ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Thymic neuroendocrine (carcinoid) tumors

Thymic neuroendocrine (carcinoid) tumors
Literature review current through: Jan 2024.
This topic last updated: Dec 06, 2022.

INTRODUCTION — Thymic neuroendocrine tumors (NETs), otherwise known as thymic carcinoid tumors, are uncommon primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum. This topic review will cover the epidemiology, pathology, classification, clinical presentation, staging, and treatment of NETs arising in the thymus. Thymomas and thymic carcinomas are addressed separately, as are the diagnostic evaluation of patients with a mediastinal mass and the differential diagnosis of an anterior mediastinal mass. (See "Clinical presentation and management of thymoma and thymic carcinoma" and "Approach to the adult patient with a mediastinal mass".)

ANATOMY — The thymus is an anterior mediastinal organ (figure 1) that weighs 12 to 15 grams at birth, reaches its maximum weight of 40 grams around puberty, and then involutes and persists in an atrophic state into old age. The gland is composed of a central medulla and an outer cortex, surrounded by an outer capsule. The thymus consists primarily of epithelial cells, keratinized epithelial cells (Hassall corpuscles), myoid cells, thymic lymphocytes ("thymocytes"), and B-lymphocytes, which may rarely form germinal centers. The thymus is primarily involved in the processing and maturation of lymphocytes, which become T-lymphocytes upon release into the circulation. (See "Normal B and T lymphocyte development", section on 'T cell development'.)

EPIDEMIOLOGY — Thymic malignancies as a group are relatively rare (0.2 to 1.5 percent of all malignancies, 0.13 cases per 100,000 population in the United States), but they are among the most common mediastinal primary tumors [1,2].

Of the primary thymic malignancies, NETs are the least common, accounting for 2 to 5 percent of thymic tumors [3,4]. A thymic primary site accounts for approximately 0.4 percent of all NETs; this corresponds to an estimated annual incidence in the United States of approximately 0.2 per million [5,6]. (See "Pathology of mediastinal tumors".)

Almost all cases have been reported in adults, with a median age of approximately 54 years and a strong male preponderance [4,5,7-11]. The largest reported series of thymic NETs consists of 160 patients who were reported to the Surveillance, Epidemiology, and End Results (SEER) database over a 33-year period [5]. The median age at presentation was 57, and the male to female ratio was 3:1. Disease was confined to the thymus, locally invasive (or involving regional lymph nodes), or distantly metastatic in 27, 36, and 28 percent of cases, respectively. Histologically, tumors were classified as well-differentiated (low-grade), moderately-differentiated (intermediate-grade), or poorly-differentiated/anaplastic (high-grade) in 58, 10, and 12 percent of cases, respectively.

Up to 25 percent of thymic NETs arise in patients with multiple endocrine neoplasia type 1 (MEN1), a genetic disorder that predisposes to the development of multiple endocrine and non-endocrine proliferations [12,13]. Among MEN1 patients, thymic NETs develop in approximately 3 to 8 percent [13,14], although the prevalence is probably underestimated [15]. Thymic NETs appear to be a relatively late manifestation of the disease [13]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary neuroendocrine tumors'.)

The vast majority of reported cases of MEN1-associated thymic NETs have occurred in males (a surprising fact given the autosomal dominant nature of the inheritance pattern), and virtually all were heavy smokers [14], suggesting that tobacco exposure may represent a risk factor. The association between cigarette smoke and sporadic thymic NETs is unclear.

Screening in MEN1 — Thymic NETs, while rare, represent a neoplasm with greater malignant potential than other multiple endocrine neoplasia type 1 (MEN1)-associated tumors, and therefore are an important cause of morbidity and mortality in MEN1 kindreds. Some experts have recommended that male MEN1 patients over the age of 25 undergo screening with annual chest radiograph and chest computed tomography (CT) every three years [12], but there is no consensus on this issue. Others recommend annual chest CT in all patients with MEN1 who are over the age of 25, particularly males [13]. The benefits of screening are debated, given that no study has shown that early diagnosis through screening improves prognosis. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors' and 'Prognosis and management' below.)

Prophylactic cervical thymectomy should be considered in patients with MEN1 to address the risk of supernumerary parathyroids in the thymus, particularly if all four parathyroid glands have not yet been discovered and managed [12,16,17]. Its effectiveness in reducing the risk of a thymic NET is unproven, however, and studies have shown the occurrence of a thymic NET in a patient with MEN1 despite a prophylactic transcervical thymectomy [13,16,18]. If prophylactic thymectomy is performed, it is imperative that complete resection of all anterior mediastinal tissue that can potentially contain thymic tissue be removed.

(See "Multiple endocrine neoplasia type 1: Management", section on 'Surgical approach'.)

PATHOLOGY AND CLASSIFICATION — Until 1972, all epithelial tumors of the thymus were referred to as "epithelial thymomas." In 1972, Rosai and Higa reported eight cases of NETs of the thymus and coined the term "thymic carcinoid" [7]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Other tumors'.)

The most recent 2021 World Health Organization classification for thymic neoplasms is outlined in the table (table 1) [19]. NETs arising in the thymus are now broadly categorized as low-grade (NET grade 1; typical carcinoid), intermediate-grade (NET grade 2; atypical carcinoid), or high-grade (large cell neuroendocrine carcinoma [NEC], small cell NEC) neoplasms.

The histologic diagnosis of a thymic carcinoid is based on the presence of neuroendocrine features such as organoid nests, trabeculae, rosettes, or palisading and homogeneous cytologic features (picture 1A-B). The cells are relatively uniform, and they have round to oval nuclei, coarsely stippled chromatin, and finely granular cytoplasm. The cells produce abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin.

The criteria used to separate typical from atypical carcinoid are the same as those applied in the classification of pulmonary NETs. However, the prognostic value of this classification for thymic lesions has not been proven [3]. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)

Typical carcinoids show no necrosis and have less than 2 mitoses per 2 mm2, while atypical carcinoids have areas of necrosis and/or 2 to 10 mitoses per 2 mm2. Among reported cases of thymic NETs, almost all are classified as atypical carcinoids [20].

There are several histologic variants of thymic NETs (table 1). While their clinical behavior is similar to that of other thymic NETs, their unusual morphology may present diagnostic problems.

The spindle cell pattern of thymic NET can be mistaken for spindle cell thymoma (picture 2) [21]. The distinction can be readily established utilizing neuroendocrine immunohistochemical markers. Pigmented thymic NETs contain intracytoplasmic melanin and should be distinguished from a melanoma. Positive staining for neuroendocrine markers and negative studies for S-100 protein and HMB-45 exclude melanoma from consideration. Thymic NET with amyloid is a spindle cell neoplasm with amyloid stroma and positivity for calcitonin, which is thought to derive from extrathyroid C cells [22].

