Review Article
Vol. 2, Issue 1, 2022 · P1-14
Management of bronchopulmonary neuroendocrine tumors (CME article)
Garima Gupta, MD,Aman Chauhan, MD,Robert A Ramirez, DO
Submission received: 2021-12-31 / Accepted: 2022-01-21 / Published: 2022-02-16
Abstract
Bronchopulmonary neuroendocrine tumors (BPNETs) are the second most common subset of NETs after gastroenteropancreatic NETs. Historically, most clinical studies have excluded BPNETs during drug development and the data is often extrapolated from non-BPNETs. However, growing burden of BPNETs and the development of novel treatment strategies including targeted therapies and radiopharmaceuticals have paved the way for revisiting treatment strategies. In this review, we go over recent advances in the management of BPNETs and summarize consensus guidelines with the help of research data and clinical scenarios.
Take home message
- Bronchopulmonary neuroendocrine tumors (BPNETs) are the second most common subset of NETs and are classified into typical carcinoid (TC) and atypical carcinoid (AC) tumors.
- A multidisciplinary approach with consideration of several factors including tumor size, location, presence of nodal/distant metastasis, comorbidities, presence of hormonal symptoms, and previous lines of therapy is essential in treatment of BPNETs.
- Surgical resection, when feasible, remains the initial treatment of choice for localized disease and provides a chance of cure.
- For patients with metastatic disease, assessment of tumor growth rate based on serial imaging is key and systemic treatment is reserved for when there is clinical or radiographic progression or high disease burden.
BACKGROUND
Neuroendocrine tumors (NETs) arise from enterochromaffin or Kulchitsky cells which are widely dispersed throughout the body and thus, can form in different locations such as the gastrointestinal (GI) tract, pancreas, and lungs. The incidence of NETs has been on the rise with bronchopulmonary NETs (BPNETs) being the second most common, comprising 20-30% of all NETs.1,2 This trend is likely attributed to increased awareness of NETs, improved radiographic technology that is more widely available, and increased screening for cancers. Based on the World Health Organization (WHO) 2015 classification, the four histologic variants of lung NETs include small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumors which are further divided into typical carcinoid (TC) and atypical carcinoid (AC) tumors.3,4 For this review, BPNETs will refer to TC and AC tumors.
While they fall under the umbrella of neuroendocrine neoplasms, SCLC and LCNEC are collectively called poorly differentiated high-grade neuroendocrine carcinomas, significantly different from well-differentiated low-grade TC and intermediate-grade AC tumors in terms of their clinical behavior and epidemiological, genetic, and molecular findings.5 BPNETs are often diagnosed in patients between 40-60 years of age and without a history of smoking, suggesting different underlying biology and etiological factors compared to other lung cancers.2 Besides various cytological and histologic characteristics including the extent of necrosis, Ki-67 nuclear expression is useful in separating high-grade SCLC and LCNEC from BPNETs.3 For further identification, the mitotic count is key in differentiating TC from AC tumors and should be performed per 2mm2 in the areas of highest activity.3,4 While TC tumors are characterized by less than 2 mitoses/2mm2 and absence of necrosis, AC tumors have 2-10 mitoses/2mm2 with presence/absence of necrosis. These findings are summarized in Table 1.
The WHO classification also recognizes diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) as a preinvasive lesion. DIPNECH is rare, manifested as hyperplasia of neuroendocrine cells which may be diffuse, or in rows or clusters, and is usually confined to the bronchial or bronchiolar epithelium. When proliferation of neuroendocrine cells extends beyond the epithelium, crossing the basement membrane into the stroma, it forms tumorlets. These lesions are often discovered incidentally as peribronchiolar nodular aggregates and are morphologically identical to TC tumors but measure less than 5 mm in size.6 DIPNECH and tumorlets can co-concurrently be seen with BPNETs.
Up to 64% of BPNETs are located centrally with a higher rate noted in TC tumors in some studies, which makes patients more prone to obstructive respiratory symptoms compared to those with peripherally located BPNETs, which are often discovered incidentally.7‑9 Patients can present with symptoms such as coughing, hemoptysis, wheezing, chest pain, and recurrent pneumonia, and they are sometimes repeatedly treated for common respiratory diseases such as chronic obstructive pulmonary disease and asthma until another pathological process is suspected, leading to a delay in diagnosis.
