Search

The classification of clonal plasmacytoid dendritic cell (pDC) proliferation associated with myeloid neoplasms remains a topic of ongoing debate. Although the fifth edition of the World Health Organization classification classifies clonal pDC proliferation into two categories, it is unclear whether this classification adequately captures the complexities of clonal pDC pathogenesis. We present a clinical case featuring myeloid sarcoma with pDC-like cells in cervical lymph nodes and bone marrow (BM). Analysis of biopsy specimens and BM aspirate revealed two distinct cellular populations expressing myeloid and pDC markers. One population exhibited myeloid leukemia and monocyte markers, including MPO, CD13, CD33, CD11b, and CD14, while the other manifested an immunophenotype reminiscent of pDCs, characterized by expression of CD56 and CD123. Additionally, whole exome sequencing and RNA sequencing of BM mononuclear cells were conducted to explore the pathophysiology of this rare malignancy, and unveiled pDC-like cell proliferation driven by IKZF1 and ETV6 mutations originating from clonal hematopoiesis initiated by a DNMT3A mutation. Notably, venetoclax-based therapy exhibited efficacy for achieving and sustaining complete remission. This case provides pivotal insights into the mechanistic aspects of pDC/pDC-like cell proliferation in myeloid sarcoma, offering valuable perspectives on therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Leukaemia is the most common cancer in children, however, there is still a big gap in knowledge about the genomic alterations in childhood acute myeloid leukaemia (AML) compared to adult AML. Relapsed AML remains as a leading cause of cancer deaths among children. This study aims to understand the molecular mechanisms of relapsed AML by elucidating the mutational landscape before and during relapse. Materials and Methods: Whole genome sequencing was performed on matched samples collected at diagnosis, remission and relapse from three patients of de novo childhood AML. Sanger sequencing was performed for validation in 47 patients' samples, followed by functional analysis. Results: Overall, we identified 312 somatic mutations including synonymous single nucleotide variants (SNVs), missense SNVs, deletions and insertion frameshifts, stopgains and splice sites. After prioritisation, only 46 variants were present at diagnosis (13-17 mutations per patient) and 49 variants at relapse (12-20 mutations per patient). Out of 81 variants, there were 35 new variants detected at relapse but not present at diagnosis. Six potential driver mutations (KIT, CDC73, HNF1A, RBM10, ZMYM4 and ETV6) were identified in predicting relapse for the 3 patients, with recurrent mutations of the ETV6 gene in 2 patients. Functional analysis of the ETV6 mutation showed that ETV6 lost its tumour suppressive function when both mutant ETV6 p.P25fs and ETV6 p.N75fs were tested in vitro. Conclusion: This study has uncovered the mutational landscape in three local childhood AML patients and contributes to a better understanding of the molecular mechanisms of relapsed AML. [ABSTRACT FROM AUTHOR]

Background: ETV6 gene rearrangement is the molecular hallmark of secretory carcinoma (SC), however; the nature, frequency, and clinical implications of atypical ETV6 signal patterns by fluorescence in situ hybridization (FISH) has not yet been systematically evaluated in salivary gland neoplasms. Methods: The clinical, histopathologic, immunohistochemical and molecular features of seven salivary SCs, including four cases with atypical ETV6 FISH patterns, were retrospectively analyzed along with a critical appraisal of the literature on unbalanced ETV6 break-apart in SCs. Results: The patients were four males and three females (31–70 years-old). Five presented with a painless neck mass and two patients with recurrent disease had a history of a previously diagnosed acinic cell carcinoma of the buccal mucosa. Histologically, there were varied combinations of microcystic, papillary, tubular, and solid patterns. All tumors were diffusely positive for S100 and/or SOX10, while 2 cases also showed luminal DOG1 staining. Rearrangement of the ETV6 locus was confirmed in 5/7 cases, of which 3 cases showed classic break-apart signals, 1 case further demonstrated duplication of the ETV6 5'end and the other loss of one copy of ETV6. Two cases harbored ETV6 deletion without rearrangement. Two of the 4 cases with atypical ETV6 FISH patterns represented recurrent tumors, one with widespread skeletal muscle involvement, bone and lymphovascular invasion. Surgical treatment resulted in gross-total resection in all 7 cases, with a median follow up of 9.5 months post-surgery for primary (n = 3) and recurrent disease (n = 1). Conclusion: Duplication of the distal/telomeric ETV6 probe represented the most common (26/40; 65%) variant ETV6 break-apart FISH pattern in salivary SC reported in the literature and appears indicative of an aggressive clinical course. [ABSTRACT FROM AUTHOR]

