Search

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

Well-differentiated (WDL) and dedifferentiated liposarcomas (DL) of the pharynx, larynx and oral cavity are rare, often mimicking benign lipomatous neoplasms or non-lipogenic mesenchymal tumors. Cases of WDL/DL arising in the upper aerodigestive tract, exclusive of the cervical esophagus, were reviewed. Morphologic features, ancillary studies, including fluorescence in situ hybridization (FISH) studies for CPM/MDM2, and clinical data was catalogued. Eight WDL/DL (4 WDL, 4 DL); were identified in patients ranging from 32 to 77 years (median 52.5 years; 6 males, 2 females) with sites of origin including hypopharynx (5 cases), larynx (2 cases) and oral cavity (1 case). Six of the 8 cases were received for expert consultation, and the remaining 2 cases were initially misdiagnosed as benign lymphangiomatous or fibroepithelial polyps. Morphologically, 4 tumors had areas mimicking various non-lipomatous soft tissue tumors including nodular fasciitis, mammary-type myofibroblastoma, low-grade myofibroblastic sarcoma and undifferentiated pleomorphic sarcoma, 2 cases simulated benign hypopharyngeal polyps, and 1 lesion was notable for a dense lymphoplasmacytic infiltrate suggestive of hematolymphoid neoplasm or IgG4-related sclerosing disease. FISH showed amplification of CPM/MDM2 (8/8 cases). All cases (4/4) with longer than 1-year of follow-up recurred (45-118 months) with 1 tumor showing progression to DL. WDL/DL presenting in the upper aerodigestive tract are rare and diagnostically challenging. Awareness of the morphologic spectrum of WDL/DL coupled with appropriate use of MDM2 FISH is essential for accurate classification and management, as these tumors appear to have a high risk for local recurrence and eventual dedifferentiation in these anatomical locations.

Prior studies have revealed that the presence of increasing number of polyclonal plasma cells (pPCs) in the bone marrow (BM) are associated with better outcomes in newly diagnosed multiple myeloma (MM) patients. This effect has not been studied in patients with MM at the time of disease relapse. We determined the prognostic value of depletion of pPCs in the BM by 7-color multiparameter flow cytometry in a series of 174 relapsing MM patients. The time to next therapy (TTNT) in those with

High-risk HPV (HR-HPV) genoprevalence was assessed in cytologic specimens co-tested for HR-HPV in a predominantly Midwestern U.S. population, of which there are limited current data. These baseline data will aid in determining future shifts in HR-HPV genoprevalence.A total of 40,739 cervical/endocervical samples collected in PreservCyt (ThinPrep) media at Mayo Clinic, Rochester, MN, underwent HR-HPV co-testing between January 2014 and December 2016 in women aged 30-98 years. This included 37,656 negative for intraepithelial lesion (NIL), 1696 atypical squamous cells of undetermined significance (ASC-US), 159 atypical squamous cells, cannot exclude HSIL (ASC-H), 911 low-grade squamous intraepithelial lesion (LSIL), 188 high-grade intraepithelial lesion (HSIL), and 129 atypical glandular cells of undetermined significance (AGUS) cases. Roche cobas 4800 classified HR-HPV genotypes as 16, 18, or "other" (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68).Of 40,739 co-tested specimens, 3786 were positive for at least one HR-HPV strain. "Other" only genotypes were most prevalent (74.3% of all HR-HPV cases). HPV16 and/or HPV18 were more common in the more significant diagnoses and were present in 59.1% of HSIL. HPV16-only was second most prevalent, with highest prevalence in HSIL (33.3%) and ASC-H (20.6%). HPV16 combined with "other" was third most prevalent, except in AGUS. HR-HPV (all genotypes) was most prevalent in those aged 30-39 years, decreasing with age (P0.0001). There was a trend toward HPV16 prevalence increasing with age (P = 0.4244).HR-HPV "other" combination was most prevalent in all diagnoses except HSIL, in which HPV16 and/or HPV18 (exclusive of "other" genotypes) were most prevalent.

