Understanding Lung and Thymic Carcinoids: A Patient Guide to Diagnosis and Treatment

Table of Contents

• Incidence and Epidemiology
• Diagnosis and Pathology/Molecular Biology
• Staging and Risk Assessment
• Management of Local/Locoregional Disease
• Management of Advanced/Metastatic Disease
• Source Information

Incidence and Epidemiology

Lung carcinoids (LCs) and thymic carcinoids (ThCs) are rare neuroendocrine tumors with distinct characteristics. Lung carcinoids affect approximately 0.2-2 people per 100,000 each year in both the United States and Europe. These tumors account for 20%-25% of all neuroendocrine tumors and only 1%-2% of all lung cancers.

Interestingly, incidence numbers are increasing, likely due to improved awareness and diagnostic techniques, though there may be a genuine overall increase. Lung carcinoids slightly more commonly affect women than men, typically appearing during the fifth or sixth decade of life for typical carcinoids and about a decade later for atypical carcinoids.

Thymic carcinoids are extremely rare, with an age-adjusted rate of 0.02-0.18 cases per 100,000 people per year in European and USA populations respectively. These account for less than 0.5% of all neuroendocrine neoplasms and represent about 5% of thymic tumors. Thymic carcinoid incidence is increasing in the USA population, prevails more in men, and the mean age at diagnosis is 55 years.

Both lung and thymic carcinoids may occur in patients with multiple endocrine neoplasia type 1 (MEN-1) syndrome or when there is a family history of carcinoid tumors. Lung carcinoids can also appear in patients with diffuse pulmonary neuroendocrine cell hyperplasia (DIPNECH).

Recommendation: The scarcity of these tumors justifies management by expert multidisciplinary teams in specialized centers within national or European networks for optimal care and research [Level V evidence, Grade A recommendation].

Diagnosis and Pathology/Molecular Biology

Lung carcinoids typically present with non-specific respiratory symptoms (mainly central tumors) or are discovered incidentally (mainly peripheral tumors). A minority of cases (7.6% in a study of 3,002 patients) present with symptoms related to hormonal overproduction, including:

• Carcinoid syndrome due to serotonin and other compound secretions
• Cushing's syndrome due to adrenocorticotropic hormone (ACTH) secretion
• Acromegaly due to growth hormone-releasing hormone (GHRH) secretion

Diagnosis involves bronchoscopic techniques, transthoracic biopsy, or less frequently mediastinoscopy or endobronchial endoscopic ultrasonography (EBUS). The diagnostic workup for both lung and thymic carcinoids includes multiple specific steps as outlined in the guidelines.

Thymic carcinoids are typically revealed by tumor-related symptoms, functionally active tumor symptoms, or discovered by chance. Diagnostic procedures may include core biopsy under ultrasonography guidance or preferably through thoracic computed tomography (CT) scan.

The histopathological diagnosis relies on characteristic morphological features and demonstration of the neuroendocrine nature through detection of specific markers including chromogranin A (CgA) and synaptophysin. Typical carcinoids (TCs) and atypical carcinoids (ACs) are distinguished based on mitotic count and presence or absence of necrosis.

While Ki-67 index (a measure of cell proliferation) isn't included in formal diagnostic criteria, it may be useful for differential diagnosis. The ratio between typical and atypical carcinoids is approximately 6:10 in surgical series but may be closer to 1:1 in advanced cases.

Thymic carcinoids follow the same classification system as lung neuroendocrine tumors with four categories. The pattern of genetic alterations differs from lung carcinoids, and a subgroup with high proliferative features has recently been recognized. The ratio between atypical and typical thymic carcinoids is about 2:1.

Recommendations:

• Management requires a multidisciplinary standardized approach in specialized centers [Level IV evidence, Grade A]
• Ki-67 (MIB 1) [Level IV, Grade A], TTF1 [Level IV, Grade B], p53/RB1 [Level IV, Grade B] biomarker analyses are recommended in selected cases for differential diagnosis

Staging and Risk Assessment

Risk assessment depends on pathology and TNM (tumor, node, metastasis) staging based on combination of intravenous contrast-enhanced cross-sectional imaging including liver late arterial phase and positron emission tomography (PET)-CT with gallium-68-labelled somatostatin analogues functional imaging.

Serum chromogranin A is measured in all patients, while specific biomarkers are assessed depending on the presence of functioning syndromes. The application of the 8th Edition of the Union for International Cancer Control (UICC) TNM staging is recommended.

More than 80% of lung carcinoids are diagnosed at TNM stage I or II. The most common sites of metastasis include liver, bone, and lung. The WHO classification and pathological TNM staging are intricately connected. In patients undergoing adequate lymph node resection (10 or more nodes), frequency of positive lymph nodes was 17% (including 6% N2-N3) for typical carcinoids or 46% (including 23% N2-N3) for atypical carcinoids.

Most thymic carcinoids are diagnosed at advanced stages. The most common sites for metastases include the pleura, pericardium, bone, lung, and liver.