Yang Gou,* Yongjie Tang,* Shuiqing Liu, Siyu Cheng, Xiaojuan Deng, Qin Wen, Yimei Feng, Xiangui Peng, Ping Wang, Xi Zhang Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Wang, Medical Center of Hematology, The Xinqiao Hospital of Army Medical University, Chongqing, People’s Republic of China, Email wpii_2002@sina.comAbstract: The ETV6::PDGFRB fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with ETV6::PDGFRB presenting myeloid and lymphoid neoplasms successively have not been reported. Here, we report the first case of a 35-year-old man with myeloid and lymphoid neoplasms harboring an ETV6::PDGFRB fusion gene who demonstrated poor response to imatinib. The patient was diagnosed with an ETV6::PDGFRB fusion gene myeloid neoplasm on initial diagnosis at our hospital. After 5 months of treatment with imatinib, he was diagnosed with T-cell lymphoblastic lymphoma. ETV6::PDGFRB turned negative after increasing the dose of imatinib, but enlarged superficial lymph nodes reappeared the following year. Notably, the patient exhibited a worse response to imatinib treatment. This study describes this rare case and speculates on a possible mechanism.Keywords: ETV6, PDGFRB, fusion, myeloid/lymphoid neoplasms, imatinib

Inherited hematologic malignancies are linked to a heterogenous group of genes, knowledge of which is rapidly expanding using panel-based nextgeneration sequencing (NGS) or whole-exome/whole-genome sequencing. Importantly, the penetrance for these syndromes is incomplete, and disease development, progression or transformation has critical clinical implications. With the earlier detection of healthy carriers and sequential monitoring of these patients, clonal hematopoiesis and somatic driver variants become significant factors in determining disease transformation/progression and timing of (preemptive) hematopoietic stem cell transplant in these patients. In this review, we shed light on the detection of probable germline predisposition alleles based on diagnostic/prognostic 'somatic' NGS panels. A multi-tier approach including variant allele frequency, bi-allelic inactivation, persistence of a variant upon clinical remission and mutational burden can indicate variants with high pre-test probability. We also discuss the shared underlying biology and frequency of germline and somatic variants affecting the same gene, specifically focusing on variants in DDX41, ETV6, GATA2 and RUNX1. Germline variants in these genes are associated with a (specific) pattern or over-/underrepresentation of somatic molecular or cytogenetic alterations that may help identify the underlying germline syndrome and predict the course of disease in these individuals. This review is based on the current knowledge about somatic drivers in these four syndromes by integrating data from all published patients, thereby providing clinicians with valuable and concise information. [ABSTRACT FROM AUTHOR]

The gene encoding for transcription factor ETV6 presents recurrent lesions in hematologic neoplasms, most notably the ETV6-RUNX1 rearrangement in childhood B-ALL. The role of ETV6 for normal hematopoiesis is unknown, but loss of its function probably participates in oncogenic procedures. In myeloid neoplasms, ETV6-locus (12p13) deletions are rare but recurrent; ETV6 translocations are even rarer, but those reported seem to have phenotype-defining consequences. We herein describe the genetic and hematologic profile of myeloid neoplasms with ETV6 deletions (10 cases), or translocations (4 cases) diagnosed in the last 10 years in our institution. We find complex caryotype to be the most prevalent cytogenetics among patients with 12p13 deletion (8/10 patients), with most frequent coexisting anomalies being monosomy 7 or deletion 7q32 (5/10), monosomy 5 or del5q14-15 (5/10), and deletion/inversion of chromosome 20 (5/10), and most frequent point mutation being TP53 mutation (6/10 patients). Mechanisms of synergy of these lesions are unknown. We describe the entire genetic profile and hematologic phenotype of cases with extremely rare ETV6 translocations, confirming the biphenotypic T/myeloid nature of acute leukemia associated to ETV6-NCOA2 rearrangement, the association of t (1;12) (p36; p13) and of the CHIC2-ETV6 fusion with MDS/AML, and the association of the ETV6-ACSL6 rearrangement with myeloproliferative neoplasm with eosinophilia. Mutation of the intact ETV6 allele was present in two cases and seems to be subclonal to the chromosomal lesions. Decoding the mechanisms of disease related to ETV6 haploinsufficiency or rearrangements is important for the understanding of pathogenesis of myeloid neoplasms and fundamental research must be guided by observational cues. [ABSTRACT FROM AUTHOR]