Large cell neuroendocrine carcinomas (LCNEC) are composed of large atypical cells with extensive areas of necrosis, often located centrally within tumor cell nests [22]. They show cytologic features of a non-small cell carcinoma, with coarse chromatin and prominent nucleoli in the majority of cells, with more than 10 mitoses per 2 mm2. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)

An unusual variant known as atypical carcinoid tumor with increased mitosis has recently been described, which has morphology most consistent with a carcinoid tumor but mitotic activity more in line with that seen in LCNEC [23]. These tumors need more study to know how they are best managed.

Small cell carcinomas are comprised of small blue cells with minimal cytoplasm, similar to their counterpart in the lung. Like LCNEC of the thymus, they also typically have a high mitotic rate (often greater than 60 per 10 high-powered fields). (See "Pathology of lung malignancies", section on 'Small cell carcinoma'.)

Histologic differential diagnosis — The differential diagnosis of a primary NET of the thymus includes multiple non-neoplastic and neoplastic lesions within the thymus gland, or extrathymic lesions within the anterior mediastinum. Histologically, a thymic NET must be distinguished from thymoma and thymic carcinoma, paraganglioma, lymphoma, germ cell tumor, parathyroid tumors, and metastasis from another primary site (figure 2) (see 'Differential diagnosis' below):

Metastasis from an NET at another site must be excluded to make the diagnosis of a primary thymic NET. (See 'Evaluation and staging' below and "Neuroendocrine neoplasms of unknown primary site", section on 'Evaluation and management'.)

The morphology of thymoma can mimic an NET if there are features such as peripheral palisading and rosettes. However, thymomas commonly have other features such as fibrous trabeculae, dilated perivascular spaces, and a dual population of thymic epithelial cells and lymphocytes that are not present in NETs.

While neuroendocrine markers can be expressed in thymomas and thymic carcinomas, in contrast to NETs, they usually lack neuroendocrine morphology and show more focal staining of neuroendocrine markers [24]. (See "Pathology of mediastinal tumors", section on 'Thymoma'.)

Paraganglioma is an unusual tumor in the mediastinum that can be misdiagnosed as an NET. Histologically, paraganglioma demonstrates an organoid nesting pattern (Zellballen) with prominent vascularity. Unlike a thymic NET, however, it has a striking variation in cellular and nuclear size [25]. By immunohistochemistry, paragangliomas are typically positive for neuroendocrine markers and often positive for GATA-3 [26], while they fail to express pancytokeratin and TTF-1. By contrast, thymic carcinoid tumors are reactive with antibodies to pancytokeratins and sometimes TTF-1, but not GATA-3 [27]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

Abnormal parathyroid glands (adenomas, carcinomas, and hyperplastic glands such as in multiple endocrine neoplasia type 1 [MEN1]) may also be confused with a carcinoid or atypical carcinoid tumor. Ectopic parathyroid glands may be found within the thymus, due to the common origin of the thymus and the inferior parathyroid glands from the third branchial pouch. Histologically, parathyroid adenomas are composed of sheets, nests, trabeculae, and tubules made of chief cells, water-clear cells, and oncocytic cells [28], the latter of which can be present in some carcinoid tumors. Neuroendocrine markers are positive in both carcinoid and parathyroid lesions. However, parathyroid hormone shows reactivity only in the latter. (See "Primary hyperparathyroidism: Clinical manifestations" and "Parathyroid carcinoma" and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Primary hyperparathyroidism'.)

CLINICAL PRESENTATION — Thymic tumors typically present as a mass in the anterior mediastinal compartment (figure 2); they rarely arise in the middle or posterior mediastinum [4]. The anterior compartment (also referred to as the anterosuperior compartment or retrosternal space) is anterior to the pericardium and includes the thymus, the extrapericardial aorta and its branches, the great veins, and lymphatic tissue. (See "Approach to the adult patient with a mediastinal mass", section on 'Mediastinal compartments'.)

Thymic NETs can be aggressive neoplasms with a tendency to invade adjacent structures (mediastinal fatty tissue, lung, pericardium, great vessels). Many are locally invasive at the time of diagnosis, and mediastinal lymph node metastases are present in approximately 50 percent of patients at presentation [8,29].

Thymic NETs can vary considerably in size [7,30]. In published reports to date, most patients present with a large locally advanced tumor and are symptomatic from local neoplastic mass effects. Symptoms vary according to disease extent, ranging from cough, dyspnea, and chest pain to superior vena cava (SVC) syndrome (in approximately 20 percent) and hoarseness from invasion of the recurrent laryngeal nerve [8,31,32]. Approximately one-third of thymic NETs are asymptomatic and incidentally discovered on a radiographic study done for an unrelated cause [4] or for multiple endocrine neoplasia type 1 (MEN1) surveillance. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors' and "Malignancy-related superior vena cava syndrome".)

Distant metastases – Metastatic spread occurs by the hematogenous and lymphatic routes. Between 20 and 40 percent have distant metastases at presentation [4,9,12]. Common sites of distant metastases include lung and pleura, bone, liver, pancreas, and chest wall [4,31,33]. Brain metastases have been described in several cases [33].

Paraneoplastic conditions – Several paraneoplastic syndromes are associated with thymic neoplasms (table 2). However, most are rare with thymic NETs:

In older series, a clinically apparent endocrinopathy has developed in up to one-half of cases of patients with thymic carcinoid [34,35]. The most common is Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (ACTH) [36-39]. (See "Establishing the cause of Cushing syndrome" and "Dexamethasone suppression tests", section on 'Low-dose DSTs'.)

Acromegaly (due to ectopic production of growth hormone releasing hormone) and hyponatremia (due to the syndrome of inappropriate antidiuretic hormone [SIADH] or production of atrial natriuretic peptide) are uncommon [40,41].

Paraneoplastic endocrinopathy is almost exclusively seen in sporadic cases. In MEN1-associated thymic NETs, acromegaly has been rarely reported [42], as has ectopic ACTH production [39,43]. (See "Diagnosis of acromegaly", section on 'Other studies'.)

In addition to endocrinopathies, other less commonly reported paraneoplastic conditions associated with these tumors are polyarthropathy, proximal myopathy, peripheral neuropathy, hypertrophic osteoarthropathy, and Lambert-Eaton syndrome [9,44]. Myasthenia gravis is rare with NETs [45]. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

Carcinoid syndrome has only rarely been reported in association with a thymic NET [46].

DIFFERENTIAL DIAGNOSIS — Most thymic NETs present as a mass in the anterior mediastinal compartment (figure 2). The differential diagnosis includes other masses that arise in this compartment, such as mediastinal cysts, thyroid tissue, parathyroid tissue, and a variety of neoplasms, benign or malignant, that can arise in the thymus [47]. (See 'Clinical presentation' above.)

Thymic cysts may be congenital or acquired, and may be associated with a thymic malignancy. Thymic cysts can generally be observed unless the diagnosis is not clear, they are enlarging, or they are causing associated symptoms.

Thymolipoma is a benign neoplasm comprised of thymic epithelium and abundant adipose tissue.

