Heterotransplantation of human choroidal melanoma into the athymic "nude" mouse.

The investigation of the structure and behavior of malignant melanoma of the uveal tract in man has been limited by the lack of a ready source of human tumor and an animal model in which the tumor resembles that in the human choroid. We now report the observation that fresh surgical specimens of human choroidal melanoma can be successfully transplanted into the posterior segment of the "nude" mouse (a homozygous mutant, nu/nu, with a defect in cellular immunity) and can be serially transplanted. This model utilizing human melanoma should be useful for the study of the natural history of this disease, as well as the response to various chemotherapeutic agents.

Vascular basophilia in ocular and orbital tumors.

The occurrence of vascular basophilia in ocular tumors has been a selective histologic feature of retinoblastomas. We recently observed a metastatic oat-cell carcinoma to the choroid which also demonstrated such a vascular hematoxyphilia. Histologic review of a variety of ocular and orbital metastatic carcinomas failed to yield a similar basophilic pattern. Examination of 100 consecutive retinoblastomas for vascular basophilia revealed an incidence of 6.0%. Similar material was not seen in any of 125 melanomas, including 10 with areas of necrosis. Histochemical studies showed the basophilic material to be DNA, and electron microscopy revealed the nuclear debris of pyknotic tumor cells to be continuous with identical material surrounding the adjacent blood vessels. The pathogenesis of vascular deposition of DNA in these two ocular tumors remains unclear. This finding most likely represents a form of tumor activity requiring comparatively healthy blood vessels to adequately precipitate liberated nucleic acids being filtered from the necrotic and degenerating tumor tissue.

Effect of dicarboxylic acids (C6 and C9) on human choroidal melanoma in cell culture.

In cell culture, azelaic acid (C9) has been shown to have an antiproliferative and cytotoxic effect on human and murine malignant cutaneous melanocytes. Normal melanocytes are unaffected, as are normal choroidal melanocytes. Here, effects on cell kinetics and ultrastructure of cells of a human choroidal melanoma line have been studied. Cells were exposed to single doses of disodium salts of azelaic (C(9)2Na) and adipic (C(6)2Na) acids at concentrations of 10(-2) M and 5 X 10(-2) M for 48 hr. C(9)2Na at 5 X 10(-2) M had a significant effect on proliferation at 24 and 48 hr and this was not reversible on removal of diacid. At 5 X 10(-2) M for 24 hr, C(6)2Na had no effect and at 5 X 10(-2) M for 48 hr had an effect which was marginally significant, but reversible. Swelling and disruption of mitochondria was seen in cells exposed to C(9)2Na at 5 X 10(-2) M for 1 hr and longer, but even at 10(-1) M, cells exposed to C(6)2Na were minimally affected. The results could encourage further investigations of the feasibility of azelaic acid therapy for uveal and ocular adnexal melanoma.

Intraocular hemangiopericytoma.

A 40-year-old woman had an intraocular lesion consistent with a choroidal hemangioma. Xenon arc photocoagulation was applied to reduce subretinal fluid, and the lesion remained stationary until the patient's death eight years later. The lesion was composed of spindle-shaped and ovoid cells with numerous inconspicuous capillaries. The tumor cells were surrounded by reticulin-positive fibers. The diagnosis of hemangiopericytoma was confirmed by electron microscopy, which demonstrated proliferating pericytes associated with basal lamina. Although hemangiopericytomas are occasionally found in the orbit, to our knowledge this report is the first of an intraocular hemangiopericytoma. Because the pericyte is an integral component of the choroidal vasculature, the origin of this tumor in the choroid is not unexpected. The diagnosis of hemangiopericytoma should be considered when evaluating vascular choroidal lesions.

Multifocal choroidal melanoma in ocular melanocytosis.

A 29-year-old white women had ocular melanocytosis with scleral pigmentation and a diffuse choroidal nevus. The eye was enucleated because of two choroidal tumors. Light and electron microscopy showed two separate choroidal melanomas with differential cytologic characteristics. The extreme rarity of multicentric choroidal melanomas support the belief that ocular melanocytosis predisposes to malignancy.

