TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.

Plexiform fibromyxoma (plexiform angiomyxoid myofibroblastic tumor) of stomach: an unusual presentation as a fistulating abscess.

Plexiform fibromyxoma (plexiform angiomyxoid myofibroblastic tumor) is a rare benign mesenchymal tumor of stomach. The plexiform growth of bland-looking spindly cells in a richly vascularized fibromyxoid stroma is distinctive. The described cases are solid tumors associated with ulceration, with the patients presenting with symptoms related to the ulcer or mass effect of the tumor. We report an unusual case presenting as a fistulating abscess. A 42-year-old woman presented with abdominal pain, fever, and elevated white cell count. Computed tomography scan revealed a 12-cm cavitating mass in the gastric antrum, with fistulation to the gastric lumen through an ulcer. Histologic examination showed transmural involvement of the stomach by plexiform islands of fibromyxoid tumor with interspersed delicate capillaries. There was a pseudocyst-like component. The unusual presentation therefore broadens the clinical and pathologic spectrum of this rare tumor type.

Multinodular reticular schwannoma in the head and neck region: a potential diagnostic pitfall.

Reticular/microcystic schwannoma is a recently described morphologic variant of schwannoma that occurs predominantly in visceral organs, most commonly the gastrointestinal tract. This report describes a case occurring in the masticator space, accompanied by focal erosion of the orbital floor, clinically and radiologically worrisome for malignancy. The 26-year-old man presented with facial swelling for 3 month. The tumor shows a multinodular appearance, with dense lymphoplasmacytic infiltrates in the fibrous septa. The tumor nodules are composed of plump spindle cells disposed in a reticular pattern. The diagnosis is confirmed by strong positive staining for S100 protein. The differential diagnoses of reticular schwannoma in the soft tissues of head and neck region are different from those in the gastrointestinal tract.

EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma.

Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon sarcoma with a deceptively bland-looking morphology that disguises its malignant clinical behavior. It shows distinctive chromosomal translocations resulting in fusion of FUS with the CREB3L2 gene in most cases and CREB3L1 in rare cases. Thus molecular studies are particularly helpful in the diagnosis of this bland-looking sarcoma. We report 2 cases of LGFMS serendipitously found to harbor a novel alternative EWSR1-CREB3L1 gene fusion, as confirmed by DNA sequencing of reverse transcriptase-polymerase chain reaction products and fluorescence in situ hybridization. One patient was a child who presented with a subcutaneous nodule on the lower leg, and the other was a middle-aged woman who had a mass lesion over the proximal thigh. Morphologically, one case showed a spindle cell tumor with hyalinization and giant rosettes, whereas the other showed classical histology of LGFMS with focal metaplastic bone formation. Immunostaining for MUC4 showed extensive positive staining. Our findings therefore expand the spectrum of gene fusions that characterize LGFMS and suggest that the EWSR1 gene may substitute for the function of FUS in gene fusions of sarcoma.