True thymic hyperplasia and thymic lymphoid hyperplasia (generally defined by the presence of large numbers of lymphoid follicles with germinal centers) may enlarge the thymus and simulate a neoplasm.

Thymoma and thymic carcinoma are epithelial malignancies with distinct clinicopathologic features. (See "Clinical presentation and management of thymoma and thymic carcinoma".)

Lymphomas may primarily or secondarily involve the thymus. (See "Primary mediastinal large B cell lymphoma".)

Mediastinal germ cell tumors may arise primarily within the thymus. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

EVALUATION AND STAGING — For most patients, we recommend contrast-enhanced computed tomography (CT) scans of the chest. The noninvasive evaluation of a newly diagnosed mediastinal mass is discussed in detail separately. (See "Approach to the adult patient with a mediastinal mass".)

The appearance of an anterior mediastinal mass on cross-sectional imaging of the chest forms the basis for deciding whether to proceed directly with resection or obtain a tissue diagnosis preoperatively. Exclusion of lymphoma and germ cell tumor is important since these two conditions may be treated medically rather than surgically. For small, seemingly encapsulated masses where surgical resection appears feasible, thymectomy should be performed, with en bloc resection of adjacent tissues based on local stage of disease. For larger masses, a surgical biopsy may be indicated.

If the diagnosis of a thymic NET is established on biopsy, we complete the evaluation with cross-sectional imaging of the abdomen and baseline somatostatin receptor imaging using either somatostatin-receptor imaging with integrated positron emission tomography ([PET]/CT; eg, Ga-68 DOTATATE or Cu-64 DOTATATE scan).

Cross-sectional imaging — A chest CT scan, preferably with intravenous contrast, refines lesion localization, allows further characterization of the morphologic features of the mass, and allows the evaluation of adjacent thoracic structures for evidence of local invasion or regional metastases. In some cases, the findings are sufficiently characteristic for specific histologies (eg, a teratoma).

A thymic NET typically manifests as a large, lobulated, usually invasive, anterior mediastinal mass with heterogeneous enhancement that may exhibit areas of hemorrhage and necrosis (image 1). Punctate and dystrophic calcifications may also be seen. There are no pathognomonic findings, and it may be difficult to distinguish a thymic NET from other thymic malignancies or from nonthymic malignancies such as lymphoma or metastatic disease [48,49].

In general, CT is the imaging procedure of choice for anterior mediastinal masses. However, magnetic resonance imaging (MRI), in particular a cardiac MRI, can be very helpful in assessing invasion of the pericardium, proximal great vessels, or heart structures in cases of large masses that are causing at least displacement of these structures due to mass effect. (See "Approach to the adult patient with a mediastinal mass", section on 'Imaging'.)

Somatostatin receptor-based diagnostic imaging — Somatostatin receptors are overexpressed in NETs (including thymic primaries) and in malignant thymic epithelial tumors [50]. Somatostatin receptor-based diagnostic imaging (eg, gallium Ga-68 DOTATATE or copper Cu-64 DOTATATE)-integrated PET/CT scanning can be used to identify these tumors, distinguish them from other malignancies arising in the anterior mediastinum, and exclude a primary NET in another site that may have metastasized to the thymus [50-54]. One benefit of somatostatin receptor imaging over cross-sectional imaging modalities is that it images the whole body [55]. Another benefit is that a positive scan indicates the presence of somatostatin receptors on the tumor and the possibility of benefit from peptide receptor radioligand therapy for advanced disease. (See 'Metastatic/unresectable disease' below.)

However, specificity is somewhat limited because somatostatin receptors can be expressed in other tumors, including thymomas and thymic carcinomas, granulomas, and autoimmune diseases. Moreover, sensitivity may be limited because many thymic NETs do not express high levels of somatostatin receptors [13,33,50].

FDG-PET — Given the aggressive behavior of many thymic neoplasms, 18-F fluorodeoxyglucose (FDG) positron emission tomography (PET) scans may be useful for initial staging and monitoring of disease activity in patients with high-grade tumors and/or to further characterize negative or equivocal somatostatin receptor-based diagnostic imaging [56-59].

Laboratory testing — NETs have the capacity to produce and secrete a variety of bioactive amines and peptides, some of which can be measured in blood and/or urine. However, the majority of thymic NETs do not produce hormones (nonfunctioning). Thus, collection of urine for 5-HIAA testing is generally not helpful in the diagnostic evaluation for a thymic NET. Although serum levels of chromogranin A (CgA) may be elevated [13], CgA cannot be recommended as a diagnostic marker for a NET because it lacks both sensitivity and specificity. CgA may be useful to follow disease activity in those with advanced or metastatic disease, in whom the CgA level is initially elevated. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)

Given the high incidence of Cushing's syndrome, some experts recommend that patients with non-MEN1-associated thymic NETs should undergo measurement of cortisol levels in the serum or in a 24-hour urine collection. We agree with guidelines from the European Society of Medical Oncology that suggest cortisol assay only if there are clinical symptoms suggestive of Cushing's syndrome [60]. (See 'Clinical presentation' above and "Establishing the diagnosis of Cushing syndrome", section on '24-hour urinary cortisol excretion'.)

Need for biopsy — In general, among patients with a mediastinal mass, the CT appearance forms the basis for deciding whether to proceed directly with resection or obtain a tissue diagnosis preoperatively. Exclusion of lymphoma and a mediastinal germ cell tumor is important since these two conditions would be treated medically rather than surgically. Some diagnoses (eg, teratoma) are associated with characteristic findings on cross sectional imaging. (See 'Cross-sectional imaging' above.)

For patients with a small, seemingly encapsulated mass that appears consistent with a thymoma, thymectomy is appropriate to establish the diagnosis and effect therapy, whereas a larger mass with indistinct margins should be biopsied before proceeding with resection to establish the histologic diagnosis and provide for decision-making about neoadjuvant therapy [61]. (See 'Neoadjuvant therapy for locally advanced disease' below and "Clinical presentation and management of thymoma and thymic carcinoma".)

If a biopsy is indicated, the diagnostic procedure of choice is CT-guided core needle biopsy. Although CT-guided fine needle aspiration (FNA) biopsy via a parasternal approach can allow preoperative identification of a thymic NET [32,62-64], it may not be possible to secure a definitive diagnosis. There may not be sufficient tumor cells in the cell block to perform immunohistochemistry for neuroendocrine markers or flow cytometry, which can help establish a diagnosis of lymphoma. Furthermore, it may not be possible to accurately establish the tumor grade. Endoscopic or transbronchial ultrasound-guided FNA may be valuable in select cases, for example when metastatic cancer to mediastinal lymph nodes is suspected (figure 3). Cervical mediastinoscopy is another excellent approach to biopsying mediastinal lymph nodes not accessible by less invasive endoscopic techniques. (See "Endobronchial ultrasound: Indications, contraindications, and complications", section on 'Indications'.)

