone. All lesions demonstrated CD3, CD56, and/or Epstein-Barr virus positivity on immunopathology studies. Therapy consisted of various chemotherapeutic regimens typically employed in the treatment of non-Hodgkins lymphoma, steroids, surgical intervention, and radiation. Seven (87.5%) patients died 5 weeks to 13 months after presentation, and 1 (12.5%) is alive without disease (5-year follow-up)., Conclusions: Natural killer/T-cell orbital lymphoma is a rare Epstein-Barr virus-associated neoplasm that may occur with or without associated sinonasal involvement. Our series, the largest cohort reported to date, demonstrates the high lethality of this condition despite aggressive conventional therapy, suggesting that new treatment options should be considered early in the course of treatment of patients with this disorder.

Objective: Presentation of a large series of patients with metastatic melanoma involving the eye and orbit., Design: Retrospective clinical study., Participants: Thirteen cases of metastatic melanoma involving intraocular tissues, 6 cases of metastatic melanoma in the orbit, and 1 case of metastatic melanoma involving both the eye and the orbit, treated in Lausanne between 1986 and 2002, were identified from the computer files of the ocular oncology and orbitopalpebral surgery units of Jules Gonin Hospital., Methods: The analysis is based on the demographic data concerning these patients, clinical data concerning the tumor, the treatment applied, the outcome, and the follow-up., Main Outcome Measures: Clinical presentation of intraocular and orbital metastasis, interval between primary tumor and ocular metastasis, survival of the patients, evaluation of various therapeutic protocols., Results: Intraocular metastases (14 cases, 15 eyes) were situated in the choroid in 11 cases (isolated lesion, 6 cases; multiple lesions, 3 cases; diffuse involvement, 2 cases), in the iris and ciliary body in 2 cases, and in the retina and vitreous in 2 other cases. The primary tumor was a cutaneous melanoma in 8 cases, a melanoma of the contralateral eye in 3 cases, a mucosal melanoma in 1 case, and was unknown in 2 cases. The mean interval between the diagnosis of ocular metastases and the patient's death was 8.8 months (range, 1-48 months). The primary tumor in the 7 cases of orbital metastases was a cutaneous melanoma in 5 cases, a uveal melanoma in the contralateral eye in 1 case, and was unknown in 1 case. The mean interval between the diagnosis of orbital metastases and death was 19.7 months (range, 5-48 months). The patients were treated by various protocols. The best results, in terms of both local tumor control and preservation of visual function, were obtained with circumscribed proton beam radiotherapy or external beam irradiation, depending on the site and extent of the tumor., Conclusions: Metastatic melanomas to the eye and orbit are rare and generally occur in patients with disseminated metastases during the terminal stages of the disease, with a short life expectancy. Treatment is palliative and, among the various possible treatment options, circumscribed proton beam radiotherapy or global photon beam radiotherapy, at relatively high irradiation doses, seems to achieve the most favorable results.

Purpose: To review the clinical presentation, histopathologic analysis, management, and ocular and systemic outcome of rhabdomyosarcoma affecting the ocular region., Design: Retrospective, noncomparative, consecutive, interventional case series., Participants: Thirty-three consecutive patients with primary ophthalmic involvement of rhabdomyosarcoma from a single tertiary care center specializing in ocular oncology., Main Outcome Measures: Final visual acuity, treatment complications, local recurrence, and distant metastasis., Results: The mean age at presentation was 10 years (median, 7 years; range, 1 month-68 years). At presentation, 8 patients (24%) were older than age 10 years and 4 patients (12%) were older than 20 years. The rhabdomyosarcoma was primarily located in the orbit in 25 cases (76%), conjunctiva in 4 cases (12%), eyelid in 1 case (3%), and uveal tract in 3 cases (9%). Symptoms or signs related to the tumor were present for a mean of 5 weeks and included proptosis in 10 patients (30%), eyelid swelling in 7 patients (21%), and blepharoptosis in 6 patients (18%). The initial diagnosis before referral to us included rhabdomyosarcoma in 8 cases (24%), conjunctivitis in 5 cases (15%), orbital or preseptal cellulitis in 5 cases (15%), idiopathic orbital inflammatory pseudotumor in 4 cases (12%), and others. Using the Intergroup Rhabdomyosarcoma Study Group staging and treatment protocols, the tumor was classified as group I in 4 cases (12%), group II in 12 cases (36%), group III in 16 cases (48%), and group IV in 1 case (3%). Treatment included surgical debulking and various regimens of chemotherapy and radiotherapy for the periocular tumors and enucleation for the three intraocular tumors. Local tumor recurrence was detected in 6 patients (18%). Orbital exenteration was necessary for tumor recurrence in 2 cases (6%). Long-term visual outcome of the 28 patients who maintained their globe was 20/20 to 20/40 in 11 patients (39%), 20/50 to 20/100 in 5 patients (18%), and 20/200 to no light perception in 12 patients (43%). Regional lymph node metastasis was detected in 2 patients (6%), one at initial visit and one after therapy. Distant metastasis occurred in 2 patients (6%), one detected at initial visit and one after therapy. With mean follow-up of 8.3 years, tumor-related death occurred in 1 patient (3%)., Conclusions: Rhabdomyosarcoma can present in the orbit, eyelid, conjunctiva, and uveal tract. After treatment, local tumor recurrence occurs in 18%, metastasis in 6%, and death in 3%.

