Leonard M. Holbach

Histology of the Parapapillary Region in High Myopia

PURPOSE To examine histomorphometrically the parapapillary region in highly myopic eyes. DESIGN Retrospective laboratory investigation. METHODS We examined a highly myopic glaucomatous group (36 human globes; axial length >26.5 mm) and a non-highly myopic group (28 globes with secondary angle-closure glaucoma; 17 eyes with malignant choroidal melanoma). Using light microscopy, pupil-optic nerve sections were assessed. RESULTS The length of the scleral flange (sclera between optic nerve border and optic nerve dura mater) increased with axial length (P < .001; correlation coefficient r = 0.70) and decreased with its thickness (P < .001; r = 0.75). In all highly myopic eyes (n = 15) with a distance of >0.5 mm between optic nerve border and beginning of Bruch membrane, the parapapillary region consisted of an elongated parapapillary scleral flange associated with a scleral flange thinning and a retrobulbar cerebrospinal fluid space extended into the retroparapapillary region. The parapapillary retina was composed of retinal nerve fiber layer (or its remnants) only, without elements of any other retinal layer, without underlying Bruch membrane or choroid. These histologic features were not detected in any of the non-highly myopic eyes. CONCLUSIONS Since parapapillary scleral thickness influences the lamina cribrosa biomechanics, the findings may partially explain the increased glaucoma susceptibility in highly myopic eyes. The implications of an absence of Bruch membrane and choroid in the highly myopic parapapillary region, and the implications of the retrobulbar parapapillary extension of the cerebrospinal spinal fluid space for the pathophysiology of the optic nerve head, have to be elucidated.

Multiple bilateral eyelid molluscum contagiosum lesions associated with TNFα-antibody and methotrexate therapy

PURPOSE To demonstrate a patient developing multiple bilateral eyelid molluscum contagiosum lesions after initiation of TNFalpha-antibody therapy for rheumatoid arthritis. DESIGN Single interventional case report. METHODS Clinical, histopathologic, and immunologic-serological findings are presented. RESULTS A 67-year-old patient with a 5-year history of rheumatoid arthritis had been treated with prednisone and methotrexate for the last 5 years. After initiation of additional TNFalpha-antibody treatment, complaints from rheumatoid arthritis subsided, but multiple bilateral molluscum contagiosum lesions of upper and lower eyelids occurred despite normal or only slightly reduced CD(4) (420-178/ microl) and CD(8) counts (143-58/microl). Histopathologic evaluation of the excised warts confirmed the clinical diagnosis. Under continued therapy, the warts have been recurring for 12 months. CONCLUSION TNFalpha-antibody treatment for rheumatoid arthritis may compromise the host response to molluscum contagiosum, especially if methotrexate is given additionally. Patients should be informed about this potential complication.

Tumors of the Lacrimal Drainage System

Tumors of the lacrimal drainage system are rare, but potentially life-threatening. They comprise a large and variable spectrum of entities grouped into three major categories of primary epithelial, primary nonepithelial and inflammatory lesions. The most common primary epithelial tumors include papilloma, squamous cell carcinoma and transitional cell carcinoma, the most frequent primary nonepithelial tumors fibrous histiocytoma, malignant lymphoma and malignant melanoma, and the most common inflammatory lesions sarcoidosis, Wegener granulomatosis and pyogenic granuloma. This review outlines the incidence, types, management and prognosis of tumors affecting the lacrimal drainage system.

Silicone oil–associated optic nerve degeneration

PURPOSE To report the frequency and extent of silicone oil migration into the optic nerve during silicone oil endotamponade. METHODS Histopathologic analysis of 74 eyes enucleated after silicone oil endotamponade. RESULTS In 14 of 74 enucleated eyes (24%), optically empty vacuoles regarded as silicone oil vacuoles were observed in the retrolaminar optic nerve. In three eyes, silicone oil in the optic nerve was surrounded by a granulomatous inflammatory reaction. In serial cross sections, the vacuoles extended up to the line of surgical transsection (up to 9 mm) of the optic nerve and constituted up to 40% of the total cross-sectional area. CONCLUSIONS After silicone oil endotamponade, silicone oil may replace a considerable amount of tissue of the retrolaminar optic nerve. A granulomatous inflammatory reaction surrounding silicone oil may add to optic nerve damage.