If this procedure does not establish a diagnosis, then a surgical biopsy may be indicated. The approach depends upon the location of the tumor and the expertise of the surgeon. If the mass abuts the anterior chest wall then a direct cutdown, an anterior mediastinotomy (Chamberlain procedure), may be the simplest approach. In cases where the mass protrudes into either side of the chest, the lesion can be approached with a video-assisted thoracoscopic (VATS) approach. VATS can often be performed with a single one centimeter incision that both provides access to the mass for a biopsy and also allows inspection/biopsy of the pleural space. This approach may be ideal if there is suspicion of lung metastases that have defied other diagnostic attempts. A disadvantage to a VATS approach is that a postoperative chest tube and at least a one night hospital admission may be needed.

Staging classification — The newest version (eighth edition, 2017) of the tumor, node, metastasis (TNM) staging classification from the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) includes a staging system for all thymic malignancies, including neuroendocrine neoplasms (table 3) [65].

PROGNOSIS AND MANAGEMENT — Because most thymic NETs represent atypical carcinoids/NET grade 2 or higher-grade neoplasms, they are generally characterized by aggressive behavior, a tendency to recur locally and metastasize, resistance to therapy, and a prognosis that is generally inferior to other NETs of similar stage and grade arising elsewhere in the body, particularly in the lung (in which low-grade NETs predominate). (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging".)

The main prognostic factors are surgical resection/resectability, tumor stage, histologic grade, and tumor size:

In a retrospective nonrandomized series of 254 patients derived from the Surveillance, Epidemiology, and End Results (SEER) database, patients who were able to undergo surgical therapy had a significantly longer median survival than those who did not (109 versus 46 months) [66].

In the largest North American series of 80 cases of thymic NET, overall five- and 10-year survival rates were 28 and 10 percent, respectively [31]. In a group of 50 with long-term clinical follow-up, disease-free survival correlated with tumor grade. Low-grade tumors had a five- and 10-year disease-free survival of 50 and 9 percent, respectively; intermediate-grade tumors had a disease-free survival of 20 percent at five years, and none were disease free at 10 years; none of the patients with high-grade tumors were disease free at five years.

Prognosis is closely related to disease stage [5,67,68]:

In a SEER database review of 160 cases of thymic NET, the median survival for patients with localized, regional, and distant metastases were 110, 59, and 35 months, respectively [5]. One, three, and five-year survival rates stratified according to disease stage are depicted in the table (table 4).

In a series of 205 surgically resected patients identified in a database of the European Society of Thoracic Surgeons, Masaoka stage (table 5) was a significant prognostic factor for survival (p = 0.02): median overall survival was 13.5 years for stages I and II, 7.3 years for stage III, 3.8 years for stage IVa, and 4.2 years for stage IVb disease [69]. Interestingly, tumor grade/differentiation did not seem to affect survival. The majority of patients received adjuvant or neoadjuvant treatment.

Tumor size also impacts outcomes. In an analysis of 35 patients with surgically resected thymic NETs, 10-year rate of survival was significantly higher for tumors <7 cm compared with those 7 cm or larger (91 versus 29 percent) [68].

Poor prognosis for larger and more advanced stage tumors is related, at least in part, to late tumor detection. A high degree of suspicion in families with multiple endocrine neoplasia type 1 (MEN1), and earlier detection of thymic NETs may improve outcomes, although this has not yet been borne out in clinical studies. As an example, in one report, 85 patients with MEN1 were prospectively evaluated over a mean of eight years with computed tomography (CT), magnetic resonance imaging (MRI), chest radiograph, and OctreoScan [13]. Seven patients were diagnosed with a thymic NET, and all underwent resection. Despite the presumably early diagnosis, all patients followed for longer than one year recurred. With the exception of male sex, no clinical, laboratory, or other feature of the MEN1 patients distinguished those who developed a NET from those who did not. The issue of screening for thymic carcinoids in patients with MEN1 is discussed in detail separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)

In other patients, the natural history can often be prolonged, with a tendency to recur and metastasize over many years (as many as 20 years [70]) after the initial operation [9,71,72]. Thus, post-treatment surveillance should be extended beyond five years. (See 'Post-treatment surveillance' below.)

Treatment for locoregional disease — Given the rarity of these tumors, data to guide optimal treatment are necessarily limited by the small size of most reports and case series and the lack of prospective trials. Surgery is the mainstay of therapy for resectable cases, whereas adjuvant or neoadjuvant radiation therapy (RT) plays a role in subtotally resected or locally advanced unresectable nonmetastatic cases.

Patients with superior vena cava (SVC) syndrome may also benefit from endovascular stent placement. (See "Malignancy-related superior vena cava syndrome", section on 'Patients without life-threatening symptoms'.)

Resection — Thymic neoplasms typically present as a mass in the anterior mediastinal compartment (figure 2 and image 1). Complete surgical resection of all thymic tissue (total [extended] thymectomy) requires resection of all mediastinal tissue anterior to the pericardium from the innominate vessels to the diaphragm and laterally to each phrenic nerve. Resection should include hilar and mediastinal lymph node sampling [59,65]. (See "Thymectomy", section on 'Extent of resection' and "Thymectomy", section on 'Lymph node dissection'.)

Completeness of resection is a strong prognostic factor for overall survival [5,8,29,32,33,36]. Whenever possible, complete surgical resection (of the primary tumor and regional nodes) is the treatment of choice. Unfortunately, microscopically complete resections are uncommonly achieved with tumors that invade contiguous mediastinal structures such as major blood vessels, pericardium, or phrenic nerve [36]. Furthermore, even after complete surgical resection, there is a high rate of local recurrence.

Thymectomy and resection of anterior mediastinal masses can be achieved via several different approaches, which are generally chosen based on thymus size and location. Transthoracic thymectomy, via a median sternotomy, is the standard approach for thymectomy, particularly for thymic neoplasms. Minimally invasive approaches (transthoracic, transcervical) may be appropriate, although the size, location, and appearance of the tumor must be carefully evaluated when considering these techniques. As the goal of surgery is complete resection with no residual disease, the approach must avoid any action that could spill tumor during either manipulation or removal. Transthoracic approaches (video-assisted thoracoscopic surgery [VATS] or robotic thymectomy) can be good options for some patients, but surgeons again must ensure that there is no risk that the oncologic efficacy of the procedure will be compromised (eg, tumor spillage, incomplete resection). Transcervical thymectomy, which can be an excellent technique for thymus removal in patients with myasthenia gravis without an associated thymoma, is discouraged due to concerns over the completeness of resection. In general, most thymic NETs are diagnosed at a size that is not amenable to minimally invasive techniques. Thymectomy is discussed in detail elsewhere. (See "Thymectomy".)

