Thymic Neuroendocrine Tumors Research Articles

Diagnostic Challenges in the Cytology of Thymic Epithelial Neoplasms.

Simple SummaryThymic epithelial neoplasms, including thymoma, thymic carcinoma, and thymic neuroendocrine neoplasms, constitute the majority of anterior mediastinal masses. Fine needle aspirations (FNA) of mediastinal masses are infrequently encountered and are highly challenging to interpret. Thymic neoplasms display a significant degree of histologic diversity and have overlapping morphologic features with tumors from other sites. However, when properly interpreted alongside ancillary studies and radiologic findings, FNAs can yield clinically actionable results. This review aims to illustrate the usefulness and diagnostic pitfalls of thymic FNAs to assist pathologists in analyzing these specimens. Thymic epithelial neoplasms are rare tumors that constitute the majority of anterior mediastinal masses. They are classified as thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. Biopsy diagnosis is not common, and most tumors are surgically resected. Biopsy, including cytology, is indicated when a non-surgical entity is suspected or in cases of locally advanced disease. Smears of thymomas consist of round or spindle epithelial cells admixed with varying amounts of lymphocytes depending on the type of thymoma. Smears of thymic carcinoma and thymic neuroendocrine neoplasms are often indistinguishable from corresponding tumor types from other organs. Accurate cytological diagnosis can be difficult due to the histological diversity of thymomas, as well as the morphological features that certain thymic tumors share with similar tumors from other organs. However, fine needle aspiration (FNA) of anterior mediastinal masses can provide clinically actionable information and can be used to determine whether lesions require surgical, systemic, or local noninvasive treatments. Ancillary studies, namely, immunocytochemical stains, flow cytometry, and radiology, are important tools in the evaluation of thymic aspirates. This review discusses the utility and limitations of thymic FNAs and illustrates the diagnostic features and pitfalls of these specimens.

A predictive model of lymph node metastasis for thymic epithelial tumours.

Thymic epithelial tumours (TETs) are relatively rare indolent malignancies in the mediastinum. Lymph node metastasis (LNM) is an important prognostic indicator for TETs; however, the pattern of LNM involved in TETs has yet to be elucidated. Patients diagnosed with histologically confirmed thymoma (A-B3), thymic carcinomas and thymic neuroendocrine tumours, between 1988 and 2016 were identified from the Surveillance, Epidemiology, and End Results database. Univariable and multivariable logistic regression analyses were applied to identify the predictors for LNM. The predictive nomogram was built from the independent risk factors and measured using the concordance statistic. The overall proportion of TETs with LNM was 18.5% (200/1048). The rate of LNM in thymoma, thymic carcinomas and thymic neuroendocrine tumours was 6.8% (42/622), 30.2% (100/331) and 61.1% (58/95), respectively. According to the logistic regression analysis, histology type and T stage were independent factors correlated with LNM. A predictive nomogram model was developed with a concordance statistic of 0.807 (95% confidence interval: 0.773-0.841), which was significantly better than the T stage (P < 0.001) while had limited benefit to the histology type (P = 0.047). The calibration curve for the nomogram comparing the predicted and actual probabilities after bias correction showed good agreement. Nodal involvement was not uncommon in TETs. Main factors related to LNM in TETs were histology type and T stage. The probability of LNM could be well calculated using the predictive model.

Molecular landscape of thymic epithelial tumors.

Thymic epithelial tumors (TETs) are extremely rare and represent the most frequent tumors of the anterior mediastinum originating from epithelial cells in the thymus. Thymic epithelial tumors include thymomas (TM), thymic carcinomas (TC) and thymic neuroendocrine neoplasms (TNEN). Thymomas are the most predominant and are associated with autoimmune diseases. The available data suggests that the different histological subtypes have specific molecular alterations. Thymic carcinoma shows recurrent gene mutations, but further investigations are needed to understand the role of those mutations in the pathogenetic of the TETs. Some of the new emerging identified molecular alterations have the potential to offer new targeted therapies opening new possibilities for the treatment of thymic epithelial tumors.

