Carcinoid Lung Tumors Guidelines

Updated: Jul 13, 2020
  • Author: Mary C Mancini, MD, PhD, MMM; Chief Editor: Jeffrey C Milliken, MD  more...
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Guidelines for Grading and Staging of Neuroendocrine Tumors

Guidelines Contributor:  Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS)  both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs). [34, 35, 36]

Tumors fall into one of the following three grades:

  • G1: Well differentiated, low grade
  • G2: Well differentiated, intermediate grade
  • G3: Poorly differentiated, high grade

However, for NETs of the lungs and thymus, the WHO includes only mitotic count and assessment of necrosis. [37]  In its 2015 consensus statement on best practices for pulmonary neuroendocrine tumors, the ENETS noted that tumor grading based on a combination of KI-67, mitotic rate, and necrosis may be of clinical importance but lacks validation. [38]

Under the WHO grading scheme, pulmonary and thymic tumors fall into one of the following three grades [37] :

  • Low-grade tumors: < 2 mitoses/10 high power field (HPF) and no necrosis
  • Intermediate tumors: 2-10 mitoses/HPF and/or foci of necrosis
  • High grade tumors: >10 mitoses/10 HPF

The European Society for Medical Oncology (ESMO) uses only mitotic count for bronchial and thymic tumors for determining tumor grade, as follows [39] :

  • Low-grade tumors:  < 10 mitoses/10 HPF
  • Intermediate tumors:  10-20 mitoses/10 HPF
  • High-grade tumors:  > 20 mitoses/10 HPF

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results. [40]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. [40]  The AJCC uses separate staging systems for carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix, as well as adrenal gland tumors. Bronchopulmonary carcinoids are staged using the same system as for other pulmonary malignancies, and pancreatic NETS are staged the same as for exocrine pancreatic tumors. [41]

For staging of GEP-NETs, the ESMO guidelines, updated in 2012, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2010 WHO grading system. [42]  For staging of bronchopulmonary and thymus NETs, the ESMO prefers the AJCC system. [39]  For adrenal carcinoma staging, the 2009 European Network for the Study of Adrenal Tumors (ENSAT) TNM system is recommended over the AJCC system. [43]

In 2012, the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) released updated guidelines for the management of GEP-NETs. Recommendations for grading and staging were as follows [44] :

  • For grading: WHO 2010 grading system
  • For staging: 7 th edition of the AJCC Cancer Staging Manual
  • Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system
  • The TNM classification used should be specified
  • Underlying features of the T-stage classification (eg, tumor size, extent of invasion) should be documented to allow for translation between different classification systems

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage. [45]


Guidelines for Treatment of Thoracic Carcinoid Tumors

The following organizations have issued clinical guidelines for the treatment of thoracic carcinoid tumors:

  • National Comprehensive Cancer Network (NCCN)
  • North American Neuroendocrine Tumor Society (NANETS)
  • European Society for Medical Oncology (ESMO)

NCCN guidelines recommend resection as the primary treatment for most carcinoid tumors of the lung and thymus. Specific recommendations vary by tumor subtype. [40]

Thymic NETs

For thymic NETs, NCCN recommendations include the following [40] :

  • Localized disease: Surgical resection
  • Locoregional disease: Reresection; if resection is incomplete, follow with radiation therapy and/or chemotherapy

The NANETS guidelines include the following additional recommendations for thymic NETs [46] :

  • Locoregional disease: Surgical resection including mediastinal lymphadenectomy
  • Metastatic or unresectable disease: Options include radiation therapy, everolimus, interferon alpha, or temozolomide

The ESMO guidelines note that a protracted follow-up should always be performed after surgical resection becuse of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatinum-based regimens have been of value and temozolomide-based treatment gives some benefit. [39]

Bronchopulmonary NETs

NCCN recommendations for bronchopulmonary NETs are as follows [40] :

  • Stage I, II, and IIIA: Lobectomy or wedge resection for peripheral low-grade neuroendocrine carcinoma and lymph node dissection or sampling
  • Stage IIIA low grade nonresectable tumors: Radiation therapy
  • Stage IIIA intermediate grade nonresectable tumors: Cisplatin/etoposide and radiation therapy
  • Stage IIIB (except for T4 due to multiple lung nodules): Cisplatin/etoposide with or without radiation therapy
  • Stage IIIBm (T4 due to multiple lung nodules) or stage IV: Systemic therapy; no preferred regimen; options include cisplatin/etoposide, temozolomide with or without capecitabine, sunitinib, or everolimus; consider octreotide for symptoms of malignant carcinoid syndrome

The NANETS guidelines and the ESMO guidelines are similar to those of the NCCN, with some minor variances. [46, 39]  The ESMO guidelines include the following additional recommendations [39] :

  • Bronchoscopic laser excision should be considered a suboptimal treatment and be reserved for inoperable patients or performed as a preoperative disobliterating procedure
  • Lobectomy and sleeve resection are preferred for locoregional tumors and systemic nodal dissection should be performed
  • Pneumonectomy should be avoided

Additionally, NANETS suggests that interferon alfa should be considered for metastatic or unresectable disease. [46]