Tatyana Milman

Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

PURPOSE This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN Prospective, multicenter study. PARTICIPANTS A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES Patients were managed for their primary tumor and monitored for metastasis. RESULTS The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Failed descemet-stripping automated endothelial keratoplasty grafts: a clinicopathologic analysis.

PURPOSE To describe the clinicopathologic findings in failed Descemet-stripping automated endothelial keratoplasty (DSAEK) grafts. DESIGN Retrospective, interventional case series. METHODS SETTING New York Eye and Ear Infirmary. STUDY POPULATION Twenty-one patients with 22 failed DSAEK grafts treated between March 1, 2006 and February 1, 2008. INTERVENTION Repeat DSAEK or penetrating keratoplasty were performed in the eyes with failed grafts. All failed grafts were examined histopathologically. MAIN OUTCOME MEASURES Histopathologic parameters studied in failed DSAEK grafts included endothelial cell count, interface characteristics, retrocorneal membrane formation, inflammation, and immunoreactivity for herpes simplex virus type 1 (HSV-1) antigen. RESULTS DSAEK failure was strongly associated with postoperative lenticle dislocation. Graft failure was primary in 19 DSAEKs and secondary to rejection, eccentric trephination with epithelial ingrowth, or bacterial infection in the remaining 3. All failed grafts demonstrated endothelial hypocellularity and stromal edema. Additional findings included stromal inflammation (68%), interface fibrosis (50%), retrocorneal membrane (36%), unplanned retention of Descemet membrane (14%), immunoreactivity for HSV-1 (14%), paucicellular stroma (14%), and uneven trephination with epithelial ingrowth (5%). CONCLUSIONS Most DSAEK failures are secondary to endothelial cell loss. Other contributing factors include interface fibrosis, retrocorneal membrane formation, retained host Descemet membrane, uneven trephination, epithelial ingrowth, graft rejection, and infection.

Ocular adnexal lymphoma staging and treatment: American Joint Committee on Cancer versus Ann Arbor

Purpose To evaluate the prognostic utility of the American Joint Committee on Cancer (AJCC) staging system for ocular adnexal lymphoma (OAL). Methods A multicenter, consecutive case series of patients with biopsy-proven conjunctival, orbit, eyelid, or lacrimal gland/sac lymphoma was performed. The electronic pathology and clinical records were reviewed for new or recurrent cases of ocular adnexal lymphoma. The main outcome measures included pathology and clinical staging (AJCC and Ann Arbor systems), treatment, and recurrence (local and systemic). Statistical analysis included demographic evaluations and the Kaplan-Meier survival probability method. Results Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue were the most common (n=60/83, 72%). The most common Ann Arbor clinical stages were IE (76%) followed by IIE (17%) and IIIE (7%). Pathology identified 13 cases (15%) that were upstaged to group IV (p=0.017). Similarly, AJCC clinical stages were cT1NOMO (21.7%), cT2NOMO (44.6%), cT3N0M0 (5%), and cT4NOMO (2.4%). Local control was achieved in 75% of treated patients. There were 19 local recurrences from which 14 (74%) belonged to the non–radiation treatment groups. Lower-risk groups (T1 and T2 without lymph node involvement or metastatic disease of AJCC and IE of Ann Arbor) had longer disease-free survival than the higher-risk groups (AJCC T1, T2 with nodal involvement or metastatic disease, T3, and T4 as well as Ann Arbor II, III, and IV). The overall mean follow-up was 43.3 months (range 6–274). Conclusions Regardless of stage, recurrence and disease-free survival were more closely related to treatment and histopathology rather than tumor size or site-specific location.

