Checkpoint Inhibition in the Treatment of Unresectable, Advanced Lymphoepithelioma-like Hepatocellular Carcinoma.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.

A rare localised nasal CD30+ primary cutaneous T-cell lymphoma following liver transplantation.

Cutaneous T-cell post-transplant lymphoproliferative disorder (PTLD) is a rare clinical presentation that can potentially turn aggressive in solid-organ transplant recipients if not detected and intervened on early. We encountered a rare case of rapidly worsening primary cutaneous CD30-positive, Epstein-Barr virus-negative anaplastic large cell lymphoma (ALCL) of T-cell origin, manifesting as an isolated nasal tip lesion in a 71-year-old man 4 years after orthotopic liver transplantation. Excisional biopsy with partial rhinectomy showed subepithelial diffuse infiltration of medium-to-large lymphoid cells having round-to-irregular nuclei, partially condensed chromatin and prominent nucleoli. Immunophenotypic studies revealed CD30-positive primary cutaneous ALCL. Positron emission tomography/CT imaging revealed a locally active disease, and radiation therapy was initiated with complete response. A high index of suspicion for PTLD when evaluating skin lesions in a post-transplant patient is paramount for its early recognition, prompt diagnosis and timely intervention while the window for curative therapy remains possible.

TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location.

Thyroid transcription factor (TTF)-1 expression in neuroendocrine tumors (NETs) has not been studied as widely as that in non-NETs, with the exception of small cell carcinomas, in which TTF-1 is highly sensitive but not specific for a primary lung tumor. The reported incidence of TTF-1 expression in pulmonary carcinoids has also been highly variable in the literature. To evaluate the expression of TTF-1 in NETs and potential value of TTF-1 in distinguishing pulmonary NETs from those of extrapulmonary origin, we performed an immunohistochemical study by using semiquantitative analysis on formalin-fixed, paraffin-embedded sections from 111 NETs, including 80 pulmonary (11 carcinoid tumorlets [TLs] or foci of neuroendocrine cell hyperplasia [NEH], 36 typical carcinoids [TCs], 17 atypical carcinoids [ACs], 16 large cell neuroendocrine carcinomas [LCNECs]), 13 thymic (3 TCs, 8 ACs, 2 LCNECs), 17 gastrointestinal or pancreatic (13 TCs, 4 ACs), and 1 ovarian (LCNEC). Pulmonary carcinoids were subdivided into those with central and those with peripheral location. TTF-1 positivity was seen exclusively in pulmonary NETs and was significantly higher in NEH or TLs (72.7%) than in TCs (27.8%), ACs (29.4%), and LCNECs (37.5%; P = 0.03). All extrapulmonary NETs were uniformly negative for TTF-1 staining. Interestingly, 12 of 14 TTF-1-positive pulmonary TCs and ACs had a peripheral location with spindle cell morphology, as did all cases of TL, a purported precursor of peripheral carcinoids. In conclusion, TTF-1 expression was 100% specific, though not so sensitive, for the lung primary in TCs and ACs and possibly also in LCNECs. Prevalent TTF-1 positivity in TLs and peripheral carcinoids suggest that they may be histogenetically distinct from the central carcinoids, which are typically composed of TTF-1-negative, more rounded cells.

Transgenic expression of cholesterol-7-alpha-hydroxylase prevents atherosclerosis in C57BL/6J mice.

C57BL/6J mice are susceptible to atherosclerosis when fed a diet consisting of fat, cholesterol, and taurocholate. The susceptibility to diet-induced atherosclerosis is linked to a reduction in plasma high density lipoprotein (HDL). Diet-induced reduction of plasma HDL shows a physiological and a genetic correlation with repression of cholesterol-7-alpha-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7-alpha-hydroxylase is responsible for initiating the metabolic alterations leading to the formation of atherosclerosis and gallstones, we determined whether constitutive transgenic expression of cholesterol-7-alpha-hydroxylase in C57BL/6J mice would confer resistance to these 2 common human diseases. When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7-alpha-hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma. Although the atherogenic diet caused a marked decrease in plasma HDL cholesterol in nontransgenic mice, HDL levels in transgenic mice remained relatively unchanged. Moreover, the ability of cholesterol-7-alpha-hydroxylase transgenic mice to maintain cholesterol and lipoprotein homeostasis completely prevented the formation of atherosclerosis and gallstones. These data establish the integral role that cholesterol-7-alpha-hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.