Inherited hematologic malignancies are linked to a heterogenous group of genes, knowledge of which is rapidly expanding using panel-based next-generation sequencing (NGS) or whole-exome/whole-genome sequencing. Importantly, the penetrance for these syndromes is incomplete, and disease development, progression or transformation has critical clinical implications. With the earlier detection of healthy carriers and sequential monitoring of these patients, clonal hematopoiesis and somatic driver variants become significant factors in determining disease transformation/progression and timing of (preemptive) hematopoietic stem cell transplant in these patients. In this review, we shed light on the detection of probable germline predisposition alleles based on diagnostic/prognostic ‘somatic’ NGS panels. A multi-tier approach including variant allele frequency, bi-allelic inactivation, persistence of a variant upon clinical remission and mutational burden can indicate variants with high pre-test probability. We also discuss the shared underlying biology and frequency of germline and somatic variants affecting the same gene, specifically focusing on variants in DDX41, ETV6, GATA2 and RUNX1. Germline variants in these genes are associated with a (specific) pattern or over-/underrepresentation of somatic molecular or cytogenetic alterations that may help identify the underlying germline syndrome and predict the course of disease in these individuals. This review is based on the current knowledge about somatic drivers in these four syndromes by integrating data from all published patients, thereby providing clinicians with valuable and concise information.

ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high‐risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia‐related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co‐mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild‐type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia. [ABSTRACT FROM AUTHOR]

The synuclein family, consisting of α-, β-, and γ-synuclein, is primarily expressed in neurons. Mutations of α- and β-synuclein have been linked to Parkinson’s disease and dementia with Lewy bodies, respectively. Recent studies have shown that synucleins are upregulated in various tumors, including breast, ovarian, meningioma, and melanoma, and high synuclein expression is associated with poor prognosis and drug resistance. We report a novel rearrangement of β-synuclein in a pediatric T-cell acute lymphoblastic leukemia (T-ALL) case, where β-synuclein (SNCB) is fused in-frame with ETS variant transcription factor 6 (ETV6), a gene frequently rearranged in acute leukemia including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-ALL. An additional case of β-synuclein rearrangement was identified in a squamous cell carcinoma of the lung through analysis of the public TCGA database. Both rearrangements involve the C-terminal of β-synuclein. Since β-synuclein shares extensive amino acid similarities with α-synuclein and α-synuclein binds to 14-3-3, an important regulator of apoptosis, the rearranged β-synuclein may contribute to tumorigenesis by deregulating apoptosis. In addition, overexpression of synucleins has been shown to increase cell proliferation, suggesting that the rearranged β-synuclein may also deregulate the cell cycle. [ABSTRACT FROM AUTHOR]

Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200–1228, 2022). [ABSTRACT FROM AUTHOR]

E26-transforming specific (ETS) variant 6 (ETV6) is a transcription factor regulating the expression of interferon stimulating genes (ISGs) and involved in the embryonic development and hematopoietic regulation, but the role of ETV6 in host response to virus infection is not clear. In this study, we show that ETV6 was upregulated in DF-1 cells with poly(I:C) stimulation or IBDV, AIV and ARV infection via engagement of dsRNA by MDA5. Overexpression of ETV6 in DF-1 cells markedly inhibited IBDV-induced type I interferon (IFN-I) and ISGs expressions. In contrast, knockdown, or knockout of ETV6 remarkably inhibited IBDV replication via promoting IFN-I response. Furthermore, our data show that ETV6 negatively regulated host antiviral response to IBDV infection by interaction with TANK binding kinase 1 (TBK1) and subsequently inhibited its phosphorylation. These results uncovered a novel role of ETV6 as a pro-viral factor in host response by inhibiting TBK1 phosphorylation, furthering our understandings of RNA virus immunosuppression and providing a valuable clue to the development of antiviral reagents for the control of avian RNA virus infection. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases—TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-κB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM. [ABSTRACT FROM AUTHOR]

Background: Atypical/unbalanced rearrangement in salivary secretory carcinoma was observed and its incidence, patterns, and clinical significance remain unknown. Methods: One hundred and ninety-six cases of diagnosed secretory carcinoma were retrospectively reviewed. Fluorescence in situ hybridization for NTRK3/ ETV6::NTRK3 was conducted on cases carrying the atypical ETV6 fluorescence in situ hybridization signals. Cases without ETV6::NTRK3 were selected for nextgeneration sequencing to reveal novel partner. Immunohistochemistry and follow-up were performed. Results: Twenty-seven cases were confirmed to carry the atypical ETV6 fluorescence in situ hybridization signal patterns. The most common type of abnormality was the duplication of ETV6 50 end (1Y1GnR, n ≥ 2) with the incidence of 81.5% (22/27). Seventeen of 19 were identified with ETV6::NTRK3 and 2 with ETV6::RET. The immunophenotype was similar to the typical secretory carcinoma group. TrkC exhibited 68.8% sensitivity and 100% specificity for NTRK3 fusion. Microscopically, 5 out of 21 were accompanied by necrosis and 3 out of 21 showed neural invasion. Four out of 19 patients showed local relapse, 2 developed distant metastasis, and 1 died of disease. The patients with distant metastasis and even dead were both harbored ETV6::RET rearrangement. Statistical analysis revealed that there were no significant differences in disease-free survival, relapse-free survival, and distant metastasis-free survival between atypical and typical groups. Conclusion: Gene rearrangement can be identified although the fluorescence in situ hybridization signals were atypical, which was instructive for secretory carcinoma diagnosis in clinical practice. The signals of partners were also always atypical which may have an impact to the efficacy of targeted drugs. There was no statistical evidence that this group possessed worse prognosis. However, secretory carcinomas with ETV6::RET have dismal prognosis than those with ETV6::NTRK3. [ABSTRACT FROM AUTHOR]

