Thymic neuroendocrine neoplasms

INTRODUCTION — 

Thymic neuroendocrine neoplasms (NENs) are uncommon primary tumors of the thymus with neuroendocrine differentiation that generally present as a mass within the prevascular (anterior) mediastinum (figure 1).

This topic review will cover the epidemiology, pathology, classification, clinical presentation, staging, and treatment of thymic NENs, which includes thymic neuroendocrine tumors (NETs) and thymic neuroendocrine carcinomas (NECs). Thymomas and thymic carcinomas, the diagnostic evaluation of patients with a mediastinal mass, and the differential diagnosis of a prevascular mediastinal mass (which in addition to thyroid NEN can include thymoma, ectopic thyroid tissue, and an enlarged parathyroid gland, among other conditions) are discussed separately. (See "Treatment of thymoma and thymic carcinoma" and "Approach to the adult patient with a mediastinal mass".)

ANATOMY — 

The thymus is a prevascular mediastinal organ (figure 2) 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 are released into circulation as mature T-lymphocytes. (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 the most common solitary lesion in the prevascular mediastinum and the mediastinum overall [1-3].

Of the primary thymic malignancies, thymic neuroendocrine tumors (NETs) are the least common, accounting for 2 to 5 percent of thymic tumors [4,5]. 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 [6,7]. (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 [5,6,8-12]. 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 [6]. 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, typical carcinoid), moderately-differentiated (intermediate-grade, atypical carcinoid), or poorly-differentiated/anaplastic (high-grade) in 58, 10, and 12 percent of cases, respectively.

Up to 25 percent of thymic NENs arise in patients with multiple endocrine neoplasia type 1 (MEN1), a genetic disorder that predisposes to the development of multiple endocrine and non-endocrine benign and malignant proliferations [13,14]. Among MEN1 patients, thymic NETs develop in approximately 3 to 8 percent [14,15], although the prevalence is probably underestimated [16]. Thymic NETs appear to be a relatively late manifestation of MEN1 [14]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Thymic and bronchopulmonary NETs'.)

The vast majority of reported cases of MEN1-associated thymic NENs have occurred in males (a surprising fact given the autosomal dominant nature of the inheritance pattern), and virtually all were heavy smokers [15], suggesting that tobacco exposure may represent a risk factor. The association between cigarette smoke and sporadic thymic NENs is unclear.

During their lifetime almost all adult patients with MEN1 will also develop primary hyperparathyroidism due to hyperplasia of all four parathyroid glands. These parathyroid glands may be found throughout the neck and upper chest including within the thymus, the prevascular mediastinum, and the middle mediastinum (see "Surgical anatomy of the parathyroid glands"). The epidemiology and clinical presentation of primary hyperparathyroidism that is associated with MEN1 or sporadic is discussed separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Primary hyperparathyroidism'.)

PATHOLOGY AND CLASSIFICATION — 

The 2021 World Health Organization classification system categorizes thymic NENs as low-grade (neuroendocrine tumor [NET] grade 1, or typical carcinoid), intermediate-grade (NET grade 2, or atypical carcinoid), or high-grade (large cell neuroendocrine carcinoma [NEC]; small cell NEC) neoplasms (table 1) [17].

Thymic neuroendocrine tumors — The histologic diagnosis of a thymic NET is based on the presence of neuroendocrine features such as organoid nests, trabeculae, rosettes, or palisading and homogeneous cytologic features (picture 1 and picture 2). 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 thymic typical carcinoid tumors (NET G1) from thymic atypical carcinoid tumors (NET G2) 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 [4]. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)

Thymic carcinoid tumors (NET G1) show no necrosis and have less than 2 mitoses per 2 mm², while thymic atypical carcinoid tumors (NET G2) have areas of necrosis and/or 2 to 10 mitoses per 2 mm² (picture 3 and picture 4). Among reported cases of thymic NETs, almost all are classified as atypical carcinoid tumor (NET G2) [18]. Notably, a Ki-67 proliferation index is not used in the formal World Health Organization grading classification for thymic NENs, even though it is commonly measured in pathology reports.

The spindle cell pattern of thymic NET can be mistaken for spindle cell thymoma (picture 5) [19]. The distinction can be readily established utilizing neuroendocrine immunohistochemical markers and p40; the latter marker will identify neoplastic cells due to a thymoma. 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 [20].

