Metaplastic thymomas are rare biphasic thymic tumors that are characteristically well-circumscribed, confined to the thymus, and follow a benign to indolent clinical course. Their relationship to ...other thymic neoplasms remains unclear, and their molecular characteristics have not been defined. We report for the first time recurrent translocation events in metaplastic thymomas involving the Yes Associated Protein 1 (YAP1) and Mastermind Like Transcriptional Coactivator 2 (MAML2) genes. Eight metaplastic thymomas were retrieved from two institutions' archives over a 21-year period. Paraffin-embedded material from all cases underwent targeted DNA-based hybrid capture next-generation sequencing. Cases showing no somatic alterations subsequently underwent targeted RNA sequencing. Allele-specific real-time polymerase chain reaction was performed to detect GTF2I c.74146970T>A (p.L424H) mutations. All cases showed characteristic histologic features of metaplastic thymoma and demonstrated no local recurrence or distant metastatic disease at 1-22 years of follow-up. Six of eight cases were successfully sequenced, all showing YAP1-MAML2 fusions; in four cases the fusions were detected by DNA sequencing and in two cases by RNA sequencing. Two distinct products were identified: 5' YAP1 exon 1 fused to 3' MAML2 exons 2-5 or 5' YAP1 exons 1-5 fused to 3' MAML2 exons 2-5. All cases underwent allele-specific real-time polymerase chain reaction and demonstrated no GTF2I L424H mutations. Metaplastic thymoma is a distinct, clinically indolent thymic epithelial neoplasm characterized by YAP1-MAML2 fusion and lacking the GTF2I mutations found in Type A and AB thymomas.
Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly ...available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.
Myeloma is a malignant neoplasm of plasma cells with complex pathogenesis. Diagnosis and risk stratification require the integration of histology, radiology, serology, and genetic data. Bone marrow ...biopsies are essential for myeloma diagnosis by providing material for histologic and cytologic assessment as well as immunophenotypic and genetic studies. Flow cytometry and genetic studies are, in particular, becoming increasingly important for diagnosis, risk stratification, and assessment of treatment response. Myeloma has traditionally been characterized by recurrent cytogenetic abnormalities that can be divided into two subtypes: hyperdiploid, characterized by trisomies, and non-hyperdiploid, characterized by translocations involving chromosome 14. These abnormalities are thought to be primary events, initiating a premalignant state, which progresses to myeloma through the acquisition of secondary mutations. The emergence of next-generation sequencing has led to the discovery of numerous mutations and gene fusions that comprise the heterogenous genomic landscape of myeloma. As the underlying pathogenesis of myeloma continues to be delineated, possible therapeutic targets have also emerged. Herein, we describe the importance of histology, immunophenotype, and mutational analysis in the assessment of myeloma.
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant ...fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
Loss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the ...healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥75% in 32. A threshold of ≥75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia OR 6.17; 95% CI = 2.15-17.68; p = 0.0007. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration.
Patients with Lynch syndrome have up to a 24% risk of developing ovarian carcinoma, but universal mismatch repair (MMR) protein testing of ovarian carcinomas is not standard practice in most ...institutions. We reviewed 104 unselected ovarian endometrioid carcinomas (OEC) for various clinicopathologic features to determine if any are predictive of MMR loss. Immunohistochemistry for all 4 MMR proteins was performed followed by MLH1 promoter methylation analysis when indicated. Overall, patients had a mean age of 55 years and tumors averaged 12 cm. Most (72%) patients had stage I tumors, 63% were grade 1, and 30% had a synchronous stage IA endometrial endometrioid carcinoma. Peritumoral lymphocytes and intratumoral stromal inflammation were rare, but tumor-infiltrating lymphocytes averaged 47/10 high-power fields. Endometriosis was noted in 71%, adenofibromatous background in 14%, and both in 14% of tumors. Metaplastic changes were common and included squamous metaplasia (63%), clear cell change (32%), mucinous differentiation (24%), and sex cord-like elements (13%). When follow-up was available (n=99), 78% of patients were alive and well, 12% died from disease, 6% died from other causes, and 4% were alive with disease. Unmethylated, MMR-deficient OECs were identified in 7% of the cohort and included MSH2/MSH6 (n=4), MSH6 (n=2), and PMS2 (n=1). All these tumors were stage I, 71% grade 1, and 57% had a synchronous endometrial endometrioid carcinoma. Among patients in this group with follow-up (n=5), all were alive without evidence of disease (mean 150 mo). Given that no clinicopathologic features were associated with MMR deficiency on univariate analysis, this study highlights the importance of universal MMR screening in OECs.
A 66-year-old man presented to the hospital for evaluation of pancytopenia and rash. Examination was notable for a scaling, erythematous rash on the legs and the absence of lymphadenopathy. ...Positron-emission tomography revealed increased
18
F-fluorodeoxyglucose uptake in the spleen. A diagnostic test was performed, and management decisions were made.
Background
Little remains known about the connection between cardiovascular (CV) risk factors and carotid plaque morphologies. This study set out to assess for any such associations.
Materials and ...methods
A retrospective review was completed of consecutive patients that had CTA neck imaging prior to CEA. Body mass index (BMI), tobacco and/or alcohol use, and history of diabetes and/or hypertension were collected from patients’ medical records. Lab values were dichotomized based on values: total cholesterol < 200 or ≥ 200; low-density lipoprotein (LDL) < 130 or ≥ 130, high-density lipoprotein < 35 or ≥ 35, and triglycerides < 200 or ≥ 200. A semiautomated analysis of CTA images computed maximum stenosis, intraplaque volumes of intraplaque hemorrhage, lipid-rich necrotic core (LRNC), and matrix, and intraplaque volume and proportional plaque makeup of calcifications of each carotid plaque.
Results
Of 87 included patients, 54 (62.1%) were male. Mean age was 70.1 years old. Both diabetes and hypertension were associated with greater intraplaque calcification volume (
p
= 0.0009 and
p
= 0.01, respectively), and greater proportion of calcification within a plaque (
p
= 0.004 and
p
= 0.01, respectively). Higher BMI was associated with greater intraplaque volume of LRNC (p=0.02) and matrix (0.0007). Elevated total cholesterol was associated with both larger intraplaque calcification volume (
p
= 0.04) and greater proportion of calcification within a plaque (
p
= 0.01); elevated LDL was associated with greater intraplaque calcification volume (
p
= 0.005).
Conclusion
Multiple CV risk factors are associated with morphological differences in carotid artery plaques. Dysregulation of both total cholesterol and LDL and higher BMI are associated with higher volumes of intraplaque LRNC, a marker of plaque vulnerability.
XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque ...destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors.
Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured.
Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median interquartile range: 1.24 2.09 versus 0.16 0.34; P<0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P<0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels (P=0.010, r=−0.30) and directly with circulating uric acid levels (P<0.001, r=0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median interquartile range: 93.37% 25 versus 46.15% 21, respectively; P<0.001).
XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.
A 68-year-old woman presented with back and pelvic pain. Twenty-five years earlier, she had received a diagnosis of invasive carcinoma of the breast. Imaging studies revealed multiple lytic and ...blastic lesions in the thoracic vertebrae, ribs, and sternum. Management decisions were made.
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