We herein report an uncommon association of intimately admixed atypical carcinoid (AC) and large cell neuroendocrine (NE) carcinoma (LCNEC) of the thymus, occurring in two 20- and 39-year-old Caucasian males. Both tumors were treated by maximal thymectomy. The younger patient presented with a synchronous lesion and died of disease after 9 months, while the other patient was associated with a recurrent ectopic adrenocorticotropic hormone Cushing's syndrome and is alive with disease at the 2-year follow-up. MEN1 syndrome was excluded in either case. Immunohistochemically, disarrayed cytoplasmic and nuclear ß-catenin expression was seen alongside an intra-tumor Ki-67 antigen labeling index (LI) ranging from 2 to 80% in the younger patient's tumor and from 3 to 45% in the other. Both exhibited upregulated cyclin D1 and retinoblastoma, while vimentin was overexpressed in the recurrent LCNEC only. Next-generation sequencing revealed CTNNB1, TP53, and JAK3 mutations in the synchronous tumor and CTNNB1 mutation alone in the metachronous tumor (the latter with the same mutation as the first tumor of 17 years prior). None of the 23 T-NET controls exhibited this hallmarking triple alteration (p = 0.003). These findings suggested that LCNEC components developed from pre-existing CTNNB1-mutated AC upon loss-of-function TP53 and gain-of-function JAK3 mutations in one case and an epithelial-mesenchymal transition upon vimentin overexpression in the other case. Both tumors maintained intact cyclin D1-retinoblastoma machinery. Our report challenges the concept of secondary LCNEC as an entity that develops from pre-existing AC as a result of tumor progression, suggesting a paradigm shift to the current pathogenesis of NET.

PURPOSE This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O6-methylguanine–DNA methyltransferase (MGMT)–silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule. RESULTS Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported. CONCLUSION The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.

PURPOSE The activity of androgen-deprivation therapy (ADT) in androgen receptor–positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non–drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.

Whether invasive mucinous adenocarcinoma (IMA) and colloid adenocarcinoma (ICA) of the lung represent separate tumour entities, or simply lie within a spectrum of phenotypic variability, is worth investigating. Fifteen ICA, 12 IMA, 9 ALK‐rearranged adenocarcinomas (ALKA), 8 non‐mucinous KRAS‐mutated adenocarcinomas (KRASA) and 9 mucinous breast adenocarcinomas (MBA) were assessed by immunohistochemistry for alveolar (TTF1, cytoplasmic MUC1), intestinal (CDX‐2, MUC2), gastric (membrane MUC1, MUC6), bronchial (MUC5AC), mesenchymal (vimentin), neuroendocrine (chromogranin A, synaptophysin), sex steroid hormone‐related (oestrogen and progesterone receptors), pan‐mucinous (HNF4A) and pan‐epithelial (keratin 7) lineage biomarkers and by targeted next generation sequencing (TNGS) for 50 recurrently altered cancer genes. Unsupervised clustering analysis using molecular features identified cluster 1 (IMA and ICA), cluster 2 (ALKA and KRASA) and cluster 3 (MBA) (p < 0.0001). Cluster 1 showed four histology‐independent sub‐clusters (S1 to S4) pooled by HFN4A and MUC5AC but diversely reacting for TTF1, MUC1, MUC2, MUC6 and CDX2. Sub‐cluster S1 predominantly featured intestinal‐alveolar, S2 gastrointestinal, S3 gastric and S4 alveolar differentiation. In turn, KRASA and ALKA shared alveolar lineage alongside residual MUC5AC expression, with additional focal CDX2 and diffuse vimentin, respectively. A proximal‐to‐distal scheme extending from terminal (TB) and respiratory (RB) bronchioles to alveolar cells was devised, where S3 originated from distal TB (cellular mucinous adenocarcinoma), S2 from proximal RB (secreting mucinous adenocarcinoma), S1 from intermediate RB (mucin lake‐forming colloid adenocarcinoma), S4 from distal RB (colloid alveolar adenocarcinoma), KRASA from juxta‐alveolar RB (KRAS‐mutated non‐mucinous adenocarcinoma) and ALKA from juxta‐bronchial alveolar cells (ALK‐translocated adenocarcinoma). TNGS analysis showed KRAS, LKB1, TP53, APC and CDKN2A mutation predominance. In conclusion, IMA and ICA are basket categories, which likely originate from distinct domains of stem/progenitor cells spatially distributed along bronchioles upon common molecular features and genetic alterations.

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