Ocular tuberculosis: a clinicopathologic and molecular study.

OBJECTIVE: To analyze the clinical profiles, histopathologic features, and Mycobacterium tuberculosis polymerase chain reaction testing in patients with ocular tuberculosis. DESIGN: Retrospective case series. PARTICIPANTS: Forty-two patients. METHODS: This retrospective study was approved by the Armed Forces Institute of Pathology (AFIP) Institutional Review Board. The AFIP data banks were screened for cases with diagnosis of ocular tuberculosis using key words such as mycobacterium; tuberculosis; and acid-fast bacilli. Files and slides stained with hematoxylin-eosin and acid-fast staining were reviewed by the Division of Ocular Pathology and by the Infectious Diseases and Parasitic Diseases Pathology Branches. When available; blocks and unstained slides were sent to the Doheny Eye Institute; Los Angeles; California; for quantitative polymerase chain reaction (qPCR) analysis to detect Mycobacterium tuberculosis-specific DNA. MAIN OUTCOME MEASURES: Tuberculin skin test (TST) results, as well as the chest radiograph results, were recorded. When acid-fast bacilli were identified in tissue, their locations-ocular or extraocular sites-were recorded. Emphasis was placed on lymph node involvement and any systemic diseases. RESULTS: In the histopathologic specimens, microscopy revealed a paucity of organisms, and often there were only 1 or 2 organisms associated with or near a giant cell or near an area of necrosis. The qPCR analysis was performed on 6 biopsy specimens. These specimens showed necrotizing granulomatous inflammation from 6 different patients; 3 had positive qPCR results. In 2 of the 3 cases with positive qPCR results, acid-fast bacilli were not found in the tissue sections. In 17 patients, TST results were available; 10 had positive results (60%) and 7 had negative results (40%). Fourteen chest radiograph results were submitted, and 8 (57%) of 14 patients had normal chest films. CONCLUSIONS: This study suggests that in dealing with those populations at increased risk of tuberculosis (e.g., immigrants from endemic areas and human immunodeficiency virus-infected patients) or patients receiving biologic therapy, the ophthalmologist should endeavor to entertain this diagnosis and to rely on the support of infectious disease specialists and pulmonologists to help solidify the diagnosis, because the current methods for the diagnosis have limited sensitivity.

The AFIP history of ocular leprosy.

PURPOSE: To investigate the Armed Forces Institute of Pathology (AFIP) experience with Ocular Leprosy. METHODS: The AFIP data banks were screened for cases with diagnosis of ocular leprosy. Files and slides stained with Hematoxylin-eosin and acid-fast staining were reviewed by the Division of Ocular Pathology and by the Infectious Diseases Pathology Branch. RESULTS: Twenty-five cases were found from 1951 to 1985 and there were 15 males and 7 females and in 3 cases the sex was not given. The disease process ran from 4 months to 50 years in this series. Three patients also had systemic mycobacterium tuberculosis infections. The clinical manifestations of leprosy did not correlate with the histopathological findings. Clinically, corneal manifestations were the most common clinical presentation in 15 cases with only one perforation, iridocyclitis following in 9 patients and eyelid abnormalities ranging from ectropion to trichiasis in 7 patients. Two patients at autopsy had lepromatous cells in the ciliary body as the only ocular manifestation. CONCLUSIONS: In summary, this paper represents a series of ocular leprosy cases from the AFIP which shows the severity of ocular involvement, the predilection of anterior segment involvement and a large number of histopathologic indeterminate cases. The current immigrant and refugee crisis warrants revisting this ancient disease in the differential diagnosis.

Myxofibrosarcoma of the orbit: an underrecognized entity? Case report and review of the literature.

PURPOSE: To describe the clinicopathologic and immunohistochemical features of a rare case of myxofibrosarcoma (MFS) involving the orbit. DESIGN: Retrospective interventional case report and review of literature. METHODS: The clinical history, systemic imaging studies, and histopathologic results of the orbital biopsy are reviewed. MAIN OUTCOME MEASURES: Clinical, radiologic, and histologic features of MFS. RESULTS: A 63-year-old Chinese male sought treatment for a history of rapidly progressive proptosis associated with decreased vision in the left eye over 10 days. Magnetic resonance imaging of the orbit revealed a homogenous mass extending to the optic canal. The mass was excised partially and was submitted for histologic and ultrastructural examination. Histologic testing revealed features of MFS with characteristic diffuse proliferation of atypical, spindle-shaped fibroblasts with prominent myxoid stroma. Tumor cells were reactive for vimentin. Ultrastructural examination revealed spindle-shaped tumor cells, rich in dilated rough endoplasmic reticulum and prominent vacuoles. CONCLUSIONS: For historical reasons, MFS involving the orbit is likely to be underrecognized and categorized erroneously as malignant fibrous histiocytoma or other soft tissue sarcoma. Although orbital MFS is an extremely rare diagnosis, ophthalmologists should be aware of the possibility and consider a diagnosis of MFS when an adult seeks treatment for an orbital tumor with aggressive growth.