Trends in Incidence and Survival of Patients With Thymic Epithelial Tumor in a High-Incidence Asian Country: Analysis of the Korean Central Cancer Registry 1999 to 2017

IntroductionTo report the trends in incidence and survival associated with thymic epithelial tumors (TETs) in Korea. MethodsData from 1999 to 2017 were obtained from the Korean Central Cancer Registry. Age-standardized incidence rates and average annual percentage changes (AAPCs) were calculated. Net survival (NS) was estimated by the Pohar-Perme method. ResultsAmong 5812 patients diagnosed with having TETs, 58.9%, 38.1%, and 3.0% were diagnosed with having thymoma, thymic carcinoma, and thymic neuroendocrine tumor (NET), respectively. Age-standardized incidence rates were 0.50, 0.30, 0.18, and 0.02 per 100,000 for all TETs and the respective subtypes. There was an increase in incidence of all TETs (AAPC = 6.1%) and subtypes: thymoma (AAPC = 5.6%), thymic carcinoma (AAPC = 7.0%), and thymic NET (AAPC = 3.4%). Proportions of patients with thymoma, thymic carcinoma, and thymic NET were 58.9%, 38.1%, and 3.0%, respectively. For thymoma, the relative proportion of distant stage decreased (19.4% in 2005 to 8.8% in 2017) and low-grade WHO subtype (A, AB, B1) increased faster than high-grade WHO type (B2, B3) (AAPC = 19.8% versus 9.6%). For thymoma, the 5-year NS was 82.3%. This increased from 64.3% in 1999 to 2002 to 90.6% in 2013 to 2017. For thymic carcinoma, the 5-year NS was 46.2% and only slightly increased from 39.4% in 1999 to 2002 to 47.9% in 2013 to 2017. ConclusionsThis study indicates a high incidence of TET and its continuous increase in Korea. The proportion of thymic carcinoma was relatively higher than in the United States or Europe. Survival for thymoma improved during the study period, whereas this was not evident for thymic carcinoma or thymic NET.

Correlation of Somatostatin Receptor 2 Expression, 68Ga-DOTATATE PET Scan and Octreotide Treatment in Thymic Epithelial Tumors.

Somatostatin receptor 2 (SSTR2) has been shown to be expressed in a subset of neuroendocrine tumors and carcinomas and plays a role in imaging studies and guiding therapy. Patients with tumors expressing SSTR2 may be successfully treated with somatostatin inhibitors or radiolabeled somatostatin analogues. We studied SSTR2 expression in TET and correlated it with 68Ga-DOTATATE PET/CT or 68Ga-DOTATATE PET/MR results and treatment outcome. An institutional database of TET was searched for thymoma, thymic carcinoma, and thymic neuroendocrine tumor (TNET) with available resection specimens. Cases were subtyped (2021 WHO classification) and staged (8th AJCC/UICC staging). A section was stained with anti-SSTR2 antibody (clone UMB1). Percent tumor cells with membranous staining was recorded if present in ≥1% of tumor cells. Medical records were searched for 68Ga-DOTATATE PET scans and treatment. Statistical analysis was performed. Eighty patients (1969-2021) with a median age of 61.3 years (range, 19.1-87.3) (37 males, 46.3%) had thymic carcinoma (N=33), TNET (N=7), or thymoma (N=40). SSTR2 expression was identified in 29 (of 80, 36.3%) TET including 2/2 (100%) small cell carcinomas, 2/5 (40.0%) atypical carcinoid tumors, 16/23 (69.6%) squamous cell carcinomas, 2/2 (100%) lymphoepithelial carcinomas, 1/1 (100%) adenosquamous carcinoma, and 6/40 (15.0%) thymomas. SSTR2 expression in ≥50% of tumor cells (vs 1-49%) was associated with younger age (p=0.023) and shorter recurrence/metastasis-free survival (p=0.007). 68Ga-DOTATATE PET scans (N=9) revealed a Krenning score of 3 in patients with atypical carcinoid tumor, small cell carcinoma, and squamous cell carcinoma (N=1 each) with SSTR2 expression in 95, 100, and 5% of tumor cells, respectively. Scans with Krenning scores of ≤2 (N=5) were seen in tumors with no SSTR2 expression in 80% of cases and a single atypical carcinoid tumor with SSTR2 expression in 10% of tumor cells. One scan resulted as “increased uptake” was in a patient with no SSTR2 expression. In conclusion, 68Ga-DOTATATE PET scans correlated with SSTR2 expression in TET in most patients and appeared to be useful to identify patients with TET who may be amenable to treatment with somatostatin analogues. Larger studies including more patients with 68Ga-DOTATATE PET scans are necessary to independently and prospectively validate our findings.

