Manisha Mehta

Idiopathic fibroinflammatory disease of the face, eyelids, and periorbital membrane with immunoglobulin G4-positive plasma cells.

Progressive sclerosing orbital pseudotumors are a subset of usually primary and localized idiopathic fibroinflammatory disorders. We report on a 66-year-old man who developed this condition along the facial tissue planes with extension into the orbit and preferential involvement of the periorbital membrane. Fibrocollagenous tissue with scattered lymphoid aggregates without follicle formation dominated the process. There was a light dispersion of B and T lymphocytes and histiocytes in the stroma. Immunoglobulin G4 (IgG4)-positive plasma cells (>35 per high-power field) were identified mostly in the lymphoid clusters, as has been discovered in similar IgG4-related fibrosclerosing conditions of other nonorbital sites. No associated systemic disease emerged during a 20-year clinical course. Previously reported orbital cases of IgG4-positive disease have all involved the lacrimal gland, usually bilaterally, and more closely resembled hypercellular reactive lymphoid hyperplasias with moderate interlobular fibrosis, rather than representing an essentially sclerosing process from the beginning.

Squamous cell carcinoma of the eyelid and conjunctiva.

Eyelid malignancies represent more than 90% of all ophthalmic tumors, among which squamous cell carcinoma (SCC) is the second most common malignancy. SCC can lead to significant life threatening metastasis as opposed to the 10 to 13-fold more common and frequently encountered basal cell carcinoma. Conjunctival SCC along with corneal intraepithelial neoplasia is termed ocular surface squamous cell neoplasia and is the most common conjunctival malignancy in the United States. Both eyelid and conjunctival SCC have a broad spectrum of macroscopic presentations, significant morbidity and mortality. Given the similarities in presentation between various other ocular pathologies, a very low threshold for biopsy should be maintained to clinch the diagnosis of SCC at its earliest. A review of numerous studies reveals the incidence, presentations, differential diagnoses, management, and treatment options of SCC of the eyelid and conjunctiva.

Role of c-Cbl–Dependent Regulation of Phospholipase Cγ1 Activation in Experimental Choroidal Neovascularization

PURPOSE Activation of phospholipase Cγ1 (PLCγ1) by vascular endothelial growth factor receptor (VEGFR)-2 is necessary for proliferation and tube formation of endothelial cells in vitro. Previous work has demonstrated that Casitas B-lineage lymphoma (c-Cbl) promotes ubiquitination of PLCγ1 and suppression of its tyrosine phosphorylation. This study was designed to evaluate the importance of PLCγ1 and c-Cbl in experimental choroidal neovascularization (CNV). METHODS The role of PLCγ1 was studied in three models of angiogenesis: the endothelial cell culture system, the chorioallantoic membrane (CAM) assay, and the laser-induced CNV model. Endothelial cells were analyzed for the role of PLCγ1 in promoting tube formation. CAMs were incubated with pharmacologic agents that either inhibit or stimulate PLCγ1. CNV was induced in wild-type and c-Cbl-knockout mice, and the progression of CNV was evaluated by fluorescein angiography. RESULTS Activation of PLCγ1 was necessary for tube formation of endothelial cells. PLCγ1 stimulation increased the growth of blood vessels and conversely, PLCγ1 inhibition decreased the growth of blood vessels in the CAM model. CNV lesions in the c-Cbl-knockout mice were significantly greater in number, more confluent, and increased in size with time, compared with those in the control wild-type mice. CONCLUSIONS The data show that PLCγ1 plays an important role in angiogenesis. Loss of c-Cbl results in enhanced CNV in the eye. The study also shows that c-Cbl plays an important role in ocular angiogenesis, suggesting that modulation of c-Cbl activity or inhibition of PLCγ1 would be a compelling target for antiangiogenesis therapy.

