Continuing Education Activity

Mediastinal carcinoid tumors are extremely rare malignancies with aggressive behavior and a grim prognosis. These malignancies often go undetected until they are finally diagnosed at advanced stages. Symptoms at the time of presentation can grossly vary and are generally equivocal. A high level of suspicion needs to be ascertained for a diligent workup. This activity reviews the evaluation and management of thymic neuroendocrine tumors and highlights the role of the healthcare team in the care of patients with this condition.

Objectives:

• Review the etiology of mediastinal carcinoid tumors.
• Describe the appropriate evaluation of mediastinal carcinoid tumors.
• Identify the management options available for mediastinal carcinoid tumors.
• Summarize the importance of collaboration and communication within the interprofessional team in the care of patients with mediastinal carcinoid tumors to improve outcomes.

Introduction

Mediastinal carcinoid tumors are represented by thymic carcinoid neoplasms. Primary carcinoid tumors of the thymus were first described in 1972.[1] The term carcinoid is an old term that refers to a carcinoma-like appearance of the tumors and is often used interchangeably with neuroendocrine tumors (NETs). Thymic carcinoid tumors are rare neoplasms arising from the thymus deriving from the foregut, being the least common of all NETs.[2] 

Contrary to most NETs that originate from the gastrointestinal tract or the lungs, thymic neuroendocrine tumors are malignant in more than 80% of cases and display aggressive biological behavior.[3] The World Health Organization (WHO) in 2015 classified thymic carcinoid tumors into 4 different categories. Typical and atypical carcinoids, which are well-differentiated neoplasms, and small-cell and large-cell carcinoid tumors, which are poorly differentiated.[3]

Etiology

The etiology of neuroendocrine thymic tumors remains unclear. Multiple endocrine neoplasia type-1 (MEN-1) is associated with 25% of cases.[2] No association with carcinogens or environmental factors have been established for sporadic cases. However, there is evidence of a higher incidence of thymic carcinoid in MEN-1 patients that are heavy smokers.[4]

Epidemiology

Thymic NETs are extremely rare tumors, representing 2% to 5% of all thymic malignancies and 0.4 % of all neuroendocrine malignancies.[5]

Most cases are found in adults with a median age of 54 years. There is a strong gender predilection for males, with a male to female ratio of 3:1.[2][6][7][8][9] The estimated annual incidence in the United States is roughly 0.2 per million.[7]

Pathophysiology

The exact pathophysiology of the development of these tumors is not fully understood. Although rare, thymic NETs have been associated with various paraneoplastic syndromes. Up to one-third present concomitantly with paraneoplastic conditions. The most common being Cushing’s syndrome presenting in 30% to 35% cases in which thymic NETs may secrete ectopic adrenocorticotropin hormone (ACTH).[10][11] 

Humoral hypercalcemia of malignancy secondary to the secretion of the parathyroid hormone-related peptide (PTH-rP) can be present in up to 30% of patients.[11] Unlike other carcinoid tumors, thymic NETs rarely present with carcinoid syndrome.[12] Acromegaly secondary to ectopic production of growth hormone-releasing hormone and syndrome of inappropriate antidiuretic hormone, albeit uncommon, have been described in the literature.[13] As previously mentioned, MEN-1 is associated with 25% of cases, and roughly 8% of patients with MEN-1 go on to develop a thymic NET.[2]

Histopathology

These tumors are cataloged based on the WHO classification for pulmonary neuroendocrine tumors, in typical and atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma.[14] Histological classification is based upon the presence or absence of necrosis, mitoses, and large cell or small cell cytology. The nuclear chromatin, in general, is finely granular, while large cell neuroendocrine carcinoma may show prominent nucleoli. Tumor cells may form trabeculae, rosettes, festoons, glands, and solid sheets.[14]

Typical carcinoids have a generally more benign course, but the opposite is true for small cell carcinoma. Atypical carcinoid and large cell neuroendocrine carcinoma lay in the middle of the spectrum. Hence, these pathologic classifications have a prognosis correlation.[11][15]

History and Physical

Thymic NETs present as a mass located in the anterior mediastinum. 

