Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
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In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections. ⋯ By immunohistochemistry, 17 of 19 (89%) tested cases were clearly positive for ALK protein expression; the remaining cases had no detectable DNA level rearrangement or had a non-canonical rearrangement not predicted to form a fusion protein. Survival analysis of patients treated with targeted ALK inhibitors demonstrates a significant difference in mean survival between patients with next-generation sequencing confirmed EML4-ALK rearrangements, and those without (20.6 months vs 5.4 months, P<0.01). Together, these data demonstrate abundant genomic heterogeneity among ALK-rearranged lung adenocarcinoma, which may account for differences in treatment response with targeted ALK inhibitors.
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There is increasing interest in the role of ductular reaction as part of the pathogenesis and characteristic histology of non-alcoholic steatohepatitis. However, earlier studies did not separately assess the contribution of periportal and centrilobular zone ductular reaction over the spectrum of non-alcoholic steatohepatitis, and their clinical significance remains unclear. We herein analyzed the character of ductular reaction in each hepatic zone in non-alcoholic steatohepatitis biopsies and for the first time evaluated the prognostic value of ductular reaction in baseline biopsies as a predictor of progression of fibrosis in subsequent biopsies. ⋯ In the longitudinal study, the frequency of centrilobular ductular reaction in the initial biopsies was significantly higher in the group of progressors and correlated with the rate of fibrosis progression (P=0.02). Centrilobular ductular reaction is common in non-alcoholic steatohepatitis and its presence correlates significantly with increasing necroinflammatory activity and fibrosis stage. Development of centrilobular ductular reaction appears to predict progression of fibrosis in subsequent biopsies.
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The diagnosis of malignant peripheral nerve sheath tumors can be challenging and other spindle cell sarcomas commonly enter in the differential diagnosis. Loss of trimethylation at lysine 27 of histone-H3 (H3K27me3) by immunohistochemistry was recently described in malignant peripheral nerve sheath tumors. However, its specificity remains controversial. ⋯ Complete H3K27me3 loss is a moderately sensitive and relatively specific marker for the diagnosis of malignant peripheral nerve sheath tumor when the differential diagnosis includes synovial sarcoma and fibrosarcomatous dermatofibrosarcoma protuberans. Partial loss has limited diagnostic utility. H3K27me3 status does not show significant association with clinical outcome in malignant peripheral nerve sheath tumors.
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The diagnosis of malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting. Malignant peripheral nerve sheath tumor is a rare malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular melanoma. Recently, inactivation of the polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of malignant peripheral nerve sheath tumors. ⋯ Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all melanomas, including 25% (n=9) of primary desmoplastic melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all malignant peripheral nerve sheath tumors and in 136 (51%) of all melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing malignant peripheral nerve sheath tumor from melanoma.
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Patients with double-hit or triple-hit lymphoma have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma without MYC rearrangement. However, the prognostic importance of extra copies of MYC, BCL2, or BCL6 has not been fully explored. We studied 663 patients with de novo diffuse large B-cell lymphoma in whom the status of MYC/8q24, BCL2/18q21, and BCL6/3q27 were assessed by fluorescence in situ hybridization. ⋯ Compared with patients with double- or triple-hit lymphoma, patients with double or triple extra copy lymphoma had a higher complete remission rate (P=0.02), but there was no significant statistical difference in overall survival (P=0.089). Intensive induction chemotherapy regimens improved the overall survival of patients with double or triple extra copy lymphoma, but there was no significant improvement of overall survival in patients with MYC-R tumors. Multivariate analysis showed that MYC extra copy in diffuse large B-cell lymphoma is an independent poor prognostic factor, similar to MYC rearrangement.