Abstract Background A small but important proportion of patients (4–10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT). Methods 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations. Results In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028). Conclusions We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.

Germline mutations in ETV6 gene cause inherited thrombocytopenia with leukemia predisposition. Here, we report on functional validation of ETV6 W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thrombocythemia (ET). In-silico analysis predicted impaired DNA binding due to W380R mutation. Functional analysis showed that this mutation prevents the ETV6 protein from localizing into the cell nucleus and impairs the transcriptional repression activity of ETV6. Based on the germline ETV6 mutation, ET probably started with somatic JAK2 V617F mutation, whereas ALL could be caused by diverse mechanisms: high-hyperdiploidity; somatic deletion of exon 1 IKZF1 gene; or somatic mutations of other genes found by exome sequencing of the ALL sample taken at the diagnosis.

Abstract Background Philadelphia‐like (Ph‐like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America. Aim This study evaluated the frequency and clinical and biological characteristics of Ph‐like ALL in a pediatric cancer center in Colombia. Methods The Ph‐like genetic profile was analyzed by a low‐density array (LDA). Samples from patients with Ph‐like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto‐oncogene 1, non‐receptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification. Results Data from 121 patients were analyzed. Fifteen patients (12.4%) had Ph‐like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph‐like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%). Conclusions Ph‐like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.

• The detection of PDGFRA rearrangements in myeloid/lymphoid neoplasms is critical for patient medical management. • Chromosomes and the FIP1L1/CHIC2/PDGFRA FISH probe set are insufficient to characterize t(4;12)(q12;p13) in hematologic neoplasms. • Next generation sequencing outperforms traditional cytogenetic techniques in the molecular characterization of t(4;12)(q12;p13). The t(4;12)(q12;p13) has been rarely reported in both myeloid/lymphoid neoplasms with eosinophilia (ETV6/PDGFRA gene fusion) and acute myeloid leukemia (AML) (ETV6/CHIC2 gene fusion). The ability to accurately characterize t(4;12) is critical as myeloid neoplasms with PDGFRA rearrangements may be amenable to tyrosine kinase inhibitor (TKI) therapy. Herein, we describe a 60-year-old male with newly diagnosed AML and t(4;12)(q12;p13) by conventional chromosome studies. While the ETV6 break-apart fluorescence in situ hybridization (FISH) probe set demonstrated a balanced ETV6 gene rearrangement, the FIP1L1/CHIC2/PDGFRA tri-color and PDGFRA break-apart FISH probe sets could not resolve the ETV6 gene fusion partner. Mate-pair sequencing (MPseq), a next-generation sequencing assay, was subsequently performed and identified an ETV6 gene rearrangement (at 12p13) that involved an intergenic chromosomal region at 4q12, located between the CHIC2 and PDGFRA gene regions. Having excluded involvement by the PDGFRA gene region, the patient will not be considered for TKI therapy at any point during his medical management. The accurate characterization of structural rearrangements by NGS-based technologies, as demonstrated in this case, highlights the clinical relevance and potential impact on patient medical management of modern cytogenetic techniques. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the sinonasal tract is relatively rare and morphologically and genetically heterogeneous. We report the case of an adult male with a left sphenoid sinus mass. A biopsy revealed an undifferentiated carcinoma composed of sheets of epithelioid cells lacking keratinization and glandular formation. The tumor was associated with a prominent lymphoplasmacytic inflammatory infiltrate. Immunohistochemical staining demonstrated diffuse expression of pankeratin and p63; it was negative for p16. In addition, EBER was also negative. Morphologically the findings raised the possibility of non-keratinizing squamous cell carcinoma. RNA sequencing was undertaken to exclude the possibility of NUT carcinoma; interestingly, this revealed a novel ETV6-TNFRSF8 fusion transcript, which was independently confirmed by fluorescence in situ hybridization. The current case is illustrative because it broadens our understanding of the molecular pathogenesis of non-keratinizing squamous cell carcinoma and adds to the diversity of ETV6-rearranged malignancies. [ABSTRACT FROM AUTHOR]