IgG4-Positive Dacryoadenitis and Küttner Submandibular Sclerosing Inflammatory Tumor

Comment. C albicans is the most frequent cause of fungal keratitis in temperate regions and is an opportunistic organism that can complicate chronic keratopathy and corneal grafting. Persistent epithelial defects and suture-related problems, along with immunosuppression, have been found to be the major predisposing risk factors. Caspofungin is a first-in-class echinocandin with potent activity against Candida and Aspergillus, the dominant human fungal pathogens. In contrast to all other antifungal drugs, echinocandins have a selective action on a target present only in fungal cell walls (not in mammalian cells): they inhibit the synthesis of an essential component, (1,3)-D-glucan. Caspofungin is fungicidal in vivo and in vitro against all Candida species, including fluconazole-resistant strains. Its activity differs from that of the azole antifungal group, which is fungistatic. In our case, we think that voriconazole stopped progression of the infiltrate but did not kill the microorganism. The presence of the fungus after 1 month could be due to poor drug penetration, fungal resistance, or both. We therefore suggest that an ideal treatment protocol should include antifungal agents chosen on the basis of in vitro susceptibility of the fungus with a duration assessed by in vivo monitoring of fungal filaments or yeasts. To our knowledge, the topical ocular use of caspofungin has been reported in rabbits. There has been only 1 report of its use in humans, although it was in association with other antifungal drugs. In conclusion, topical caspofungin, 0.5%, is a new, promising option in the treatment of refractory fungalrelated corneal ulcers with no evidence of ocular toxic effects. However, future studies with larger samples are indicated to further evaluate its efficacy and tolerance.

Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis

Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2.

Amniotic membrane grafting in the management of conjunctival vascular malformations.

Purpose: Vascular malformations of the conjunctiva are symptomatically distressing and surgically challenging. Because their expansive nature necessitates broad conjunctival sacrifice in some cases, epithelial reconstitution may be the best way to avoid symblepharon formation. Amniotic membrane grafts have been useful for conjunctival reconstruction after excision of squamous cell carcinoma and melanoma but have not been used after excision of extensive conjunctival vascular malformations. The authors report the use of amniotic membrane grafts in the management of large conjunctival vascular malformations. Methods: The authors reviewed the clinical records and photographs of 4 patients with combined orbital and conjunctival vascular malformations. The operative details including amniotic membrane grafting and postoperative results were included. The average follow-up period was 9 months. Results: Four patients underwent a total of 6 resections; 2 patients required reoperation. Three of these lesions were lymphatic and 1 was venous. Dehydrated amniotic membrane was initially used in 2 patients who were subsequently grafted with cryopreserved amniotic membrane. Postoperative trauma in 1 case and staged surgery in the other necessitated these second surgeries. Cryopreserved amniotic grafting was successful in all 4 patients with no signs of graft dislocation, rejection, or tumor overgrowth after an average postoperative period of 9 months. Conclusions: Large conjunctival vascular malformations, when extensively resected, leave large, denuded epibulbar and palpebral surfaces that would likely produce severe symblepharon. Conversely, incomplete resection can lead to early recurrent growth. Commercially available amniotic membrane grafts now provide a method for reconstructing these defects, allowing more extensive resection of the tumor.

Immunohistochemical differences between normal and chronically inflamed conjunctiva: diagnostic features.

