Glenn C. Cockerham

Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases.

The majority of primary lymphoproliferative lesions of the uvea represent low‐grade B cell lymphomas and often display a prominent plasmacellular differentiation. The purpose of the current study was to classify the uveal lymphoproliferations according to the REAL classification; examine the immune profile of the plasmacellular differentiated tumour cells using the plasma cell‐related antigens multiple myeloma oncogene‐1‐protein (MUM1), Vs38c, CD38 and CD138; and to compare this profile with that of mature reactive plasma cells. Following fixation, 13 lymphoproliferative lesions of the uvea were categorized on the basis of their morphology and immunophenotype according to the REAL classification. Included in the immunohistochemistry were B cell‐specific activator protein (BSAP), MUM1, Vs38c, CD38 and CD138. Nested polymerase chain reaction (PCR) was also performed on DNA extracted from paraffin sections for the detection of gene rearrangements of the heavy immunoglobulin chain (IgH). All of the 13 uveal tract lymphoproliferative lesions represented malignant lymphoma of B cell non‐Hodgkin type and could be diagnosed as ‘extranodal marginal zone B cell lymphomas’ (EMZL). The degree of plasmacellular differentiation varied between the tumours. In contrast to their non‐plasmacytoid counterparts, the ‘plasmacytoid’ EMZL tumour cells were negative for the B cell markers CD20 and BSAP, and demonstrated heterogeneous positivity for the markers MUM1, Vs38c, CD38 and CD138. The most consistent marker was MUM1, being observed in all tumours. Co‐expression of all plasma cell markers was observed in four (31%) uveal EMZL. Loss of CD138 expression was observed in six (46%) tumours, of Vs38c expression in five (38%) and of CD38 in one (7%) tumour. Although the diagnosis of malignant lymphoma was unequivocally based on morphological and immunophenotypical features, the molecular analysis was able to demonstrate clonal B cell populations in only one uveal EMZL. All uveal lymphoid proliferations investigated represented EMZL, with the corresponding morphology and immunophenotype as seen in EMZL in other extranodal locations. MUM1, followed by CD38 expression, were the most constant plasma cell antigens in the plasmacytoid EMZL tumour cells, with both Vs38c and CD138 positivity being lost in many tumours. Aberrant immune profiles of plasma cell‐related antigens may be of help in the establishment of malignancy in uveal lymphoproliferative lesions, particularly where interpretation of light chain expression and/or PCR results is difficult. Copyright

Re-evaluation of “reactive lymphoid hyperplasia of the uvea”: An immunohistochemical and molecular analysis of 10 cases

OBJECTIVE Cases of uveal lymphoid proliferation previously classified as reactive lymphoid hyperplasia (RLH) were studied to correlate pathologic features with clinical outcome. DESIGN Retrospective case series. PARTICIPANTS Ten cases of RLH of the uvea on file at the Armed Forces Institute of Pathology with sufficient formalin-fixed, paraffin-embedded tissue for analysis. METHODS Clinical, histologic, immunohistochemical, and molecular (polymerase chain reaction [PCR]) characteristics of uveal lymphoid proliferations were studied. MAIN OUTCOME MEASURES Morphologic, immunohistochemical, and PCR characteristics of study cases. RESULTS Patient age ranged from 40 to 73 years at time of enucleation, with a mean age of 55 years. Retinal detachment was noted clinically in nine patients and glaucoma in eight. All patients were treated with enucleation, and three received radiotherapy. Histologically, two cases were interpreted as RLH and eight were well-differentiated small-cell lymphoma (WDSCL). Systemic lymphoid infiltrate developed in two patients, but there were no deaths with a mean follow-up of 9.9 years. Mature lymphocytes were noted in the iris and angle structures; the atypical cells of uveal lymphoma were found in the choroid and ciliary body. Eight cases were monoclonal by B-cell and T-cell markers and/or immunoglobulin light chain restriction. Amplifiable DNA was present in 6 of 10 cases by PCR. Three cases monoclonal by cell markers were also monoclonal by PCR, but two cases monoclonal by cell markers could not be confirmed by PCR. Lymphoid follicles with germinal centers were found in two cases of RLH and five cases of WDSCL. Nine specimens demonstrated extraocular lymphoid involvement of the episclera and orbit; most appeared more benign morphologically than the choroidal infiltrates. Extraocular infiltrates of WDSCL were monoclonal by immunohistochemistry in five cases, polyclonal in one case, and indeterminate in two cases. CONCLUSIONS Most cases (8 of 10) previously described as RLH were low-grade B-cell lymphomas histologically and by immunohistochemistry. PCR results agreed with histologic diagnosis in four of six cases. Open-angle glaucoma was common and related mostly to lymphocytic infiltration of the angle structures. Extraocular involvement is common but may not be representative of the choroidal lesion. Prognosis is excellent in low-grade uveal lymphoid neoplasia.

Closed-Eye Ocular Injuries in the Iraq and Afghanistan Wars

Comprehensive ophthalmic evaluation was conducted in 46 veterans hospitalized because of traumatic brain injury after blast exposure in Iraq or Afghanistan. Evidence of closed-eye injury was found in 20 of these patients.