Although the pathologic classification of thoracic NETs (including thymic) has not evolved to fully categorize tumors with well-differentiated morphology and high-proliferative activity (eg, mitotic count >10), such tumors do exist [21]. These tumors need more study to know how they are best managed. Well-differentiated high-grade NETs that arise in the gastroenteropancreatic tract also demonstrate these pathologic characteristics but are a separate clinical entity. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)

Thymic neuroendocrine carcinomas — Large cell NECs are composed of large atypical cells with extensive areas of necrosis, often located centrally within tumor cell nests [20]. 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'.)

Small cell carcinomas are comprised of small blue cells with minimal cytoplasm, similar to their counterpart in the lung. Like large cell NECs 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 prevascular 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 1) (see 'Differential diagnosis' below):

●Metastasis from an NET at another site must be excluded to make the diagnosis of a primary thymic NET. (See 'Diagnostic evaluation' 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 [22]. Furthermore, the neoplastic cells of thymoma and thymic squamous cell carcinomas express p40, which is negative in NET. (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 [23]. By immunohistochemistry, paragangliomas are typically positive for neuroendocrine markers and often positive for GATA-3 [24], while they fail to express pancytokeratin and TTF-1. By contrast, thymic NETs are reactive with antibodies to pancytokeratins and sometimes TTF-1, but not GATA-3 [25]. (See "Epidemiology, clinical presentation, and diagnosis of paragangliomas".)

●Abnormal parathyroid glands (adenomas, carcinomas, and hyperplastic glands such as in multiple endocrine neoplasia type 1 [MEN1]) may also be confused with a thymic NET. Parathyroid glands of inferior embryologic origin may be found within the thymus, due to the common origin of the thymus and the inferior parathyroids 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 [26], the latter of which can be present in some thymic NETs. Neuroendocrine markers are positive in both thymic neuroendocrine 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 prevascular mediastinal compartment (figure 1); they rarely arise in the visceral (middle) or paravertebral (posterior) mediastinum [5]. 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 neuroendocrine tumors (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 [9,27].

Symptoms — Thymic NETs can vary considerably in size [8,28]. 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 [9,29,30]. Approximately one-third of thymic NETs are asymptomatic and incidentally discovered on a radiographic study done for an unrelated cause [5] 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 [5,10,13]. Common sites of distant metastases include lung and pleura, bone, liver, pancreas, and chest wall [5,29,31]. Brain metastases have been described in several cases [31].

Screening for thyroid NEN in patients with MEN1 — The benefits of screening for thymic neuroendocrine neoplasm (NEN) in patients with multiple endocrine neoplasia type 1 (MEN1) 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.)

Thymic NETs, while rare, represent a neoplasm with similar malignant potential to other MEN1-associated tumors. Some experts have recommended that male patients with MEN1 over the age of 25 undergo screening with annual chest radiograph and chest computed tomography (CT) every three years [13], but there is no consensus on the issue. Others recommend annual chest CT in all patients with MEN1 who are over the age of 25, particularly males [14].

In patients with MEN1 who are undergoing initial or re-operative surgery for primary hyperparathyroidism, cervical thymectomy is an option to address the possibility of parathyroid residence within the thymus, particularly if an embryologically inferior parathyroid gland has not yet been discovered and managed [32]. However, prophylactic cervical thymectomy during parathyroid exploration for patients with MEN1 is controversial with unclear advantages, although it is still advocated by some experts [13,33,34]. Its parallel effectiveness in reducing the risk of a thymic NET is unproven, and studies have demonstrated the occurrence of a thymic NET in patients with MEN1 despite a prophylactic transcervical thymectomy [14,33,35]. If prophylactic thymectomy is performed, it is imperative that all prevascular mediastinal tissue that can potentially contain thymic tissue be completely resected. (See "Multiple endocrine neoplasia type 1: Management", section on 'Surgical approach'.)

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

●In less contemporary observational series, a clinically apparent endocrinopathy has developed in up to one-half of cases of patients with thymic NETs [36,37]. The most common is Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (ACTH) [38-41]. (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 [42,43].

●Paraneoplastic endocrinopathy is almost exclusively seen in sporadic cases. In MEN1-associated thymic NETs, acromegaly has been rarely reported [44], as has ectopic ACTH production [41,45]. (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 [10,46]. Myasthenia gravis is rare with NETs [47]. (See "Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis".)