Macular Bruch's Membrane Defects and Axial Length: Association with Gamma Zone and Delta Zone in Peripapillary Region

PURPOSE To examine histomorphometrically the macular region of highly myopic eyes. METHODS On horizontal anterior-posterior histological sections, we examined the posterior pole of 138 human globes (axial length: 20-35 mm). In the parapapillary region, we differentiated between the beta zone (Bruchs membrane without RPE), gamma zone (parapapillary region without Bruchs membrane), and delta zone (elongated and thinned gamma zone). RESULTS In 12 (8.7%) eyes, a macular Bruchs membrane defect (MBMD) was detected. The MBMD showed a complete lack of RPE and choriocapillaris, and an almost complete lack of photoreceptors. Presence of MBMD was associated with longer axial length (P < 0.001), longer gamma zone (P = 0.04) and delta zone (P < 0.001), thinner peripapillary scleral flange, and thinner sclera just outside of the optic nerve meninges (P < 0.001) and at the posterior pole (P < 0.001). An MBMD was found only in eyes with an axial length of 27 mm or longer. MBMD prevalence in highly myopic eyes was 12/39 or 30.8%. MBMD presence was not significantly related to length of beta zone (P = 0.09). In multivariate binary regression analysis, MBMD presence was significantly (P < 0.001) associated only with axial length. CONCLUSIONS Highly myopic eyes (axial length ≥27mm) can show an MBMD associated with complete loss of RPE and choriocapillaris, and marked reduction of photoreceptors and large choroidal vessels. MBMD presence was strongly associated with axial length and indirectly with parapapillary gamma zone and delta zone. The myopia-associated secondary MBMDs may occur parallel to the myopia-associated widening of Bruchs membrane opening around the optic nerve head.

Intraocular Tumor-Associated Lymphangiogenesis: A Novel Prognostic Factor for Ciliary Body Melanomas with Extraocular Extension?

PURPOSE To evaluate whether intraocular tumor-associated lymphangiogenesis contributes to prognosis of ciliary body melanomas with extraocular extension and to study its association with other tumor characteristics. DESIGN Nonrandomized, retrospective case series. PARTICIPANTS Twenty consecutive patients enucleated for a malignant melanoma of the ciliary body with extraocular extension. METHODS Lymphatic vessels were identified using lymphatic vascular endothelial-specific hyaluronic acid receptor-1 (LYVE-1) and podoplanin as specific immunohistochemical markers for lymphatic vascular endothelium. Baseline tumor characteristics included intra- and extraocular tumor size, 2009 tumor, node, metastasis (TNM) classification, route of extraocular spread, tumor cell type, mitotic rate, Ki-67 proliferation-index, microvascular patterns and density, tumor-infiltrating lymphocytes and macrophages, and expression of human leukocyte antigen (HLA) class I and insulin-like growth factor-1 receptor. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed. MAIN OUTCOME MEASURES Prevalence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels and association with intraocular tumor characteristics and metastasis-free survival. RESULTS Intraocular LYVE-1(+) and podoplanin(+) lymphatic vessels could be detected in 12 (60%) of 20 ciliary body melanomas with extraocular extension. Presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels was significantly associated with larger intra- (P = 0.002) and extraocular tumor size (P<0.001), higher TNM categories (P = 0.004), epithelioid cellularity (P = 0.016), higher mitotic rate (P = 0.003), higher Ki-67 proliferation-index (P = 0.049), microvascular networks (P = 0.005), higher microvascular density (P = 0.003), more tumor-infiltrating macrophages (P = 0.002), higher expression of HLA class I (P = 0.046), and insulin-like growth factor-1 receptor (P = 0.033), but not significantly with route of extraocular spread (P = 0.803), and tumor-infiltrating lymphocytes (P = 0.069). Melanoma-specific mortality rates increased significantly with the presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels (P = 0.008). By multivariate Cox regression, tumor size (hazard ratio, 14.40; P = 0.002), and presence of intraocular lymphatic vessels (hazard ratio, 8.09; P = 0.04) were strong prognostic predictors of mortality. CONCLUSIONS Intraocular peritumoral lymphangiogenesis seems to be associated with an increased mortality risk in patients with ciliary body melanomas and extraocular extension. This association may be primarily because of an association of intraocular lymphangiogenesis with greater tumor size and increased malignancy.

Prognostic Significance of Tumor-Associated Lymphangiogenesis in Malignant Melanomas of the Conjunctiva