Swept-Source Optical Coherence Tomography Features of Choroidal Nevi

PURPOSE To investigate the morphologic characteristics of choroidal nevi using swept-source optical coherence tomography and compare this with enhanced-depth optical coherence tomography. DESIGN Retrospective observational case series. METHODS One choroidal nevus each from 30 eyes of 30 patients was included and received imaging with swept-source OCT (SS-OCT) and enhanced-depth imaging OCT (EDI-OCT). For SS-OCT, a scan acquisition protocol was used involving 12 mm horizontal and vertical scans in the posterior fundus. The main outcome measures were morphologic features of choroidal nevi obtained with SS-OCT imaging. These features were compared to images obtained with EDI-OCT. A 2-tailed Fisher exact test was the statistical method used. RESULTS SS-OCT allowed for an appreciation of intralesional details: Of the 30 nevi imaged, intralesional vessels were apparent in 30 (100%), intralesional cavities in 6 (20%), intralesional granularity in 14 (47%), abnormal choriocapillaris in 25 (83%), and abnormal choriocapillaris confined to the tumor apex in 17 (58%). Distended bordering vessels were identified in 22 nevi (73%) and were significantly associated with the presence of previous or persistent subretinal fluid. Intrinsic hyperreflectivity with hyporeflective shadowing was significantly (P = .05) more apparent in 14 of 21 melanotic nevi (67%) compared with 2 of 9 amelanotic nevi (22%). Visualization of the complete nevus-scleral interface was significantly (P = .02) more apparent in 7 of 9 amelanotic nevi (78%) compared with 6 of 21 melanotic nevi (29%), and was not significantly related to tumor thickness (measured by ultrasound) or to tumor configuration. Tumor diameter (but not tumor height) was statistically significantly associated with secondary retinal changes (P = .05) and configuration (P = .01). EDI-OCT was equivalent at determining secondary retinal changes (P = .29), the presence of distended bordering vessels (P = 1), visualization of the nevus-scleral interface (P = .6), and hyporeflective gradation at the nevus-scleral interface (P = .33). However, in melanotic lesions, SS-OCT was significantly superior at visualizing intralesional vessels (P = .0002), intralesional granularity (P = .0005), and abnormal choriocapillaris (P = .0001). CONCLUSION Imaging of choroidal nevi with SS-OCT enables visualization of intralesional details such as vessels (present in 100% of tumors imaged), cavities, and granularity. For melanotic lesions, SS-OCT is significantly better at depicting certain intralesional characteristics compared to EDI-OCT. Distended bordering vessels were recognized in over two thirds of the nevi imaged and were significantly associated with previous or persistent subretinal fluid.

Ocular manifestations of multiple myeloma: Three cases and a review of the literature

BACKGROUND Multiple myeloma is the most common plasma cell tumor; however, ocular plasmacytomas are rare and can appear in almost any structure of the eye. We present 3 cases, including 2 with unique ophthalmic ultrasound images of ocular plasmacytoma. CASE REPORTS Three patients with ocular manifestations of multiple myeloma are described. All were noted to have known synchronous systemic disease. In this study, patients presented with epibulbar (n = 2), iridociliary (n = 1), and orbital (n = 2) plasmacytomas. Presenting signs included clinically visible tumor (n = 2), blurred vision (n = 2), diplopia (n = 2), and glaucoma (n = 1). The iridociliary plasmacytoma was defined by high-frequency 35-MHz ultrasonography that revealed 360° of anterior chamber involvement, secondary angle-closure, and extent of iridociliary invasion. In another case, low-frequency B-scan ultrasonography found multiple myeloma of the orbit. Ocular manifestations of multiple myeloma, histopathology, treatment, and prognosis are described. CONCLUSION Ocular manifestations of plasma cell neoplasms are rare. In multiple myeloma, plasmacytomas can present as a solitary tumor, as an initial sign of systemic disease, or as recurrence. This study presents 3 cases in which epibulbar, orbital, and iridociliary plasmacytoma with secondary glaucoma were presenting signs of uncontrolled multiple myeloma.

Diagnostic utility of adipophilin immunostain in periocular carcinomas.