It is unclear whether surgical debulking of large tumors without curative intent confers any survival benefit [73]. However, palliative surgical resection or debulking of a large primary tumor causing compression symptoms may provide benefits in terms of symptom control [4]. Proceeding with a major operation with palliative intent should only be undertaken in highly selected cases, and ideally the decision made in with multidisciplinary team input. Palliative resection could also be considered if a hormonal secretory condition such as Cushing's syndrome, hypercalcemia, or carcinoid syndrome is debilitating. Patients with refractory Cushing's syndrome may need end-organ ablation (ie, bilateral adrenalectomy). (See "Overview of the treatment of Cushing syndrome", section on 'Cushing disease'.)

Recurrent local disease should also be addressed surgically, when possible [4,10,30].

Postoperative therapy — There are no randomized trials, and no consensus as to the optimal postoperative strategy. For patients with well-differentiated (typical) or moderately differentiated (atypical) thymic NETs that are incompletely resected we suggest maximal resection followed by local RT rather than resection alone for control of residual disease. For poorly-differentiated neuroendocrine carcinomas (NECs), even those that are completely resected, we suggest postoperative chemoradiotherapy in conjunction with platinum/etoposide-based chemotherapy, as is typically used for small cell lung cancer, rather than RT alone (see "Limited-stage small cell lung cancer: Initial management", section on 'Integration of chemotherapy with RT').

The use of a platinum plus etoposide with RT for patients with atypical carcinoid tumors (NET grade 2) is more controversial. It is likely that the higher the histologic tumor grade, the more likely the patient is to benefit from the addition of platinum/etoposide-based chemotherapy to RT. Nevertheless, expert group guidelines differ:

We agree with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), which suggest RT in patients with an incomplete resection, with or without chemotherapy (concurrent use of radiosensitizing doses of fluorouracil or capecitabine), and systemic chemotherapy (cisplatin or carboplatin plus etoposide) being considered appropriate for patients with incompletely resected atypical carcinoid (NET grade 2) or poorly-differentiated (grade 3 NEC) thymic neoplasms [74].

European Society of Medical Oncology guidelines similarly acknowledge absence of evidence on benefit of adjuvant treatment. They recommend observation or adjuvant radiation for any R0 resection or R1 resection of typical carcinoid; observation or radiation with or without systemic treatment for R1 resection of atypical carcinoid or R2 resection of typical carcinoid, and systemic therapy with or without radiation for R2 resection of atypical carcinoid [60].

Otherwise, the available literature suggest no benefit from adjuvant chemotherapy alone for most completely resected well-differentiated thymic NETs [5,66,69].

Benefit of RT — The evidence supporting benefit for adjuvant or definitive RT is extremely limited. While there are series and case reports suggesting that the addition of local RT improves local control following complete resection, there is no evidence that this confers a survival benefit. As examples:

In one series of 12 patients undergoing resection for a thymic carcinoid, nine had a complete resection, three of whom received adjuvant RT with no recurrence documented [33]. By contrast, four of the six who did not receive adjuvant RT recurred locally. Distant metastases developed in nine patients, and only two of the entire cohort were alive and disease free at 67 and 81 months, only one of whom had received adjuvant RT.

Evidence of improved local control has been seen in other series as well, including patients with incompletely resected tumors [10,29,32,75]. However, as in the prior series, although local control appeared to be improved by RT, distant metastases developed in 10 of the 13 completely resected patients, and only one remained tumor free and alive beyond five years.

In an analysis of 160 cases in the SEER registry, patients receiving adjuvant or definitive radiation experienced poorer outcomes than those who did not, and in multivariate analysis, there was no survival benefit for RT delivered as part of primary therapy [5]. However, due the non-randomized nature of this analysis, it is difficult to draw definitive conclusions.

Neoadjuvant therapy for locally advanced disease — For patients with locally advanced disease, there has been interest in neoadjuvant therapy using chemotherapy or a combination of chemotherapy and RT to increase resectability. The feasibility of such an approach has been demonstrated in case reports [76,77], but whether this improves outcomes over maximum resection followed by adjuvant RT is unknown.

Treatment of recurrent and metastatic disease — Options for recurrent and/or metastatic disease include resection, RT, and systemic therapy.

Potentially resectable recurrent disease — In the rare circumstance where a disease recurrence is potentially resectable, surgical resection should be considered, if possible.

Metastatic/unresectable disease — There are several systemic treatment options: long-acting somatostatin analogs, everolimus, temozolomide-based chemotherapy, and peptide receptor radioligand therapy using a radiolabeled somatostatin analog such as lutetium Lu-177 dotatate (177Lu-dotatate). Somatostatin analogs should probably be chosen first line for patients with relatively low-volume, relatively asymptomatic, somatostatin receptor-positive disease. Beyond that, there are no data for selecting or sequencing these treatments except that 177Lu-dotatate is limited to somatostatin receptor-expressing tumors. Even in those tumors, there is no real basis for choosing 177Lu-dotatate over everolimus, or vice versa, as the second-line treatment.

Long-acting somatostatin analogs — A therapeutic trial of a long-acting somatostatin analog is reasonable for patients with evidence of somatostatin receptor expression on radiolabeled somatostatin analog imaging studies (preferably gallium Ga-68 DOTATATE, Ga-68 DOTATOC, or Cu-64 DOTATATE positron emission tomography scan), particularly if they have low-volume, relatively asymptomatic disease.

Whether somatostatin analogs exert any stabilizing effect on tumor growth, as they do with some gastrointestinal tract NETs, is unclear; few data are available [14]. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

Consensus-based guidelines from the NCCN suggest octreotide or lanreotide as a first-line option for patients with locoregional unresectable disease and/or distant metastases, and/or those with carcinoid syndrome [74].

Everolimus — Everolimus may be a modestly active agent:

In the phase III RADIANT 4 study, everolimus demonstrated significant improvement in progression-free survival (PFS) compared with placebo in patients with progressive gastrointestinal and lung NETs [78]. Subgroup analysis of the lung NET cohort confirmed significant improvement in PFS in this population. Thymic NETs were not included in this study. However, given their biological and clinical similarity to lung NETs, extrapolation of the results to this population is not unreasonable.

Efficacy in thymic neuroendocrine neoplasms is supported by a small series of four patients with progressing tumors (two well-differentiated intermediate grade tumors, and two intermediate grade tumors with large cell characteristics) who were treated with everolimus 10 mg per day after the failure of at least one prior medical therapy [79]. Despite no objective responses, all patients had stable disease for a median of 20.8 months (range 7 to 42 months), and the progression-free interval was longer in the two patients with well differentiated tumors (24 and 42 months, respectively) compared with the two with large cell differentiation (7 and 10 months).

Based on these limited data a trial of everolimus is reasonable for patients with progressive thymic NETs. Molecularly targeted treatments for advanced NETs involving the gastrointestinal tract and lung are discussed in more detail separately. A more extensive description of the results of the RADIANT-4 trial is provided separately. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Everolimus' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Molecularly targeted therapy'.)