Myxomas and angiomyxomas of the orbit: a clinicopathologic study of 6 cases.

PURPOSE: To report clinical and histopathologic features and biologic behavior of orbital myxomas and angiomyxomas. DESIGN: Noncomparative retrospective case series. PARTICIPANTS: Patients with histopathologic diagnoses of orbital myxoma or angiomyxoma. METHODS: Clinical metadata and features were obtained from the medical record. Neoplasms were studied by routine histopathology, special stains, and immunohistochemistry. MAIN OUTCOME MEASURES: Final diagnosis, based on histopathology, special stains, and immunohistochemistry, and clinical course from analysis of metadata and clinical features. RESULTS: Three myxomas and 3 angiomyxomas were identified in 5 males and 1 female. Median age at presentation was 56 years (range, 4-69), with a follow-up ranging from 6 months to 8 years. Two angiomyxomas occurred in children ages 4 and 7 years whose tumors were locally aggressive and recurred. Recurrence also complicated one case of myxoma after incomplete excision. Pathologically, the tumors were poorly circumscribed. Histopathology showed them to be hypocellular, containing stellate and spindled cells in an abundant, loose, myxoid stroma rich in hyaluronic acid. Small blood vessels were rare in myxomas but abundant in angiomyxomas. Tumor cells were frequently immunoreactive for vimentin, CD34, and factor XIIIa. CONCLUSIONS: Myxomas rarely involve orbital tissue, and no angiomyxomas of the region have been previously reported. Angiomyxomas in children may be aggressive. Vascularity and bone involvement appear to be important prognostic features for recurrence. Complete resection with a margin of healthy tissue appears to be the treatment of choice. Tumor cell immunopositivity for vimentin, CD34, and factor XIIIa may assist in the histopathologic diagnosis.

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.

Corneoscleral transplantation in congenital corneal staphyloma and Peters' anomaly.

An infant born with bilateral corneal clouding diagnosed clinically as congenital anterior staphyloma and Peters' anomaly was confirmed histopathologically. This case report demonstrates one clinical spectrum of Peters' anomaly. The clinical course and histopathologic findings are detailed as is a unique surgical approach of corneoscleral graft used to perserve the right globe.

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.

Granulomatous keratitis following corneal tattooing.

We report a patient who developed granulomatous keratitis following corneal tattooing.

WT1 and Bcl2 expression in melanocytic lesions of the conjunctiva: an immunohistochemical study of 123 cases.

OBJECTIVE: Recent studies indicate that WT1 and Bcl2 protein are detected in melanocytic lesions of the skin. We examined, for the first time, WT1 and Bcl2 expression in a variety of conjunctival melanocytic lesions to evaluate their diagnostic utility compared with other melanocytic markers. METHODS: Protein expression and localization of WT1 and Bcl2 were studied by means of immunolabeling and semiquantification in 123 conjunctival melanocytic lesions (71 benign nevi, 21 atypical nevi, 11 primary acquired melanosis, and 20 malignant melanomas). Ancillary immunohistochemical studies were performed with Bcl2, S100, HMB45, and Melan A antibodies. RESULTS: WT1 showed a graded increase in expression in lesions with increasing atypia. Higher mean numbers of WT1-positive cells correlated with increasing atypia in melanocytes. In all cases, Bcl2 expression was positive and more robust than was S100, HMB45, or Melan A expression. WT1 and HMB45 frequently showed diffuse and strong staining in atypical nevi, primary acquired melanosis with atypia, and malignant melanomas compared with benign lesions. CONCLUSIONS: Bcl2 is a highly sensitive immunohistochemical marker for melanocytic tumors of the conjunctiva; HMB45 and WT1 staining distinguishes benign from malignant lesions. CLINICAL RELEVANCE: Our results show that HMB45 and WT1 immunolabeling is helpful in the evaluation of conjunctival melanocytic lesions. Accordingly, we recommend the development of an immunohistochemical panel to classify these lesions.

Novel corneal phenotype in a patient with alport syndrome.

