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:
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G1: Well differentiated, low grade
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G2: Well differentiated, intermediate grade
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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] :
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Low-grade tumors: < 2 mitoses/10 high power field (HPF) and no necrosis
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Intermediate tumors: 2-10 mitoses/HPF and/or foci of necrosis
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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] :
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Low-grade tumors: < 10 mitoses/10 HPF
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Intermediate tumors: 10-20 mitoses/10 HPF
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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 2020, 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 are as follows [44] :
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For grading: WHO 2010 grading system
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For staging: 7th edition of the AJCC Cancer Staging Manual
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Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system
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The TNM classification used should be specified
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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
Thymic NETs
For thymic NETs, NCCN recommendations include the following [40] :
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Localized disease: Surgical resection
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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] :
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Locoregional disease: Surgical resection including mediastinal lymphadenectomy
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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 because of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatin-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] :
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Stage I-II: Lobectomy or wedge resection and lymph node dissection or sampling or stereotactic body radiation therapy (SBRT), if surgery is contraindicated; thermal ablation, if surgery and SBRT are contraindicated
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Stage IIIA resectable tumors: Lobectomy or wedge resection and lymph node dissection or sampling
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Stage III (A/B/C) low grade (typical) nonresectable tumors: Observation, if asymptomatic; octreotide or lanreotide, if SSR-positive and/or hormonal symptoms are present; other options include everolimus, temozolomide with or without capecitabine or radiation therapy
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Stage III (A/B/C) intermediate grade nonresectable tumors: Observation, if asymptomatic and nonprogressive; octreotide or lanreotide, if SSR-positive and/or hormonal symptoms are present; other options include radiation therapy with or without cisplatin/etoposide or carboplatin/etoposide, cytotoxic chemotherapy, or everolimus
The ESMO guidelines are similar to those of the NCCN, with some minor variances. [39, 46] The ESMO guidelines include the following additional recommendations [39] :
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Bronchoscopic laser excision should be considered a suboptimal treatment and be reserved for inoperable patients or performed as a preoperative disobliterating procedure
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Lobectomy and sleeve resection are preferred for locoregional tumors and systemic nodal dissection should be performed
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Pneumonectomy should be avoided
In 2020, the Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs) and NANETS released joint guidelines on the managment of lung neuroendocrine tumors, which included the following recommendations for resectable tumors [47] :
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Lobectomy or sleeve resection are preferred; sublobar resection is an alternative for peripheral tumors < 2 cm if complete resection is achievable; complete resection and systematic nodal dissection for patients with peripheral tumors. Lung parenchyma–sparing surgery is preferred over pneumonectomy; endobronchial resection for patients at unacceptably high risk for surgical resection or as a possible bridge to surgery.
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Radiation and thermal therapies may be used for locoregional control of primary lung neuroendocrine tumors or for palliation therapy in patients who are not surgical candidates.
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Adjuvant therapy with somatostatin analogues (SSAs), chemotherapy, or radiation is not recommended following complete resection.
For nonresectable tumors, locally advanced or metastatic disease, the key recommendations include the following [47] :
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Observation, if asymptomatic
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SSAs for first- line treatment of carcinoid syndrome and as antiproliferative treatment of advanced tumors with good prognosis
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For somatostatin receptor–positive tumors, peptide receptor radionuclide therapy
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External-beam radiation for palliative treatment in advanced and metastatic tumors
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Everolimus should be considered in progressive nonfunctional tumors and may be considered in functional tumors.
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Use of streptozocin-based, oxaliplatin-based, etoposide-based, or temozolomide-based chemotherapy may be considered to treat advanced tumors
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Posteroanterior chest radiograph of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis.
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Lateral chest radiograph of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis.
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Computerized tomographic study of a 37-year-old woman with a carcinoid lung tumor of the left mainstem bronchus and resultant left upper lobe atelectasis.
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Posteroanterior chest radiograph showing a carcinoid lung tumor presenting as a coin lesion in the right lower lobe of a 40-year-old, asymptomatic woman.
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Lateral chest radiograph showing a carcinoid lung tumor presenting as a coin lesion in the right lower lobe of a 40-year-old, asymptomatic woman.