In most cases, thymic NETs go unrecognized until advanced stages as patients commonly remain asymptomatic or symptoms at presentation are ambiguous.[6] 

These tumors display aggressive behavior with a tendency for local invasion. Hence 50% of patients present with invasion to local organs at the time of diagnosis, and 20%-30% have distant metastatic disease, which occurs via lymphatic or hematogenous spread.[1][2] 

The majority of patients present with symptoms of mass compression to local structures, while only a third of cases are asymptomatic. Symptoms can vary depending on the extent of invasion. Common complaints include cough, dyspnea, chest pain, and hoarseness from recurrent laryngeal nerve invasion.[2] Superior vena cava syndrome has been observed in up to 20% of patients at presentation.[2]

Evaluation

Thymic NETs pose a diagnostic challenge as symptoms at presentation are typically equivocal. Therefore, a high level of suspicion by clinicians must be attained. On occasion, thymic NETs may be found incidentally while undergoing workup for other causes.

Imaging Studies

Initial evaluation with computed tomography (CT) of the chest with intravenous (IV) contrast is the test of choice for anterior mediastinal masses. Cross-sectional imaging, along with IV contrast use, helps characterize the mass and improves localization but also provides information regarding local invasion or regional metastases. Findings of a large, heterogeneous, lobulated, and most often invasive, anterior mediastinal mass with areas of hemorrhage or necrosis are suggestive of thymic NETs. Magnetic resonance imaging (MRI), more specifically, cardiac MRI, can play a valuable role in delineating more detailed information regarding invasion to local structures such as proximal great vessels, heart structures, or pericardium. 

The use of somatostatin-receptor-based imaging has become, over the past decade, a more popular tool in the diagnosis and staging of NETs. Thymic NETs, just like other NETs, flaunt an overexpression of somatostatin receptors, thus the use of radiolabeled somatostatin analogs, such as the gallium Ga-68 DOTATOC, (OctreoScan) allows thymic NETs to be identified and distinguished from other malignancies that arise in the anterior mediastinum.[16] Other advantages of these techniques are the identification or primary malignancies in the thymus versus metastatic disease as it is able to scan the whole body. In addition, the sole recognition of somatostatin receptors on the tumor allows the early utilization of peptide receptor radioligand therapy in advanced cases.[17][18] Ruling out lymphomas or germ cell tumors is critical as these malignancies are routinely medically treated rather than surgically as it is the case for thymic NETs. 

Laboratory Studies

As previously discussed, the greater number of thymic NETs cases do not produce hormones. Therefore the utility of laboratory evaluation is limited to specific circumstances. Chromogranin A (CGA) levels, if initially elevated at the time of diagnosis, may be helpful in the monitoring of disease activity, especially in patients with metastatic disease.[19] However, CGA is not used as a diagnostic tool due to insufficient sensitivity and specificity of the test.[20]

In cases of paraneoplastic syndromes, such as Cushing’s syndrome, a high concentration of cortisol can be found in serum and in 24-hour urine cortisol. Hypercalcemia and hypophosphatemia can be seen in humoral hypercalcemia of malignancy along with high levels of PTHrP concentration, and might also be used to monitor for recurrence of the disease.[19] 

Biopsy

Based on CT chest findings and characteristics of the mass and level of invasion, medical teams are able to determine if mass resection or tissue biopsy is indicated. For small, encapsulated masses, surgical resection of the tumor should be attempted. On the other hand, for larger masses with unclear margins, a tissue biopsy is recommended prior to attempting a surgical resection to ascertain the need for a possible role of chemotherapy.[20][21]

Most biopsies are performed through a CT guided core needle biopsy, which is able to identify a thymic NET in most cases.[21] In alternative situations, in which there may not be enough tumor cells to secure a definitive diagnosis through immunohistochemistry or flow cytometry, or the tumor location does not allow for a CT guided approach, endoscopic or transbronchial ultrasound-guided fine needle biopsy (EUS-FNA) (EBUS-TBNA) might be preferred.[2] These techniques are also favored in the presence of mediastinal lymph node metastatic disease.

If biopsy results are still not definitive, a surgical approach is indicated. The type of surgical approach will be determined by the location of the tumor. Anterior mediastinotomy is indicated in cases where the mass invades towards the anterior chest wall. On the other hand, if the mass has invaded towards either side of the chest, a video-assisted thoracoscopic (VATS) approach is warranted.[2] A VATS approach is also useful if there are concerns for possible lung metastases.