Ovoid bodies in choroidal neurofibromatosis.

We studied the ultrastructure of the ovoid bodies in choroidal neurofibromatosis. Ovoid bodies consisted of groups of the same kind of elongated cells arranged in lamellar patterns. The elongated cell was characterized by a fragmented circumferential basal lamina, groups of pinocytotic vesicles, a desmosomelike intercellular contact, and intimate contact with axons. These findings suggest that elongated cells are proliferated Schwann's cells and ovoid bodies do not correspond with real sensory nerve end organs; rather, they are enlarged peripheral nerves due to neoplastic hyperplasia of Schwann's cells around axons.

Heterotopic smooth muscle in the choroid of two patients with cryptophthalmos.

The mode of inheritance in the complete cryptophthalmic syndrome is not clear in all cases. In two of our patients with complete cryptophthalmos, one showed a probable autosomal-recessive inheritance, while in the other patient, the mode of transmission could not be determined. Light and electron microscopic studies of the globes demonstrated heterotopic smooth-muscle tissue in the anterior part of the choroid in these two patients. Although these findings might be explained on the basis of a lack of directional growth of the embryonic ciliary muscle cells during the early embryonic period, we favor a simple anatomical explanation based on differentiation arrest of the anterior segment. During the fourth month of gestation, the growing optic cup presumably fails to advance forward normally and to differentiate. The relatively normally developing posterior segment extends posteriorly. The "stretching" backward of the ora serrata during the seventh month of gestation "drags" with it the ciliary smooth muscle that did not advance forward due to the earlier arrest. Thus, in the definite cryptophthalmic eye, the smooth-muscle tissue is localized within the anterior choroid.

Vessels of intraocular malignant melanomas.

The vessel walls of six malignant choroidal melanomas were thin; only thin basal membranes and narrow endothelial linings could be observed with the electron microscope. The endothelium was even absent in some places. Tumor cells were released into the bloodstream through disruptions of the vessel walls in the epithelioid and spindle cell B type tumors.

Bilateral choroidal neonatal neuroblastoma.

We treated a bilateral, well-differentiated neuroblastoma of the choroid in a patient who had congenital abdominal neuroblastoma. Although orbital metastasis of neuroblastoma is common, intraocular metastasis is not. In our patient, there was no amplification of the N-myc oncogene in the tumor of either eye. This is consistent with early-stage primary neuroblastoma. Histologically, the tumors were identical in each eye and well differentiated with Homer Wright rosettes; most neuroblastoma metastases have few rosettes and are composed of more undifferentiated, anaplastic cells. We believe that our patient had bilateral primary tumors and not metastatic tumors.

Macular edema and cystoid macular edema.

We examined the foveomacular regions from three eyes in which fluorescein angiography had demonstrated the characteristic appearance of cystoid macular edema by light and electron microscopy. Cystoid macular edema was present in two eyes (one of which was from a 63-year-old diabetic man) that contained peripheral choroidal melanomas, and in a third eye from a patient with diabetes only. By light microscopy, cystoid macular degeneration was obvious only in the third eye. The electron microscopic findings common to all three eyes were widespread swelling and necrosis of Müller cell cytoplasm. There was no enlargement of intercellular spaces. There was secondary neuronal degeneration. Retinal vascular changes, consisting mainly of endothelial cell abnormalities, were found in all cases but were far more common in the two eyes from diabetic patients. The retinal vascular changes were probably the cause of the cystoid macular edema.

The effect of rapid freezing on uveal melanomas.