Objective: This study aimed to evaluate various combinations of therapeutic approaches in an attempt to improve the poor outcome of advanced cases of orbital involvement of intraocular retinoblastoma., Design: The study design was a retrospective, uncontrolled descriptive case series of consecutive patients with massive orbital retinoblastoma treated and observed at a referral center., Participants: Sixteen patients with unilateral orbital involvement of intraocular retinoblastoma were studied. Eight patients had orbital involvement at initial presentation and eight children presented with orbital tumor after enucleation for intraocular retinoblastoma. Patients having microscopic evidence of tumor invasion at surgical section of the optic nerve and subsequently receiving other forms of treatment were not included in the study., Intervention: Six patients had orbital exenteration followed by external beam radiation therapy (4600-6000 cGy in fractionated doses) and chemotherapy. Five patients received chemotherapy only. Three patients were treated by exenteration and chemotherapy, whereas two patients underwent radiation therapy and chemotherapy., Main Outcome Measures: Tumor regression monitored by clinical observations and imaging studies and patient survival was studied., Results: The median follow-up was 22 months (range, 4-168 months). All forms of treatment caused satisfactory local and systemic tumor regression. Two children achieved a survival of more than 10 years. However, two patients in the exenteration followed by chemotherapy and radiation therapy group and one who received chemotherapy only had central nervous system metastases develop and died. Only one patient was lost to follow-up., Conclusion: Highly individualized aggressive treatment by combining radical surgery, chemotherapy, and external beam radiation therapy allowed most of the authors' patients to have longer survival and disease-free intervals than expected.

Objective: To describe the clinical features, treatment, and outcome of a series of patients with perineural spread (PNS) of cutaneous squamous cell carcinoma (SCC) via the orbit., Design: A cohort study., Participants: Twenty-one patients identified with PNS of cutaneous SCC via the orbit., Intervention: Patients were treated with various combinations of conservative or radical surgery, external beam radiation therapy, and chemotherapy., Results: Of 21 cases, 17 (81%) were male. Age at presentation with PNS ranged from 38 to 82 years (median, 66 years). The forehead and eyebrow were the most common site of the primary lesion. All but one had altered or decreased sensation, but only nine presented with pain. Fourteen (67%) had ophthalmoplegia at presentation, and 14 (67%) had evidence of PNS involving branches of the facial nerve. Despite combinations of radical surgery, conservative surgery, and radiation therapy, no method of treatment appeared more effective, and 14 patients died from 9 months to 5 years after presentation with PNS (median, 3 years), usually from local and intracranial disease. Two survived to 14 and 18 years, one is alive at 3 years with recurrent local and distant disease, and four are alive without evidence of disease at 2, 3, 4 and 12 months after radiation therapy., Conclusions: Perineural spread of cutaneous SCC via the orbit carries a poor prognosis. Early radiation therapy may offer the best form of palliation. The role of radical surgery probably is limited once orbital involvement is apparent, as the cavernous sinus and facial nerve branches usually are involved.

