Neuroendocrine Neoplasms

A broad, biologically heterogeneous group of tumours arising from cells of the diffuse neuroendocrine system. They can arise in virtually any organ, though most commonly in the gastroenteropancreatic tract and the bronchopulmonary system.

They are unified by shared histological and immunohistochemical features, including expression of general neuroendocrine markers such as chromogranin A and synaptophysin. Clinical behaviour, hormonal functional status, and prognosis vary substantially with site of origin, grade, and stage.

This overview gives the classification and general management framework across the whole group. Site specific detail for pancreatic and carcinoid tumours is in their own articles.

Classification

• The World Health Organization grading system is based on proliferative index (Ki-67 labelling index and mitotic count). It classifies well differentiated neuroendocrine tumours into grade 1 (low proliferative index, generally indolent behaviour), grade 2 (intermediate), and grade 3 (higher proliferative index though retaining well differentiated histological architecture).
• This grading is distinct from poorly differentiated neuroendocrine carcinoma, and generally has more favourable prognostic implications.
• Poorly differentiated carcinoma behaves far more aggressively, akin to other high grade epithelial malignancies, regardless of primary site.
• Tumours are further classified by primary site: bronchopulmonary, gastroenteropancreatic (with further subdivision by segment of origin), and less common sites.
• They are also classified by functional status. Functioning tumours produce a recognisable clinical hormonal syndrome, including carcinoid syndrome, insulinoma and gastrinoma.
• Non-functioning tumours retain neuroendocrine differentiation on histology but produce no clinically apparent hormonal syndrome. They typically present instead because of mass effect or metastatic burden.

• Non-functioning neuroendocrine tumours account for the majority of cases across most primary sites. They typically present insidiously with symptoms of local mass effect or metastatic disease burden: abdominal pain, jaundice from biliary obstruction, or symptoms of hepatic metastases.
• Presentation is frequently at a relatively advanced stage, because no hormonal syndrome prompts earlier diagnosis.
• Functioning tumours present with the hormonal syndrome corresponding to the hormone secreted, as in carcinoid syndrome, insulinoma, gastrinoma and other functioning pancreatic neuroendocrine tumour syndromes.
• Bronchopulmonary neuroendocrine tumours (typical and atypical carcinoid) may present with cough, haemoptysis, or recurrent pneumonia from bronchial obstruction. Less commonly they present with carcinoid syndrome where hepatic metastatic disease is present.
• Primary bronchial carcinoid, unlike its gastrointestinal counterpart, can occasionally produce enough serotonin to enter the systemic circulation directly. It does not require hepatic metastases to bypass first pass hepatic metabolism. This distinction is covered under carcinoid syndrome.
• Poorly differentiated neuroendocrine carcinoma, wherever the primary site, typically has a rapidly progressive course and often extensive metastatic disease at diagnosis. This reflects aggressive tumour biology, in clear contrast to the generally more indolent course of well differentiated tumours.

• Histological confirmation is essential for diagnosis and grading. It uses immunohistochemical staining for chromogranin A and synaptophysin, and Ki-67 proliferative index assessment. Obtain tissue by biopsy of the primary tumour or an accessible metastatic site.
• Accurate grading directly informs prognosis and treatment selection.
• Biochemical assessment for a functional syndrome is guided by the clinical presentation and primary site. It supports diagnosis and subsequent disease monitoring.
• Chromogranin A is a general but non-specific circulating tumour marker. 24 hour urinary 5-hydroxyindoleacetic acid is used for suspected carcinoid syndrome. Specific hormone panels are used for suspected functioning pancreatic neuroendocrine tumours, as detailed under those conditions.
• Somatostatin receptor imaging (gallium-68 DOTATATE positron emission tomography combined with computed tomography) is the imaging modality of choice for localisation and staging of well differentiated tumours. The great majority express high levels of somatostatin receptors.
• Fluorodeoxyglucose positron emission tomography is preferred for poorly differentiated, high grade neuroendocrine carcinoma. These tumours generally have lower somatostatin receptor expression but higher metabolic activity.

• Surgical resection is the only potentially curative treatment for localised, well differentiated neuroendocrine tumours. The extent of resection is determined by primary tumour site and stage.
• Somatostatin analogues (octreotide or lanreotide, given as long acting depot injections) are effective symptomatic treatment for functioning tumours. They are also an important antiproliferative treatment for somatostatin receptor positive, well differentiated metastatic disease.
• They are generally well tolerated and are an effective first line systemic option for this tumour category.
• Everolimus (an mTOR inhibitor) and sunitinib (a tyrosine kinase inhibitor) are effective targeted options for progressive, well differentiated tumours, particularly of pancreatic origin. They are used after progression on somatostatin analogues, or as an alternative to them.
• Peptide receptor radionuclide therapy (lutetium-177 DOTATATE) is an effective targeted treatment for somatostatin receptor positive, progressive metastatic well differentiated tumours. It delivers radiation directly to receptor expressing tumour cells.
• Poorly differentiated neuroendocrine carcinoma is managed with platinum based combination chemotherapy, typically cisplatin or carboplatin combined with etoposide. This is analogous to other high grade, aggressive malignancies including small cell lung cancer.
• Somatostatin receptor directed treatments used for well differentiated disease have generally limited efficacy in this more aggressive category.
• Liver directed therapy (transarterial embolisation or radiofrequency ablation) is considered for liver dominant metastatic disease, given the propensity for hepatic metastatic spread across several primary sites.
• Multidisciplinary team discussion underpins individualised management, given the heterogeneity in behaviour, grade and treatment options. It incorporates endocrinology, oncology, surgery, interventional radiology and nuclear medicine input.