PURPOSE To determine the efficacy of adipophilin immunohistochemistry in the diagnosis of sebaceous carcinoma of the ocular adnexal region and to provide the guidelines for interpretation of this immunostain. DESIGN Retrospective, histopathologic case series. PARTICIPANTS A total of 25 patients with sebaceous carcinoma, 21 patients with basal cell carcinoma, 22 patients with conjunctival squamous cell carcinoma, 9 patients with cutaneous squamous cell carcinoma, and 5 patients with conjunctival mucoepidermoid carcinoma. METHODS Immunohistochemical staining for adipophilin was performed on paraffin-embedded tissues and correlated with hematoxylin-eosin, periodic acid-Schiff (PAS), and mucicarmine-stained preparations. Immunostaining was quantified by light microscopy and with a computerized image analysis system of scanned images. Statistical analysis was performed to compare immunostaining patterns within the tumor categories by stage and grade, between the different neoplasms, and for correlation between light microscopy observations and computerized image analysis. MAIN OUTCOME MEASURES Localization of adipophilin immunostain, intensity of immunostaining, percent of immunoreactive cells, percentages of vacuolar staining and granular staining, and vacuole size. RESULTS Adipophilin expression was observed in 100% of sebaceous carcinomas, 100% of cutaneous squamous cell carcinomas, 95% of basal cell carcinomas, 73% of conjunctival squamous cell carcinomas, and 60% of mucoepidermoid carcinomas. Sebaceous carcinomas demonstrated significantly stronger adipophilin expression, a greater number of intracytoplasmic vacuoles, and larger vacuoles. The specificity and sensitivity of adipophilin immunostaining in the diagnosis of sebaceous carcinoma were both 100% when more than 5% of the staining occurred in vacuoles (<95% granular staining). The diagnostic sensitivity and specificity were 100% and 96%, respectively, when the staining was graded as moderately or strongly intense and were 92% and 85% when the vacuoles were greater than 1.5 μm in diameter. CONCLUSIONS Although upregulation of neoplastic steatogenesis is observed in both sebaceous and nonsebaceous carcinomas, the pattern and intensity of adipophilin immunostaining are helpful in distinguishing sebaceous carcinoma from other neoplasms with overlapping histology.

Multifocal iris melanoma treated with total anterior segment palladium-103 plaque radiation therapy

BackgroundA 73-year-old patient presented in our clinic with multiple pigmented iris nodules in the left eye. Though asymptomatic, there was a reported increase in size and number of the nodules during the past year.MethodsInterventional case report describing a biopsy-proven multifocal iris melanoma treated with a palladium-103 plaque to include the entire anterior chamber within the targeted zone. Biopsy was performed utilizing a 25-gauge aspiration-cutter under viscoelastic. The cornea was protected during radiation therapy with the amniotic membrane buffer technique. Evaluation parameters included visual acuity and clinical assessments aided by slit-lamp photography as well as high-frequency ultrasound imaging.ResultsPlaque radiation therapy was well tolerated. Her visual acuity has remained within five letters at 20/25 at 1-year follow-up. Clinical evaluation revealed no evidence of corneal epitheliopathy, iris neovascularization, or visually significant cataract. High-frequency ultrasound imaging revealed a 15% reduction of the tumor’s height. Serial abdominal imaging revealed no metastatic uveal melanoma.ConclusionsWe present a biopsy-proven iris diffuse melanoma treated with palladium-103 plaque radiation therapy. Though the entire anterior segment was irradiated, there were no significant side-effects. Local tumor control was excellent during the first postoperative year.

Syringocystadenoma papilliferum of the eyelid.

Purpose: To describe 6 patients with syringocystadenoma papilliferum of the eyelid and to review the literature regarding this rare eyelid tumor. Methods: Clinicopathologic series of 6 cases, diagnosed at the New York Eye and Ear Infirmary from 1990 to 2006. The PubMed database was searched for reported cases of syringocystadenoma papilliferum of the eyelid (keywords: syringocystadenoma, eyelid, apocrine, eccrine). Results: Fourteen patients (6 from the current case series and 8 previously reported) with syringocystadenoma papilliferum of the eyelid were identified. Patient age ranged from 8 to 82 years (mean, 44.6 years). Most cases had a preoperative diagnosis of basal cell carcinoma or cyst. Histopathologic evaluation of excised lesions revealed proliferation of duct-like channels in the dermis. These channels were lined by nonkeratinizing epithelium and communicated with the epidermis. Papillary structures with plasma cell-rich stromal infiltrate protruded in the cystic invaginations. Nine lesions (64%) were associated with apocrine, eccrine, or sebaceous tumors or malformations. None of the lesions was associated with a malignant neoplasm. One lesion recurred after incomplete excision. None of the completely excised lesions recurred. Conclusions: Syringocystadenoma papilliferum can rarely affect eyelid skin. This lesion is frequently clinically misdiagnosed as basal cell carcinoma or cyst. Although syringocystadenoma papilliferum of the eyelid can be associated with other benign lesions, no malignant transformation or association with malignant neoplasms has been reported. The evidence suggests that this tumor should be managed with conservative complete excision.