Cytotoxic chemotherapy — There are several small retrospective series evaluating the efficacy of cytotoxic temozolomide or platinum-based chemotherapy for thymic NETs:

One retrospective analysis of temozolomide for advanced NETs included seven patients with thymic NET, among whom five (71 percent) experienced stable disease as their best response [80]. In another report, nine patients with thymic NET received temozolomide alone or temozolomide plus sorafenib, and there were seven cases of stable disease, one partial response, and one case of progressive disease [81]. Most of these were intermediate grade tumors by virtue of a Ki-67 labeling index of 5 to 10 percent. Three patients with thymic atypical NET were treated with capecitabine plus temozolomide; there was one objective partial response, one minor response, and one patient with stable disease [82].

Some patients with intermediate to poorly-differentiated tumors respond to platinum-based chemotherapy regimens [81,83]. In particular, we treat poorly-differentiated thymic NECs with platinum-based regimens, such as carboplatin and etoposide, as per treatment guidelines for poorly-differentiated NETs at other sites. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Treatment and prognosis'.)

Peptide receptor radioligand therapy — Another option for patients whose tumors have a high level of expression of somatostatin receptors (as determined by somatostatin receptor-based diagnostic imaging) is peptide receptor radioligand therapy using the radiolabeled somatostatin analog 177Lu-dotatate.

177Lu-dotatate has been studied mainly for the treatment of gastroenteropancreatic NETs. Among patients with advanced midgut NETs, the benefits of 177Lu-dotatate were shown in the NETTER-1 trial, which demonstrated significant improvement in PFS with 177Lu-dotatate compared with high-dose octreotide [84]. These data are discussed in detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

The data on thymic NET are limited to two reported patients treated with 177Lu-dotatate, one of whom had stable disease as the best response [85]. The US Food and Drug Administration (FDA) approved 177Lu-dotatate for the treatment of somatostatin receptor-positive gastroenteropancreatic NETs in adults [86]. While the approval did not cover thymic NETs, off-label use could be considered in appropriate patients. (See 'Somatostatin receptor-based diagnostic imaging' above and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

Radiation therapy — RT may provide palliation of a symptomatic site of recurrent and/or metastatic disease.

POST-TREATMENT SURVEILLANCE — There are no evidence-based guidelines for post-treatment surveillance, and the optimal post-treatment surveillance strategy is not established.

Consensus-based guidelines are available from the National Comprehensive Cancer Network (NCCN) and the North American Neuroendocrine Tumor Society (NANETS):

NCCN guidelines recommend history and physical examination with cross-sectional imaging of the chest between 3 and 12 months postresection, with biochemical evaluation "as clinically indicated" [74]. After one year postresection, they recommend assessment every 12 to 24 months with history and physical examination, "consideration" of cross-sectional imaging, and biochemical evaluation as clinically indicated.

Guidelines from NANETS recommend clinical follow-up three to six months following resection, and then every 6 to 12 months for at least seven years. Cross-sectional imaging is recommended, but no guidance is provided as to the appropriate interval for retesting. For advanced disease, follow-up is recommended every three to six months; the interval may be lengthened to every six months for patients with long duration (>12 months) of stable disease. Biochemical testing should be considered if abnormal at baseline.

It is recommended to do the first imaging within six months of definitive locoregional treatment, then every 4 to 12 months depending on tumor-grade differentiation. After five years, imaging frequency can be decreased if there is no evidence of recurrence. Because histology cannot reliably predict NET prognosis, after resection, long-term surveillance (up to 10 years) is suggested (by imaging and, if applicable, tumor markers).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

Epidemiology and classification

Thymic neuroendocrine tumors (NETs) are exceedingly uncommon primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum (figure 2). Even if well differentiated, thymic NETs are characterized by relatively aggressive clinical behavior and a high propensity for locoregional invasion, local recurrence, and distant metastases. (See 'Anatomy' above.)

Approximately 25 percent of thymic NETs occur in patients with multiple endocrine neoplasia type 1 (MEN1), in whom they arise primarily in male smokers. (See 'Epidemiology' above.)

The most recent 2021 World Health Organization classification for thymic neoplasms is outlined in the table (table 1). (See 'Pathology and classification' above.)

Clinical presentation

Thymic NETs may manifest with symptoms from local mass effect, asymptomatically as an incidental finding on radiographic imaging, with symptoms and/or signs related to distant metastases, or rarely, with symptoms related to an associated paraneoplastic endocrinopathy, of which Cushing's syndrome is the most common. (See 'Clinical presentation' above.)

Common sites of distant metastases include lung and pleura, bone, liver, pancreas, and chest wall.

Evaluation and staging

If the diagnosis of a thymic NET is established, cross-sectional imaging of the abdomen (in addition to the chest), and baseline somatostatin receptor-based imaging are strongly suggested. For most patients, integrated PET/CT using one of the radiolabeled somatostatin analogs (Ga-68 DOTATATE, or CU-64 DOTATATE) is superior to the OctreoScan because of greater sensitivity. (See 'Evaluation and staging' above.)

Patients with non-MEN1-associated thymic NETs should be evaluated for Cushing's syndrome by history and physical examination.

If the diagnosis is not established, the appearance of an anterior mediastinal mass on cross-sectional imaging of the chest forms the basis for deciding whether to proceed directly with resection or obtain a tissue diagnosis preoperatively. Exclusion of lymphoma and germ cell tumor is important since these two conditions may be treated medically rather than surgically.

For patients with a small, seemingly encapsulated mass that appears consistent with a thymoma, thymectomy is appropriate to establish the diagnosis and effect therapy. For a larger mass with indistinct margins, a biopsy is strongly suggested before proceeding with resection to establish the diagnosis and provide for decision-making about neoadjuvant therapy. (See 'Need for biopsy' above.)

Treatment and prognosis

For patients with an established diagnosis of a thymic NET we suggest maximal surgical resection if feasible (Grade 2B). (See 'Resection' above.)

For patients with a well-differentiated (typical) or moderately differentiated (intermediate grade, atypical) thymic NET with positive margins or gross residual disease we suggest adding postoperative radiation therapy (RT) following maximal surgical resection rather than resection alone to enhance local control (Grade 2C). For patients who undergo complete resection of a poorly-differentiated thymic neuroendocrine carcinoma (NEC), we suggest postoperative platinum/etoposide-based chemotherapy plus chemoradiotherapy, as is used for localized small cell lung cancer, rather than RT alone (Grade 2C). (See 'Postoperative therapy' above.)

The use of platinum/etoposide in conjunction with RT for atypical (intermediate grade) tumors is controversial. The benefit of these chemotherapy agents is likely correlated to the grade of the tumor (higher grade correlates with increased benefit).

Systemic therapy is an appropriate option for patients with unresectable recurrent or metastatic tumors.

-For patients with well-differentiated tumors, systemic therapy options include long-acting somatostatin analogs, everolimus, temozolomide-based chemotherapy, and peptide receptor radioligand therapy using a radiolabeled somatostatin analog such as lutetium Lu-177 dotatate (177Lu-dotatate).