The translocation between chromosomes 15 and 17 t(15;17) at the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) is thought to be specific for acute promyelocytic leukemia (APL). We present a case of acute leukemia with evidence of t(15;17) by banding karyotype, FISH, and PCR, with rare microgranular promyelocytes and significant basophilia detected on marrow aspirate, and an ETV6 missense mutation by molecular diagnostic testing. The patient underwent treatment with isotretinoin (ATRA) and arsenic trioxide (ATO) with attainment of a morphologic remission at the end of induction. There was no evidence of coagulopathy or basophil granule release with therapy. To our knowledge, this is the first report of the co-occurrence of APL with marrow basophilia in conjunction with an ETV6 mutation. The prognostic impact of an ETV6 mutation in this setting is unclear. [ABSTRACT FROM AUTHOR]

Translocation t(4;12)(q11-13; p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis. [ABSTRACT FROM AUTHOR]

Background: A small but important proportion of patients (4–10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT). Methods: 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations. Results: In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028). Conclusions: We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them. [ABSTRACT FROM AUTHOR]

We and others recently described families with germline heterozygote mutations in ETV6 leading to autosomal dominant highly penetrant thrombocytopenia, red cell macrocytosis and predisposition to leukemia.The bone marrow of affected individuals shows erythroid dysplasia and hyperplasia of small, hypolobulated immature megakaryocytes suggesting a differentiation arrest. This discovery led to subsequent studies that confirmed our findings and to additional larger studies that demonstrated a 1% frequency of germline ETV6 mutations among 4405 individuals with acute lymphoblastic leukemia. Additionally, a 4.5% prevalence of ETV6 germline mutations was reported in families with inherited thrombocytopenia. Preliminary data suggest that decreased ETV6 function leads to MK maturation arrest, impaired platelet production and differentially expressed platelet transcripts among individuals affected with ETV6 mutations when compared to control relatives. Additionally, individuals with some ETV6 mutation exhibit bleeding that appears disproportionate to the mildly reduced platelet count, suggesting a platelet function deficit. Furthermore, recent studies describe decreased ability of platelets from individuals with ETV6 mutations to spread on fibrinogen covered surfaces. Overall, ETV6 germline mutations represent a new cancer predisposition thrombocytopenia with platelet dysfunction.

ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia, characterized by a bleeding tendency and predisposition to hematological malignancies. The similarity in symptoms makes differentiating immune and congenital thrombocytopenia challenging. We report a 5-year-old girl who presented with chronic thrombocytopenia associated with repetitive and long-lasting epistaxis, leading to blood transfusion for severe anemia. Blood tests showed thrombocytopenia (52 × 103/µL) with normal-sized platelets and transiently low von Willebrand factor (VWF) levels (VWF:RCo 13%, VWF:Ag 50%); therefore, von Willebrand disease type 2 was initially suspected. Repetition of the blood tests revealed normal levels of VWF. Exome and Sanger sequencing identified a germline ETV6 heterozygous variant, c.641C > T:p.(P214L). No additional pathogenic variants were found, including VWF, in the gene panel testing of the 53 known target causative genes for thrombocytopenia. High-throughput exome sequencing for chronic thrombocytopenia can be utilized to differentially diagnose ETV6-related thrombocytopenia from chronic/intractable immune thrombocytopenia and to effectively monitor malignancy. [ABSTRACT FROM AUTHOR]