Thymic carcinomas and thymic neuroendocrine tumors: a tribute to Dr. Juan Rosai.

SummaryThroughout his career, Dr. Juan Rosai greatly impacted our understanding of mediastinal tumors, both as a scientist and as a teacher. This review highlights his manifold contributions in the field of thymic carcinomas and thymic neuroendocrine tumors from a historical perspective.

Clinicopathological characteristics and prognosis of 21 patients with thymic neuroendocrine tumors

目的： 探讨胸腺神经内分泌肿瘤（TNET）临床病理学特征及其预后的影响因素。 方法： 收集2007年3月至2020年7月福建省肿瘤医院诊断的21例TNET的临床病理特征，并随访及复习相关文献。 结果： 21例TNET患者年龄21~72岁（中位年龄63岁）；男性18例，女性3例（男女比例6∶1）；肿物最大径3~17 cm。通常以上腔静脉综合征（9/21）、胸痛（5/21）、腰痛（2/21）、颈部肿物（2/21）就诊，4例（4/21）于体检时发现。4例（4/21）行单纯手术切除，3例（3/21）手术联合放化疗。根据WHO胸腺神经内分泌肿瘤分类标准将其分为11例不典型类癌，9例小细胞癌，1例大细胞神经内分泌癌。20例获得随访，随访时间1~115个月，死亡12例，存活8例。单因素分析结果显示：手术切除（P=0.041）、肿物最大径（P=0.049）、Ki-67阳性指数（P=0.034）是影响患者预后的因素。 结论： TNET较为少见，且症状常不典型，组织学特征及免疫表型有助于该肿瘤的诊断。手术切除、肿物≤5 cm、Ki-67阳性指数<50%的患者预后较好。.

Thymic neuroendocrine tumor and mortality in MEN 1 patients: the spanish registry

Thymic neuroendocrine tumor and mortality in MEN 1 patients: the spanish registry

SATB2 Is Expressed in a Subset of Pulmonary and Thymic Neuroendocrine Tumors

To evaluate SATB2 expression and prognostic implications in a large cohort of thoracic neuroendocrine tumors. Surgical pathology files (1995-2017) and an institutional thymic epithelial tumor database (2010-2020) were searched for resected neuroendocrine tumors. Cases were stained with SATB2 (clone EP281). Percent SATB2-positive tumor cells and expression intensity were scored. In the lung, SATB2 was expressed in 5% or more of tumor cells in 29 (74.4%) of 39 small cell carcinomas and 9 (22.5%) of 40 atypical and 26 (40.6%) of 64 typical carcinoid tumors. SATB2 percent tumor cell expression and intensity were higher in small cell carcinomas than in carcinoid tumors (both P < .001, respectively). After adjusting for tumor subtype, SATB2 expression did not correlate with outcome. In the thymus, four (100%) of four atypical carcinoid tumors and one large cell neuroendocrine carcinoma but no small cell carcinoma (n = 2) expressed SATB2 in 5% or more of tumor cells. SATB2 (clone EP281) is expressed in a large subset of pulmonary and thymic neuroendocrine tumors and therefore does not appear to be a useful marker to identify the origin of neuroendocrine tumors. Validation studies are needed, specifically including thymic neuroendocrine tumors, as the expression pattern might be different in those tumors.