●Carcinoid syndrome has only rarely been reported in association with a thymic NET [48].

DIFFERENTIAL DIAGNOSIS — 

Most thymic neuroendocrine tumors (NETs) present as a mass in the prevascular mediastinal compartment (figure 1). 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 (figure 1) [49]. (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, diagnosis, and staging of thymoma and thymic carcinoma".)

●Primary, secondary, or tertiary hyperparathyroidism can present on imaging before a biochemical diagnosis is reached.

●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".)

DIAGNOSTIC EVALUATION — 

For most patients, we obtain a contrast-enhanced 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 a prevascular 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 neuroendocrine tumor (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, gallium Ga-68 dotatate, gallium Ga-68 dotatoc [where available], or copper Cu-64 dotatate imaging).

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, prevascular 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 [50,51].

In general, CT is the imaging procedure of choice for prevascular 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 [52,53]. Somatostatin receptor-based diagnostic imaging (eg, Ga-68 dotatate, Ga-68 dotatoc [where available], or Cu-64 dotatate)-integrated PET-CT scanning can be used to identify these tumors, distinguish them from other malignancies arising in the prevascular mediastinum, and exclude a primary NET in another site that may have metastasized to the thymus [52,54-57]. One benefit of somatostatin receptor imaging over cross-sectional imaging modalities is that it images the whole body [58]. Another benefit is that a positive scan indicates the presence of somatostatin receptors on the tumor and the possibility of benefit from peptide receptor radionuclide 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 [14,31,52].

FDG-PET — Given the aggressive behavior of many thymic neoplasms, 18-F fluorodeoxyglucose (FDG)-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 [59-62].

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-hydroxyindoleacetic acid testing is generally not helpful in the diagnostic evaluation for a thymic NET. Although serum levels of chromogranin A (CgA) may be elevated [14], 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-multiple endocrine neoplasia type 1 (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 [63]. (See 'Clinical presentation' above and "Establishing the diagnosis of Cushing syndrome", section on '24-hour urinary cortisol excretion'.)

Need for biopsy — If the diagnosis of thymic NEN is not established, among patients with a mediastinal mass and without hyperparathyroidism, 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.)

However, in a patient with hyperparathyroidism, any type of presurgical biopsy is contraindicated to prevent track metastasis of endocrinologically functional cells. In addition, a benign parathyroid can show biopsy-induced changes on final surgical pathology that could falsely suggest parathyroid carcinoma [32].

For patients with a small, seemingly encapsulated mass that appears consistent with a thymoma, thymectomy is appropriate to establish the diagnosis and select therapy. For a patient without hyperparathyroidism, 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 [64]. (See 'Neoadjuvant therapy for locally advanced disease' below and "Treatment 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 biopsy via a parasternal approach can allow preoperative identification of a thymic NET [30,65-67], 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. Endoscopic or transbronchial ultrasound-guided fine needle aspiration may be valuable in select cases, for example when metastatic cancer to mediastinal lymph nodes is suspected (table 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 SYSTEM — 

The ninth version 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 4) [68].

PROGNOSIS AND MANAGEMENT — 

Because most thymic neuroendocrine tumors (NETs) represent 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) [69].

●In an observational series of 80 cases of thymic NET, overall five- and 10-year survival rates were 28 and 10 percent, respectively [29]. In a group of 50 cases 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 [6,70-72]. In an observational study from the SEER database of 160 cases of thymic NET, five-year overall survival for patients with localized, regional, and distant metastases was 80, 48, and 31 percent, respectively [6].

●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) [71].

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 CT, MRI, chest radiograph, and OctreoScan [14]. 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. Screening for thymic NETs 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 [73]) after the initial operation [10,74,75]. 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 'Without severe or life-threatening symptoms'.)

Resection — For patients with an established diagnosis of a thymic NET we suggest maximal surgical resection if feasible. Thymic neoplasms typically present as a mass in the prevascular mediastinal compartment (figure 1 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 [62,76]. (See "Thymectomy", section on 'Extent of resection' and "Thymectomy", section on 'Lymph node dissection'.)

Completeness of tumor resection is a strong prognostic factor for overall survival [6,9,27,30,31,38]. 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 [38]. Furthermore, even after complete surgical resection, there is a high rate of local recurrence.