We studied the immediate effects of rapid freezing on 19 variously sized uveal melanomas that were subjected to cryoenucleation using liquid nitrogen and a cryoring by light and electron microscopy and tissue culture. The freezing time and the temperature of 11 lesions were recorded. The light microscopic finding of an intranuclear clear center with peripheral displacement of clumped chromatin against the nuclear membrane was suggestive of intranuclear ice crystal formation but did not indicate cellular death of the tumors. The major ultrastructural changes, including plasmalemmal breaks, dissolution of cytoplasmic matrix, and damage to various organelles, however, suggested acute necrosis in tumors not exceeding 7 mm in elevation. Failure of the melanoma cells to grow in tissue culture and positive staining with trypan blue support the contention of tumor death. The late effects of rapid freezing were also evaluated in another case of uveal melanoma. The eye was enucleated six months after cryopexy. Histopathologic findings showed that the tumor was necrotic. Failure of the neoplasm to regress (noted clinically) was related to edema and inflammatory infiltrates.

Retinal ultrastructural findings in cone degeneration.

We studied an eye from a 73-year-old man with a sporadic type of retinal cone degeneration and choroidal melanoma. Histologic and ultrastructural studies of the nasal retina unaffected by the choroidal melanoma showed alterations at the outer retina predominantly involving the photoreceptors and retinal pigment epithelium. A wide spectrum of pathologic changes were observed, ranging from near normal retina showing only photoreceptor outer segment disease (distortion and kinking) to grossly pathologic regions where photoreceptor cell bodies were sparse and their outer segments absent. The retinal pigment epithelium in minimally affected regions of the retina showed an increased proportion of the melanin complement of the cell within complex granules. In severe disease, many cells showed only giant complex granules with no free melanin. Retinal pigment epithelial cell migration and relocation around blood vessels was also noted in severe disease.

An ultrastructural study of melanocytomas (magnocellular nevi) of the optic disk and uvea.

We examined by light and electron microscopy five melanocytomas from four patients. Two types of cells were observed in each tumor. The predominant cell type in most of the tumors studied consisted of plump polyhedral nevus cells that contained numerous giant melanosomes. These cells showed advanced differentiation. They appeared to be metabolically inactive and to have been the cause of the heavy pigmentation and benign nature of these tumors. The second variant of melanocytoma cells were smaller spindle-shaped cells that were lightly pigmented. Other morphologic features of these cells such as high nucleus-cytoplasm ratio, prominent nucleolus, nuclear membrane infolding, numerous mitochondria, prominent rough endoplasmic reticulum, and free ribosomes, indicated a metabolically active cell, which may explain the infiltrating behavior of these tumors.

Congenital fibrosarcoma metastatic to the choroid.

A 2 1/2-year-old boy developed a choroidal metastasis from a congenital fibrosarcoma of the lower left limb that had been amputated shortly after birth. To our knowledge this is the first reported case of a congenital fibrosarcoma that metastasized to the choroid.

Balloon cell malignant melanoma of the choroid: ultrastructural studies.

I reported the clinical, pathological, and ultrastructural findings in 2 cases of balloon cell malignant melanoma of the choroid. Degradation of the melanosomes of the tumour cells appeared to be the primary biological disturbance in the cell organelles, followed by secondary increase in intracellular lipid secretion and accumulation, leading ultimately to the formation of the balloon cells. Despite the fact that balloon cells are indicative of degeneracy and impending necrosis of the tumour cells, metastases were present in both cases. One of the conclusions this article provides is that the presence of balloon cells does not alter the prognosis of malignant melanomas of the choroid.

Orbital squamous cell carcinoma after retinal detachment surgery.

We report on a 76-year-old patient with a squamous cell carcinoma of the left orbit. The tumour had no connection with the conjunctiva but was located at the site of an encircling band which had been inserted 13 years before. A major part of the tumour presented as a well circumscribed solid mass within the extraocular tissues next to the inferior equator, but the exenteration specimen also showed tumour extension within the adjacent choroid. Histological examination showed a well differentiated keratinising squamous cell carcinoma with numerous mitotic figures and many epithelial pearls. A thorough examination in search of a primary carcinoma of the lacrimal gland or the sinus, with invasion into the orbit, or an epithelial neoplasm elsewhere suggestive of metastatic disease into the choroid did not reveal any specific pathological findings. Thus the most probable origin of the tumour seems to be epithelium which had been misplaced during retinal detachment surgery and had subsequently undergone malignant transformation.