Ectopic Cushing’s syndrome due to thymic neuroendocrine tumours: a systematic review

Knowledge of ectopic Cushing's syndrome (CS) due to thymic neuroendocrine tumours (NETs) comes from short series or single cases. Our aim is to perform a systematic review using PubMed, Embase, Scopus, Ovid Medline and Biosis Previews of all cases with ectopic CS due to thymic NETs reported in the last 40years and describe one illustrative patient attended in our institution. Search of literature: From 162 patients, 58.6% were male and mean age was 34.6 ± 13.9years-old. Median of symptoms until diagnosis was 6 [2-24] months and 62% had aggressive CS. Imaging was positive in 93.7% (chest X-ray), 97.8% (computed tomography), 80.7% (somatostatin receptor scintigraphy) and median tumour size was 47 [25-68.5] mm. At presentation, 18% had localized disease, 26.2% locally invasive and 55.7% advanced. Eighty-eight present underwent surgery and histological subtypes were atypical (46.7%), typical (30.4%) and carcinoma (21.7%). Tumour persisted or recurred in 70.1%, 63% received radiotherapy and 45.2% chemotherapy. Follow-up median was 26.6 [14.5-57.5] months and mortality was reported in 35.8% with median survival of 38 [19-60] months. MEN-1 mutation was referred in 3.1%. Comparatively, carcinomas had aggressive CS more frequently while atypical showed advanced disease more often. In conclusion, thymic NETs causing ectopic CS are presented as aggressive hypercortisolism in the middle aged population. The disease is commonly extended at diagnosis and persists or recurs after surgery in most patients with a short term high mortality.

Thymoma and Not Just Thymic Carcinoid Can Be Associated With Multiple Endocrine Neoplasia Type 1

Background: Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome with autosomal dominant inheritance. Thymic neuroendocrine tumors (NETs) are known manifestations of MEN1 occurring in 2-8% of patients. However, thymomas, a type of thymic epithelial tumors, have only been described in rare case reports. They markedly differ from thymic NETs in their natural history, morphology, prognosis, and therapeutic options. Here we present a case of an aggressive, recurrent thymoma associated with MEN1. Case Report: A 58-year-old Caucasian female with a family history of MEN1 was diagnosed with a prolactinoma at age 15 when she presented with irregular menses, galactorrhea, headaches and visual field defects. She was referred to our institution for further evaluation where genetic testing confirmed the diagnosis of MEN1. Throughout the years, she developed primary hyperparathyroidism, non-functional pancreatic neuroendocrine tumors, Zollinger-Ellison syndrome, bilateral adrenal hyperplasia, and bronchial carcinoid. At the age of 49, magnetic resonance imaging (MRI) and computed tomography (CT) scan of the chest incidentally demonstrated a 2.5 x 6 x 10-cm anterior mediastinal mass, with marked compression of the left brachiocephalic vein and encasement of the superior vena cava. Biopsy was consistent for malignant cells of thymic epithelial origin. A median sternotomy with en bloc resection with SVC resection and reconstruction, mediastinal lymph node dissection and placation of the right hemidiaphragm were performed. Pathology revealed WHO type B3 thymoma extending into the pulmonary parenchyma with positive tissue margins but negative lymph node involvement. Following surgery, she underwent adjuvant radiation therapy with a total dose of 59 Gy. Annual screening showed disease remission. However, nine years after initial presentation, surveillance CT scans revealed a pleural base mass with mass effect on the superior portion of the IVC, as well as hypoattenuated masses within the liver. Positron emission tomography with fluorodeoxyglucose (18FDG PET-CT) confirmed multiple metastatic lesions involving thorax and abdomen. Biopsy of the retrocaval soft tissue subxiphoid mass revealed epithelioid cells in a background of lymphocytes consistent with recurrent thymoma. She was subsequently staged as IV B thymoma and was recommended to start systemic chemotherapy. Conclusion: We described a case of an aggressive thymoma in a patient with MEN1 syndrome demonstrating that their association exists and the clinical presentation can be aggressive. Thus, it is important for practitioners to screen for thymic tumors routinely in patients with MEN1 for early detection as they can be a major cause of mortality. Although further studies are needed, improving the detection of these tumors could significantly contribute to reducing MEN1-related deaths.

Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors.

Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, p = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens.

Mutational landscape of thymic epithelial tumors in a Chinese population: insights into potential clinical implications.

