Choroidal Neovascular Membranes in Retinal and Choroidal Tumors: Origins, Mechanisms, and Effects.

Choroidal neovascularizations are historically associated with exudative macular degeneration, nonetheless, they have been observed in nevus, melanoma, osteoma, and hemangioma involving the choroid and retina. This review aimed to elucidate the possible origins of neovascular membranes by examining in vivo and in vitro models compared to real clinical cases. Among the several potential mechanisms examined, particular attention was paid to histologic alterations and molecular cascades. Physical or biochemical resistance to vascular invasion from the choroid offered by Bruch's membrane, the role of fibroblast growth factor 2 and vascular endothelial growth factor, resident or recruited stem-like/progenitor cells, and other angiogenic promoters were taken into account. Even if the exact mechanisms are still partially obscure, experimental models are progressively enhancing our understanding of neovascularization etiology. Choroidal neovascularization (CNV) over melanoma, osteoma, and other tumors is not rare and is not contraindicative of malignancy as previously believed. In addition, CNV may represent a late complication of either benign or malignant choroidal tumors, stressing the importance of a long follow-up.

Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature.

BACKGROUND: Multiple miliary osteoma cutis (MMOC) is a rare nodular skin disease characterized by tiny bone nodules which usually form on the facial skin, typically in middle age. The aetiology of this phenomenon is poorly understood. OBJECTIVES: To search for possible bone formation progenitors and to look for a possible association with mutations in the GNAS gene (encoding the G-protein α-stimulatory subunit) and related hormonal parameters in patients with MMOC. We also reviewed the literature and discuss the aetiology and pathogenesis of adult-onset primary osteomas. METHODS: We report four cases of MMOC. Histological samples were analysed for bone morphogenetic protein (BMP)-2, BMP-4 and oestrogen receptor-α known to be involved in bone formation. Endocrinological laboratory investigations and hand X-rays were performed to exclude a systemic disease. The GNAS gene was sequenced from DNA extracted from peripheral blood in all four patients and from a skin sample in one patient to exclude somatic mutations. RESULTS: Histological analyses revealed intramembranous cutaneous bone formation resembling the findings seen in GNAS gene-based osteoma cutis disorders. However, we did not find any germline or somatic GNAS gene mutations in our patients and all laboratory investigations gave normal results. BMP-2 and -4 were expressed normally in MMOC samples, but oestrogen receptor-α was not expressed. Altogether 47 MMOC cases, 41 female and six male, have been published between 1928 and 2009. Of these cases, 55% had a history of pre-existing acne and only 15% had extrafacial osteomas. CONCLUSIONS: MMOC is a rare but distinct disease entity of unknown aetiology. Histologically, the tiny nodular osteomas show intramembranous superficial ossification but the aetiology appears to be different from GNAS-related disorders. The osteomas seem to increase slowly in number after appearing in middle age.

[Specific features of mineral and protein metabolism in patients with paranasal osteoma].

A comparative analysis of biochemical blood picture was made in 20 patients with osteoma of the paranasal sinuses before and after surgical treatment. A total of 17 tests characterizing metabolism and 680 biochemical examinations were made. Investigation of mineral and other kinds of metabolism may be important in diagnosis of osteomas, hyperostosis, exostosis and malignant tumors, determination of activity and tumor growth rate.

Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy.

It is generally accepted that oxygen has a limited ability to diffuse into solid tumor masses. However, the question of the ability of chemotherapy agents to penetrate solid tumor masses has not been evaluated. This clearly would have an impact on the ability of chemotherapy to control microscopic disease during the "avascular" phase of growth. An attempt was made to evaluate the ability of methotrexate to penetrate solid tumor masses when grown in three dimensions (spheroids). Since methotrexate is used in the clinical management of human osteosarcoma, we chose this drug-tumor combination for our studies. This was done by growing human osteosarcoma cells into spheroids and exposing spheroids of various sizes to tritiated methotrexate. Audioradiographs were obtained from sections through the center of spheroids of various sizes. Our findings suggest that methotrexate has a limited ability to penetrate into avascular tumor masses when grown in three dimensions. This is most evident when the tumor masses are approximately 250 micron and larger in diameter. In addition, we compared the degree of penetration of methotrexate to the growth fraction of the tumor, as measured by tritiated thymidine, and found that the growth fraction was much greater than the fraction of cells reached by methotrexate. We conclude that the limited ability of methotrexate to penetrate solid tumor masses offers an alternative explanation for the limited effectiveness of methotrexate when used as an adjuvant for osteosarcoma. We question whether the established biochemical mechanisms for methotrexate resistance are comprehensive explanations for its limited clinical effectiveness.

Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton.