Somatostatin analogs should probably be chosen first line for patients with relatively low-volume, relatively asymptomatic, somatostatin receptor-positive disease. Beyond that, there are no data for selecting or sequencing these treatments except that 177Lu-dotatate should be limited to patients with somatostatin receptor-expressing tumors.

-For patients with advanced high-grade NECs we treat with combined platinum plus etoposide, similarly to small cell carcinoma of the lung. (See "Limited-stage small cell lung cancer: Initial management", section on 'Integration of chemotherapy with RT' and "Extrapulmonary small cell cancer" and "Small cell neuroendocrine carcinoma of the cervix", section on 'Chemotherapy' and "Small cell carcinoma of the bladder".)

RT may provide palliation of a symptomatic site of recurrent and/or metastatic disease. (See 'Metastatic/unresectable disease' above.)

Post-treatment surveillance

The optimal post-treatment surveillance strategy is not established. Imaging within six months of resection, then every 4 to 12 months depending on tumor differentiation/grade is a reasonable approach. After five years, imaging frequency can be decreased if there is no evidence of recurrence.

Because histology cannot reliably predict prognosis after resection, long-term surveillance (up to 10 years) is recommended with scans at least annually. Patients with aggressive histological features (intermediate- and high-grade tumors) should be monitored more frequently. (See 'Post-treatment surveillance' above.)