PURPOSE: To report the clinical and histopathologic findings of an unusual keratopathy, which may represent a new corneal dystrophy in a patient with Alport syndrome (ATS). METHODS: A 59-year-old woman with longstanding diagnosis of autosomal recessive ATS was evaluated for progressively decreasing vision in the left eye. She had anterior lenticonus and cataract and central corneal stromal opacification with significant thinning and flattening bilaterally. She underwent penetrating keratoplasty and cataract extraction with posterior chamber intraocular lens implantation. We describe the light microscopic and ultrastructural findings from the cornea. RESULTS: Histopathology of the corneal button revealed marked stromal thinning with decreased keratocytes. The endothelial cells were attenuated and focally lost. Immunohistochemical stains for cytokeratin were positive, findings consistent with posterior polymorphous dystrophy (PPMD). Transmission electron microscopy showed necrosis and a marked loss of keratocytes. Multilayering of the endothelium was consistent with PPMD, but mature desmosomes and microvilli were absent. In vivo confocal microscopy on the fellow eye showed linear hyporeflective bands at the level of Descemet's membrane consistent with PPMD. In addition, there were fine linear changes in the deep stroma and diffuse hyperreflectivity of the mid and superficial stroma with lack of identifiable keratocytes throughout. CONCLUSIONS: We believe this to be the first reported case to demonstrate some histopathologic features of PPMD in ATS. However, the clinical, histopathologic, and ultrastructural characteristics are not typical of PPMD. This may represent a new phenotypic expression of PPMD or may be a distinct clinicopathologic dystrophy associated with ATS.

Chronic granulomatous disease presenting as retinal mass.

1-year-old girl was admitted for fever of unknown origin. Funduscopy revealed juxtapapillary retinal inflammatory mass in one eye with a differential diagnosis of sarcoidosis, tuberculosis, retinoblastoma or metastatic disease. Retinal biopsy showed necrotizing granulomatous retinitis. Extensive workup and therapeutic trials failed to confirm the diagnosis of tuberculosis or sarcoidosis. Her 7-month brother and 4-year-old male cousin presented with nystagmus, poor vision, paravascular pigmentary changes and were initially diagnosed as recessive retinal dystrophy. The girl died at age 2 from tuberculous meningitis and the boys had recurrent tuberculous and Aspergillus infections. Awareness of the typical fundus findings in chronic granulomatous disease allows early diagnosis of the disorder.

Keratectasia after laser in situ keratomileusis: a histopathologic and immunohistochemical study.

OBJECTIVE: To examine histopathologic and immunohistochemical features of human corneal buttons from patients who developed keratectasia after laser in situ keratomileusis (LASIK). METHODS: Five corneal buttons were obtained during penetrating keratoplasty from patients who developed keratectasia after LASIK. Histologic features were examined by hematoxylin-eosin staining using paraffin-embedded sections and by transmission electron microscopy. Immunostaining for alpha(1)-proteinase inhibitor, Sp1, and matrix metalloproteinases 1, 2, and 3 was performed with 2 healthy corneas and 2 corneas with keratoconus as controls. RESULTS: Central stromal thinning was observed after hematoxylin-eosin staining in all corneas with keratectasia. No histologic features specific to keratoconus, including Bowman layer disruption, were identified in the corneas with keratectasia. By transmission electron microscopy, collagen fibril thinning and decreased interfibril distance were observed in the stromal bed. Immunostaining intensity and/or pattern for alpha(1)-proteinase inhibitor and Sp1 in the corneas with keratectasia was comparable to that of healthy corneas and differed from that in the corneas with keratoconus. No significant staining with anti-matrix metalloproteinases 1, 2, and 3 antibodies was observed in either the corneas with keratectasia or the healthy corneas. CONCLUSIONS: Histologic findings suggest that post-LASIK keratectasia results in collagen fibril thinning and decreased interfibril distance within the residual stromal bed. Discrepant results between keratectasia and keratoconus suggest that the pathogenesis of the 2 conditions differ.

Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients.

Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.

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.

Renal medullary carcinoma metastatic to the orbit: a clinicopathologic report.

A 39-year-old black man with sickle cell trait presented with a rapidly progressive, painful proptosis of the left eye. A computed tomographic scan was interpreted as revealing a cavernous hemangioma. Medial orbitotomy revealed a hard, gray mass supranasal to the optic nerve and invading the medial rectus muscle. Intraoperative frozen section specimens were read initially by the pathologist as metastatic adenocarcinoma. On gross examination, the conspicuous hemorrhage, necrosis, and bright yellow color characteristic of renal cell carcinoma were not present. Final pathologic analysis of the orbital lesion revealed metastatic renal medullary cell carcinoma. The primary lesion was located in the right kidney. Renal medullary carcinoma is a rare tumor, often affecting young individuals with sickle cell trait or disease. We report the first confirmed case of renal medullary carcinoma metastatic to the orbit with orbital symptoms preceding the diagnosis of the primary tumor.

Orbital hemangioblastoma arising in a rectus muscle.

We describe the clinical and histologic features of the first case, to our knowledge, of hemangioblastoma of the orbit arising from an extraocular muscle. We examined a 73-year-old woman with conjunctival injection, 2 mm of proptosis, and limitation of abduction of the right eye. A medial-lateral orbitotomy was used to approach the medial rectus enlargement noted on orbital imaging. Histopathologic examination with light microscopy and immunohistochemistry demonstrated the characteristic findings of a hemangioblastoma.

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.

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.