The products of c-fos and c-jun proto-oncogenes form the heterodimeric complex AP-1 (activator protein 1), which play an important part in the control of bone cell proliferation and differentiation and in the development of bone tumours. We examined the expression of c-fos and c-jun in a series of 52 primary skeletal neoplasms, using an immunohistochemical method on formalin-fixed, paraffin-embedded sections. The expression of c-fos and c-jun was restricted to bone-forming lesions, while cartilaginous tumours were devoid of immunoreactivity. In benign osteoblastic lesions moderate c-fos and c-jun expression was found in 2 cases (18.1%). The highest levels of c-fos and c-jun expression were detected in high-grade central osteosarcomas (7 of 15 cases with moderate/diffuse expression) while 1 telangiectatic osteosarcoma, 2 low-grade central osteosarcomas, 1 low-grade periosteal osteosarcoma and 7 low-grade parosteal osteosarcomas were either negative or had low expression. The high-grade component of a dedifferentiated parosteal osteosarcoma showed diffuse immunoreactivity for both oncoproteins. Comparison of c-fos and c-jun expression by histological grade showed that high-grade osteosarcomas had a significantly higher expression of both oncoproteins than did low-grade osteosarcomas (P = 0.01, Fisher's exact test). Thus, c-fos and c-jun overexpression may be implicated in the development of high-grade osteosarcomas, but they appear to have little or no relevance for the development of low-grade osteosarcomas and cartilaginous skeletal neoplasms.

CD138 (syndecan-1) expression in bone-forming tumors.

CD138 (syndecan-1), a cell surface proteoglycan, is sensitive and specific for plasmacytic differentiation in hematologic disorders. Expression of CD138 has been observed in a majority of epithelial neoplasms and, rarely, soft tissue tumors. However, its expression in bone tumors has not been evaluated. We studied CD138 expression in 27 osteosarcomas, 12 benign bone-forming tumors (osteoid osteoma and osteoblastoma), and 17 reactive bone cases. CD138 expression was also evaluated in a tissue microarray (TMA) constructed from 24 osteosarcomas, 24 chondrosarcomas, 12 giant cell tumors of bone, and 9 normal bone samples. Membranous expression of CD138 was found in an average of 31% of osteosarcoma cases (16/51; 14/27 [52%] in in-house cases; 2/24 [8%] in TMA cases) and in 83% of osteoid osteoma/osteoblastoma cases (10/12). Subsequent immunoglobulin κ and λ stains were negative in the CD138+ cases. All cases of chondrosarcoma, giant cell tumor of bone, and normal/reactive bone tested were nonreactive with anti-CD138. Our results show that CD138 reactivity for neoplastic cells in bone is not a definitive marker for plasmacytic origin, and caution is required to interpret CD138+ cells from a bony lesion for which a hematologic etiology has not been established.

Spontaneous decalcification of a choroidal osteoma.

A 23-year-old woman presented with a clearly defined, pale orange choroidal tumor superior to the right optic disc in 1976. The patient was followed. After a choroidal osteoma was first reported in 1977, this diagnosis was confirmed in this patient using ultrasonography and orbital tomography. The lesion grew very slowly over the next 5 years. In 1981, the choroidal osteoma began to thin and decalcify. Subretinal neovascularization developed in 1982 and was treated with argon laser photocoagulation. In 1983, the tumor was thinner and less calcified. During the next 18 months, it became completely decalcified and essentially disappeared leaving only a bed of pigment epithelial and choriocapillaris atrophy. This was confirmed with fluorescein angiography and ultrasonography.

A study of bone formation in osteoma cutis employing biochemical, histochemical and in situ hybridization techniques.

A female presenting multiple osteoma cutis lesions without underlying endocrinological disturbance was studied. Histologically, lesions revealed true bone formation with multiple osteoblastic cells. This was confirmed by demonstrating high alkaline phosphatase activity and osteonectin expression in osteoma cutis lesions. Interestingly, tenascin and type III procollagen were in close association to bony lesions, indicating that these matrix proteins may be somehow involved in bone formation. In situ hybridization revealed fibroblastic cells around bony lesions, which actively deposited type I collagen and osteonectin. One of the activators of bone formation, TGF beta, was also present in some osteoblastic cells. The results thus indicate that in osteoma cutis, fibroblasts have the ability to differentiate into osteoblastic cells, which have some properties of osteoblasts, such as high alkaline phosphatase activity and a high expression of osteonectin.

Tumor-induced osteomalacia: long-term follow-up of two patients cured by removal of their tumors.

Two patients with mesenchymal tumors had osteomalacia associated with marked hypophosphatemia and renal phosphate wasting. Their serum calcium and parathyroid hormone levels were normal. The first patient also had aminoaciduria and glucosuria in addition to phosphaturia. Both patients were treated with very large doses of vitamin D2 and phosphate without improvement in the osteomalacia or normalization of the serum phosphate. Complete removal of a low-grade fibrosarcoma in the second patient and removal of an ossifying fibroma in the first patient resulted in a cure in both patients despite no further therapy with vitamin D or phosphate. The excessive aminoaciduria and glucosuria of the first patient also remitted. During a 14-year follow-up period, there has been no evidence of tumor recurrence, hypophosphatemia, or osteomalacia in either patient. The levels of 1,25-dihydroxycholecalciferol remain within the normal range in both patients.