  1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5:S260.
  2. Strollo DC, Rosado de Christenson ML, Jett JR. Primary mediastinal tumors. Part 1: tumors of the anterior mediastinum. Chest 1997; 112:511.
  3. Goto K, Kodama T, Matsuno Y, et al. Clinicopathologic and DNA cytometric analysis of carcinoid tumors of the thymus. Mod Pathol 2001; 14:985.
  4. Chaer R, Massad MG, Evans A, et al. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002; 74:1733.
  5. Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg 2010; 251:1117.
  6. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063.
  7. Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 1972; 29:1061.
  8. de Montpréville VT, Macchiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996; 111:134.
  9. Wick MR, Scheithauer BW. Thymic carcinoid. A histologic, immunohistochemical, and ultrastructural study of 12 cases. Cancer 1984; 53:475.
  10. Economopoulos GC, Lewis JW Jr, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg 1990; 50:58.
  11. Valli M, Fabris GA, Dewar A, et al. Atypical carcinoid tumour of the thymus: a study of eight cases. Histopathology 1994; 24:371.
  12. Teh BT, McArdle J, Chan SP, et al. Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Medicine (Baltimore) 1997; 76:21.
  13. Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2003; 88:1066.
  14. Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab 2005; 90:2603.
  15. Ferolla P, Urbani M, Ascani S, et al. [Prevalence of the neuroendocrine phenotype in thymus neoplasms]. Chir Ital 2002; 54:351.
  16. Duh QY, Hybarger CP, Geist R, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 1987; 154:142.
  17. Powell AC, Alexander HR, Pingpank JF, et al. The utility of routine transcervical thymectomy for multiple endocrine neoplasia 1-related hyperparathyroidism. Surgery 2008; 144:878.
  18. Burgess JR, Giles N, Shepherd JJ. Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2001; 55:689.
  19. WHO Classification of Tumours Editorial Board. Thoracic tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2021 [cited YYYY Mmm D]. (WHO classification of tumours series, 5th ed.; vol. 5). Available from: https://tumourclassification.iarc.who.int/chapters/35. (Accessed on August 19, 2021).
  20. Marx A, Shimosato Y, Kuo TT, et al. Thymic neuroendocrine tumours. In: Pathology & genetics: Tumours of the lung, pleura, thymus and heart, Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (Eds), IARC Press, Lyon, France 2004.
  21. Moran CA, Suster S. Spindle-cell neuroendocrine carcinomas of the thymus (spindle-cell thymic carcinoid): a clinicopathologic and immunohistochemical study of seven cases. Mod Pathol 1999; 12:587.
  22. Rosai J. Histological Typing of Tumours of the Thymus, 2nd ed, Springer, Berlin 1999.
  23. Dinter H, Bohnenberger H, Beck J, et al. Molecular Classification of Neuroendocrine Tumors of the Thymus. J Thorac Oncol 2019; 14:1472.
  24. Hishima T, Fukayama M, Hayashi Y, et al. Neuroendocrine differentiation in thymic epithelial tumors with special reference to thymic carcinoma and atypical thymoma. Hum Pathol 1998; 29:330.
  25. Moran CA, Suster S, Fishback N, Koss MN. Mediastinal paragangliomas. A clinicopathologic and immunohistochemical study of 16 cases. Cancer 1993; 72:2358.
  26. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 2014; 38:13.
  27. Weissferdt A, Kalhor N, Liu H, et al. Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases. Hum Pathol 2014; 45:2463.
  28. Shimosato Y, Mukai K. Tumors of the Mediastinum, 3rd ed, Armed Forces Institute of Pathology, Washington, DC 1995.
  29. Fukai I, Masaoka A, Fujii Y, et al. Thymic neuroendocrine tumor (thymic carcinoid): a clinicopathologic study in 15 patients. Ann Thorac Surg 1999; 67:208.
  30. Wick MR, Carney JA, Bernatz PE, Brown LR. Primary mediastinal carcinoid tumors. Am J Surg Pathol 1982; 6:195.
  31. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100.
  32. Wang DY, Chang DB, Kuo SH, et al. Carcinoid tumours of the thymus. Thorax 1994; 49:357.
  33. Tiffet O, Nicholson AG, Ladas G, et al. A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus. Chest 2003; 124:141.
  34. Wick MR, Rosai J. Neuroendocrine neoplasms of the thymus. Pathol Res Pract 1988; 183:188.
  35. de Perrot M, Spiliopoulos A, Fischer S, et al. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome. Ann Thorac Surg 2002; 73:675.
  36. Gal AA, Kornstein MJ, Cohen C, et al. Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study. Ann Thorac Surg 2001; 72:1179.
  37. Dixon JL, Borgaonkar SP, Patel AK, et al. Thymic neuroendocrine carcinoma producing ectopic adrenocorticotropic hormone and Cushing's syndrome. Ann Thorac Surg 2013; 96:e81.
  38. Neary NM, Lopez-Chavez A, Abel BS, et al. Neuroendocrine ACTH-producing tumor of the thymus--experience with 12 patients over 25 years. J Clin Endocrinol Metab 2012; 97:2223.
  39. Ghazi AA, Dezfooli AA, Mohamadi F, et al. Cushing syndrome secondary to a thymic carcinoid tumor due to multiple endocrine neoplasia type 1. Endocr Pract 2011; 17:e92.
  40. Jansson JO, Svensson J, Bengtsson BA, et al. Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6. Clin Endocrinol (Oxf) 1998; 48:243.
  41. Okada S, Ohshima K, Mori M. The Cushing syndrome induced by atrial natriuretic peptide-producing thymic carcinoid. Ann Intern Med 1994; 121:75.
  42. Boix E, Picó A, Pinedo R, et al. Ectopic growth hormone-releasing hormone secretion by thymic carcinoid tumour. Clin Endocrinol (Oxf) 2002; 57:131.
  43. Takagi J, Otake K, Morishita M, et al. Multiple endocrine neoplasia type I and Cushing's syndrome due to an aggressive ACTH producing thymic carcinoid. Intern Med 2006; 45:81.
  44. Lowenthal RM, Gumpel JM, Kreel L, et al. Carcinoid tumour of the thymus with systemic manifestations: a radiological and pathological study. Thorax 1974; 29:553.
  45. Wu MH, Tseng YL, Cheng FF, Lin TS. Thymic carcinoid combined with myasthenia gravis. J Thorac Cardiovasc Surg 2004; 127:584.
  46. Soga J, Yakuwa Y, Osaka M. Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg 1999; 5:285.
  47. Strollo DC, Rosado-de-Christenson ML. Tumors of the thymus. J Thorac Imaging 1999; 14:152.
  48. Ferrozzi F, Ganzetti A, Mugnoli E, et al. [Thymic carcinoid: CT and MR findings]. Radiol Med 1997; 94:652.
  49. Adolph JM, Kimmig BN, Georgi P, zum Winkel K. Carcinoid tumors: CT and I-131 meta-iodo-benzylguanidine scintigraphy. Radiology 1987; 164:199.
  50. Guidoccio F, Grosso M, Maccauro M, et al. Current role of 111In-DTPA-octreotide scintigraphy in diagnosis of thymic masses. Tumori 2011; 97:191.
  51. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20:716.
  52. Lastoria S, Vergara E, Palmieri G, et al. In vivo detection of malignant thymic masses by indium-111-DTPA-D-Phe1-octreotide scintigraphy. J Nucl Med 1998; 39:634.
  53. Nilsson O, Kölby L, Wängberg B, et al. Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours. Br J Cancer 1998; 77:632.
  54. Silva F, Vázquez-Sellés J, Aguilö F, et al. Recurrent ectopic adrenocorticotropic hormone producing thymic carcinoid detected with octreotide imaging. Clin Nucl Med 1999; 24:109.
  55. Granberg D, Sundin A, Janson ET, et al. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol (Oxf) 2003; 59:793.
  56. Whitaker D, Dussek J. PET scanning in thymic neuroendocrine tumors. Chest 2004; 125:2368.
  57. Groves AM, Mohan HK, Wegner EA, et al. Positron emission tomography with FDG to show thymic carcinoid. AJR Am J Roentgenol 2004; 182:511.
  58. Fujishita T, Kishida M, Taki H, et al. Detection of primary and metastatic lesions by [18F]fluoro-2-deoxy-D-glucose PET in a patient with thymic carcinoid. Respirology 2007; 12:928.
  59. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42:557.
  60. Baudin E, Caplin M, Garcia-Carbonero R, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 2021; 32:439.
  61. Kaiser LR. Surgical treatment of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008; 22:475.
  62. Shabb NS, Fahl M, Shabb B, et al. Fine-needle aspiration of the mediastinum: a clinical, radiologic, cytologic, and histologic study of 42 cases. Diagn Cytopathol 1998; 19:428.
  63. Zakowski MF, Huang J, Bramlage MP. The role of fine needle aspiration cytology in the diagnosis and management of thymic neoplasia. J Thorac Oncol 2010; 5:S281.
  64. Wakely PE Jr. Fine needle aspiration in the diagnosis of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008; 22:433.
  65. Detterbeck FC, Marom EM. Thymus. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), AJCC, Chicago 2017. p.423.
  66. Sullivan JL, Weksler B. Neuroendocrine Tumors of the Thymus: Analysis of Factors Affecting Survival in 254 Patients. Ann Thorac Surg 2017; 103:935.
  67. Weksler B, Holden A, Sullivan JL. Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors. J Thorac Oncol 2015; 10:1642.
  68. Cardillo G, Rea F, Lucchi M, et al. Primary neuroendocrine tumors of the thymus: a multicenter experience of 35 patients. Ann Thorac Surg 2012; 94:241.
  69. Filosso PL, Yao X, Ahmad U, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. J Thorac Cardiovasc Surg 2015; 149:103.
  70. Hayashi R, Hanyu N, Moriyama S. Efficacy of steroid therapy on liver metastasis of thymic carcinoid. Intern Med 1994; 33:45.
  71. Sugiura H, Morikawa T, Itoh K, et al. Thymic neuroendocrine carcinoma: a clinicopathologic study in four patients. Ann Thorac Cardiovasc Surg 2000; 6:304.
  72. Tsuchida M, Yamato Y, Hashimoto T, et al. Recurrent thymic carcinoid tumor in the pleural cavity. 2 cases of long-term survivors. Jpn J Thorac Cardiovasc Surg 2001; 49:666.
  73. Asbun HJ, Calabria RP, Calmes S, et al. Thymic carcinoid. Am Surg 1991; 57:442.
  74. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf (Accessed on July 25, 2023).
  75. Lin FC, Lin CM, Hsieh CC, et al. Atypical thymic carcinoid and malignant somatostatinoma in type I multiple endocrine neoplasia syndrome: case report. Am J Clin Oncol 2003; 26:270.
  76. Filosso PL, Actis Dato GM, Ruffini E, et al. Multidisciplinary treatment of advanced thymic neuroendocrine carcinoma (carcinoid): report of a successful case and review of the literature. J Thorac Cardiovasc Surg 2004; 127:1215.
  77. Dham A, Truskinovsky AM, Dudek AZ. Thymic carcinoid responds to neoadjuvant therapy with sunitinib and octreotide: a case report. J Thorac Oncol 2008; 3:94.
  78. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387:968.
  79. Lang M, Hackert T, Anamaterou C. Long-term effect of everolimus in recurrent thymic neuroendocrine neoplasia. Clin Endocrinol (Oxf) 2021; 95:744.
  80. Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007; 13:2986.
  81. Crona J, Björklund P, Welin S, et al. Treatment, prognostic markers and survival in thymic neuroendocrine tumours. a study from a single tertiary referral centre. Lung Cancer 2013; 79:289.
  82. Saranga-Perry V, Morse B, Centeno B, et al. Treatment of metastatic neuroendocrine tumors of the thymus with capecitabine and temozolomide: a case series. Neuroendocrinology 2013; 97:318.
  83. Takahashi T, Hatao K, Yamashita Y, Tanizawa Y. Ectopic ACTH syndrome due to thymic atypical carcinoid treated with combination chemotherapy of cisplatin and etoposide. Intern Med 2003; 42:1197.
  84. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376:125.
  85. van Essen M, Krenning EP, Bakker WH, et al. Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. Eur J Nucl Med Mol Imaging 2007; 34:1219.
  86. FDA approval announcement for lutetium Lu 177 dotatate available online at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm (Accessed on January 29, 2018).
Topic 16667 Version 44.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