In about 90% of the cases, BPNETs are diagnosed as solitary lesions.7 Variable rates of lymph node involvement at the time of diagnosis have been reported. Overall, a higher rate is observed in AC tumors, with one study reporting lymph node involvement in 57% of patients with AC compared to 14% in patients with TC tumors.7,10‑12 Besides intrathoracic spread, the most common sites of distant metastasis are bone and liver, noted in about 20% of patients with AC and 3% with TC tumors.2,11 Metastasis to the central nervous system has been reported as well and was seen in patients with AC tumors.13
In 2-5% of cases, the tumor may be functional and present with carcinoid syndrome. This has been noted especially in the presence of liver metastases but is less common in BPNETs compared to patients with GI NETs.11,14,15 Cushing's syndrome is also rarely found, however, up to 40% of patients with ectopic Cushing's have been reported to have a BPNET.16 Other rare presentations that have been reported include acromegaly and hypoglycemia secondary to tumors secreting growth hormone-releasing hormone and insulin-growth factor 2.17,18 There is limited utility of routine baseline plasma chromogranin A (CgA) testing in patients with BPNETs and poor correlation with disease status.19 CgA can also be falsely elevated with renal impairment, atrophic gastritis, and the use of proton pump inhibitors.20 Other biochemical tests such as histamine, urine 5-hydroxyindoleacetic acid (HIAA), cortisol, and adrenocorticotropic hormone (ACTH) should be obtained as clinically indicated.
The initial gold standard radiological test is contrast-enhanced computed tomography (CT), which identifies both the primary lesion and intrathoracic lymphadenopathy. BPNETs usually range in size from 2-5 cm and may either be purely intraluminal appearing as a polypoid lesion or purely extraluminal. More frequently though, they are partially intraluminal with an extraluminal component, referred to as iceberg morphology.21,22 Since DIPNECH primarily affects the bronchial wall, it presents with CT changes characteristic of airway-related diseases. Bilateral mosaic attenuation, air trapping, and multifocal micronodules on expiratory CT have been reported.23 Multiphase CT or magnetic resonance imaging (MRI) of the abdomen should also be used to evaluate for metastasis to the liver and bone.
The role of positron emission tomography (PET)/CT in the diagnosis of NETs has evolved significantly over the years. NETs are known to overexpress somatostatin receptors (SSTRs), which provides a molecular basis for functional imaging and therapeutic application of somatostatin analogs (SSAs). In one study, investigators studied the expression of SSTR1 to SSTR5 in 178 BPNETs and found that 75% of tumors expressed SSTR2.24 Therefore, besides Fluorine 18-fluorodeoxyglucose (18F-FDG), SSAs such as 68Ga DOTANOC, DOTATOC, DOTATATE labeled with 68Ga and 64Cu are now widely used as part of the standard diagnostic workup. 68Ga and 64Cu-DOTATATE are now both approved by the Food and Drug Administration (FDA) and available for diagnostic purposes in the US. When available, these are preferred over somatostatin receptor scintigraphy (SRS) due to higher sensitivity.25 Not surprisingly, PET/CT using 68Ga-DOTATOC has been reported to be superior to 18F-FDG in diagnoses of TC. The reverse has been observed in patients with AC.26,27 This is because AC tumors have a higher grade than TC tumors and are, therefore, hypermetabolic and more aggressive. The degree of uptake on 18F-FDG PET/CT can help provide prognostic information and uptake on PET/CT with somatostatin analogs is a prerequisite for peptide receptor radionuclide therapy (PRRT).28
To obtain a histologic diagnosis, bronchoscopy for central tumors and either an endoscopic transbronchial or CT-guided transthoracic biopsy for peripheral tumors is performed. When there is evidence of distant metastasis, a metastatic lesion easier to access may be biopsied instead of the primary lesion. Since there is not a staging system that has been designed specifically for BPNETs, the Tumor-Node-Metastasis (TNM) model for lung cancers in the 8th edition of the American Joint Committee on Cancer (AJCC) is used.29
The overall 5-year survival rate of patients with BPNETs has been reported to be 73.5% with rates as high as 92% reported in patients with TC tumors.2,9,11,12 Nodal involvement and presence of distant metastases are independently associated with a negative impact on survival.30,31 Absence of nodal involvement, referred to as N0 disease, confers excellent prognosis compared to patients with N1 or N2 disease with 5-year survival rates as high as 97%.9,10 While not validated by the WHO for BPNETs, Ki-67 was found to be an independent prognostic marker in one study.31
Treatment of BPNETs requires a multidisciplinary approach and given their rarity, referral to a tertiary academic NET center is preferred. There are several factors to be considered in optimal management of BPNETs such as tumor size, location, presence of nodal/distant metastasis, comorbidities, presence of hormonal symptoms, and previous lines of therapy. For patients with metastatic disease, an assessment of the tumor growth rate based on serial imaging is important. Systemic treatment is reserved for when there is clinical or radiographic progression, uncontrolled or worsening symptoms or if there is high disease burden, especially in the liver. In this review, we summarize current literature including guidelines from North American Neuroendocrine Tumor Society (NANETS), The European Neuroendocrine Tumor Society (ENETS), and National Comprehensive Cancer Network (NCCN), and provide updates on recent developments in the management of BPNETs.
