Cystic angiomatosis is a rare disease characterized by multifocal bony cysts with a honeycombed appearance and thin-walled blood vessel proliferation with bone destruction. Bone trabecula under cortex is gradually replaced by hemangiomatous or lymph angiomatous tissue. The first decades of life, particular puberty, is one of the highest rates of cystic angiomatosis and adult older than 60 years of age may be the second peak of occurrence. The clinical symptom varies from accidentally found by radiograph to pathologic fracture or skeletal abnormalities of slowly progression, or rare severe visceral lymphangiomatosis, especially for lung, liver, or spleen. Radiograph imaging shows multifocal, skeletal intramedullary cysts, with a thinned and relatively well-preserved bony cortex and without peripheral soft tissue involvement and periosteal reaction.
The typical characteristics of cystic angiomatosis reveals multifocal intramedullary skeletal cysts with relatively well-preserved cortical bone without periosteal reaction and peripheral involvement of soft tissues in the lesion of bone, while metastasis, multiple myeloma, or other malignant disease are usually involved of peripheral or tissue reaction[3, 4]. Bone cysts are oriented along the long axis of the bone with a sclerotic peripheral ring. Cystic angiomatosis and Gorham-Stout disease (GSD) present the similar features in the destruction and resorption of bone[4, 8]. But, cystic angiomatosis shows the sclerotic appearance in the margin of cysts and sclerosing lesion rather than osteolysis in affected bone, which is the important performance in GSD. Most previous studies showed that GSD could lead to the progressive massive osteolysis resulting in cortical bone loss, and leading to severe deformations and disability, whereas there was medullary cavity without progress of disease in cystic angiomatosis. Thus, cystic angiomatosis usually has a better prognosis than GSD.
It is known that bone biopsy is the standard method in the treatment of cystic angiomatosis. However, those previous studies have usually reported that histological diagnosis is significantly difficult in some diseases and repeated bone biopsy was usually needed for final diagnosis. In our study, the first biopsy surgery was performed in other hospital and the lesion of lib and humerus was filled with bone fluid as result of undefined diagnosis regrettably. In the second bone biopsy, we found that fibrous connective tissue and dilated blood vessels with bleeding in the trabecular bone, the dilated lymphatic vessels with lymphocytes and cystic wall of endothelial lining. The cystic wall of endothelial lining was reported in most literatures[6, 11]. We considered that these were consecutive phases in development process of cystic angiomatosis as result of different histological result. Thus, we should evaluate the different radiological performance in the content of bone cystic before the bone biopsy.
There was an increase in ALP and bone marker osteoprotegerin, osteopenia, and interleukin-6 in cystic angiomatosis. In our case, ALP was 393U/L with the normal of 20–110 U/L, and VEGF was 287.26 pg/ml with the normal of 0-142 pg/ml. VEGF represents a growth factor with important pro-angiogenic activity and promote the vascular permeability and cell migration. Besides, VEGF and their endothelial tyrosine kinase receptors are involved of vasculogenesis, angiogenesis and lymphangiogenesis and VEGF signalling through VEGFR-2 could promote the angiogenic pathway. VEGFR1 and VEGFR2 is mainly focus on vascular endothelial cells, and VEGFR-3 is especially focus on lymphangiogenesis. Histological examination shows that the vessels of vascular or lymphangiomatous is involved of vascular endothelial growth factor (VEGF) and podoplanin. CD31 is other notable markers of cystic angiomatosis, indicating a hematopoietic lineage. In our case, CD31 is also positive in the immunohistochemistry indicating the lymphatic or angiomatous proliferations. The current medical treatment in cystic angiomatosis in mainly involved of bisphosphonates, interferon-a, and calcitonin. Thus, anti-VEGF and anti-VEGFRs therapy may be potential in blocking angiogenesis or pathological processes in cystic angiomatosis.
In the whole exome sequencing, we found some single nucleotide substitution in the coding region including BRIP1, CHEK2, GRM4, and MUC16. Besides, the up-regulated genes in the result were involved of CASC15, CENPF, ABCA13, ALK, BLM, FGFR3 and so on. Those genes may indicate the pathogenesis of cystic angiomatosis. BRIP1 pathogenic germline variants may have a causal role in CRC as moderate cancer susceptibility alleles and be associated with hereditary CRC predisposition. It could increase the risk of developing hereditary ovarian cancer. CASC15 is involved in the regulation of biological processes in many diseases, which could be a new biological therapeutic target. CASC15 has been found to be down-expressed abnormally in ovarian cancer, glioma and neuroblastoma. CENPF plays a key role in the regulation of the cell cycle. CENPF levels contributed to increased cell proliferation by mediating apoptosis and cell cycle in osteosarcoma with the poor prognosis of osteosarcoma. GO functional enrichment analysis revealed that the BPs of upregulated gene included regulation of ossification, embryonic cranial skeleton morphogenesis, chondrocyte differentiation. CC analysis revealed that upregulated DEGs were primarily enriched in ciliary membrane, spectrin-associated cytoskeleton and spectrin. The MFs of upregulated DEGs were demonstrated to include bHLH transcription factor binding, ionotropic glutamate receptor binding and Wnt-protein binding.