The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

Malignancy rates of salivary gland tumors in Greenlandic Inuit comparable to non-endemic populations; epidemiological mapping of salivary gland tumors 1990-2019.

BACKGROUND: Salivary gland tumors are assumed to be predominantly malignant in the Greenlandic Inuit population, but there is limited literature on the subject. We conducted a retrospective cohort study using national registers to describe the histological tumor types, location, incidence, and survival of benign and malignant salivary gland tumors. METHODS: We analyzed data on all Greenlandic Inuit with an epithelial-derived salivary gland tumor from 1990 to 2019. We extracted data from the Central Personal Registry and crossmatched it with the Danish Pathology Data Bank. All specimens were reviewed by a specialized pathologist. We noted patient and histological characteristics, calculated crude and age-adjusted incidence rates, overall survival, and excess mortality. RESULTS: Our study found that 76% of salivary gland tumors in the Greenlandic Inuit population were benign, with pleomorphic adenoma being the most common. Malignant tumors accounted for 24% of cases, with lymphoepithelial carcinoma being the most common type. The most common place of origin for malignant tumors was the parotid gland (71%) and the submandibular gland (15%). The median age of onset for malignant tumors was 47 years. Age-adjusted incidence rates of malignant tumors for men and women were 3.00 and 4.12 per 100,000 person-years, respectively. CONCLUSION: Our findings suggest that the proportion of malignant salivary gland tumors in the Greenlandic Inuit population is similar to other nonendemic populations. Our incidence rates are higher than previously reported, likely due to differences in methodology and definitions of the Inuit population. This study provides valuable insights into the epidemiology of salivary gland tumors in the Greenlandic Inuit population and may have implications for other Inuit populations as well.

Sinonasal B-cell lymphomas: A nationwide cohort study, with an emphasis on the prognosis and the recurrence pattern of primary diffuse large B-cell lymphoma.

Lymphomas of the nasal cavity and paranasal sinuses (NPS) are rare. Knowledge on sinonasal B-cell lymphoma (SNBCL) primarily comes from case series or single-center studies on small cohorts. We sought to determine the subtype distribution, clinical characteristics, disease behavior, and prognosis on a nationwide scale, with an emphasis on prognostic factors for the most common sinonasal lymphoma, primary sinonasal diffuse large B-cell lymphoma (PSDLBCL). We collated all data from medical records and national databases on patients registered with SNBCL from 1980 through 2018 in the national pathology registry and collected all tissue samples for validation of diagnosis. We included 205 patients and found 10 different subtypes of lymphoma. Diffuse large B-cell lymphoma (DLBCL) was the predominant subtype (80%). The incidence of SNBCL was 0.14/100,000 person-years. The five-year progression-free survival (PFS) and overall survival rates for PSDLBCL were 50% and 56%, respectively. For PSDLBCL, Rituximab showed a statistically significant effect (Hazard Ratio 0.22, p < 0.001), whereas consolidative radiotherapy combined with immunochemotherapy was of limited value (PFS, p = 0.93). When treatment failure occurred, DLBCL showed a distinct pattern of recurrence/dissemination to the NPS, skin, breast, central nervous system (CNS), and/or testis. Collectively, DLBCL comprised a clear majority of SNBCLs, although nine other subtypes were represented. Data showed that immunochemotherapy increased survival for PSDLBCL and that the addition of radiotherapy did not benefit patients. Furthermore, treatment failure for sinonasal DLBCL showed a possible common pathogenesis with primary extranodal lymphomas of specific locations (e.g., CNS, skin, breast, and testis).

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Sinonasal DLBCL: molecular profiling identifies subtypes with distinctive prognosis and targetable genetic features.

ABSTRACT: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.

Prevalence and prognostic value of MYD88 and CD79B mutations in ocular adnexal large B-cell lymphoma: a reclassification of ocular adnexal large B-cell lymphoma.