Table 1. 2021 WHO Pathological Classification of Lung Carcinoids
MANAGEMENT
1. SURGERY AND ADJUVANT TREATMENT
Surgical resection, when feasible, remains the initial treatment of choice for localized disease and provides a chance of cure. The choice of technique and extent of surgical resection depends on tumor location, size, pre-operative degree of suspicion for nodal involvement, and whether it is a TC or an AC tumor. Pre-operative histologic diagnosis is usually known, however, if only a small specimen was obtained during initial biopsy, it may become challenging to differentiate between TC and AC tumors.10,32 In some cases, patients are taken directly to surgery or rarely, these tumors may be incidentally discovered on surgical specimens post-operatively. Overall, the guiding principles for surgical resection of non-small cell lung cancer (NSCLC) are applied for BPNETs with lobectomy being the gold standard, however with special considerations due to their low grade and indolent clinical behavior. Minimally invasive and parenchymal sparing techniques have become increasingly preferable when possible. The choice of lung-sparing surgical technique is often dependent on the institution and surgeon's training and experience.
For peripherally located TC tumors measuring less than 2 cm, lung-sparing surgery is an option if an R0 resection can be achieved.33 However, for larger peripheral tumors and when there is concern for AC, patients with adequate pulmonary reserve should be considered for a lobectomy.34 Similarly, for centrally located tumors, most of which are TC, parenchymal-sparing resections including bronchoplastic procedures, bronchial sleeve, or sleeve lobectomy are preferred over pneumonectomy or bilobectomy. In studies with patients with N0 TC tumors, lobectomy versus sublobar resection yielded similar 5-year overall survival (OS) rates.35,36 In the same population, a clear survival advantage was noted for patients who underwent surgery versus observation. However, the 5-year disease-specific survival was still high at 88% in patients who underwent observation-only, suggesting it may be reasonable to consider this approach in patients who are at high risk for surgery-related morbidity and mortality.36 In one study, due to a high rate of lymph node involvement and multicentric forms noted in their patients, authors recommended an aggressive approach with lobectomy and lymph node dissection for all patients.10 Typically, a 5 mm negative margin is considered appropriate.