Inherited thrombocytopenias correspond to a group of hereditary disorders characterized by a reduced platelet count, platelet dysfunction, and a family history of thrombocytopenia. It is commonly associated with mucocutaneous bleeding. Thrombocytopenia results from mutations in genes involved in megakaryocyte differentiation, platelet formation, and clearance. Here we report on a patient presenting with severe syndromic inherited thrombocytopenia manifesting as spontaneous mucocutaneous bleeds, requiring frequent platelet transfusions. Thrombocytopenia was explained by the presence of 4 mutations in 3 hematopoietic transcription factor genes: FLI1, RUNX1, and ETV6. The patient was successfully treated with high-dose eltrombopag at 150 mg/day, an orally available non-peptide thrombopoietin receptor agonist. Since the start of treatment 23 months ago, the manifestations of bleeding have resolved, and no platelet transfusions or corticosteroids have been required. The patient has no clinical or laboratory evidence of myeloid malignancy so far. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare CD4+/CD56+ hematological malignancy with aggressive clinical course and poor prognosis. Histologically, BPDCN is characterized by a diffuse, monomorphous infiltration of cutaneous, subcutaneous, and sometimes other tissues such as lymph nodes and bone marrow, by medium-sized neoplastic cells with blastoid morphology. Typically, there is absence of lymphocytic infiltrate. Diagnosis relies on immunophenotypic expression of CD4, CD56, and the more specific markers of plasmacytoid dendritic cells CD123, CD303/BDCA2, and TCL1.We report a case of a 57-year-old man who presented a 4 cm-long solitary, erythemateous lesion on the right cheek, corresponding to a BPDCN but initially misdiagnosed as T-cell lymphoma. The case was characterized by conservation of skin appendages and a diffuse T-cell infiltrate, which strongly expressed PD1. ETV6 and MYC fluorescent in situ hydridization and next-generation sequencing were performed on this tumor.The main difficulties to diagnose BPDCN were the atypical cytology of tumor cells and their CD4 and CD43 expression, as can be seen in T-cell lymphomas. The diffuse T-cell infiltrate was also challenging. The patient is still alive 29 months after diagnosis, suggesting a potential prognostic impact of T-cell infiltration and the absence of MYC translocation. The presence of TET2 and ASXL1 mutations supporting BPDCN and reinforcing the hypothesis of a myeloid origin.

Abstract Background ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance. Methods Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs). Results ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity. Conclusions Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs.

Germline pathogenic ETV6 variants have been discovered in families with inherited thrombocytopenia and predisposition to hematological and solid malignancies. We present a patient with short stature who was initially diagnosed with chronic immune thrombocytopenia. Subsequently, the patient developed acute lymphoblastic leukemia, followed by mammary analog secretory carcinoma. Sequencing analysis identified an ETV6 c.641C > T (p.Pro214Leu) germline variant. The variant protein exhibited attenuated nuclear localization, increased protein degradation, and reduced transcription repression function. Our findings suggest that the ETV6 gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in patients with pathogenic ETV6 variants. [ABSTRACT FROM AUTHOR]

Background: Secretory carcinoma of the salivary gland (SC) is a new entity that harbours a specific ETV6 gene rearrangement. The clinical behaviour of this tumour is not well-known as it is a relatively new entity but it is generally considered as a tumour of low malignant potential. The objective of the study was to find out the frequency of ETV6 translocation in cases diagnosed based on histology and immunohistochemistry, to study morphological features and immunohistochemical findings of our cases and to determine the survival and disease-free status of our patients. Methods: Twenty-five diagnosed cases of SC were retrieved from the archives of SKMCH and RC. Diagnosis was made primarily based on morphology and immunohistochemistry. Immunohistochemistry includes S100, p63, mammaglobin, DOG 1, GCDFP-15, TTF-1, GATA3, SMA, AMA, and AR. The diagnosis was further confirmed by molecular testing, i.e., Fluorescence in situ hybridization (FISH) studies to observe specific ETV6 gene break. Follow up of the patients was done by developing a questionnaire. Statistical analysis of the data was done using SPSS-23.0. Results: The mean age of diagnosis was 41±17.4 and the male to female ratio was 1.5:15. The mean size of the tumour was 45.48±27.35. The most common site of the tumour was parotid gland (60%). On morphology, SC showed a wide range of morphological patterns, most common being the tubular, microcystic, intraductal, and papillary. Immunohistochemical stains mammaglobin (22/22), GCDFP-15(15/15) and GATA3 (10/10) showed 100% positive result. However, all cases were negative for p63 (0/18) and DOG 1(0/11). ETV6 break was seen in 17/17 cases (100%). The mean disease-free survival was 75 months and the overall survival was 51.90±2.80 months. Conclusion: This study highlights the presence of specific molecular alteration in all cases, which were diagnosed based on morphology and immunohistochemistry. [ABSTRACT FROM AUTHOR]

Keywords: thrombocytopenia; germline predisposition; RUNX1; ETV6; ANKRD26 EN thrombocytopenia germline predisposition RUNX1 ETV6 ANKRD26 e119 e122 4 05/19/20 20200515 NES 200515 Germline mutations in runt-related transcription factor 1 ( I RUNX1 i ), ETS variant transcription factor 6 ( I ETV6 i ) and ankyrin repeat domain 26 ( I ANKRD26 i ) have been recognised as responsible of autosomal dominant inherited thrombocytopenia or platelet disorder, with an increased risk of developing haematological malignancies (HM), mainly acute leukaemia (AL) and myelodysplastic syndrome (MDS) (Duployez I et al. i , [6]). Only a few studies have focussed on the morphological aspects in bone marrow (BM) from patients with a germline disorder. BM from all six patients with congenital thrombocytopenia displayed baseline morphological abnormalities in the megakaryocyte (MK) lineage. On the other hand, the presence of a characteristic dysmegakaryopoiesis in a patient with unexplained thrombocytopenia and normal platelet size should alert to the possibility of an underlying germline disorder, especially in young patients. [Extracted from the article]

