Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter.

We have previously shown that postnatal expression of the viral oncoprotein SV40 T antigen in rod photoreceptors (transgene MOT1), at a time when retinal cells have withdrawn from the mitotic cycle, leads to photoreceptor cell death (Al-Ubaidi et al., 1992. Proc. Natl. Acad. Sci. USA. 89:1194-1198). To study the effect of the specificity of the promoter, we replaced the mouse opsin promoter in MOT1 by a 1.3-kb promoter fragment of the human IRBP gene which is expressed in both rod and cone photoreceptors during embryonic development. The resulting construct, termed HIT1, was injected into mouse embryos and five transgenic mice lines were established. Mice heterozygous for HIT1 exhibited early bilateral retinal and brain tumors with varying degrees of incidence. Histopathological examination of the brain and eyes of three of the families showed typical primitive neuroectodermal tumors. In some of the bilateral retinal tumors, peculiar rosettes were observed, which were different from the Flexner-Wintersteiner rosettes typically associated with human retinoblastomas. The ocular and cerebral tumors, however, contained Homer-Wright rosettes, and showed varying degrees of immunoreactivity to antibodies against the neuronal specific antigens, synaptophysin and Leu7, but not to antibodies against photoreceptor specific proteins. Taken together, the results indicate that the specificity of the promoter used for T antigen and/or the time of onset of transgene expression determines the fate of photoreceptor cells expressing T antigen.

Expression of the functional cone phototransduction cascade in retinoblastoma.

Retinoblastoma is a malignant intraocular tumor that primarily affects small children. These tumors are primitive neuroectodermal malignancies, however some of them show morphologic evidence of differentiation into photoreceptors. Phototransduction cascades are a series of biochemical reactions that convert a photon of light into a neural impulse in rods and cones. The components of these cascades are uniquely expressed in photoreceptors and, although functionally similar, distinct components of these cascades are expressed in rods and cones. Using HPLC anion exchange chromatography, Western blot analysis, and specific monoclonal and polyclonal antibodies, we found that the cone but not the rod cGMP phosphodiesterase is functionally expressed in all six primary retinoblastomas examined and in three continuous retinoblastoma cell lines. Morphologic evidence of differentiation did not correlate with the expression of the enzyme. Furthermore, GTP analogues could activate the phosphodiesterase activity suggesting that an intact phototransduction cascade is present in the tumors. The presence of the cone phototransduction cascade in retinoblastoma confirms that this tumor has biochemically differentiated along the cone cell lineage.

Intracellular inclusions in meningothelial meningioma. A histochemical and ultrastructural study.

This is a study on the histochemical and electron microscope findings of the intracellular inclusions in a case of meningothelial meningioma of the frontoethmoidal region with orbital involvement. The inclusions are PAS-positive, diastase resistant, and stain strongly positive with the modified Morel-Sisley reaction for protein-bound tyrosine and weakly with dihydroxy-dinaphthyl-disulfide (DDD) for the demonstration of sulfhydryl (SH) and disulfide (S-S) groups of proteins. These staining reactions suggest the inclusions are composed of conjugated proteins (glycoproteins). Ultrastructurally, the inclusions are located within intracellular spaces lined by microvilli and are composed of granular material, usually forming a dense core that is intermixed with small vacuoles. Numerous desmosomes and whorls of tonofibrils are concentrated around them. Our findings support the view that the intracellular inclusions, which are rarely found in meningiomas, represent an active secretory product of the meningothelial cells rather than a degenerative or phagocytic process.

Melanotic schwannoma of soft tissues. Electron-microscopic observations and review of literature.

This is a report of an unusual case of melanotic schwannoma located in the soft tissue of the shoulder. By light microscopy, the partially pigmented, encapsulated mass showed tumor lobules displaying an organoid pattern and benign cytologic features. By electron microscopy, the tumor cells disclosed numerous interdigitating blunt cytoplasmic processes invested by a thin, continuous basal lamina with formation of mesaxons and moderate amount of glycogen as well as immature and mature melanosomes. The patient was reported to be alive and well 7 years after local excision of the mass. We also reviewed 21 additional cases from the literature. The most frequent sites of involvement were: the spinal nerve roots and adjacent structures (12 cases), soft tissues (five cases), heart (one case), esophageal wall (one case), acoustic nerve (one case), and mandible (one case). Twelve patients were alive and well (follow-up periods ranging from 9 months to 13 years after surgical resection), and one died of surgical complications. Eight patients were lost to follow-up. Three patients had local recurrences due to incomplete excision of the mass. Ten tumors were studied electron microscopically and displayed characteristic features of both Schwann cells and melanocytes. This unique dual differentiation probably reflects their common ancestry from neural crest cells.

