Guideline sources The following summarized guidelines for the evaluation and management of bronchopulmonary neuroendocrine tumors are prepared by our editorial team based on guidelines from the American Association for Thoracic Surgery (AATS/ESTS 2022), the European Society of Medical Oncology (ESMO 2021), the European Neuroendocrine Tumor Society (ENETS 2015), the American College of Chest Physicians (ACCP 2013), and the Endocrine Society (ES 2012). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Indications for screening: Obtain chest CT or MRI every 1-2 years to detect bronchopulmonary carcinoid tumors in patients with MEN1. B Do not obtain biochemical evaluation with urinary 5-HIAA or chromogranin A. D Diagnosis: Recognize that: https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 1/6 6/29/23, 3:21 AM Bronchopulmonary neuroendocrine tumors Pathway pulmonary carcinoids as a whole are well-differentiated NETs as opposed to poorly differentiated small-cell lung carcinoma and large-cell neuroendocrine carcinoma and include low-grade malignant tumors (typical carcinoids) and intermediate-grade malignant tumors (atypical carcinoids) typical carcinoid is closest to the G1 gastroenteropancreatic NETs, and atypical carcinoid is closest to the G2 gastroenteropancreatic NETs small cell lung carcinoma and large-cell neuroendocrine carcinoma generally correspond to the neuroendocrine carcinoma category of the gastrointestinal tract according to the current WHO classification diagnostic criteria rely primarily on histology. B 2. Classification and risk stratification Prognostic assessment: use the WHO and pTNM classifications for prognostic classification. B Show 2 more 3. Diagnostic investigations Diagnostic imaging: obtain contrast-enhanced chest CT for the diagnosis of bronchopulmonary NETs. B Consider obtaining HRCT if contrast administration is contraindicated. B Show 3 more Laboratory tests: Obtain liver and renal function tests, calcium, glucose, and plasma chromogranin A measurements in patients with bronchopulmonary NETs. B Obtain laboratory testing for paraneoplastic syndrome based on clinical symptoms and features, including 24-hour urine 5-HIAA, ACTH, and GH-releasing hormone as appropriate. B Evaluation for MEN1: Recognize that pulmonary carcinoids may be associated with MEN1 in < 5% of patients. Elicit family history and obtain a clinical assessment and minimal laboratory screening for the evaluation of MEN1. B Obtain genetic testing for MEN1 in patients with a family history suggestive of a MEN1 or a second MEN1 feature. B Imaging for staging: As per ESMO 2021 guidelines, obtain contrast-enhanced cross-sectional conventional imaging, including liver late arterial phase and positron emission tomography-CT with 68-galium-labeled somatostatin analogs, for staging. B As per ENETS 2015 guidelines, obtain chest and abdomen CT for preoperative staging. B Show 2 more https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 2/6 6/29/23, 3:21 AM Bronchopulmonary neuroendocrine tumors Pathway 4. Diagnostic procedures Diagnostic bronchoscopy: Consider performing a bronchoscopy, preferably flexible bronchoscopy, for preoperative staging and assessment of central airway tumors. B Consider preferring rigid bronchoscopy for obtaining biopsy specimens in patients at high risk for bleeding. C Insufficient evidence regarding the added value of new bronchoscopic techniques to increase the sensitivity of detection of primary tumors or recurrence. I Biopsy and histopathology: obtain pathological diagnosis of any pulmonary NET. B Show 8 more 5. Medical management Management of local/locoregional disease, watchful waiting: As per ESMO 2021 guidelines, consider offering initial imaging follow-up without treatment to determine the tumor growth rate in patients with cT1N0 lung carcinoid within the setting of diffuse pulmonary neuroendocrine cell hyperplasia or MEN1, multifocal primaries, or comorbid conditions. C As per ENETS 2015 guidelines, consider offering watchful waiting in a subgroup of asymptomatic patients mainly with typical carcinoids or atypical carcinoids of low proliferative index. C Management of local/locoregional disease, surgery and locoregional procedures: As per ESMO 2021 guidelines: Perform anatomic pulmonary resection (segmentectomy, lobectomy, or bilobectomy) or bronchoplastic procedures (sleeve resections) along with lymph node dissection in patients with localized lung carcinoids. Avoid performing pneumonectomy, where possible. B Consider performing sublobar surgical resection (including wedge resection) or offering nonsurgical locoregional therapeutic procedures as an alternative to anatomic pulmonary resection to preserve lung function in patients with cT1N0 lung carcinoid with functioning syndromes or morphological progression. C As per ENETS 2015 guidelines, offer surgery, transarterial embolization, or radiofrequency as locoregional treatment options for primary tumor in patients with slow progressive pulmonary carcinoids. B Show 5 more As per ES 2012 guidelines, perform curative surgery, where possible, as the treatment of choice in patients with bronchial carcinoid tumors. A Management of local/locoregional disease, systemic therapy: As per ESMO 2021 guidelines: Consider offering somatostatin analogs as an alternative to anatomic pulmonary resection to preserve lung function in patients with cT1N0 lung carcinoid with functioning syndromes or https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 3/6 6/29/23, 3:21 AM Bronchopulmonary neuroendocrine tumors Pathway morphological progression. C Do not offer routine adjuvant therapy in patients with lung carcinoids. Consider offering cytotoxic chemotherapy (dacarbazine/temozolomide- or oxaliplatin-based chemotherapy), with or without radiotherapy, in selected fit patients with a particularly high risk of relapse (atypical carcinoid N2) after multidisciplinary discussion. D As per ENETS 2015 guidelines: Offer peptide