Thymectomy and resection of prevascular 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 separately. (See "Thymectomy".)

It is unclear whether surgical debulking of large tumors without curative intent confers any survival benefit [77]. However, palliative surgical resection or debulking of a large primary tumor causing compression symptoms may provide benefits in terms of symptom control [5]. 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 [5,11,28].

Postoperative therapy — There are no randomized trials and no consensus as to the optimal postoperative strategy.

For patients with a thymic NET that is incompletely resected (ie, positive margins or gross residual disease), we suggest maximal resection followed by postoperative RT rather than resection alone for control of residual disease.

For patients with high-grade thymic neuroendocrine carcinomas (NECs) who undergo a complete resection, we suggest postoperative chemoradiation in conjunction with platinum plus etoposide-based chemotherapy rather than RT alone. This approach is extrapolated from the management of limited-stage small cell lung cancer. (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 thymic NET grade 2 or higher proliferative activity is controversial. It is likely that the higher the histologic tumor grade, the more likely the patient is to benefit from the addition of platinum plus 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 NET grade 2 or high-grade NEC thymic NENS [78].

●European Society of Medical Oncology guidelines similarly acknowledge absence of evidence on benefit of adjuvant treatment. They recommend observation or adjuvant RT for any R0 resection or R1 resection of NET G1, observation or RT with or without systemic treatment for R1 resection of NET G2 or R2 resection of NET G1, and systemic therapy with or without RT for R2 resection of NET G2 [63].

Otherwise, the available literature suggest no benefit from adjuvant chemotherapy alone for most completely resected well-differentiated thymic NETs [6,69,72].

Benefit of RT — The evidence supporting benefit for adjuvant or definitive radiation therapy (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 NET, nine had a complete resection, three of whom received adjuvant RT with no recurrence documented [31]. 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 [11,27,30,79]. 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 RT 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 [6]. 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 [80,81], 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 radionuclide therapy using a radiolabeled somatostatin analog such as lutetium Lu-177 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 Lu-177 dotatate is limited to somatostatin receptor-expressing tumors. Even in those tumors, there is no real basis for choosing Lu-177 dotatate over other agents, 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, gallium Ga-68 dotatoc [where available], or copper 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 [15]. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors".)

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 [82].

Everolimus — Everolimus may be a modestly active agent:

●In the phase III RADIANT 4 study, everolimus demonstrated significant improvement in progression-free survival compared with placebo in patients with progressive gastrointestinal and lung NETs [83]. Subgroup analysis of the lung NET cohort confirmed significant improvement in progression-free survival in this population. Thymic NETs were not included in this study. However, given their biologic 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 [84]. 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, preferred in most cases' and "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Everolimus'.)

Chemotherapy — There are several small retrospective series evaluating the efficacy of 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 [85]. 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 [86]. Most of these were intermediate grade tumors by virtue of a Ki-67 labeling index of 5 to 10 percent. Three patients with thymic NET G2 were treated with capecitabine plus temozolomide; there was one objective partial response, one minor response, and one patient with stable disease [87].

●Some patients with intermediate to poorly differentiated tumors respond to platinum-based chemotherapy regimens [86,88]. In particular, we treat poorly differentiated thymic NECs with platinum-based regimens, such as platinum plus etoposide, as per treatment guidelines for poorly differentiated NENs at other primary tumor sites. (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" and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

Peptide receptor radionuclide 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 radionuclide therapy using the radiolabeled somatostatin analog Lu-177 dotatate.

Lu-177 dotatate has been studied mainly for the treatment of gastroenteropancreatic NETs. These data are discussed in detail separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors" and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)

The data on thymic NET are limited to two reported patients treated with Lu-177 dotatate, one of whom had stable disease as the best response [89]. The US Food and Drug Administration approved Lu-177 dotatate for the treatment of somatostatin receptor-positive gastroenteropancreatic NETs in adults [90]. While the approval did not cover thymic NETs, off-label use could be considered in appropriate patients. (See 'Somatostatin receptor-based diagnostic imaging' above.)

Cabozantinib — Cabozantinib is a treatment option for patients with advanced unresectable or metastatic thymic NET. In a double-blind, placebo-controlled phase III trial (CABINET) of 298 patients with treatment-refractory pancreatic and extrapancreatic NETs (including thymic NETs), cabozantinib improved progression-free survival and was well-tolerated [91]. However, the precise benefit of cabozantinib among those with thymic NETs is difficult to discern due to the limited number of thymic NETs enrolled in the study (10 patients). Further details on the results of the CABINET trial are discussed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Cabozantinib' and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Cabozantinib'.)