Pulmonary blastoma with rhabdomyosarcomatous differentiation: an electron microscopic and immunohistochemical study.

Pulmonary blastoma is a rare lung tumor composed of epithelial and mesenchymal elements; the latter element may show various patterns of differentiation toward mature tissue, such as cartilage, smooth muscle, and bone. Rhabdomyoblastic differentiation in pulmonary blastoma is quite rare; only five such cases have been reported. We report two cases of pulmonary blastoma with rhabdomyoblastic differentiation documented for the first time by electron microscopy and immunohistochemistry including documentation for myoglobin, actin, vimentin and desmin. The diffuse and prominent rhabdomyoblastic differentiation in one case is most unusual.

Detection of varicella zoster virus DNA in some patients with giant cell arteritis.

PURPOSE: The purpose of this study was to determine whether an association exists between giant cell arteritis (GCA) and the presence of varicella-zoster virus (VZV), by using histologic, molecular, immunohistochemical, and ultrastructural analyses of temporal artery biopsy specimens. METHODS: In a randomized masked study, 64 temporal artery biopsy specimens were analyzed by PCR for VZV DNA. The samples included 35 specimens histologically positive and 29 specimens histologically negative for GCA. Immunohistochemical staining for VZV viral antigen IE-63 was performed on seven of the specimens positive for GCA and five negative specimens. Transmission electron microscopy (TEM) was performed on five of the specimens positive for GCA. RESULTS: PCR was positive for VZV DNA in 9 (26%) temporal arteries tested that showed histologic evidence of GCA. The remaining 26 histologically positive temporal arteries and all 29 histologically negative arteries tested gave negative PCR results for VZV DNA. Statistical analysis (z-test) comparing the association of VZV DNA between the specimens that were positive and negative for GCA showed a significant difference (P = 0.010). Immunohistochemical studies were positive in several biopsy specimens within adventitial histiocytes-macrophages, but these results did not correlate with either the presence or absence of VZV DNA or with the histologic evidence of GCA. No viral particles were observed by TEM. CONCLUSIONS: This study showed a significant association of VZV DNA to temporal artery biopsy samples positive for GCA compared with the negative specimens. The results support the hypothesis that VZV may play a role in the pathogenesis of some cases of GCA. However, PCR, immunohistochemical, and electron microscopic findings suggest the virus is present at extremely low quantities, is abortively replicating, or is latent.

Trilateral tumors in four different lines of transgenic mice expressing SV40 T-antigen.

PURPOSE: A line of transgenic mice containing the simian virus (SV) 40 T-antigen (T-ag) gene driven by the beta-luteinizing hormone (BLH) promoter developed bilateral retinoblastoma and primitive neuroectodermal tumors (PNET) of the midbrain. Midbrain tumors arose from the subependymal layer of the cerebral aqueduct. Bilateral ocular and brain tumors ("trilateral") were found in three other SV40 T-ag transgenic murine lines containing different promoters (murine interphotoreceptor retinoid-binding protein (IRBP), human IRBP, and alpha A-crystallin). To gain insight into the regulatory mechanisms involved in central nervous system tumorigenesis, the authors examined brain tumors from four lines of SV40 T-ag mice with different promoters. METHODS: Formalin-fixed brain tumors were examined from four lines of transgenic mice containing different promoters linked to the protein coding region of the enhancerless SV40 T-ag oncogene. Transgenes contained the following promoters: BLH, mouse 1.8-kb IRBP, human 1.3-kb IRBP, and alpha A-crystallin. RESULTS: Mice with a 1.8-kb IRBP promoter develop retinal photoreceptor and pineal tumors. Intracranial tumors arising from the subependymal layer of the third ventricle also were observed. Mice with a 1.3-kb IRBP promoter exhibit bilateral retinal PNET and PNET originating from the subependymal layer of the third ventricle. Mice with the alpha A-crystallin promoter exhibit bilateral lens tumors and PNET of the midbrain. CONCLUSIONS: Ocular tumors in these mice may be ascribed to the promoter-driven, tissue-specific expression of SV40 T-ag. The common finding of PNET arising from the subependymal layer of the diencephalon is unlikely to be promoter related. These findings indicate that a regulatory region specific to the subependymal layer of the cerebral aqueduct and third ventricle resides in the structural region of the SV40 T-ag gene.