Thymic epithelial tumors (TETs) are a heterogeneous group of rare malignancies which may be devastating, difficult to treat, and for which treatment options are limited. Herein, we investigated the comprehensive genomic alterations of TETs in a Chinese population for providing clinical management, especially targeted therapy. Comprehensive genomic profiling (CGP) was performed with DNA targeted sequencing of cancer-associated genes (CSYS) from a cohort of 40 Chinese TET patients. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score. The expression status of PD-L1 was estimated by immunohistochemistry. The mutational profiling of thymomas (Ts) and thymic neuroendocrine tumors (TNETs) showed scattered mutation distributions with no recurrently mutated genes. In contrast, thymic carcinomas (TCs) did show highly recurrent mutations including CDKN2A, CYLD, CDKN2B, and TP53. Among them, CDKN2A and CDKN2B mutations were the top potentially actionable alterations in TCs. PD-L1 expression was mainly present in Ts and TCs, and was predominant in males and smokers. Our study provided a comprehensive genetic alteration view on the largest Chinese cohort of TETs to date. The results identified different genomic mutational profiles of Ts, TCs, and TNETs, and analyzed potential druggable biomarkers with clinical implications in Chinese TET patients, which provided the evidence for precision medicine of rare TET patients.

An Overview on Molecular Characterization of Thymic Tumors: Old and New Targets for Clinical Advances.

Thymic tumors are a group of rare mediastinal malignancies that include three different histological subtypes with completely different clinical behavior: the thymic carcinomas, the thymomas, and the rarest thymic neuroendocrine tumors. Nowadays, few therapeutic options are available for relapsed and refractory thymic tumors after a first-line platinum-based chemotherapy. In the last years, the deepening of knowledge on thymus’ biological characterization has opened possibilities for new treatment options. Several clinical trials have been conducted, the majority with disappointing results mainly due to inaccurate patient selection, but recently some encouraging results have been presented. In this review, we summarize the molecular alterations observed in thymic tumors, underlying the great biological differences among the different histology, and the promising targeted therapies for the future.

P26.05 Comprehensive Genomic Sequencing in Thymic Epithelial Tumors: Identification of Multiple Poor Prognosis Biomarkers in Chinese Patients

Thymic squamous carcinomas (TSCC) and thymic neuroendocrine tumor (NETT) are two types of thymic tumor which have higher risk of relapse and death. TSCC is a malignant neoplasm of the thymus with morphological features of squamous cell carcinoma as seen in other organs. However, the research about genetic profile and its relationship with prognosis of both tumors are rare. 47 patients who diagnosed with TSCC/NETT at Shanghai Jiao tong University Affiliated Chest Hospital between 2015 and 2017 were sequenced by FoundationOne CDx (F1CDx) which is a FDA approved platform conducted by DIAN (Hangzhou Lab) with the licensed technologies. During the follow up, the clinical information and the survival information was also collected. The cox regression model was used to analyze the relationship between genomic alteration and the survival data. A total of 47 patients’ (including 29 men, 14 ever smokers) surgical specimens were sequenced. The histological types include TSCC(N=27), NETT (N=14) and mixed of both(N=6). The median age of TSCC, NETT and mixed subtype was 59.5, 65 and 74, respectively. The top ranked altered genes in TSCC were TP53 (30%), CDKN2A (26), CDKN2B (19%) and ASXL1 (15%). In NETT, the top mutated genes were MEN1 (36%), STAG2 (14%), CDKN2A (14%) and HRAS (14%). The top ranked mutated genes in mixed subtype were TP53 (29%) and CDKN2A (29%). Notably, TP53, ASXL1, TET2, MLL2, EP30, BAP1 were only mutated in TSCC or mixed subtypes. However, mutated of MEN1, STAG2 and HRAS were also founded in NETT subtype. The TMB of three groups have no significant differences. 13 of 47 patients (27.7%) showed CDKN2A deletion and 7 of 47 tumors (14.9%) showed CDKN2B deletion which both were correlated with worse recurrence-free survival (RFS) (P<0.001). 5 (10.6%) patients showed MTAP loss, which was correlated with worse RFS (P =0.018). 6 (12.8%) patients showed TSC2 missense, which was correlated with worse RFS (P =0.017). 3 (6.4%) patients showed EPHB4 missense, which was also correlated with worse RFS (P =0.0081). Our study found that: TSCC and NETT have very different gene alternation landscape, while the mixed subtype was more similar with TSCC than with NETT. The most altered genes are focused on signal pathways of cell cycle control, Chromatin remodeling/DNA methylation, PI3K/AKT1/MTOR, MAP kinase signaling and others.In addition, we firstly identified multiple poor prognosis biomarkers in Chinese thymic epithelial tumors patients. These poor prognosis biomarkers are mainly enriched in cell cycle control and PI3K/AKT1/MTOR pathways.