AIMS: To (1) reclassify ocular adnexal large B-cell lymphomas (OA-LBCLs) per 2016 WHO lymphoma classification and (2) determine the prevalence of MYD88 and CD79B mutations and their association with clinical parameters among OA-LBCLs. METHODS: This study is a retrospective analysis of all OA-LBCLs diagnosed in Denmark between 1980 and 2018. Medical records and tissue samples were retrieved. Thirty-four OA-LBCLs were included. Fluorescence in situ hybridisation and Epstein-Barr-encoded RNA in situ hybridisation were used for the reclassification. Mutational status was established by allele-specific PCR and confirmed by Sanger sequencing. Primary endpoints were overall survival, disease-specific survival (DSS) and progression-free survival (PFS). RESULTS: Two LBCL subtypes were identified: diffuse large B-cell lymphoma (DLBCL) (27 of 32; 84%) and high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (5 of 32; 16%). cMYC/BCL2 double-expressor DLBCLs had a poorer DSS than non-double-expressor DLBCLs (5-year DSS, 25% vs 78%) (HR 0.23; 95% CI 0.06 to 0.85; p=0.014). MYD88 mutations were present in 10 (29%) of 34 lymphomas and carried a poorer PFS than wild-type cases (5-year PFS, 0% vs 43%) (HR 0.78; 95% CI 0.61 to 0.98; p=0.039). CD79B mutations were present in 3 (9%) of 34 cases. CONCLUSION: OA-LBCL consists mainly of two subtypes: DLBCL and HGBL with MYC and BCL2 and/or BCL6 rearrangements. MYD88 mutations are important drivers of OA-LBCL. MYD88 mutations, as well as cMYC/BCL2 double-expressor DLBCL, appear to be associated with a poor prognosis. Implementing MYD88 mutational analysis in routine diagnostics may improve OA-LBCL prognostication.

EUSICA/COST IMMUNO-model workshop fostering collaboration to advance sinonasal cancer research: A meeting report.

Sinonasal cancer is a clinically and histologically heterogeneous group of rare tumors with generally poor clinical outcomes. Their low incidence hampers the advancement of clinical management as well as translational research, and calls for multicenter and multinational collaboration between physicians and researchers. This report describes the proceedings of a two-day conference organized by the European Network for Sinonasal Cancer Research (EUSICA) and COST Action 'IMMUNO-model', fostering such collaboration and focusing on preclinical tumor and immuno models, surgical and radio-oncological treatments, core facilities for genetic characterization and molecular tumor classification, and cancer registry.

Clinical Presentation and Outcome of Sinonasal Extraosseous Plasmacytoma in Denmark: A Nationwide Cohort From 1980 to 2017.

OBJECTIVES: Extraosseous plasmacytoma (EOP) is a rare plasma cell neoplasm that tends to convert to plasma cell myeloma (PCM) in about 11% to 35% of cases. It has a predilection for the upper respiratory tract, prototypically affecting the nasal cavity and paranasal sinuses. Contemporary first-line treatment is radiotherapy, with more recent studies showing an added benefit of combining radiation with surgery. In this cohort study, we aimed to examine clinical presentation, treatment, and prognosis for all patients nationwide from 1980 through 2017. Furthermore, we determined the size and extension of tumors, investigating the rate at which minimally invasive surgery would have been possible. METHODS: Patients were found in the national pathology registry, and all biopsies were collected for pathology review by a hematopathologist. We performed survival statistics for overall survival (OS), progression-free survival (PFS), and the cumulative incidence of conversion to PCM. RESULTS: Twenty-three patients were included. The median age was 65, and patients were primarily men (78%). Tumors were located in either the nasal cavity (57%), maxillary sinus (39%), or sphenoid sinus (4%). In most cases, the tumor was <5 cm (65%) without extension to adjacent structures (60%). The national incidence was 0.02/100,000 person-years, the median symptom duration until diagnosis was 5 months, and none of the patients presented with contiguous spread to regional lymph nodes. Stand-alone radiotherapy was the predominant treatment (61%). In the entire cohort, one patient died from the initial disease, and six patients died from either relapse of EOP or PCM. The 5-year OS, PFS, and conversion rate to PCM were 78%, 56%, and 23%, respectively. CONCLUSION: SN-EOP responds well to radiotherapy, but relapse and conversion to PCM were not uncommon and entailed a poor prognosis. Most tumors were endoscopically resectable and non-invasive, making the majority of tumors suitable for surgery as an addition to radiation.

NK- and T-cell lymphoma of the nasal cavity and paranasal sinuses in Denmark 1980-2017: a nationwide cohort study.

