Genes, Chromosomes & Cancer最新文献

EWSR1::CREM fusion positive intrabdominal sarcomas defines a rare emerging group of aggressive mesenchymal neoplasms with a predilection for the celomic cavity and often manifesting perplexing immunophenotypic profile. There is no specific standard of care therapeutic option though anecdotal reports response to pazopanib have been reported. We report herein a case of a 62-year-old lady who presented with lower abdominal mass and pain. Right hemicolectomy performed showed a malignant epithelioid neoplasm. By immunohistochemistry, the tumor cells were positive for CD117, keratins, and mutation analysis was positive for KIT p.V5301 mutation, initially prompting a diagnosis of epithelioid gastrointestinal stromal tumor. However, the patient developed omental relapses while on imatinib and progressive disease persisted despite change to sunitinib. A re-review of the histopathology of both the hemicolectomy and relapsed omental sites showed marked cellular atypia, increased cellularity and mitosis in metastatic omental sites. By immunohistochemistry, the tumors in addition to CD117 positivity were also immunoreactive to keratins, synaptophysin, chromogranin, CD56, and MUC4. Next generation sequencing performed on both the primary and relapsed sites were positive for EWSR1::CREM gene fusion in addition to the KIT. P.V5301 mutation. The tumor was then reclassified as EWSR1::CREM fusion positive intrabdominal unclassified epithelioid sarcoma with concomitant KIT mutation of unknown significance. The patient was treated with cytotoxic chemotherapy and radiation therapy with partial response, but treatment was stopped because of complications and lack of tolerance. Pazopanib as a single agent was then initiated, and patients have continued to respond for the past 7 months. We highlight the significant immunophenotypic heterogeneity in these tumors and perform an extensive review of the literature of this specific entity and broader group of EWSR1::CREM/FUS fusion positive tumors ranging from quasi-benign to malignant and finally we underscore the therapeutic utility of pazopanib as a single agent in this rare group of aggressive sarcomas.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the t(5;14)(q31;q32) chromosomal translocation resulting in an IGH::IL3 fusion is an exceptionally rare lymphoid malignancy presenting with hypereosinophilia. Germline PAX5 alterations, including sequence variants and deletions, are associated with a selective susceptibility to BCP-ALL and lymphomas, based on a limited number of affected families worldwide. Here, we report a 6-year-old male with BCP-ALL with the t(5;14)(q31;q32) translocation and harboring a novel constitutional PAX5 variant (NM_016734.3:c.[295dup];[=], p.[(Ile99Asnfs*3)];[(=)]). Despite the low representation of the leukemic clone in the bone marrow, the IGH::IL3 fusion was identified by both fluorescent in situ hybridization (FISH) and optical genome mapping (OGM). Although hypereosinophilia poses a risk of multiorgan damage, our patient exhibited only pneumonia and asymptomatic neuroimaging alterations in the central nervous system. The patient achieved remission by the end of induction and is currently continuing maintenance therapy. In line with existing literature, familial segregation of the PAX5 variant demonstrated high but incomplete penetrance, as two leukemia-free mutation carriers displayed only subclinical B lymphocyte maturation abnormalities without hypogammaglobulinemia. Our report underscores the diagnostic utility of OGM, which unequivocally demonstrated the characteristic translocation. Typically, BCP-ALL in affected family members exhibits secondary somatic aberrations involving the wild-type PAX5 allele, including structural variants or loss of heterozygosity (LOH) of chromosome 9p, as well as PAX5 somatic mutations. To our knowledge, this is the first human report aligning with animal models, which suggests that secondary alterations activating the JAK–STAT pathway may potentially contribute to leukemogenesis in a PAX5 mutation background.

With the increasing use of next-generation sequencing, the classification of heretofore unclassified neoplasms is evolving rapidly. Specifically, gene fusions have emerged as context-specific defining genetic markers for an increasing number of entities, mostly of soft tissue, bone, and salivary gland origin. We describe four myoepithelial-like neoplasms of salivary (two) and pulmonary (two) origin, carrying recurrent NFATC2 fusions involving NUTM2B (three) and NUTM2A (one) as fusion partners. Patients were two females and two males aged 24–67 years (median, 33). The tumor size ranged from 1 to 4.5 cm. Treatment was surgery without (three) or with (one) adjuvant radiochemotherapy. No metastases or other primary tumors were found at the time of diagnosis. Three patients with follow-up (two with salivary, one with pulmonary tumor) were disease-free at 9, 11, and 31 months. Original diagnoses were “unclassified neoplasm” with consideration of adamantinoma-like Ewing sarcoma and myoepithelial neoplasm. Histology revealed infiltrating monotonous epithelioid to basaloid cells arranged into lobular aggregates, nests, and cords within variably sclerosed stroma containing extensive basement membrane-like hyaline material. Frankly malignant features (malignant cytology, high mitotic activity, necrosis, perineural or lymphovascular invasion) were absent. IHC showed coexpression of low and high molecular weight keratins (AE1/AE3 and CK5/6; 4/4), EMA (2/2), and CD99 (2/2). Negative markers included p63 (0/4), NUT (0/4), S100 (0/4), SOX10 (0/4), p40 (0/2), and SMA (0/2). This study introduces a novel salivary and lung tumor entity driven by NFATC2::NUTM2A/B fusions and displaying myoepithelial-like morphology but imperfect myoepithelial immunophenotype. Report of more cases should shed light on the biological properties and appropriate therapeutic strategies of this novel neoplasm.