Clinicopathologic evaluation of the Mueller muscle in thyroid-associated orbitopathy.

Purpose: To study the histopathologic features of the Mueller muscle in chronic eyelid retraction caused by thyroid-associated orbitopathy. To investigate if the degree of eyelid retraction correlates with any histopathologic finding. Methods: A prospective case series of 23 consecutive patients with thyroid-associated orbitopathy was studied. Specimens were obtained during a standard muellerectomy. Formalin-preserved specimens were studied with the use of hematoxylin-eosin, periodic acid–Schiff, Masson trichrome, and Giemsa stains. Immunostaining against leukocyte common antigen, L26, CD3, and KP-1 was performed. Three control specimens were also evaluated in a similar fashion. Fresh tissue was placed in cold glutaraldehyde overnight, postfixed, dehydrated, and infiltrated with epoxy resin. Silver (70 nm) sections were cut and stained with uranyl acetate and lead citrate for electron microscopic examination. Results: On light microscopy, fibrosis and mast cell infiltration was present in all 23 specimens. Fat infiltration was noted in 16 of 23 specimens and did not correlate with increasing age of the patient. Interstitial edema and lymphocytic infiltration were not observed. On immunohistochemistry, leukocyte common antigen was positive, confirming the presence of inflammation. L26, CD3, and KP1 were negative. Electron microscopy demonstrated fibrosis, mast cells, and abundant contracting Mueller cells. The degree of clinical retraction in millimeters did not correlate with fibrosis, inflammation, or fat infiltration. The control specimens demonstrated rare fat and mast cell infiltration and no fibrosis. Conclusions: Contrary to previous reports, the Mueller muscle is involved in the inflammation and fibrosis that characterizes thyroid-associated orbitopathy. The Mueller muscle is grossly enlarged. On histopathologic inspection, fibrosis, fatty infiltration, and increased mast cell presence accompany focal atrophy of the Mueller muscle. In concordance with prior descriptions, many Mueller cells are in an actively contracting state on electron microscopy.

Primary graft failure : a clinicopathologic and molecular analysis.

OBJECTIVE Primary graft failure (PGF) corneal tissues were analyzed for herpes simplex virus (HSV) and varicella-zoster virus (VZV). DESIGN Retrospective, noncomparative case series. MATERIALS Formalin-fixed, paraffin-embedded tissue of 21 donor corneas and 14 recipient corneas of PGF cases, as well as 10 control corneas. METHODS Clinical, histologic, immunohistochemical, polymerase chain reaction (PCR), and, in selected cases, transmission electron microscopic characteristics were studied. MAIN OUTCOME MEASURES Evidence of HSV or VZV in donor tissues. RESULTS Median patient age was 65 years, and median donor age was 48 years. Donor cornea parameters, including endothelial cell counts, death-to-preservation time, and time in storage, were generally within accepted standards. Stromal edema was found in all 21 donor corneas with PGF. Eighteen donor corneas demonstrated severely reduced or absent endothelium and mild to moderate lymphocytic infiltration without necrosis. Three donor corneas (14%) had necrotizing stromal keratitis (NSK) with keratic precipitates. Positive immunohistochemical staining of keratocytes for HSV was present in two of two donor corneas with NSK and was negative in 18 other donor corneas. Polymerase chain reaction analysis revealed the DNA of HSV type 1 (HSV1) in all donor corneas with NSK and in four donor corneas without NSK (33%). Recipient corneal tissue was negative for HSV1 DNA in three patients with NSK and positive in two of the four other PCR-positive patients. Transmission electron microscopy analysis showed viral particles in two donor corneas with NSK. Polymerase chain reaction analysis revealed no evidence of HSV type 2 or VZV in any cornea. All control corneas were negative for viral DNA. Sixteen corneas remained clear and two had failed after regraft for PGF, with a median follow-up of 3.6 years. CONCLUSIONS Herpes simplex virus type 1 DNA was present in 33% of patients of PGF. Herpetic stromal keratitis was found in some failed corneas; the lack of HSV in the paired recipient suggests importation within the donor cornea. The overall prognosis for regrafting after PGF is good.

An immunohistochemical analysis and comparison of posterior polymorphous dystrophy with congenital hereditary endothelial dystrophy.

Purpose. To evaluate the immunohistochemical profiles of the abnormal endothelial cells of posterior polymorphous dystrophy (PPMD) and congenital hereditary endothelial dystrophy (CHED). Methods. Formalin-fixed, paraffin-embedded sections of seven corneas with the diagnosis of PPMD (seven patients), six corneas with the diagnosis of CHED (four patients), and five control corneas were stained with hematoxylin-eosin. Adjacent histologic sections were stained with monoclonal antibodies that react with pancytokeratin, AE1/AE3, cytokeratin (CK) 7, CK 20, CAM 5.2, and epithelial membrane antigen. The immunoreactivity of the corneal endothelium was assessed by light microscopy. Results. The endothelial cells stained positive for pancytokeratin and CK 7 in seven of seven corneas of patients with PPMD and five of six corneas of patients with CHED; variable positivity was seen to AE1, AE3, and CAM 5.2. The endothelium was uniformly negative to staining by CK 20. The epithelium stained positive with pancytokeratin, AE1, and AE3. All control corneas were negative for pancytokeratin, CK 7, and CK 20. Conclusion. The abnormal endothelium in both PPMD and CHED expresses similar CKs, including CK 7, which is not present in normal endothelium or surface epithelium. This may indicate a shared developmental abnormality in these conditions, as previously suggested by ultrastructural studies and genetic mapping.