WW domain binding protein 1‐like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6‐RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non‐haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4‐family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l‐deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis. [ABSTRACT FROM AUTHOR]

Purpose: Mammary analogue secretory carcinoma (SC) of the parotid gland is a relatively uncommon cancer associated with the ETV6–NTRK3 fusion product similar to breast cancer. The clinical characteristics and outcome of treatment were reviewed for patients with this tumor at our hospital. Methods: In this retrospective case series, 24 patients with a diagnosis of acinic cell carcinoma (AcCC) of the parotid gland were classified as having either SC or AcCC based on analysis of the ETV6–NTRK3 fusion gene. These two groups were compared with respect to their clinical and imaging characteristics (MRI/US), cytologic findings, accuracy of fine-needle aspiration cytology and frozen section, treatment outcomes, and immunohistochemical findings. Results: Based on re-classification by ETV6–NTRK3 fusion gene analysis, the diagnosis was SC in 14 patients and AcCC in 10 patients. The SC group had a significantly higher proportion of male patients and was also significantly younger than the AcCC group. Imaging studies revealed that SC was significantly more likely to show internal heterogeneity. Correct grading of both tumors was comparable by fine needle aspiration, with the rate being 60% for AcCC and 50% for SC. Diagnosis by frozen section biopsy diagnosis obtained the correct grade in 90% of the AcCC group and 93% of the SC group. Conclusions: In 24 patients previously diagnosed with AcCC, re-analysis of the ETV6–NTRK3 fusion product indicated that 14 patients actually had SC. Although AcCC and SC show similarities of their biological aggressiveness and prognosis, patients with SC were significantly more likely to be male and younger. [ABSTRACT FROM AUTHOR]

Human thirty-eight-negative kinase-1 (TNK1) is implicated in cancer progression. The TNK1 ubiquitin-associated (UBA) domain binds polyubiquitin and plays a regulatory role in TNK1 activity and stability. No experimentally determined molecular structure of this unusual UBA domain is available. We fused the UBA domain to the 1TEL variant of the translocation ETS leukemia protein sterile alpha motif (TELSAM) crystallization chaperone and obtained crystals diffracting as far as 1.53 Å. GG and GSGG linkers allowed the UBA to reproducibly find a productive binding mode against its host 1TEL polymer and crystallize at protein concentrations as low as 0.2 mg/mL. Our studies support a mechanism of 1TEL fusion crystallization and show that 1TEL fusion crystals require fewer crystal contacts than traditional protein crystals. Modeling and experimental validation suggest the UBA domain may be selective for both the length and linkages of polyubiquitin chains. [Display omitted] • Structure of the unusual TNK1 UBA domain was determined from a 1TEL-UBA fusion construct • 1TEL-UBA fusions crystallize at protein concentrations as low as 0.2 mg/mL • The structure of the TNK1 UBA domain allows prediction of ubiquitin interactions Nawarathnage et al. use the 1TEL protein crystallization tool to determine the atomic structure of the human thirty-eight negative kinase 1 ubiquitin association (UBA) domain, implicated in cancer progression. They additionally use the 1TEL-UBA fusion protein to probe the mechanism by which 1TEL facilitates protein crystallization. [ABSTRACT FROM AUTHOR]

Abstract Background Wnt and Wnt‐associated pathways play an important role in the genetic etiology of oligodontia, a severe form of tooth agenesis. Loss‐of‐function mutations in LRP6 , encoding a transmembrane cell‐surface protein that functions as a coreceptor in the canonical Wnt/b‐catenin signaling cascade, also contribute to genetic oligodontia. Methods and results We describe a three‐generation family with hereditary thrombocytopenia and oligodontia. Genome wide array analysis was performed. The array results from the index patient revealed an interstitial loss of 150 kb in 8p23.1 (chr8:6,270,299–6,422,558; hg19) encompassing MCPH1 and ANGPT2 and an interstitial loss of 290 kb in 12p13.2 (chr12:12,005,720–12,295,290; hg19) encompassing ETV6, BCL2L14 and LRP6. Conclusion This case report shows a three‐generation family with hereditary thrombocytopenia and oligodontia with a heterozygous 290 kb novel contiguous gene deletion in band p13.2 of chromosome 12, encompassing LRP6 and ETV6. In this report we discuss the clinical relevance of the deletion of both genes and illustrate the importance of thorough examination of oligodontia patients. Comprising not only the oral status but also the medical history of the patients and their relatives.