Fibrous histiocytoma of the orbit. A clinicopathologic study of 150 cases.

This is a clinicopathologic study of 150 cases of fibrous histiocytoma of the orbit. The tumors occurred in adults (median age, 43 years). The upper and nasal portions of the orbit were the most common sites of involvement. The most common signs and symptoms were proptosis (60 per cent), mass (46 per cent), and decreased vision (25 per cent). Based on the histopathologic features, the tumors were classified in three groups: benign (94 cases), locally aggressive (39 cases), and malignant (17 cases). The biological behavior correlated well with the duration of symptoms, the size and margins of the mass, and the histologic classification. The rate of recurrence was 31 per cent for the benign tumors, 57 per cent for the locally aggressive tumors, and 64 per cent for the malignant tumors. Follow-up data were obtained for 123 patients, with a mean duration of seven years. The ten-year survival of patients with benign, locally aggressive, and malignant fibrous histiocytoma was 100 per cent, 92 per cent, and 23 per cent, respectively. Nine patients died as a result of the tumor, six from local invasion of adjacent structures and three from metastatic disease. Fibrous histiocytoma is the most common primary mesenchymal orbital tumor of adults. The origin of the neoplasm is probably a primitive mesenchymal cell. Complete surgical excision appears to be the treatment of choice.

Adenoid cystic carcinoma of the lacrimal gland: the clinical significance of a basaloid histologic pattern.

The authors reviewed 74 adenoid cystic carcinomas of the lacrimal gland, 54 of which had sufficient follow-up data for analysis of survival. Patients with a basaloid pattern in their tumor had a five-year survival rate of 21 per cent and a median survival of three years, whereas patients whose tumor contained no trace of a basaloid component had a five-year survival rate of 71 per cent and a median survival rate of eight years. Nonparametric statistical analysis revealed that this difference in survival was significant at the 0.0005 level. The authors propose that, in the future, pathologists label all adenoid cystic carcinomas as either "basaloid" or "nonbasaloid" and code each case accordingly.

Hemangiopericytoma of the orbit: a clinicopathologic study of 30 cases.

The clinical and pathologic features of 30 orbital hemangiopericytomas were reviewed. An effort was made to determine the clincopathologic characteristics that may correlate with the biologic behavior. Histopathologic criteria evaluated included degree of cellularity, nuclear atypia, mitotic activity, tumor size, and the presence of hemorrhage and necrosis. Histopathologically, 16 tumors were classified as benign, five as borderline, and nine as malignant. Follow-up information was obtained in 27 cases (mean duration of follow-up period was five and one-half years). Eight tumors recurred (30 per cent). Five patients died, four with widespread metastases (15 per cent) and one of unrelated causes. Tumors that recurred or metastasized were distributed among all three histologic groups. The interval between the onset of symptoms and metastasis for three of the four lethal tumors was 31 years, 28 years, and 8 1/2 years; in the fourth case it was unknown. For the entire series, the five-year actuarial survival rate was 89 per cent. Although the number of cases is too small to serve as a basis for firm conclusions, the lack of unequivocal correlation between the histologic features and clinical behavior is consistent with the unpredictable behavior of this neoplasm, as concluded by other investigators. Because of the apparent circumscription of most of these tumors, complete surgical excision rather than exenteration is recommended. Metastasis usually develops late in the clinical course of the disease, indicating that long-term follow-up studies are required before a cure can be assumed.

Alveolar soft-part sarcoma of the orbit: a clinicopathologic analysis of seventeen cases and a review of the literature.