Purpose:There is widespread misinterpretation of normal conjunctival fibrinogen. In differentiating between normal conjunctiva and cicatrizing conjunctivitis, including ocular cicatricial pemphigoid, atopic keratoconjunctivitis, and lichen planus, it is important to properly evaluate and characterize the histologic appearance of the structures seen and not base a diagnosis on just the presence or absence of certain features. One feature of conjunctival histology prone to misinterpretation and misdiagnosis is the presence of subepithelial fibrinogen, particularly when the diagnosis of lichen planus is being considered. Although the presence of subepithelial fibrinogen in oral mucous membranes and in skin can be indicative of lichen planus, such is not the case for conjunctiva. An erroneous diagnosis of lichen planus based on the presence of conjunctival subepithelial fibrinogen can initiate prolonged treatment with topical steroids leading to avoidable, blinding, complication, and further, delay therapy for the real cause of the conjunctivitis. We conducted a cross sectional, controlled, blinded and prospective Institutional Review Board–approved study on the occurrence and pattern of fibrinogen at the epithelial basement membrane zone (BMZ) of normal and inflamed conjunctiva. Methods:Bulbar conjunctiva was obtained from 10 cases of undiagnosed chronic conjunctivitis of at least 6 months duration and 8 patients with normal conjunctiva. Immunofluorescent staining with antifibrinogen antibodies, periodic acid-schiff stain (PAS), and Giemsa staining were performed. Results:BMZ fibrinogen was found in all cases. This layer was linear, smooth, and continuous in normal conjunctiva and 7 cases of chronic conjunctivitis. It was fragmented and lumpy in 1 case of ocular cicatricial pemphigoid (OCP) and showed spikes and spurs in 2 cases of lichen planus. Conclusions:BMZ fibrinogen is a normal component of the conjunctiva and its morphological features rather than its mere presence should be assessed as a diagnostic tool.

The white caruncle: sign of a keratinous cyst arising from a sebaceous gland duct.

Purpose: To describe an acquired, smooth white lesion of the caruncle and to underscore the role of subsurface keratinizing squamous epithelium in its formation. Methods: Clinical photographic documentation, histopathologic evaluation, and immunohistochemical staining of an excised specimen from a 25-year-old woman. Results: A cyst was found that was lined by keratinizing squamous epithelium without a keratohyaline layer (trichilemmal keratinization), typical of lesions of the pilosebaceous unit. A portion of the cysts lining was replaced by granulomatous inflammation resulting from an earlier spontaneous partial rupture. Ki-67 immunolabeling demonstrated relatively few nuclei in S-phase (DNA synthesis) in comparison with the overlying epithelium, thereby suggesting an obstructive, nonproliferative cause for the cyst. Conclusion: A white caruncular lesion is a very rare finding according to the literature. It is most likely caused by a cyst lined by squamous epithelium elaborating trichilemmal-type keratin. A sebaceous gland duct was established as the source for the current lesion.

Keratinous cyst of the palpebral conjunctiva.

A whitish-opalescent, mildly elevated superior tarsal conjunctival lesion measuring 3.0 mm in diameter caused a refractory corneal abrasion in a 54-year-old man. Complete local excision without entering the tarsus produced relief of symptoms. There has been no recurrence during 9 months of follow-up. Histopathologically, a unique keratinous cyst was delimited mostly by basaloid cells resembling the matrical cells in pilomatrixoma. There were no keratohyalin granules in the lining cells, which focally transformed in ghost cells. These histopathologic features are characteristic of trichilemmal keratinization, a heretofore undescribed metaplasia of the conjunctival epithelium.

Trigeminal Dermatome Distribution in Patients with Glaucoma and Facial Port Wine Stain

Purpose: The importance of glaucoma screening in patients with upper eyelid involvement of facial port wine stain (PWS) is well known. This study questions the validity of this concept and reports the cutaneous patterns of PWS in 66 patients known to have glaucoma. Methods: Clinical records of 66 patients with glaucoma were reviewed, and the pattern of facial PWS involvement of the dermatomes of the trigeminal nerve was catalogued. The Pearson χ2 test was applied. The literature supporting previous conclusions was reviewed. Results: 39 cases had ipsilateral and 27 had bilateral PWS; 9.3% had isolated ophthalmic branch (V1) involvement, 30.2% had ophthalmic and maxillary branch (V1V2) involvement, 5.8% had maxillary and mandibular branch (V2V3) involvement, and 52.3% had all 3 branches (V1V2V3) involved. Conclusions: Patients demonstrated to have glaucoma and facial PWS are approximately 7 times more likely to have multiple dermatomes of the trigeminal nerve involved (88.3%) in contrast to isolated V1 involvement (9.3%). PWS patterns did not correlate with embryological segments of facial development. A review of the relevant literature resolves conflicting concepts and emphasizes the importance of glaucoma screening in all patients with trigeminal dermatome involvement of the PWS.