Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas.

A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

Primary mediastinal neoplasms: a report of 1,005 cases from a single institution.

BACKGROUND: This study was an epidemiological analysis of all primary mediastinal neoplasms (PMNs) diagnosed between 2000 and 2016 at the National Tuberculosis and Lung Diseases Research Institute, Poland. METHODS: All patients with any mediastinal abnormality were included in the analysis. The patients' age and gender were obtained from the institutional database. RESULTS: From a cohort of 5,108 patients, 3,691 primary mediastinal lesions were found, including 1,005 (19%) PMNs: lymphomas (533, 53% of PMNs), thymomas (215, 21%), neurogenic tumors (NTs) (100, 10%), germ cell tumors (GCTs) (62, 6%), soft tissue tumors (STTs) (47, 5%) and thymic carcinomas/thymic neuroendocrine tumors (TCs/TNETs) (37 in total, 4%). The most frequent lymphomas were classical Hodgkin lymphomas [256] and primary mediastinal large B-cell lymphomas [163]. Type AB [73] predominated in thymomas and squamous cell carcinomas [9] and carcinoids [10] in TCs/TNETs. NTs encompassed mainly schwannomas [49], ganglioneuromas [21] and neurofibromas [10]. The most frequent STTs were hemangiomas [13] and lymphangiomas [11]. Lymphomas, thymomas and NT were more often in women, TCs/TNETs in men (P<0.001). Lymphomas predominated between the 2nd and 4th decade of life, NTs under the 3rd decade and thymic epithelial tumors between the 6th and 8th decade (P<0.001). There was no correlation between the subtypes of thymomas and the patients' gender (P=0.389) but it was found between histology and patients' age: in patients <30 years of age type B2 and B3 thymomas and >70 years of age AB type and micronodular thymomas with lymphoid stroma (P<0.001) predominated. In the group of GCTs half of them were malignant and these were noted exclusively in men. No correlation between subtypes of NTs or TCs/TNETs and patients' age and gender was found (P>0.05). CONCLUSIONS: PMNs are rare conditions thus awareness of basic epidemiology may be very helpful for final diagnosis.

Two neoplasms rich in small lymphocytes, B1B2 thymoma and small lymphocytic lymphoma, intermingled in one tumor mass. A case report.

We present a case of a 52-year-old man with myasthenia gravis and a mediastinal tumor who was admitted to our hospital for surgical treatment. The pathologic examination of the resected tumor revealed a very rare case of a collision tumor: a B1B2 thymoma and a small lymphocytic lymphoma. Flow cytometry of the peripheral blood revealed the presence of a small number of leukemic cells. After postoperative irradiation of the mediastinum and chemotherapy a complete response in both diseases was achieved. The case confirms that a pathologist should always be aware that two different neoplasms can coexist in rare cases.

D2-40 Antibody is a Specific Marker for B2 Thymomas.

The correlation between the worse outcome of thymomas and expression of podoplanin (D2-40 antibody) in neoplastic cells has been proved in recent studies. We investigated the expression of podoplanin in thymic epithelial tumors of different histologic types and stages resected in our institution. The presence and type of reaction (membranous or cytoplasmic) with D2-40 antibody were assessed. Analyzed group consisted of 72 tumors: 3 type A, 19 type AB, 5 type B1, 24 type B2, 4 type B3, 2 micronodular, 1 metaplastic, and 9 combined B2B3 thymomas and 5 thymic carcinomas. Positive reaction with D2-40 was detected in 7 cases (37%) of AB type, 2 (40%) of B1, 28 (85%) of B2, 3 (23%) of B3, and 1 case (100%) of metaplastic thymoma. All positive B2 and 2 cases of B3 thymomas revealed membranous type of reaction, whereas other subtypes showed less conspicuous cytoplasmic reactivity. A correlation between B2 thymoma and membranous type of reaction was statistically significant (P<0.0001). There was also a slight relationship between cytoplasmic type of reaction and AB or B1 thymomas (P=0.0256). No correlation was detected between D2-40-reactivity and stage (P=0.4) or myasthenic symptoms (P=0.21). In conclusion, membranous type of reaction with D2-40 antibody in thymomas is highly specific for B2 subtype, but antipodoplanin immunoreactivity has no relationship with the tumor stage.