Conventional and dedifferentiated chondrosarcoma encompass a group of malignant neoplasms that produce cartilaginous matrix and arise within or on the surface of bone. Conventional chondrosarcomas are graded on a three-tiered scale, whereas dedifferentiated chondrosarcoma is typically not graded but is considered a high-grade sarcoma and represents the most aggressive subtype with a poor prognosis. IDH1 (isocitrate dehydrogenase-1) and IDH2 (isocitrate dehydrogenase-2) are the most commonly mutated genes in conventional and dedifferentiated chondrosarcoma, followed in frequency by COL2A1 and TP53. IDH1/2 driver mutations are also commonly found in enchondroma, considered a benign precursor lesion of chondrosarcoma, and other malignancies such as gliomas, cholangiocarcinoma, and acute myeloid leukemia. In acute myeloid leukemia, the presence of concurrent BCOR (BCL-6 corepressor) loss-of-function mutations has been linked to disease relapse and resistance to treatment with IDH inhibitors. After identifying an index case of conventional chondrosarcoma with unusually aggressive clinical evolution, we investigated the clinicopathological features of 12 cases of BCOR-mutated conventional and dedifferentiated chondrosarcomas against a control group of 15 BCOR-wildtype (WT) cases to determine whether BCOR-mutated tumors had patterns of biological progression different from tumors with intact BCOR. All identified BCOR alterations led to loss-of-function by either missense or nonsense mutations. The prevalence of BCOR mutations occurred in 5% of conventional and dedifferentiated chondrosarcoma, and these were associated with larger tumor size (p = 0.024), metastasis at the time of diagnosis (p ≤ 0.001) and higher T category (3–4 vs. 1–2) (p = 0.009). Although larger studies are necessary to clarify the full impact of BCOR mutations on patients with conventional and dedifferentiated chondrosarcoma, our data indicate that BCOR genetic aberrations are associated with adverse clinical features.

We report a uterine myxoid mesenchymal tumor with a novel SS18::VEZF1 gene fusion. The current lesion was identified in a 53-year-old woman who presented with symptomatic “fibroids” showing accelerated growth and heterogeneous morphology on radiologic assessment. Microscopic examination revealed a well-demarcated neoplasm, and the tumor exhibited alternating hypocellular/hyalinized and hypercellular areas, composed of a monomorphic proliferation of spindle, ovoid, and epithelioid cells arranged in sheets. These cells were embedded within either a hyalinized collagenous stroma or abundant myxoid stroma. Tumor cells were frequently located around blood vessels and exhibited amphophilic or eosinophilic cytoplasm and elongated or ovoid-shaped nuclei with coarsely clumped chromatin. No mitoses, pleomorphism, or necrosis was identified. Immunohistochemically, the tumor was positive for CD10, CD34, TLE1, estrogen, and progesterone receptors. It was negative for h-caldesmon, desmin, smooth muscle actin, smoothelin, myosin, cyclin D1, S100, ALK, EMA, panTRK, and SS18-SSX. Targeted RNA sequencing revealed an SS18::VEZF1 gene fusion (breakpoint: exon 9–exon 2), which was confirmed by FISH (SS18). In conclusion, RNA sequencing was useful in identifying the fusion event, thereby excluding potential mimics with uncommon morphology or ambiguous immunophenotype.

Fusions involving the PLAG1 gene are associated with multiple cancers and benign tumors, including lipoblastoma and the more recently described pediatric fibromyxoid soft tissue tumor. We report two PLAG1-rearranged mesenchymal tumors arising in adults which, although largely similar histologically to the fibromyxoid tumors reported in infants, display limited adipocytic differentiation. In both cases, the novel fusion partner was DLEU2. Whole genome sequencing of one of the tumors also showed loss of 13p including the RB1 locus. Expression of PLAG1 was demonstrated by extensive immunoreactivity in both cases. We discuss the similarities of our cases to the previously described fibroblastic variants of lipoblastomas and the recently reported cases of PLAG1-rearranged fibromyxoid soft tissue tumors, highlighting the overlapping morphological and molecular features. We consider that there is growing evidence that these histological entities are related to conventional lipoblastoma and represent tumors of adipocytic lineage exhibiting different stages of cellular maturation.