Lymph node upstaging has been found to be a strong independent predictor of OS.35 Systemic hilar and mediastinal lymph node dissection is, therefore, highly advocated in patients due to this reason and high rates of nodal involvement, especially in patients with AC tumors. Pre-operative mediastinal staging should especially be considered in patients with clinical concern for N1 or N2 disease or peripherally located N0 tumors but with suspicion for AC.34
In cases of intraluminal BPNETs without an extraluminal component, endobronchial mechanical or laser-assisted resection can be considered.37,38 In one study, patients with purely intraluminal BPNETs measuring less than 20 mm in diameter on CT were noted to be good candidates despite histological grade with procedure-associated bleeding in 9% of patients. Interestingly, endobronchial treatment was also successfully performed in 28% of patients with possible extraluminal disease noted on CT.39 In a small study, cryotherapy was performed as adjunctive treatment to endobronchial resection and was noted to be safe and effective with only 1/18 patients noted to have recurrence after seven years. In another study, presurgical endoscopic resection of large tissues specimens performed in nine patients allowed for more accurate histological diagnosis and assessment of tumor base and improvement in respiratory status with potential impact on the ability to perform a lung-sparing surgery.40
There are no large prospective studies to evaluate the role of adjuvant therapy for BPNETs. The NCCN, NANETS, and European Society of Medical Oncology (ESMO) have varying recommendations for adjuvant chemotherapy of BPNETs. NCCN recommends against adjuvant treatment for stage I and II BPNETs but recommends considering it for stage IIIA patients based on expert opinion. Specifically, they recommend considering either a platinum doublet (cisplatin/carboplatin + etoposide) or temozolomide for patients with stage IIIA disease with either intermediate grade and negative margins or positive margins irrespective of histology. However, they also state the lack of data to support this recommendation.41 Chemotherapy may also be combined with radiation if considered appropriate. ESMO recommends the consideration of adjuvant treatment for patients with AC and nodal disease. NANETS recommends against adjuvant treatment.33,42 Current literature does not suggest a consistent benefit in OS with adjuvant chemotherapy.43 Some authors have recommended its use in a subset of patients with adverse pathologic features and lymph node involvement based on a trend towards improved OS compared to published literature, however, this evidence is limited.44,45 In fact, in one study, in patients with TC tumors, adjuvant treatment was associated with significantly worse outcomes46 and should, therefore, not be used outside of a clinical trial.
For patients who are not surgical candidates or have unresectable locally advanced BPNET, NCCN recommendations are based on tumor grade.41 For intermediate grade stage III A/B/C BPNETs, platinum-doublet chemotherapy with or without radiation may be considered. For low-grade stage III A/B/C BPNETs, observation versus other systemic therapy options discussed under medical management below may be considered. If patients with intermediate-grade stage III A/B/C BPNETs are poor candidates for aggressive treatment with chemotherapy, other systemic therapies may be used with or without radiation. SSA are overall well-tolerated and can manage symptoms and also provide an anti-proliferative effect. Radiation alone may be used for palliation if systemic therapy is contraindicated.
2. MEDICAL MANAGEMENT
The goal of systemic therapy in the treatment of NETs includes control of both symptoms and tumor growth. Systemic treatment options for BPNETs include SSAs, targeted therapies, chemotherapies, PRRT, and clinical trials. These treatment options are used for patients with unresectable or metastatic disease. The sequencing of these treatment options is not well defined. An individualized patient-centered approach based on clinical status and radiological findings is essential in formulating an optimal treatment plan.
CONCLUSIONS
While the mainstay for operable BPNETs is surgical resection, the role of different systemic therapies in the treatment of advanced/metastatic disease has evolved significantly over the years. We have summarized recommendations in a treatment algorithm (Figure 1). The timing of initiating treatment and choice and sequence of therapies is crucial. A multidisciplinary and patient-centered approach is necessary for optimizing a treatment plan.
Figure 1. Treatment algorithm for bronchopulmonary neuroendocrine tumors
FUTURE DIRECTIONS
Management of BPNETs has come a long way and has seen rapid advancements in our understanding of its molecular biology, histopathological classification, diagnostic modalities, and treatment options. The next big challenge for us is to define the efficacy of these novel agents in BPNET specific clinical trials and define treatment sequencing based on prospectively conducted studies with meaningful clinical endpoints. The rarity of BPNETs often poses enrollment challenges but a concerted effort between industry and oncology cooperative groups is the only way forward in pursuing meaningful and much needed clinical studies.
FUNDING INFORMATION
N/A
ETHICAL STATEMENTS
N/A
ACKNOWLEDGEMENT
N/A
AUTHOR CONTRIBUTIONS
Garima Gupta: conception and design, manuscript writing and proofreading
Robert A Ramirez: support to Garima Gupta
Aman Chauhan: support to Garima Gupta
All authors have approved the manuscript
CONFLICT OF INTEREST
RAR: Consulting for Amgen, Ipsen, Novartis, Advanced Accelerator Applications, Curium, EMD Serono; Speaking Fees from Ipsen, Astra-Zeneca, Merck; Research Funding (to institution) from Merck, AADI Bioscience
AC: Consulting for Novartis, Ipsen, Lexicon, TerSera; Research Funding from NCI CTEP, BMS, Clovis Oncology, TerSera, EMD Serono, Nanopharmaceuticals, ECS Progastrin
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