receptor radiotargeted therapy in patients with tumors demonstrating strong expression of somatostatin receptors. B Insufficient evidence to recommend adjuvant therapy after complete resection of pulmonary carcinoids. Consider offering adjuvant therapy in patients with atypical lung carcinoids with a high proliferative index. I Management of advanced/metastatic disease (watchful waiting): consider offering watchful follow-up in asymptomatic patients with slowly radiologically progressing lung carcinoids. C Management of advanced/metastatic disease, systemic therapy: As per ESMO 2021 guidelines, discuss systemic options for patients with advanced carcinoids with bulky or progressing tumors in an interdisciplinary setting. Show 7 more As per ENETS 2015 guidelines, recognize that cytotoxic treatment has been the standard for aggressive metastatic pulmonary carcinoids, although the available chemotherapy regimens demonstrate a limited effect. B Consider offering temozolomide monotherapy. B Offer a combination of cisplatinum and etoposide in patients with high-proliferating pulmonary carcinoids. B Show 2 more As per ES 2012 guidelines, consider offering radiotherapy and chemotherapy in patients with advanced diseases where curative surgery is impossible. C Management of advanced/metastatic disease, surgery and locoregional procedures: As per ESMO 2021 guidelines: Consider offering palliative surgery or locoregional procedures (radiofrequency ablation, cryoablation, endobronchial treatment) of the primary tumor in patients with advanced disease at risk of local events or refractory carcinoid syndrome. C Offer locoregional therapies, including surgery (with or without somatostatin analogs), as first- line therapy to decrease the tumor burden, control hormonal secretions, and prevent local complications in patients with advanced, slowly progressing lung carcinoids. B As per ENETS 2015 guidelines: Offer surgery, transarterial embolization, or radiofrequency as locoregional treatment options for metastases in patients with slow progressive pulmonary carcinoids. B Perform resection of liver metastases whenever possible in patients planned for curative-intent treatment and in syndromic patients when > 90% of tumor burden can be removed. View the following as the minimal requirements for curative intent: resectable typical carcinoid and low-grade atypical carcinoid https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 4/6 6/29/23, 3:21 AM Bronchopulmonary neuroendocrine tumors Pathway < 5% mortality absence of right HF absence of unresectable lymph node and extra-abdominal metastases absence of unresectable peritoneal carcinomatosis. B Management of functioning syndromes: As per ESMO 2021 guidelines, consider controlling functioning syndromes before any invasive therapeutic intervention in patients with local/locoregional disease. B Show 4 more As per ENETS 2015 guidelines, offer somatostatin analogs as first-line therapy in patients with carcinoid syndrome and acromegaly. B Show 2 more 6. Perioperative care Preoperative cardiorespiratory evaluation: Obtain functional respiratory tests to assess the surgical risk and the association with chronic obstructive airway disease and to screen for bronchostenosis. B Obtain echocardiography in patients with carcinoid syndrome. Assess left and right-side valves in patients with pulmonary carcinoids. B Perioperative thromboprophylaxis (lobectomy/segmentectomy): consider administering parenteral anticoagulation with subcutaneous LMWH or UFH for VTE prevention in patients undergoing lobectomy or segmentectomy. C Consider preferring LMWH over UFH. C Show 7 more Perioperative thromboprophylaxis (pneumonectomy): consider administering parenteral anticoagulation with subcutaneous LMWH or UFH for VTE prevention in patients undergoing pneumonectomy or extended lung resection. C Consider preferring LMWH over UFH. C Show 6 more 7. Follow-up and surveillance Follow-up: As per ESMO 2021 guidelines, obtain life-long follow-up in patients with lung carcinoids since recurrences remain very common. B Obtain life-long follow-up with low-radiation imaging and increasing interval of time, adjusted to prognostic factors, after radical resection of lung carcinoids. B Show 3 more As per ENETS 2015 guidelines, obtain long-term follow-up after primary surgery in patients with typical or atypical carcinoids. B As per ACCP 2013 guidelines, involve the original treating physicians in decision-making during the follow-up and surveillance of patients with bronchopulmonary carcinoid tumors treated with https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 5/6 6/29/23, 3:21 AM Bronchopulmonary neuroendocrine tumors Pathway curative-intent therapy. B Show 2 more Clinical findings Symptoms Past medical history Chest pain Acromegaly Cough Carcinoid syndrome Hemoptysis Cushing's syndrome Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Family history Recurrent pneumonia MEN1 Respiratory exam Imaging findings Wheezing Atelectasis Hilar lymphadenopathy Lung mass Lung nodule Mediastinal enlargement Mediastinal lymphadenopathy Mediastinal mass Pleural effusion References 1. M E Caplin, E Baudin, P Ferolla et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015 Aug;26 8 1604 20. Open 2. E Baudin, M Caplin, R Garcia-Carbonero et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Apr;32 4 439 451. Open 3. Rajesh V Thakker, Paul J Newey, Gerard V Walls et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 MEN1 . J Clin Endocrinol Metab. 2012 Sep;97 9 2990 3011. Open 4. Frank C Detterbeck, Sandra Zelman Lewis, Rebecca Diekemper et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143 5 Suppl):7S 37S. Open 5. Yaron Shargall, Wojtek Wiercioch, Alessandro Brunelli et al. Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer- associated venous thromboembolism in thoracic surgery. Eur J Cardiothorac Surg. 2022 Dec 2;63 1):ezac488. Open https://web.pathway.md/diseases/recNaF7ifeeiz8JWz 6/6