Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis. METHODS: Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals. RESULTS: Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis. CONCLUSION: The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.

Xanthogranuloma of bone: a challenging imitator of malignancy.

Xanthogranulomatous disease of bone is exceptionally uncommon. Clinically, radiologically and pathologically, it is a great imitator of malignancy. While there are few reports on the surgical pathology of this rare entity, there is no published report on its cytopathologic characteristics. We report herein the case of a 44-year-old male who was evaluated at The Johns Hopkins Hospital for a 2.3-cm painful soft tissue mass present within the medullary canal of the distal tibia with destruction of the overlying cortex. A computed tomography-guided fine needle aspiration biopsy revealed abundant histiocytes and occasional giant cells in an inflammatory background. This was interpreted as a 'histiocyte-rich lesion,' and an excisional biopsy was recommended. Subsequent curettage was performed, and the histological material was diagnosed as 'xanthogranuloma of bone.' The rarity of xanthogranuloma of bone and its resemblance to the more common reactive and malignant bone neoplasms may present diagnostic challenges.

Nuclear protein in testis midline carcinoma with unusual elevation of α-fetoprotein and synaptophysin positivity: a case report and review of the literature.

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare cancer that displays a characteristic chromosomal rearrangement of BRD4-NUT t(15;19)(q14;q13.1). Despite occasional dramatic responses to radiation and chemotherapy, NMC usually behaves aggressively and becomes rapidly progressive. Immunohistochemical staining is usually limited to p63, cytokeratins, and monoclonal NUT antibody. Here, we report a NMC case in a 36-year-old man with elevated serum α-fetoprotein (AFP), synaptophysin positivity, and a 9.0 cm mass involving the right lung and mediastinum. Tumor cells demonstrated BRD4-NUT fusion on fluorescence in situ hybridization. To our knowledge, only one other case with elevated serum AFP and one case with synaptophysin positivity have been described. This diagnosis will undoubtedly grow more common as informed physicians become more aware of the disease and begin testing for NMC. Further study is needed to establish the prevalence of NMC and to elucidate the significance of elevated AFP and synaptophysin positivity in this rare tumor.

Cytopathologic diagnosis of liver mass lesions.

The liver is a common site for metastatic malignancies, particularly from the gastrointestinal tract. It also may be involved by primary neoplasms, both benign and malignant. Cytopathologic examination of mass lesions of the liver with pertinent use of ancillary studies is a useful method of establishing a correct diagnosis for patient management. The authors reviewed the literature for articles pertaining to cytologic characteristics of specific tumor types, utility of immunohistochemical markers and pertinent molecular studies, differential diagnoses and pitfalls.

Cytopathology of the pancreatobiliary tract-the agony, and sometimes, the ease of it.

Pancreatic cytopathology is recognized as a rapid, reliable, safe and cost-beneficial modality of investigation of pancreatic mass lesions. Optimal cytodiagnosis depends on multiple factors including sample quality, and expertise of the cytopathologist and endoscopist. This article discusses key cytologic features of specific tumor types, specimen handling, differential diagnoses and pitfalls.

Osteoclast-rich undifferentiated carcinoma of the urinary tract: cytologic findings and literature review.

The association of urothelial carcinoma with osteoclast-like giant cells is an exceptionally rare event. To our knowledge, there are no published reports of the cytopathologic characteristics of osteoclast-rich undifferentiated carcinoma of the urinary tract. We report herein, the case of a 63-year-old man who was evaluated at The Johns Hopkins Hospital for gross hematuria of 4 months duration. Urinary cytology displayed high-grade malignant cells with scattered osteoclast-like giant cells in a background of acute inflammation and abundant red blood cells. Subsequently, a transurethral tumor resection was performed, which revealed infiltrating undifferentiated carcinoma with osteoclast-like giant cells. The rarity of this neoplasm and its resemblance to other giant cell-rich processes may pose diagnostic difficulties. A review of the important differential diagnoses is also presented.

Metastatic retinoblastoma presenting as a left shoulder soft tissue mass: FNA findings and review of the literature.

Retinoblastoma is a relatively rare malignant pediatric tumor accounting for approximately 3% of childhood cancers and 1% of all cancer deaths in children under 15 years of age. During the clinical course of the disease, a metastasis usually occurs within the first year of diagnosis and is seen in 2% of retinoblastoma patients. Metastases to the intracranial region are common and account for approximately 50% of the metastatic cases. Metastasis to the soft tissue is very rare. Herein, we report a case of metastatic retinoblastoma presenting as a left shoulder soft tissue mass in a 14-year-old female with a 14-year history of familial bilateral retinoblastoma status post radiation therapy. In our case, the FNA cytology shows some features of the small round blue cell tumor group with inconspicuous Flexner-Wintersteiner or Homer-Right rosette formation. The unusual clinical presentation and morphology give rise to a diagnostic dilemma, with the differential diagnosis centering on the small round blue cell tumors such as lymphoma, rhabdomyosarcoma, nephroblastoma (Wilms' tumor), Ewing's sarcoma/PNET, and desmoplastic small round cell tumor. It also prompts concern for the development of a second primary tumor. The purpose of our study is to discuss the FNA cytology of metastatic retinoblastoma, its differential diagnoses, and the utility of immunohistochemistry. An accurate diagnosis is imperative due to the differences in prognosis and treatment implications for the various diseases.

Nonsebaceous lymphadenoma of the parotid gland: cytopathologic findings and differential diagnosis.

Lymphadenomas (sebaceous and nonsebaceous types) of the salivary glands are extremely uncommon benign neoplasms. There are rare published reports of cytopathologic characteristics of "nonsebaceous lymphadenomas" of the parotid gland. We report herein, the case of an 80-year-old female who was evaluated at The Johns Hopkins Hospital for a 4.0 cm, nontender, mobile asymptomatic left parotid mass present for 3 months. An ultrasound-guided fine-needle aspiration revealed a uniform population of cohesive basaloid-type cells associated with scant myxoid stroma and was interpreted as "epithelioid neoplasm with basaloid features." Subsequently, a superficial parotidectomy was performed, which revealed a nonsebaceous type lymphadenoma. The rarity of this neoplasm and its superficial resemblance to more common salivary gland neoplasms may present diagnostic issues on FNA.