Epithelial metaplasia of the corneal endothelium in Fuchs endothelial dystrophy

Purpose: To evaluate the immunohistochemical characteristics of human corneas with the diagnosis of Fuchs endothelial dystrophy (FED). Methods: Formalin-fixed, paraffin-embedded sections of corneas with the diagnosis of FED (15 patients) and 10 control corneas were stained with hematoxylin-eosin and periodic acid-Schiff (PAS). Adjacent histologic sections were stained with monoclonal antibodies that react with epithelial antigens: pancytokeratin, cytokeratins (CK) 7 and 20 CAM 5.2, epithelial membrane antigen (EMA), and Ber EP4. Eight corneas were stained with antibodies to vimentin, smooth-muscle actin (SMA), and CD 68. Results: The endothelial cells in FED were attenuated and atrophic; some contained pigment consistent with melanin. The endothelial cells stained for pancytokeratin, CK 7, and vimentin in all corneas of FED, whereas variable staining was noted with CAM 5.2. No staining of endothelium was noted with CK 20, EMA, BerEP4, SMA, or CD 68. Conclusion: Some cytokeratins that are normally restricted to true epithelium are present in the endothelium of FED. Epithelial metaplasia of endothelium in FED may represent a nonspecific response of distressed endothelial cells, as previously reported in posterior polymorphous dystrophy, congenital hereditary endothelial dystrophy, and iridocorneal endothelial syndrome.

The clinical spectrum of schwannomas presenting with visual dysfunction: a clinicopathologic study of three cases.

Schwannomas (neurilemomas) are benign tumors that arise from Schwann cells in the peripheral nervous system. The most commonly involved nerves that cause neuro-ophthalmic manifestations are cranial nerves V and VIII. In this series of three women, schwannomas presented as intraconal masses that mimicked a cavernous hemangioma, a superior orbital mass transgressing the superior orbital fissure, and an expansive frontal lobe mass with clinical symptoms and signs of increased intracranial pressure. Although all three complained of visual blurring, none of our patients presented with Vth or VIIIth cranial nerve dysfunction. Histopathologic studies demonstrated well-circumscribed, encapsulated spindle-cell lesions with classic Antoni A and B patterns. Histopathologic examination is essential to confirm the diagnosis of a schwannoma that may be otherwise clinically confusing. Direct optic nerve compression, globe indentation with induced hyperopia, or increased intracranial pressure with optic nerve compromise may be responsible for visual symptoms. A multidisciplinary approach is often required because of the size and location of schwannomas.

Retrocorneal membrane with myofibroblasts after perforating injury: an immunohistochemical and ultrastructural study of 11 cases.

PURPOSE Retrocorneal membranes (RCMs) are sometimes present after perforating corneal injury, including failed corneal grafts. This study was performed to understand the origin and cellular composition of these RCMs. METHODS Eleven cases of fibrous RCM associated with perforating injury and ulceration were studied by light and electron microscopy. Monoclonal antibodies against vimentin, actin, and alpha-smooth muscle actin (SMA) were used for immunohistochemical analysis. RESULTS Retrocorneal membranes varied in thickness, extent, and cellularity. There was invariably a direct connection between RCM and wound scar through a gap in Descemets membrane. Eight RCM and three scars of perforating wounds showed actin- or SMA-positive, vimentin-positive, spindle-shaped cells consistent with myofibroblasts. Electron microscopy showed fibroblasts and myofibroblasts in RCM. Descemets membrane was often wrinkled in proximity to RCM with myofibroblasts. CONCLUSIONS The scar tissue in corneal wounds is an apparent source of RCM components after perforating corneal injury, extending through gaps in Descemets membrane. Contractile myofibroblasts are present in some RCMs and may be responsible for wrinkling of Descemets membrane.

Radiosensitive orbital inflammation associated with temporal arteritis.

A 75-year-old woman developed acute loss of vision in the OD, ipsilateral periocular pain, an afferent pupillary defect, sectoral optic disc edema, and later ipsilateral proptosis and an intraconal mass. She denied any symptoms of temporal arteritis, and a sedimentation rate was normal. Orbital biopsy demonstrated chronic granulomatous inflammation with perivasculitis. A temporal artery biopsy disclosed findings consistent with temporal arteritis. Following 2000 cGy of external beam radiation, her visual function and orbitopathy completely resolved. This unusual presentation of orbital inflammation in association with temporal arteritis demonstrates that pathologic findings of temporal arteritis may be clinically nonspecific and that external beam radiation may be an effective therapy in this setting.