Mucin-producing Sweat Gland Carcinoma of the Eyelid: Diagnostic and Prognostic Considerations

PURPOSE To describe the clinical and pathologic characteristics of mucin-producing sweat gland carcinoma of the eyelid and to determine whether neuroendocrine differentiation is of prognostic significance. DESIGN Retrospective interventional case series. METHODS Search of the New York Eye and Ear Infirmary pathology database between 1990 and 2011 identified 16 patients with mucin-producing sweat gland carcinoma. Clinical, histopathologic, and immunohistochemical analyses were performed on all identified cases. RESULTS The patients presented with vascularized, focally cystic, nonulcerated eyelid margin lesions. Histopathologic evaluation showed that 4 lesions (25%) had a cystic, papillary, and solid growth pattern with an in situ component, 7 (44%) were pure invasive mucinous carcinomas, and 5 (31%) demonstrated both growth patterns. Immunohistochemical analysis of 15 tumors showed that pure cystic/papillary lesions had a significantly greater percentage of synaptophysin-immunoreactive cells (P = .036). There was no significant difference in the number of neuroendocrine markers expressed or in the intensity of immunostaining among the 3 different growth patterns. Re-excision for margin clearance was performed in 8 of 13 cases (61.5%). Two of 13 lesions recurred (15%); 1 of these was an in situ tumor with cystic morphology and neuroendocrine differentiation and the other was pure invasive mucinous carcinoma. None of the lesions metastasized. CONCLUSIONS Mucin-producing sweat gland carcinoma pathologically represents a continuum, from an in situ lesion to a classic, invasive mucinous carcinoma. Immunohistochemical evidence of neuroendocrine differentiation can be observed in all lesions and does not appear to have a prognostic significance, arguing against the utility of immunohistochemical subtyping of mucinous sweat gland carcinomas.

Scleral Patch Grafts in the Management of Uveal and Ocular Surface Tumors

OBJECTIVE To evaluate the outcome of scleral patch grafts in a series of patients undergoing management for uveal and ocular surface tumors. DESIGN Case series. PARTICIPANTS Ten patients underwent scleral patch grafting. Five patients had uveal melanoma with extrascleral extension, 2 patients had scleromalacia secondary to plaque radiotherapy for uveal melanoma, 2 patients had suspicious uveoscleral nevi, and 1 patient had invasive conjunctival squamous cell carcinoma with scleral necrosis. METHODS Retrospective, interventional, noncomparative chart review of patients undergoing treatment for ocular tumors followed by scleral grafts in a tertiary eye care center in the United States between September 2003 and January 2011. Sclera was reconstructed with allogenic scleral grafts. Clinical observations were performed after grafting. MAIN OUTCOME MEASURES Structural integrity, appearance, and stability of the grafts. RESULTS Ten patients were reviewed. All melanoma cases received plaque radiotherapy with palladium 103. The cases with nevi and squamous cell carcinoma underwent local resection with cryotherapy as primary treatment. In 8 cases, scleral grafting was performed as part of the initial surgery. In all of these cases, satisfactory anatomic and functional outcomes were achieved. In 2 cases with scleromalacia secondary to radiotherapy for uveal melanoma, grafts were placed several years after the initial treatment. In these 2 cases, one showed signs of graft retraction, whereas another showed graft thinning. No patients experienced graft infection, rejection, or tumor recurrence. CONCLUSIONS In this series, scleral grafts were well accepted when placed as part of the primary tumor management despite synchronous radiotherapy, scleral resection, or cryotherapy. Grafting was less successful when performed as a late procedure for radiation-induced scleromalacia. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.