Contractile protein antigens in the cells of malignant melanoma of the choroid and their diagnostic significance.

Sera from patients with proved and suspected melanoma of the uvea and from patients with innocuous uveal naevi were found by immunohistological techniques to have an affinity for the cytoplasm of malignant choroidal melanoma cells in an appreciable proportion of cases. The responsible antibodies were subsequently shown to react with smooth muscle protein in a variety of tissues and not to be melanoma-specific. It was also shown by electron microscopy that microfilaments consistent with contractile protein are a feature of the cytoplasm of malignant choroidal melanoma cells. The latter observations, which do not appear to have been reported previously, mean that false positives are to be expected if immunodiagnostic techniques are used for the recognition of malignant disease of the uvea, especially as smooth muscle antibodies can occur in non-neoplastic ocular diseases.

Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study.

AIMS: To describe the clinical and histopathological findings in a patient with polypoidal choroidal vasculopathy. METHODS: A 76 year old Japanese man had a discrete, orange-red lesion of 1 disc diameter in the macula, with the fluorescein and indocyanine green angiographic and optical coherence tomographic findings compatible with polypoidal choroidal vasculopathy. He underwent a surgical removal of the macular lesion, followed by light and electron microscopic examinations. RESULTS: The histopathological examination revealed that the specimen consisted of degenerated retinal pigment epithelium-Bruch's membrane-choriocapillaris complex and inner choroid. A tortuous, unusually dilated venule was present adjacent to an arteriole with marked sclerotic changes, appearing to form arteriovenous crossing. These vessels seemed to represent native inner choroidal vessels, and had haemorrhage per diapedesis. Blood cells and fibrin filled the lumina of the vessels and accumulated in the extravascular spaces, indicating vascular stasis. CONCLUSION: Hyperpermeability and haemorrhage due to stasis of a dilated venule and an arteriole involved by sclerosis at the site where they cross in the inner choroid might cause oedema and degeneration of the tissue. Voluminous accumulation of blood cells and fibrin might generate elevation of tissue pressure sufficient to displace the weakened lesion anteriorly. The result suggests that the polypoidal vessels in this case represent abnormality in the inner choroidal vasculature.

Convolution in human rods: an ageing process.

In a morphological survey of 73 human retinae spanning 9 decades, and including 20 retinae which were obtained from eyes enucleated for malignant melanomas, nodular excrescences were noted in the outer segments of rods with an incidence which increased with age. These structures were sectioned in both their vertical and horizontal axes and on electron microscopical examination were seen to result from the localised convolution of affected outer segments. The topographic morphology of such convolutions is described and their modes of formation are discussed.

Possibilities and limitations of radioimmunoscintigraphy and conventional diagnostic modalities in choroidal melanoma.

A prospective clinical study to assess the value of immunoscintigraphy with a monoclonal antibody (MoAb) against high molecular weight melanoma associated antigen (225.28S) was performed in 43 patients with choroidal melanoma; in six patients with a lesion suspected of being choroidal melanoma, and in seven patients with a benign lesion simulating a choroidal melanoma. The results of immunoscintigraphy in choroidal melanoma were compared with results of conventional diagnostic modalities like ultrasonography and fluorescein angiography. Planar scintigraphy showed a detection rate of 49% which is comparable with other studies. The detection with scintigraphy was correlated to the size of the choroidal melanoma. The use of single photon computed tomography did not increase the sensitivity of immunoscintigraphy. Ultrasonography yielded a correct diagnosis in 37 of 42 melanomas (88%). With fluorescein angiography a correct diagnosis was obtained in 11 of 30 melanomas (36.6%). The value of immunoscintigraphy with MoAb 225.28S in small choroidal melanomas is limited; its reliability increases in large tumours. Immunohistochemistry with MoAb 225.28S showed antigen expression in 95% of the stained tissue specimens of choroidal melanoma.