P34 Aggressive Rapidly Enlarging Thymic Mass - a Rare Diagnosis of Thymic Large Cell Neuroendocrine Carcinoma

Thymic large cell neuroendocrine carcinomas are a rare subset of thymic neuroendocrine tumours.

Clinicopathological features and current treatment outcomes of neuroendocrine thymic tumours.

Neuroendocrine thymic tumours (NETTs) are a distinct subgroup of rare malignancies. An international, multicentre retrospective analysis was used to study the clinicopathological features, current pattern of diagnosis, treatment and outcomes of patients with NETT. One hundred and forty-six NETT treated from 1989 to 2016 at 21 centres in China, Europe and North America were retrospectively collected and reclassified according to the World Health Organization histological type and International Thymic Malignancy Interest Group (ITMIG)/International Association for Studies in Lung Cancer (IASLC)/Union for International Cancer Control (UICC) staging. Clinicopathological features, diagnostic and therapeutic approaches and outcomes were investigated. Results in the earlier and latter halves of the study period were also compared. The pretreatment work-up relied exclusively on computed tomography in 85.6% (125/146) of cases. Most patients had advanced disease, with 32.2% (47/146) having lymph node involvement. Higher-grade histological type was associated with more advanced disease (P < 0.05). Induction therapies and surgical procedures were used more often in the latter half of the study. However, the complete resection rate remained unchanged, being 71.5% (98/137) in the whole group. Complete resection was associated with significantly longer 5-year overall survival (77.2% vs 51.2%; P < 0.001) than incomplete or no resection. Significant survival differences were seen with the T, N and M categories of ITMIG/IASLC/UICC staging. Poorly differentiated carcinoma, ITMIG/IASLC/UICC stage IIIa or above and incomplete or no resection were independent risk factors for worse survival. No survival difference was noted between the earlier and the latter halves of the study (58.2% vs 71.9%; P = 0.299). Current management similar to that for thymomas is unsatisfactory in providing disease control or long-term survival for patients with NETT. Specific diagnostic tools and novel therapeutic agents are needed to improve management outcomes of this disease.

Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing

BackgroundThymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. Patients and MethodsWe tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. ResultsWe detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. ConclusionsIn this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous cell carcinoma.

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients. Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed. EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN. The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas. ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol.

Effect of Lymph Node Dissection on the Prognosis of Thymic Carcinomas and Thymic Neuroendocrine Tumors

We aimed to analyze the effect of lymph node dissection (LND) and accurate lymph node (LN) status on the survival and prognosis of patients with thymic carcinomas (TCs) and thymic neuroendocrine tumors (TNETs) undergoing surgical treatment. The Surveillance, Epidemiology, and End Results database was queried for patients who underwent surgical resection for TCs and TNETs during 1998-2016. LN status were defined as no LND (LND-), pathologically negative with LND (N0), and LN metastasis positive (N+). We investigated outcomes of LN status together with other clinicopathological features for overall survival (OS). Subgroup analyses were performed between LND-, N0, and N+ cohorts using propensity score matching, to analyze the significance of LND in prognosis. A total of 812 patients were enrolled, including 623 with TCs and 189 with TNETs. The proportion of LN metastasis positive in TNETs was 58.8% which was significantly higher than that in TCs (30%) (P < 0.001). In multivariable Cox analysis of OS, patients with LND- had a significantly worse prognosis than those with N0 (P = 0.018); there was no difference between N+ and LND- (P = 0.560). After propensity score matching, patients with N0 still had better survival than those with LND- and N+ in subgroup univariable and multivariable analyses of OS; however, the survival of patients with LND- and N+ was not significantly different in multivariable analysis. It was demonstrated that LND in TCs and TNETs can clarify the status of LN metastasis, to more accurately evaluate patients' long-term prognosis.