This is a clinicopathologic study of 17 cases of alveolar soft-part sarcoma of the orbit. The mean age of patients was 23 and the median was 18 (range, 11 months to 69 years); 13 patients (76.5 per cent) were women and four were men (ratio, 3.25:1). The right and left orbits were equally involved (eight patients each), and in one the laterality was not specified. Histologically, the tumors had a distinctive organoid pattern outlined by thin-walled capillaries and were composed of nests of large polyhedral cells with abundant, finely granular, acidophilic cytoplasm. Approximately two thirds of the tumors had diagnostic PAS-positive diastase-resistant crystalline structures. Histologically, the differential diagnosis included nonchromaffin paraganglioma, granular cell tumor, metastatic renal cell carcinoma, vascular tumor, alveolar rhabdomyosarcoma, and amelanotic malignant melanoma. Electron microscopic studies of one tumor disclosed mitochondria with abnormal cristae, increased amounts of glycogen, and cytoplasmic crystalline structures with a periodicity of 8 to 10 nm. Smaller membrane-bound electron-dense granules appeared to be precursors of the crystals. Follow-up studies showed that eight patients were alive and well (median follow-up period, 11.4 years). Six of the eight patients at the time of diagnosis were 20 years of age or younger. A ninth patient was alive and well 13 years after excision of the orbital mass and four years after bilateral thoracotomy with resection of nine pulmonary nodules. Two patients died as a result of metastatic disease, one 14 years and the other 21 years after initial orbital surgery. Two patients died of other causes, one of whom had pulmonary metastases at autopsy. The follow-up period on two recent cases was less than three years, and two patients were lost to follow-up. The disease pursued an indolent clinical course. Surgery offers the best chance to control the disease.

Carcinoid tumors of the eye and orbit: a clinicopathologic study of 15 cases, with histochemical and electron microscopic observations.

This clinicopathologic study includes 15 cases of carcinoid tumors of the eye and orbit. The patients ranged in age from 14 to 86 years (median, 53). No prediction for either gender was found. Seven tumors involved the orbit, seven the choroid, and one the iris. The primary site of origin of the carcinoid tumor was known in 12 cases: seven in the bronchus, one in the trachea, and four in the ileum. In three cases an orbital tumor was present but no other known primary neoplasm was clinically apparent. The postoperative follow-up period ranged from 0 to 4 years. The urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) were elevated in four of ten patients tested, each of whom had a known primary tumor and two of whom had clinical evidence of the carcinoid syndrome. Four main histologic patterns were recognized: pattern A (solid lobules or masses), pattern B (trabecular or cord-like), pattern C (tubular or rosette-like) and pattern D (mixed). The apparently primary carcinoid tumors and the orbital or ocular metastases were closely related by their histologic patterns, histochemical staining characteristics, and ultrastructural features.

Hemangioblastomas: histogenesis of the stromal cell studied by immunocytochemistry.

Twenty-one cases of hemangioblastoma from the cerebellum, spinal cord and retina were studied using the unlabeled antibody peroxidase-antiperoxidase technique with antibodies directed against glial fibrillary acidic protein (GFAP) and factor VIII related antigen (VIIIR:Ag). In 19 of 21 cases studied with anti-GFAP, astrocytes were identified peripherally, and in 13 cases they were found centrally within the tumor. In no instance did stromal cells react positively for GFAP. Sixteen cases with anti-VIIIR:Ag antibody were examined, and in all cases many stromal cells showed positive staining. It is concluded that the stromal cells were of endothelial origin. The occasional stromal cells that other investigators have identified as reacting positively for GFAP may represent stromal cells capable of ingesting extracellular GFAP derived from reactive astrocytes within the tumor, or they may be lipidized astrocytes.

Sebaceous gland carcinoma of the eyelid.

A 37-year old woman had received multiple radiation treatments between the ages of 6 months and 15 years for an extensive cavernous hemangioma of the left side of the face. At the age of 27 years, a biopsy specimen from a lesion of the left buccal commissure disclosed squamous cell carcinoma arising in chronic radiodermatitis. Multiple cutaneous lesions were excised surgically, and extensive skin grafting of the left side of the face was performed. At the age of 35, she developed a tumor of the left upper and lower eyelids that extended into the orbit, which proved to be a sebaceous gland carcinoma. Following left orbital exenteration, the tumor promptly recurred in the socket. The patient died with widespread metastatic lesions nine months after exenteration. This case, which, to our knowledge, represents the fourth example of postradiation sebaceous gland carcinoma of the eyelids, differs from the previously reported cases in that the radiation therapy had been given for a benign cutaneous condition.

Plasmacytic conjunctivitis with crystalline inclusions. Immunohistochemical and ultrastructural studies.

A 17-year-old girl had bilateral papillary conjunctivitis. Histologically, the lesion showed mature plasmacytes, plasmacytoid cells, and large mononuclear cells that exhibited myriad intracytoplasmic crystals. Electron microscopic studies disclosed that the large mononuclear cells, which showed plasmacytic differentiation, contained numerous crystalline inclusions. The crystals were formed within the rough-surfaced endoplasmic reticulum and exhibited a regular periodicity (8 nm). Histochemical methods disclosed that the composition of the crystals was mainly protein (immunoglobulin crystals). Immunoperoxidase techniques for demonstration of immunoglobulins showed that the crystalline inclusions contained IgG. The results of immunohistochemical findings correlated with the results of immunoelectrophoresis of the patient's serum.