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" [82]. 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: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

●General principles – Thymic neuroendocrine neoplasms (NENs) are uncommon primary tumors of the thymus with neuroendocrine differentiation that generally present as a mass within the prevascular (anterior) mediastinum (figure 1). (See 'Introduction' above.)

●Epidemiology – Approximately 25 percent of thymic NENs occur in patients with multiple endocrine neoplasia type 1 (MEN1). Most MEN1-associated thymic NENs occur in male smokers. (See 'Epidemiology' above.)

●Classification – The 2021 World Health Organization classification system is used to categorize thymic neoplasms (table 1). (See 'Pathology and classification' above.)

●Clinical presentation

•Even grade 1 or 2 thymic neuroendocrine tumors (NETs) are characterized by relatively aggressive clinical behavior and a high propensity for locoregional invasion, local recurrence, and distant metastases.

•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, by detection during screening for MEN1, or rarely, with symptoms related to an associated paraneoplastic endocrinopathy (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. (See 'Distant metastases' above.)

●Evaluation and staging

•If the diagnosis of a thymic NEN is established, cross-sectional imaging of the abdomen (in addition to the chest), and baseline somatostatin receptor-based imaging are obtained. For most patients, integrated positron emission tomography (PET)-CT using one of the radiolabeled somatostatin analogs (gallium Ga-68 dotatate, gallium Ga-68 dotatoc [where available], or copper Cu-64 dotatate) is superior to the OctreoScan because of greater sensitivity. (See 'Diagnostic evaluation' above.)

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

•If the diagnosis of thymic NEN is not established, among patients without hyperparathyroidism, the appearance of a prevascular 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.

In a patient with hyperparathyroidism, any type of presurgical biopsy is contraindicated to prevent track metastasis of endocrinologically functional cells. In addition, a benign parathyroid can show biopsy-induced changes on final surgical histology that could falsely suggest parathyroid carcinoma.

For patients with a small, seemingly encapsulated mass that appears consistent with a thymoma, thymectomy is appropriate to establish the diagnosis and select therapy. For a patient without hyperparathyroidism and a larger mass with indistinct margins, a biopsy is warranted before proceeding with resection to establish the diagnosis and provide for decision-making about neoadjuvant therapy. If a biopsy is indicated, the diagnostic procedure of choice is a CT-guided core needle biopsy. Other options include fine needle aspiration biopsy or even an open surgical biopsy. (See 'Need for biopsy' above.)

●Treatment of locoregional disease

•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 thymic NET with positive margins or gross residual disease, we suggest maximal resection followed by postoperative radiation therapy (RT) rather than resection alone to enhance local control (Grade 2C). (See 'Postoperative therapy' above.)

For patients with a poorly differentiated thymic neuroendocrine carcinoma (NEC) who undergo a complete resection, we suggest postoperative chemoradiation in conjunction with platinum plus etoposide-based chemotherapy rather than RT alone (Grade 2C). (See 'Postoperative therapy' above.)

The use of platinum/etoposide in conjunction with RT for thymic NET G2 or higher proliferative activity is controversial. The benefit of these chemotherapy agents is likely correlated to the grade of the tumor (higher grade correlates with increased benefit).

●Treatment of unresectable or metastatic disease

•Systemic therapy is an appropriate option for patients with unresectable recurrent or metastatic tumors. (See 'Metastatic/unresectable disease' above.)

-For patients with grade 1 or 2 tumors, systemic therapy options include long-acting somatostatin analogs, everolimus, temozolomide-based chemotherapy, cabozantinib, and peptide receptor radionuclide therapy (eg, lutetium Lu-177 dotatate).

Somatostatin analogs should be chosen as first-line therapy 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 Lu-177 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 poorly differentiated NENs at other primary tumor sites. (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" and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

•RT may provide palliation of a symptomatic site of recurrent and/or metastatic disease. (See 'Radiation therapy' 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. (See 'Post-treatment surveillance' above.)

•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 histologic features (intermediate- and high-grade tumors) should be monitored more frequently.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges James R Jett, MD, who contributed to earlier versions of this topic review.