Cystic angiomatosis is a rare disease characterized by multifocal bony cysts with a honeycombed appearance and thin-walled blood vessel proliferation with bone destruction, where bone trabecula under the cortex is gradually replaced by hemangiomatous or lymph angiomatous tissue. The first decades of life, particularly puberty, is one of the periods with the highest rates of cystic angiomatosis, and ages higher than 60 years may be the second stage for occurrence peak [3]. The clinical symptoms vary from accidental findings of radiograph to pathologic fracture or skeletal abnormalities of slow progression, or manifesting as rare severe visceral lymphangiomatosis, especially for the lung, liver, or spleen [6]. Radiograph imaging reports multifocal and skeletal intramedullary cysts, with a thinned and relatively well-preserved bony cortex, without a peripheral soft tissue involvement and periosteal reaction [7].
The cystic angiomatosis is typically characterized as multifocal intramedullary skeletal cysts with relatively well-preserved cortical bone, without periosteal reaction and peripheral involvement of soft tissues in the lesion of the bone, while metastasis, multiple myeloma, or other malignant diseases often involve peripheral or tissue reaction [3, 4]. Bone cysts are oriented along the long axis of the bone developing a sclerotic peripheral ring. Cystic angiomatosis and Gorham-Stout disease (GSD) present similar features in the destruction and resorption of the bone [4, 8]. However, cystic angiomatosis exhibits sclerosis appearance in the margin of cysts and sclerosing lesions rather than osteolysis in the affected bone, which is the critical manifestation in GSD. Most previous studies demonstrated that GSD could elicit progressive massive osteolysis, resulting in cortical bone loss, causing severe deformations and disability, whereas cystic angiomatosis-induced medullary cavity without progress of disease [9], which demonstrates that cystic angiomatosis usually has a better prognosis than GSD [10].
Bone biopsy is a standard method in the diagnosis of cystic angiomatosis. However, previous studies have usually argued that histological diagnosis is significantly difficult in some diseases, requiring repeated bone biopsy for final diagnosis [5]. In our study, the first biopsy surgery was performed in other hospitals, which, as a result of an undefined diagnosis, caused the lesion of the lib and humerus regrettably filled with bone fluid. In the second bone biopsy, we found bleeding in the trabecular bone from fibrous connective tissue and dilated blood vessels, lymphocytes, and cystic wall of endothelial lining in the dilated lymphatic vessels, where the cystic wall was reported by most literature [6, 11]. We considered these as consecutive phases in the development process of cystic angiomatosis, which are different histological results. Thus, the different radiological performances in the content of bone cystic should be evaluated before the bone biopsy.
There showed an increase in ALP and bone marker osteoprotegerin, osteopenia, and interleukin-6 in cystic angiomatosis [7], where ALP was 393 U/L with the normal of 20–110 U/L, and VEGF of 287.26 pg/ml with a normal of 0–142 pg/ml, which serves as a growth factor with critical pro-angiogenic activity, promoting the vascular permeability and cell migration. Besides, VEGF and their endothelial tyrosine kinase receptors are involved in vasculogenesis, angiogenesis, and lymphangiogenesis, promoting the angiogenic pathway through signaling with VEGFR-2. VEGFR1 and VEGFR2 are mainly focused on vascular endothelial cells and VEGFR-3 on lymphangiogenesis especially [12]. Histological examination shows that the vessels of vascular or lymphangiomatous are involved in VEGF and podoplanin. CD31 is another notable marker of cystic angiomatosis, indicating a hematopoietic lineage. In our case, CD31 also exhibited positive in the immunohistochemistry, indicating lymphatic or angiomatous proliferations. The current medical treatment for cystic angiomatosis mainly refers to bisphosphonates, interferon-a, calcitonin propranolol, steroids, alpha-interferon, surgery, and radiation therapy [5, 7]. Thus, anti-VEGF or anti-VEGFR therapy may have the potential capability in blocking angiogenesis or pathological processes in cystic angiomatosis.
In the whole exome sequencing, we found some single-nucleotide substitutions in the coding region including BRIP1, CHEK2, GRM4, and MUC16. Besides, the upregulated genes involved CASC15, CENPF, ABCA13, ALK, BLM, and FGFR3, which may indicate the pathogenesis of cystic angiomatosis to some extent. BRIP1 pathogenic germline variants may play a causal role in CRC as moderate cancer susceptibility alleles, with association to hereditary CRC predisposition, which could elevate the risk of developing hereditary ovarian cancer [13]. CASC15 is involved in the manipulation of biological processes in various diseases, which could be a new potential biological therapeutic target [14], as its abnormal down-expression has been found in ovarian cancer, glioma, and neuroblastoma [15]. CENPF plays a key role in the regulation of the cell cycle [16], of which the levels contributed to increased cell proliferation by mediating apoptosis and cell cycle in osteosarcoma with a poor prognosis of osteosarcoma [17]. GO functional enrichment analysis revealed that the BPs of upregulated genes covered regulation of ossification, embryonic cranial skeleton morphogenesis, and chondrocyte differentiation. CC analysis revealed the primary enrichment of upregulated DEGs in the ciliary membrane, spectrin-associated cytoskeleton, and spectrin. The MFs of upregulated DEGs were demonstrated to participate in bHLH transcription factor binding, ionotropic glutamate receptor binding, and Wnt-protein binding.