Purpose: To evaluate whether the use of iridium-192 brachytherapy would reduce the incidence of complications noted with external beam radiation therapy in patients with orbital tumors., Methods and Materials: This study is a retrospective review of a clinical series of 25 patients with various orbital tumors treated with brachytherapy between 1988 and 1995., Results: Patients were observed for an average of 40 months (range, 16-88 months) during which one patient died of metastatic disease and 24 patients are alive with no evidence of disease. Recurrent disease was observed in four patients. In 3 patients, exenteration was necessary and in 22 patients, the eye was preserved. The visual acuities after therapy ranged from no light perception to 20/20 (average, 20/40)., Conclusions: Since brachytherapy has been used as an alternative to exenteration, the results of this treatment have been excellent in most patients. However, in advanced disease, external radiation therapy or even mutilating surgery still remains inevitable.

Purpose: Primary orbital melanomas are rare tumors with a poorly defined biologic course. Most recorded experiences concern single case reports. The authors evaluated the applicability of several of the histopathologic prognostic indicators used for uveal melanomas to a series of primary orbital melanomas with known clinical follow-up., Methods: Twenty-one primary orbital melanomas, each with at least a 1-year follow-up after diagnosis, were evaluated for (1) modified Callender cell type, (2) mitotic count per 40 high-power fields, (3) lymphocyte count (less than versus greater than 100/20 high-power fields), (4) blue nevus component, and (5) largest tumor diameter., Results: All patients for whom race was recorded were white. The mean age at diagnosis was 42 years (range, 15-84 years). There was an associated blue nevus in 19 patients (90 percent), and in 10 patients (47.5 percent) there was some form of congenital melanosis. With a mean follow-up period of 4.5 years (range, 1-13 years), mortality from metastatic tumor occurred in 8 (38 percent) of 21 patients. Of these eight patients, there were liver metastases in seven (88 percent) and brain metastases in one (12 percent). Indicators of poor prognosis were tumors of mixed cell type with high mitotic count and greater patient age with underlying congenital melanosis., Conclusion: Most primary orbital melanomas occur in white patients and are associated with blue nevi. These tumors are similar to uveal melanomas with respect to prognostic indicators and pattern of metastasis.

The clinical characteristics and microscopic features of the biopsy specimens of 66 patients with orbital lymphoid tumors were analyzed with respect to clinical outcome (disease remaining localized to the orbit or developing associated extraorbital lesions). The patients' average age was 63 years, and their tumors had a marked tendency to arise in the anterosuperior orbit. No clinical or radiographic findings helped to distinguish the cases of localized disease from disseminated disease. The lesions were divided microscopically into three categories: reactive lymphoid hyperplasia (16), atypical lymphoid hyperplasia (38), and malignant lymphoma (12). Extraorbital lesions developed in 25%, 50%, and 75% of cases, respectively. The five-year mortality rates were also significantly different for each type of lesion: 6%, 19%, and 58%, respectively.

Eighty-eight patients with ocular adnexal lymphoid lesions examined at the Mayo Clinic between 1970 and 1982 were evaluated. The histopathologic type was reclassified using the working formulation. Paraffin sections were evaluated with immunoperoxidase staining. There were 11 "pseudotumors" and 77 lymphomas. Sixty lymphomas were small lymphocytic type A; 27 tissues had a monoclonal staining pattern, and 4 had a polyclonal staining pattern. Five of the pseudotumors had a polyclonal staining pattern; none had a monoclonal pattern. The remainder did not stain or tissue was not available. Thirty-six of the 44 lymphomas that presented in the ocular adnexa remained localized. There were no distinguishing features between conjunctival and orbital lymphomas. Significant damage to the ocular tissue occurred in 15 of the 63 patients treated with radiation therapy. Older, asymptomatic patients with a favorable histologic type may not require treatment; therapy is reserved for specific indications. The probability of survival to five or seven years differs little from that expected in the general population.

Children with rhabdomyosarcoma (RMS) (1461 total cases) were included in two prospective, randomized protocols conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Committee from November 1972 to June 1983. Treatment assignment was determined by extent of tumor at diagnosis (clinicopathologic group) and not by primary site. Accordingly, 127 patients with RMS confined to the region of the eyelid and orbit were treated by a variety of regimens characterized by initial partial tumor resection followed by concurrent multiagent chemotherapy and orbital radiation therapy. Recurrent tumor developed in ten patients. Seven relapsed initially in the orbit (of whom 4 were salvaged) and three in regional nodes. In addition to the six patients who died of tumor, three died of other causes for a 93% 3-year actuarial survival rate. In 89 children who had subtotal resection or biopsy only, the local control rate with radiotherapy and chemotherapy was 94%.