Compared to Asian and Latin American populations, sinonasal NK- or T-cell lymphoma is rare in Europe. All patients with sinonasal NK- or T-cell lymphoma in Denmark from 1980 to 2017 were validated histologically, and the disease behavior and demographics were extracted from medical records and national registries. Prognostic factors associated with mortality were determined using survival statistics. We included 56 patients: 40 extranodal NK/T-cell lymphoma (nasal type) (ENKTCL) and 16 peripheral T-cell lymphoma (not otherwise specified) (PTCL). The median age was 66, and most patients were male (72%). The ENKTCL and PTCL 5-year overall survival was 48% and 50%, respectively; progression-free survival was 38% for both. With ENKTCL, stage and performance status increased mortality significantly (HR = 8.6; p < 0.001 and HR = 4.23; p = 0.04). In conclusion, disseminated disease had a dismal outcome and the onset of ENKTCL in this ethnically homogeneous European cohort was about a decade later than reported in Asian populations.

Lymphoma of the Uvula: Clinical, Morphological, Histopathological, and Genetic Characterization. A Nationwide Danish Study From 1980 to 2019.

Background: In the head and neck region the uvula is a rare site for extranodal lymphomas to develop. In this national study, we present six cases and provide an overview of the current literature, characterizing the clinical and histopathological features of lymphomas involving this location. Materials and Methods: Clinical information was obtained retrospectively from patient records in a nationwide Danish study covering from 1980 through 2019. In order to validate the diagnoses, uvular tissue specimens were examined histologically and immunohistochemically and if relevant for subtyping, cytogenetic rearrangements were investigated. Results: We present six cases of lymphomas involving the uvula, of which four of the cases were diagnosed with a B-cell lymphoma (two diffuse large B-cell lymphomas, one extranodal marginal zone B-cell lymphoma and one Mantle cell lymphoma), while two were diagnosed with a T-cell lymphoma (one peripheral T-cell lymphoma and one natural killer/T-cell lymphoma). Presenting symptoms included swelling, pain and ulceration of the uvula. Treatment was comprised of radiotherapy and/or chemotherapy, with T-cell lymphomas showing a poorer outcome than B-cell lymphomas. Conclusion: Lymphoma of the uvula is rare, with few case reports being reported in the literature. The most frequent histological subtypes reported are extranodal marginal zone B-cell lymphoma and peripheral T-cell lymphoma. When encountering a swollen, painful and/or ulcerated uvula, the clinician should always consider malignancy as a possible cause. Lymphoma of the uvula is a possible diagnosis and if this is the case, there is a high risk of disseminated disease at the time of diagnosis.

Clinicopathologic characteristics of Burkitt lymphoma of the head and neck in a non-endemic region-a Danish nationwide study.

BACKGROUND: Burkitt lymphoma rarely presents in head and neck (H&N) in Western countries. AIMS/OBJECTIVES: We aimed to characterise clinicopathological features of H&N Burkitt lymphoma in Denmark representing a non-endemic region. MATERIAL AND METHODS: Clinical records were reviewed for a nationwide cohort of patients diagnosed with H&N Burkitt lymphoma in Denmark between 1980 and 2018. The diagnosis was histologically validated. RESULTS: Thirty-four patients with H&N Burkitt lymphoma (highest incidence in age group 0-9 years, male-to-female ratio 4.7:1) were included. Thirty-three lymphomas (97%) were extranodal. The tumour was visible at the clinical examination in 81% (n = 22) of the cases. The palatine tonsils were the most frequent location (n = 13, 38%) and 52% (n = 17) of the patients were diagnosed in advanced stage. Lymphoma was the tentative clinical diagnosis in 23% of the cases. The 5-year overall- and disease-specific survival was 78% and 81%, respectively. CONCLUSIONS: Due to the rarity of Burkitt lymphoma of the H&N, there is a high risk of clinical misdiagnosis. Our findings suggest which symptoms and clinical presentations to be aware of in the diagnostics work up that could lead to the diagnosis of Burkitt lymphoma.

Lymphoma of the Sublingual Gland: Clinical, Morphological, Histopathological, and Genetic Characterization.

