Comparative genomic hybridization analysis of thymic neuroendocrine tumors

Abstract

Thymic neuroendocrine (carcinoid) tumors are a rare neoplasm of the anterior mediastinum. The tumors frequently exhibit a wide spectrum of histology and appear to follow a more aggressive behavior than their nonthymic counterparts. Given the differing clinicopathologic manifestations, thymic neuroendocrine tumors may also possess different cytogenetic abnormalities from those that occur in foregut carcinoid tumors. In this study, we employed comparative genomic hybridization to detect genomic instability in 10 sporadic thymic neuroendocrine tumors and one multiple endocrine neoplasia type 1 (MEN1)-associated case. Gross chromosomal imbalances were found in nine cases, including gains of chromosomal material on regions X, 8, 18 and 20p and losses on 3, 6, 9q, 13q and 11q. We did not observe deletion at locus 11q13 where the MEN1 gene is located. These findings were essentially dissimilar to those reported in sporadic and MEN1-associated foregut carcinoid tumors. Consequently, we consider that a distinctive cytogenetic mechanism is at work in the development of thymic neuroendocrine tumors, which is different from that of foregut carcinoid tumors. The term thymic carcinoid tumor was first introduced by Rosai and Higa 1 to denote a group of thymic neoplasms that histologically resemble the carcinoid tumors of other systems. Later series of studies demonstrated that this group of neoplasms frequently displays a diversity of morphologic features ranging from typical carcinoid as those seen in the bronchopulmonary and digestive tracts, to poorly differentiated small-cell carcinoma. In addition, many such tumors behave more aggressively than the conventional nonthymic carcinoid tumors. Reportedly around half of the cases invaded the surrounding mediastinal structures, and 30-40% metastasized.2-4 Consequently, Moran and Suster 3 proposed to designate the entity as thymic neuroendocrine carcinoma with a threetiered (low, intermediate and high) grading system, which is roughly equivalent to the classic carcinoid, atypical carcinoid and small-cell undifferentiated carcinoma of the World Health Organization (WHO) classification. 5Owing to differing pathologic and clinical presentation, we postulate a different cytogenetic oncogenesis between the thymic and foregut neuroendocrine tumors. Nevertheless, few cytogenetic studies specifically addressing the thymic neuroendocrine tumors are available. So far, only a total of 12 cases in three reports of multiple endocrine neoplasia type 1 syndrome (MEN1)-associated thymic neuroendocrine tumors were examined by using loss of heterozygosity (LOH) study at the 11q13 locus where MEN1 gene is located.6-8 The cytogenetic and molecular events underlying the development of thymic neuroendocrine tumor remain largely unknown. In this study, we aim to characterize the chromosomal aberrances in thymic neuroendocrine tumors with comparative genomic hybridization (CGH) analysis and compare our findings with those of previous reports. Materials and methods Case SelectionWe retrieved 11 cases of ...

Tumor genetics and survival of thymic neuroendocrine neoplasms: A multi‐institutional clinicopathologic study

“…Many of the recurrent alterations (gains on 7, 8, and 12q and losses on 3, 4q, 11q, and 13q) in TTC and TAC as observed in our study were in good agreement with two previous smaller studies (Rieker et al ; Pan et al ). In line with many previous observations (Teh et al ; Teh et al ; Gibril et al ; Pan et al ), the MEN1 gene locus on 11q13 was unaltered in all cases. It is interesting to note that there were both shared and unique genetic alterations among carcinoids and HGNEC.…”

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

“…This is corroborated by the previous studies showing differences between chromosomal alterations of midgut WDNTs and PETs (Terris et al, 1998;Lö llgen et al, 2001;Tö nnies et al, 2001;Wang et al, 2005). In contrast, lung WDNTs have loss of chromosomal arms 11q and 6q and gain of chromosome 19, 17, and 20 (Walch et al, 1998), and thymic WDNTs have loss of chromosome 6 and 13q and gain of chromosomes X, 8, and 18 (Pan et al, 2005). The data present in this study and previous studies suggest that chromosomal alterations are different among neuroendocrine tumors from different sites, including pancreas, thymus, lung, and subsites of the gastrointestinal tract.…”

Classification of pulmonary neuroendocrine tumors: new insights

“…All tumor components, either AC or LCNEC, presented with CTNNB1 mutations, which were likely responsible for cyclin D1-RB1 axis-dependent tumor growth, along with subsequent TP53 and JAK3 mutations in one case and EMT activation in the other case leading to de-differentiation and further tumor expansion (23). Chromosomal imbalances, whether loss or gain (95,169,170), and aneuploidy (171) are differentially distributed among the diverse subtypes of T-NETs, with the mean number of chromosomal imbalances being 0.8, 1.1 and 4.7 in TC (31% aberrant cases), AC (44% aberrant cases) and high-grade T-NET (75% aberrant cases), respectively. Gains of 8q24 mapping to MYC gene locus was the most frequent alteration and one of the overlapping features between carcinoids and high-grade T-NENs (95).…”