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention.

Background Untreated calciphylaxis is a fatal disease of intra- and extravascular calcification, most commonly presenting in end-stage renal disease (ESRD) patients. While early identification is critical for timely treatment, early-stage clinical and histopathological descriptions have not, to our knowledge, been elucidated. As early clinical recognition is essential to prompt definitive histopathological diagnosis, this study describes a range of clinical and histopathological manifestations of early-stage calciphylaxis. Methods Five patients with clinical photographs of lesions of early-phase calciphylaxis were chosen from a recent database of 101 patients. Their clinical histories were reviewed and correlated with their respective clinical and histopathological images of early-stage disease and progression of the disease. Results Two of the five patients were identified early to have calciphylaxis and were promptly initiated on aggressive, multimodal therapy, resulting in complete resolution and remission of calciphylaxis. The other three patients were also recognized in early stages, one without renal disease, although the disease had progressed to more advanced stages associated with greater morbidity and mortality. Conclusions These cases demonstrate that calciphylaxis may be clinically misdiagnosed due to ill-defined presentations, particularly in the early stages without the characteristic features of livedo racemosa and ulceration. However, recognition in the early stages is critical to implement timely treatment. As such, definitively diagnostic skin biopsy should be considered early in suspected cases to confirm the diagnosis of calciphylaxis and ensure prompt management of this lethal disease.

Background: Prior studies suggest that the presence of >5% polyclonal plasma cells (pPCs) among total plasma cells (PCs) within the bone marrow (BM) is associated with a longer progression-free survival, higher response rates, and lower frequency of high-risk cytogenetic abnormalities in patients with newly diagnosed multiple myeloma (MM). However, the incidence and prognostic utility of this factor in patients with relapsed and/or refractory MM has not been previously evaluated. Thus, we evaluated the prognostic value of quantifying the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM. Methods: We evaluated all MM patients with actively relapsing disease (biochemical and/or symptomatic) seen at the Mayo Clinic, Rochester, from 2012 to 2013, who had BM samples evaluated by seven-color multiparametric flow cytometry. All patients had at least 24 months of follow-up from the date of flow evaluation. Cell surface antigens were assessed by direct immunofluorescence antibodies for CD45, CD19, CD38, CD138, cytoplasmic Kappa and Lambda Ig light chains, and DAPI nuclear stain. The flow cytometry data was collected using the Becton Dickinson FACSCanto II instruments that analyzed 150,000 events (cells); this data was then analyzed by multi-parameter analysis using the BD FACS DIVA Software. PCs were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. Clonal PCs were separated from pPCs based on the differential expression of CD45, CD19, DAPI (in non-diploid cases), and immunoglobulin light chains. The percentage of pPCs was calculated in total PCs detected. Survival analysis was performed by the Kaplan-Meier method and differences were assessed using the log rank test. Results: There were 180 consecutive patients with actively relapsing MM who had BM biopsies analyzed via flow cytometry as part of their routine clinical evaluation. The median age of this group was 65 years (range: 40 - 87); 52% were male. At the time of this analysis, 104 patients had died, and the 2-year overall survival (OS) rate for the cohort was 58%. The median number of therapies received was 4 (range: 1 - 15). Of these patients, 61% received a prior ASCT, and almost all (99%) received prior regimens containing either immunomodulators or proteasome inhibitors. There were 55 (30%) patients with >5% pPCs among the total PCs in their BM. The median percentage of pPCs among total PCs in these 55 patients was 33% (range: 5 - 99). The median OS for those with >5% pPCs was not reached compared with 22 months for those with Conclusion: Quantitative estimation of the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM was determined to be a predictor of worse OS. As such, this parameter is able to identify a group of patients with MM with actively relapsing disease who have a particularly poor outcome. Further studies evaluating its biological significance are warranted. Figure 1 Kaplan-Meier curve comparing OS between patients with ≥5% pPCs and Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gertz:Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Kumar:AbbVie: Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy; BMS: Consultancy.