Trichilemmoma of eyelid and eyebrow. A clinicopathologic study of 31 cases.

Thirty-one cases of trichilemmoma of the eyelid and eyebrow were studied. All lesions were solitary, small, and asymptomatic. Unlike basal cell carcinoma of the eyelid, trichilemmoma rarely involves the lid margin or the inner canthus. The age range of our patients was from 22 to 88 years old (mean, 56 years). There were 19 men and 12 women. The most frequent clinical diagnoses were verruca vulgaris and cutaneous horn. Typically, the tumor displayed a lobular pattern and was composed mostly of glycogen-rich clear cells. The periphery of the lobules showed palisading of columnar cells and a distinct basement membrane. Histologically, the tumor was frequently misinterpreted as basal cell carcinoma. Review of the literature, including our own series, discloses that the eyelid is the second most common site for trichilemmoma after the nose.

Large cell lymphoma of the orbit with microvillous projections ('porcupine lymphoma').

A 57-year-old man had a diffuse mass in the lacrimal gland area associated with extensive bony destruction. A malignant epithelial tumor of the lacrimal gland was suspected clinically, and a biopsy specimen disclosed an undifferentiated malignant neoplasm of uncertain origin. Ultrastructural studies, however, revealed features of a lymphoid tumor with myriad cytoplasmic microvillous projections. The patient has had no evidence of systemic lymphoma after more than three years of follow-up. To our knowledge, this is the first report of orbital involvement of a large cell lymphoma with microvillous projections ("porcupine lymphoma"). The role of electron microscopy in the differential diagnosis of this orbital tumor was important, since epithelial tumors of the lacrimal gland are best managed by surgical excision, whereas lymphoid tumors usually respond satisfactorily to radiotherapy.

Intravenous pyogenic granuloma of the ocular adnexa. Report of two cases and review of the literature.

Intravenous pyogenic granuloma is a recently described form of pyogenic granuloma (PG) in which the angiomatous proliferation is confined entirely within the lumen of a vein. To our knowledge, only four cases involving the ocular adnexa, including two that we encountered, have been described. Histologically, this benign lesion is similar to PG of other locations and is characterized by lobular congeries of capillaries embedded in a fibromyxoid matrix containing scattered chronic inflammatory cells. The whole lesion appears as a single polypoid mass projecting into the lumen of a dilated vein. The histogenesis of this lesion remains obscure. Complete local excision is the treatment of choice. Intravenous PG can be differentiated from other intravascular fibroangiomatous proliferations, including intravascular papillary endothelial hyperplasia, intravenous atypical vascular proliferation, intravascular fasciitis, and organized thrombus.

Diffuse toxoplasmic retinochoroiditis in a patient with AIDS.

Ocular toxoplasmosis typically presents as a focal necrotizing retinochoroiditis. We report a case of diffuse necrotizing retinochoroiditis due to toxoplasmosis in a patient with the acquired immunodeficiency syndrome (AIDS). The appearance at initial presentation was similar to the acute retinal necrosis syndrome. We recommend that toxoplasmosis be considered in the differential diagnosis of diffuse retinal necrosis in patients with AIDS. Although systemic disseminated toxoplasmosis is not rare in AIDS, this is, to our knowledge, the first reported case of diffuse ocular involvement.

Botryomycosis of limbal conjunctiva with Splendore-Hoeppli phenomenon.

An 84-year-old man complained of irritation of the left eye of several months' duration. He had had several previous surgical procedures including removal of bilateral pterygia and bilateral cataract extraction. Examination of the bulbar conjunctiva on the left eye disclosed a collection of cilia (eyelashes) located adjacent to the limbus at the 11:30-o'clock position. This aggregate of cilia was associated with irregular yellowish deposits 1.5 mm in diameter. The cilia and redundant conjunctival tissues were surgically excised. Histopathologic examination showed a botryomycotic granule surrounded by a prominent acidophilic ring (Splendore-Hoeppli phenomenon). Gram stains demonstrated the presence of microcolonies of gram-positive cocci and gram-negative rods within the granule. We postulate that the entrapment of displaced cilia provided a nidus for the bacterial colonization forming the botryomycotic granule. To our knowledge, botryomycosis of the conjunctiva has not been reported previously.