Background: Lymphoma of the sublingual gland is rare, representing 1% of all salivary gland lymphomas. In this case report, we present three new cases and compare them to previously published cases, with the aim of characterizing the clinical, morphological, histopathological, and genetic features of this type of malignancy. Materials and Methods: We provide a clinical description of three cases along with a characterization of the microscopic features, including morphology, and immunohistochemistry. In addition, we analysed possible cytogenetic rearrangements with the use of fluorescence in situ hybridization (FISH). Results: Case 1: A 61-year-old male presenting with a painless swelling of the floor of the mouth diagnosed as extranodal marginal zone lymphoma (EMZL) of the left sublingual gland. The patient is alive with no evidence of disease after his fourth treatment regimen following several relapses. Case 2: A 68-year-old female with a prior history of mantle cell lymphoma (MCL) presenting with a tender swelling of the left sublingual gland as well as the right submandibular gland. The lesions were diagnosed as relapsing MCL. The patient died of unrelated causes after 18 months of treatment. Case 3: A 75-year-old female presenting with a swelling of the floor of the mouth diagnosed as follicular lymphoma (FL) of the left sublingual gland. The patient received chemotherapy along with radiotherapy and was still alive 10 years after the diagnosis. Conclusion: The three cases of sublingual gland lymphomas presented in this case report resemble lymphomas of other major salivary glands. The clinician should be aware of this type of malignancy and that the clinical presentation may not differ from benign lesions or other more common malignancies in this location.

Infected "Mycotic" Aneurysm of the Common Carotid Artery-A Differential Diagnosis to Tumor of the Neck.

Introduction: Infected "mycotic" Aneurysm (IA) of the extracranial carotid artery is a rare condition that can be fatal if mistaken for other pathology. An 83-year-old man presented with a mass on the neck initially suspected malignant. Weeks later it grew rapidly and was found to be an IA, thus requiring acute surgery. Via this case report, we discuss diagnostics and approach when diagnosing masses in relation to vessels of the neck not readily explained. Case Report: After diagnostic imaging and clinical assessment an unknown primary tumor of the neck was suspected. Fine needle aspiration was inconclusive. The patient did not present with any signs of infection or neurological symptoms-only discomfort and pain. Approximately two weeks later, the mass grew and the patient became dysphagic, febrile, and confused. Computed tomography angiography revealed an IA of the right common carotid artery. The patient underwent acute surgery consisting of ligation of the internal and external carotid arteries and resection of the internal jugular vein. The pathogen found was E. coli, supposedly from the bladder after surgical intervention due to polyposis. Conclusion: IA is a very rare entity and can have many etiologies. Since it can be fatal, it is necessary to keep IA in mind when diagnosing masses in relation to vessels of the neck. As shown in this case of a E. coli-induced IA, patients can present with atypical symptoms, on diagnostic imaging it can be mistaken for other pathology, and pathogenesis can be unclear.

Risk of bias and brand explain the observed inconsistency in trials on glucosamine for symptomatic relief of osteoarthritis: a meta-analysis of placebo-controlled trials.

OBJECTIVE: To determine whether study sponsor, chemical formulation, brand of glucosamine, and/or risk of bias explain observed inconsistencies in trials of glucosamine's efficacy for treating pain in osteoarthritis (OA). METHODS: A systematic review and stratified meta-analysis of randomized placebo-controlled trials was performed, and random-effects models were applied with inconsistency (I(2) ) and heterogeneity (tau(2) ) estimated using Review Manager and SAS, respectively. The major outcome was reduction of pain; the standardized mean difference (SMD [95% confidence interval (95% CI)]) served as effect size. RESULTS: The inclusion criteria yielded 25 trials (3,458 patients). Glucosamine moderately reduced pain (SMD -0.51 [95% CI -0.72, -0.30]), although a high level of between-trial inconsistency was observed (I(2) = 88%). The single most important explanation (i.e., covariate) was brand, reducing heterogeneity by 41% (P = 0.00032). Twelve trials (1,437 patients) using the Rottapharm/Madaus product resulted in significant pain reduction (SMD -1.07 [95% CI -1.47, -0.67]), although a sensitivity analysis of 3 low risk of bias trials using the Rottapharm/Madaus product showed less promising results (SMD -0.27 [95% CI -0.43, -0.12]), which is only a small effect size. Thirteen trials (1,963 patients) using non-Rottapharm/Madaus products consistently failed to show a reduction in pain (SMD -0.11 [95% CI -0.46, 0.24]). The second most important explanation was overall risk of bias (reducing heterogeneity by 32%). CONCLUSION: Most of the observed heterogeneity in glucosamine trials is explained by brand. Trials using the Rottapharm/Madaus glucosamine product had a superior outcome on pain in OA compared to other preparations of glucosamine. Large inconsistency was found, however. Low risk of bias trials, using the Rottapharm/Madaus product, revealed a small effect size.