Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.
The diagnosis of dedifferentiated liposarcoma (DDLPS) is challenging when an atypical lipomatous tumor component is absent or obscure. To analyze the utility and limitations of ancillary techniques, we studied 11 cases of DDLPS in challenging conditions and 17 cases of nonlipogenic high-grade sarcomas with immunohistochemistry (IHC) for p16, CDK4, and MDM2 and automated dual-color in situ hybridization (DISH) for MDM2 amplification. All DDLPS specimens lacked clear lipogenic components and were immunoreactive for p16, CDK4, and MDM2. DISH analyses also revealed high-level amplification of MDM2 in all DDLPS. In contrast, among nonlipogenic sarcomas, p16, CDK4, and MDM2 were expressed in 8, 9, and 3 cases, respectively. MDM2 amplification was detected in 3 of 8 studied. The MDM2-amplified tumors were the same as the MDM2-immunoreactive tumors. After careful reevaluation of these 3 sarcomas, 2 were reclassified as DDLPS because small areas of lipogenic components were detected in the original specimens. The respective sensitivities and specificities of these markers were as follows: p16 IHC (100% and 60%), CDK4 IHC (100% and 53.3%), MDM2 IHC (100% and 93.3%), and MDM2 DISH (100% and 83.3%). The results of MDM2 IHC completely coincided with those of MDM2 DISH. The present study confirmed the substantial utility of MDM2 IHC and MDM2 DISH in the diagnosis of DDLPS, especially when lipogenic components were indistinct compared with IHC for p16 and CDK4. Furthermore, automated DISH was more practical than fluorescent in situ hybridization.
Patient: Male, 78Final Diagnosis: Giant cell tumor of soft tissueSymptoms: Fatigue • weight lossMedication: —Clinical Procedure: Surgical resectionSpecialty: SurgeryObjective:Rare diseaseBackground:Giant cell tumor of soft tissue (GCT-ST) is a rare disease generally generated from superficial tissue. We report an extremely rare case of giant cell tumor of soft tissue arising from retroperitoneal tissue.Case Report:A 78-year-old man visited our medical center with the chief complaint of fatigue and weight loss for 1 month. He had a hard and immobilized mass without pain in the left upper quadrant. Contrast-enhanced CT showed a huge tumor (22×20×16 cm) in the retroperitoneal space, and it invaded into the stomach, colon, pancreas, spleen, and left kidney. MRI demonstrated the tumor had a serous cystic component as T1 was low, T2 was high, and DWI was slightly high. We diagnosed the retroperitoneal malignant tumor, and tumor resection was performed with total gastrectomy, partial colectomy, distal pancreatectomy, left nephrectomy, and left adrenal-ectomy for complete resection, without any postoperative complications. The tumor predominantly consisted of a solid mass, and had necrotic lesions, cystic lesions, and calcification. The histological exam showed it was composed of spindle and multinucleated giant cells; however, there was no cellular atypia or pleomorphism. Immunohistochemical staining characterized the tumor with CD68+, SMA+, CD34–, Desmin–, and S-100–. We finally diagnosed it as GCT-ST with the intermediate group of malignancy, according to WHO criteria. Thereafter, the patient had no recurrence at 1 year after resection.Conclusions:The huge GCT-ST arising from the retroperitoneal space, which has never before been reported, was successfully resected. We report it with pathological findings to add to the relevant literature.
Gastric duplication cysts (GDCs) are a relatively rare congenital anomalies and are mostly diagnosed in the early years of life. Herein, we report a very rare surgical case of adenocarcinoma arising from a GDC with lymph node metastasis. A 78-year-old woman was referred to our hospital because of elevated serum levels of cancer antigen (CA) 19-9. Endoscopic ultrasound, contrast fistulography, and computed tomography showed a cystic lesion communicating with the lesser curvature of the stomach. The serum levels of CA 19-9 were high, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging demonstrated a slightly enlarged lymph node with high FDG uptake after four months. The size of the cyst was unchanged. It was diagnosed as a GDC. The enlarged lymph node was highly likely to be malignant. Hence, we performed a distal gastrectomy involving the origin of entry and whole body of the GDC with en bloc regional lymphadenectomy. The postoperative pathology was consistent with GDC with moderately differentiated adenocarcinoma and lymph node metastasis. Adjuvant chemotherapy with tegafur-gimeracil-oteracil potassium (S-1) was administered for 12 months. At present, the patient is alive, with no recurrence of the lesion even four years after the operation. GDCs in adults are rare and may predispose to malignancy. Early diagnosis and prompt surgical intervention are important for favorable outcomes.
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