Background/aim: Mixed phenotype acute leukemia (MPAL) is a rare hematologic malignancy in which the leukemic cells cannot be assigned to any specific lineage. The lack of well-defined, pathogenetically relevant diagnostic criteria makes the clinical handling of MPAL patients challenging. We herein report the genetic findings in bone marrow cells from two pediatric MPAL patients., Patients and Methods: Bone marrow cells were examined using G-banding, array comparative genomic hybridization, RNA sequencing, reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization., Results: In the first patient, the genetic analyses revealed structural aberrations of chromosomal bands 8p11, 10p11, 11q21, and 17p11, the chimeras MLLT10::PICALM and PICALM::MLLT10, and imbalances (gains/losses) on chromosomes 2, 4, 8, 13, and 21. A submicroscopic deletion in 21q was also found including the RUNX1 locus. In the second patient, there were structural aberrations of chromosome bands 1p32, 8p11, 12p13, 20p13, and 20q11, the chimeras ETV6::LEXM and NCOA6::ETV6, and imbalances on chromosomes 2, 8, 11, 12, 16, 19, X, and Y., Conclusion: The leukemic cells from both MPAL patients carried chromosome aberrations resulting in fusion genes as well as genomic imbalances resulting in gain and losses of many gene loci. The detected fusion genes probably represent the main leukemogenic events, although the gains and losses are also likely to play a role in leukemogenesis., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Secretory carcinoma (SC) of salivary glands is a newly described low‐grade malignancy characterized by the presence of ETV6 rearrangement. Only a few cases and very small series with cytomorphology were reported so far. Six cases of fine‐needle aspirations (FNAs) from afterward histologically, immunohistochemically and genetically confirmed SCs were retrieved from the archives of the authors. Ancillary immunocytochemistry (ICC) and translocation detection were performed on cell blocks (CBs). All aspirates were sufficiently cellular and cells were arranged in more or less cohesive groups with only mild nuclear polymorphism. The cytoplasm was eosinophilic, granulated and vacuolated, especially in CBs. Secretory material within the microcystic spaces was periodic acid‐Schiff (PAS) positive. Triple positivity of immunomarkers S‐100 protein, mammaglobin and vimentin was present. The proliferation index was low. Ancillary techniques suggested the possibility of SC in a few cytology cases; nevertheless, the final diagnosis was based on histomorphology, immunohistochemistry and genetics. The SC of salivary glands is detectable pre‐operatively using ICC and genetics. The presence of the diagnostic ETV6 rearrangement increases the accuracy of FNA to the maximum. According to the Milan system, cases genetically not confirmed should be categorized as Suspicious for Malignancy or Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP), both requiring surgery. [ABSTRACT FROM AUTHOR]

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi‐ or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi‐allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6. [ABSTRACT FROM AUTHOR]

Mammary analogue secretory carcinoma of the salivary glands has morphological shares molecular similarities to secretory carcinoma of the breast. Here, we report a 46‐year‐old woman who presented with a right submandibular gland mass. Fine needle aspiration differential diagnosis included oncocytosis, oncocytoma, acinic cell carcinoma and mammary analogue secretory carcinoma. We also review the current literature regarding clinical presentation and diagnostic workup of this entity. This is a case report of secretory carcinoma occurring in the submandibular salivary gland with extensive nerve involvement, unusual behaviour for this tumour which also more commonly involves the parotid gland. [ABSTRACT FROM AUTHOR]

Background: Our aim was to identify the number of cases of secretory carcinoma (SC) of the major salivary gland in a population‐based cohort and review its clinical behavior with long‐term follow‐up. Methods: All malignant salivary gland tumors (MSGTs) diagnosed between 1980 and 2014 were assessed for histological features compatible with SC and 140 were selected for further analysis. Results: Twenty two new cases of SC were identified, 19 of which were originally classified as acinic cell carcinoma, and 3 as adenocarcinoma, not otherwise specified (NOS). Lymph node involvement was less common in SC tumors (5%) than in the control group (11%). Disease recurrence was seen less frequently in SC (9%) than the control group (20%). Mean disease‐free survival was 192 months for SC compared with 162 months for controls (P = 0.15). Conclusion: The clinical course of SC is typically indolent with a low risk of relapse not significantly different from other low‐grade MSGT. [ABSTRACT FROM AUTHOR]