Overall survival is mainly influenced by WHO pathology and pTNM classifications. In stage I, II, III, or IV lung carcinoid patients, 10-year disease-specific survival is:

• 96%, 85%, 81%, 59% for typical carcinoids
• 88%, 75%, 47%, 18% for atypical carcinoids

This demonstrates the major prognostic influence of the WHO classification. After resection, WHO classification and pathological lymph node status constitute the two main prognostic parameters.

At the metastatic stage, WHO classification, performance status, chromogranin A levels, tumor burden, somatostatin receptor imaging uptake, tumor growth rate, and functioning syndrome should all be considered for adequate risk assessment. The prolonged survival of most lung carcinoid patients (including 60% 5-year overall survival for metastatic cases) makes adjusted toxicity profile of therapeutic interventions critical.

The prognosis of patients with thymic neuroendocrine tumors remains poor: in retrospective series, 5- or 10-year overall survival was 28%-72% or 26%-60%, respectively. No specific staging system has been validated for thymic carcinoids, so both TNM and Masaoka-Koga staging systems are recommended together with WHO classification and resection status.

Recommendations:

• WHO and pTNM classifications form the basis of prognostic classification [Level II, Grade B]
• IV contrast-enhanced cross-sectional imaging including liver late arterial phase and PET-CT with gallium-68-labelled somatostatin analogues form the basis of TNM evaluation [Level II, Grade B]
• Specific prognostic factors including tumor growth rate or presence of functioning syndromes are considered in advanced-stage cases [Level IV, Grade B]
• Prolonged survival of most lung carcinoid patients makes adjusted toxicity profile of therapeutic interventions critical [Level V, Grade A]

Management of Local/Locoregional Disease, Local Recurrence and Adjuvant Therapy

Control of functioning syndrome must be considered before any invasive therapeutic intervention. Surgery represents the treatment of choice for both typical and atypical lung carcinoids, even with N2 lymph node metastases.

The surgical approach depends on tumor size, location, and preoperative biopsy assessment. Choices between open surgery and minimally invasive approaches depend on surgeon experience. The preferred approach includes anatomic pulmonary resection and lymph node resection with a minimum of six nodal stations.

Wedge resection may increase the risk of tumor recurrences, especially in node-positive typical carcinoids or intermediate-grade atypical carcinoids. In atypical carcinoids and node-positive typical carcinoids, lobectomy is reported as superior to segmentectomy in terms of overall survival in some studies.

Bronchoplastic procedures are preferred for suitable centrally located tumors to avoid pneumonectomy. Transfer of patients to specialist centers for sleeve resection should be discussed. Systematic lymph node dissection is recommended as lymph node metastases may be observed in up to 27% of typical carcinoids and up to 47% of atypical carcinoids.

Complete resection (R0) is achieved in over 85% of cases. Watchful radiological follow-up may be considered for small tumors without node involvement in certain situations including DIPNECH, MEN-1 patients, and patients with comorbid conditions.

After a median follow-up of 54-121 months, recurrences occur in up to 7% of typical carcinoids and up to 35% of atypical carcinoids, with one-third being local recurrences. For local recurrence, surgical resection with radical intent is recommended when technically feasible.

Large retrospective studies have reported no benefit of adjuvant therapy in both typical and atypical carcinoids. Therefore, routine adjuvant therapy is not recommended, though it may be considered in selected fit patients with particularly high risk of relapse after multidisciplinary discussion.

For thymic carcinoids, available literature suggests no benefit from adjuvant therapy. The majority of experts suggest individually discussing postoperative therapies with patients who had advanced-stage resection.

Recommendations:

• Control of functioning syndrome before any invasive intervention [Level V, Grade A]
• Anatomic pulmonary resection with lymph node dissection recommended [Level IV, Grade B]
• Watchful follow-up or sublobar resection considered for certain patient subgroups [Level V, Grade C]
• No routine adjuvant therapy recommended [Level IV, Grade C for AC; Level IV, Grade D for TC]
• Thymectomy with lymph node dissection recommended for thymic carcinoids [Level IV, Grade B]

Management of Advanced/Metastatic Disease

The goals of therapeutic management for advanced disease are control of tumor growth and functioning syndromes, aiming to improve both quality of life and survival. The optimal treatment strategy and sequencing remains unknown due to the low number of dedicated trials and absence of predictors of response.

This information should be shared with patients. Prognostic factors (but not predictive factors) guide decision-making. Treatment approaches must balance efficacy with toxicity considerations given the prolonged survival of many patients.

Source Information

Original Article: Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Authors: E. Baudin, M. Caplin, R. Garcia-Carbonero, N. Fazio, P. Ferolla, P.L. Filosso, A. Frilling, W.W. de Herder, D. Hörsch, U. Knigge, C.M. Korse, E. Lim, C. Lombard-Bohas, M. Pavel, J.Y. Scoazec, A. Sundin, A. Berruti on behalf of the ESMO Guidelines Committee

Publication: Annals of Oncology, Volume 32, Issue 4, 2021

This patient-friendly article is based on peer-reviewed research from the European Society for Medical Oncology clinical practice guidelines.