Treatment / Management

Localized Disease

Official guidelines for the treatment of thymic NETs are not available, as data lacks prospective trials and is mainly based on case reports and case series. Complete surgical resection, which remains the therapy of choice, entitles the resection of all the anterior mediastinal compartment, including hilar and mediastinal lymph nodes.[1][2] Unfortunately, most thymic NETs are deemed not amenable for resection at the time of diagnosis due to their size. The role of neoadjuvant chemotherapy or radiation therapy (RT) remains unclear as data is based solely on case reports.[1][2]

In cases of local invasion, despite total complete surgical resection, microscopic resection may not be achieved, and the rate of recurrence is high.[2] Adjuvant chemotherapy and RT are reasonable options following total resection for control of the residual disease. According to the National Comprehensive Cancer Network (NCCN), in patients that have had an incomplete resection, RT preferably with chemotherapy based on cisplatin or carboplatin plus etoposide are recommended for patients with moderately or poorly differentiated disease.[2] However, the evidence supporting adjuvant RT or chemotherapy is limited.

Metastatic or Recurrent Disease

Even in the instance of recurrent disease, if the tumor is deemed to be resectable, surgical resection should be attempted.[1] In cases of unresectable or metastatic disease, systemic therapy is favored.[22] For tumors with evidence of somatostatin receptor expression, somatostatin analogs are chosen, although data is scant regarding the benefits of this therapy for thymic NETs. In such circumstances, octreotide and lanreotide are considered reasonable options, especially in the rare instance of patients presenting with carcinoid syndrome.[23] 

A platinum-based chemotherapy regimen, such as carboplatin and etoposide, is used for intermediate to poorly differentiated tumors, based again on treatment guidelines for poorly differentiated NETs of the gastrointestinal tract and lung.[24] Other systemic therapies such as everolimus, which have demonstrated survival benefits in patients with advanced lung and gastrointestinal NETs, have been adopted as a therapeutic option for thymic NETs, as it has been hypothesized to work given the similarities of these tumors.[25]

The role of radiation therapy remains palliative for symptomatic patients with recurrent or metastatic disease.

Differential Diagnosis

• Thymic carcinoma
• Thymoma
• Paraganglioma
• Lymphoma
• Germ cell tumors

Staging

The eighth edition of the tumor, node, metastasis staging system (TNM), comprises classifications for thymic neoplasms, including NETs. This system, in addition, encompasses prognostication based on staging.

Prognosis

Prognosis is determined by tumor stage, resectability, histologic grade, proliferation index, and size.[7][26][27] Overall, the prognosis of thymic NETs is worse compared to their counterparts of the gastrointestinal tract or the lungs.[1] These tumors have aggressive behavior, with a tendency to metastasize or recur locally. The poor prognosis can also be attributed to late tumor detection.

In an analysis of the surveillance, epidemiology, and end results database, the overall survival for the localized disease was estimated to be 110 months, compared to a significantly lower survival for those patients with regionally spread and metastatic disease with 59 and 35 months respectively.[7]

Complications

Disease-related complications include carcinoid or paraneoplastic syndromes such as Cushing’s or humoral hypercalcemia of malignancy.[1] Treatment and intervention-related complications may arise, following thymectomy, including phrenic and recurrent laryngeal nerve injury, surgical site infection, mediastinitis, and wound dehiscence.[28][29]

Deterrence and Patient Education

The only environmental factor associated with thymic NETs has been described in patients with MEN-1 with heavy smoking status.[2] Therefore, smoking cessation is highly recommended for this group.

Pearls and Other Issues

For thymic NETs, surveillance guidelines have not been established, and current recommendations are based on expert consensus. The North American Neuroendocrine Tumor Society and the National Comprehensive Cancer Network have released guidelines for post-treatment surveillance. There are no evidence-based guidelines for post-treatment surveillance, and the optimal post-treatment surveillance strategy is not established. Both societies recommend close follow up starting at 3 months post-resection, including a physical examination and cross-sectional imaging. The monitoring of tumor markers might be useful if they were initially elevated. Long-term surveillance is recommended for up to 10 years, given a high incidence of recurrence.

Enhancing Healthcare Team Outcomes

Guidelines for this neuroendocrine malignancy and others can be found at the North American Neuroendocrine Tumor Society and the National Comprehensive Cancer Network, which emphasize the need for an interprofessional approach for better outcomes. The management of thymic NETs requires the participation of thoracic surgeons, oncologists, radiologists, and nursing staff. Because of the high recurrence rate and aggressive behavior of these tumors, lifelong surveillance might be recommended in specific cases.