PURPOSE To evaluate whether tumor-associated lymphangiogenesis contributes to prognosis of conjunctival malignant melanomas and to study its association with other tumor characteristics. DESIGN Nonrandomized, retrospective case series. PARTICIPANTS A total of 109 consecutive patients with primary conjunctival malignant melanoma. METHODS Proliferating lymphatic vessels were identified immunohistochemically using lymphatic vascular endothelial hyaluronan receptor-1 and podoplanin as specific lymphatic endothelial markers and Ki-67 as proliferation marker. Baseline tumor characteristics included tumor location, tumor thickness, tumor diameter, tumor origin, and tumor growth pattern. Kaplan-Meier and Cox regression analyses of the risk of local recurrence, lymphatic spread, distant metastasis, and melanoma-related death were performed. MAIN OUTCOME MEASURES Intratumoral lymphatic vascular density and its association with tumor characteristics and recurrence-free, lymphatic spread-free, distant metastasis-free, and melanoma-specific survival. RESULTS Intratumoral and peritumoral proliferating lymphatic vessels could be detected in all of the 109 conjunctival melanoma samples. High intratumoral lymphatic density was significantly associated with palpebral tumor location (P<0.001), greater tumor thickness (P<0.001), larger tumor diameter (P = 0.001), tumor origin de novo (P = 0.002), and nodular tumor growth pattern (P = 0.037). Patients with high intratumoral lymphatic density revealed significantly lower recurrence-free, lymphatic spread-free, distant metastasis-free, and melanoma-specific survival rates (P<0.001 for all). By multivariate Cox regression, factors predictive of local recurrence included palpebral tumor location (hazard ratio [HR] 2.66, P = 0.014), large tumor diameter (HR 5.48, P<0.001), and high intratumoral lymphatic density (HR 2.48, P = 0.043); factors predictive of lymphatic spread included palpebral tumor location (HR 4.13, P = 0.009), high tumor thickness (HR 12.17, P<0.001), and high intratumoral lymphatic density (HR 6.79, P = 0.019); factors predictive of distant metastasis included palpebral tumor location (HR 7.63, P<0.001), high tumor thickness (HR 8.60, P<0.001), large tumor diameter (HR 0.30, P = 0.029), and high intratumoral lymphatic density (HR 8.90, P = 0.047); and factors predictive of melanoma-related death included palpebral tumor location (HR 7.74, P<0.001), high tumor thickness (HR 10.88, P<0.001), large tumor diameter (HR 0.28, P = 0.018), and, with borderline significance, high intratumoral lymphatic density (HR 8.46, P = 0.052). CONCLUSIONS Tumor-associated lymphangiogenesis seems to be associated with an increased risk of local recurrence, lymphatic spread, distant metastasis, and melanoma-related death in patients with conjunctival malignant melanomas. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Bruch′s membrane thickness in high myopia

To measure the thickness of Bruch′s membrane (BM) and assess its associations with axial length.

Infection of the corneal endothelium in herpes simplex keratitis

PURPOSE To describe viral infection of the corneal endothelium in a patient with recurrent herpes simplex virus keratitis in the corneal graft. METHODS Case report. A healthy 28-year-old man presented with necrotizing stromal keratitis and corneal perforation in the corneal graft. A second penetrating keratoplasty was performed. The corneal button was processed for histopathologic, immunohistochemical, and electron microscopic studies. RESULTS Histopathologically, the corneal endothelium showed viral inclusion bodies. Herpes simplex virus antigens and viral particles were identified in stromal keratocytes and corneal endothelial cells. CONCLUSION Productive herpes simplex virus infection of the corneal endothelial cells may contribute to corneal graft failure in recurrent herpes simplex virus infections.

Tumor-associated lymphangiogenesis in the development of conjunctival melanoma.

PURPOSE To analyze whether tumor-associated lymphangiogenesis is concurrent with the progression of premalignant conjunctival melanocytic intraepithelial neoplasia (C-MIN) into invasive conjunctival melanoma (CM) and to study its association with prognosis. METHODS Twenty patients with CM were closely matched with 20 patients with C-MIN with atypia and 20 with C-MIN without atypia regarding tumor size, tumor location, tumor extension, and patients age. All conjunctival specimens were analyzed for the immunohistochemical presence of proliferating lymphatic vessels, with LYVE-1 and podoplanin used as specific lymphatic endothelial markers and Ki-67 as a proliferation marker. Lymphatic vascular density was measured within the mass (intratumoral) and within an area ≤ 500 μm from the tumor border (peritumoral) and was correlated with recurrence, metastasis, and survival rates. RESULTS Intratumoral and peritumoral proliferating lymphatic vessels were detected in none of the C-MINs without atypia, in 10 of the 20 C-MINs with atypia, and in all 20 CMs. Invasive CM showed a significantly higher intra- and peritumoral density of proliferating lymphatics than did C-MIN with atypia (P ≤ 0.001). Patients with high intratumoral lymphatic density revealed significantly lower recurrence-free survival rates (P = 0.041) in C-MIN with atypia and significantly lower recurrence-free (P = 0.006), lymphatic-spread-free (P = 0.041), distant-metastasis-free (P = 0.029), and melanoma-specific survival rates (P = 0.029) in CM. CONCLUSIONS Development of CM from premalignant precursors is concurrent with the outgrowth of lymphatic vessels. This active lymphangiogenesis seems to be associated with an increased risk of local recurrence in patients with C-MIN with atypia and with an increased risk of local recurrence, lymphatic spread, distant metastasis, and tumor-related death in patients with invasive CM.