Neuroendocrine Tumors Initial Assessment

Clinical Presentation

A thorough medical history, physical examination, and evaluation of signs and symptoms of genetic syndromes associated with NETs is recommended.  

Clinical Manifestations

• Flushing: It is usually the dry type and may be secondary to prostaglandins, kinins and serotonin. The characteristics depend on the location of the tumor
• Diarrhea: It is commonly the secretory type and produces large-volume stools. This persists with fasting and is relieved by proton pump inhibitor (PPI)
• Abdominal pain: It is usually severe, persistent and disturbs sleep
• Dyspepsia
• Ulcer: It is highly suggestive of gastrinoma if relieved by PPI use
• Steatorrhea
• Bronchoconstriction: Wheezing due to bronchospasm is seen in ⅓ of patients with carcinoid syndrome that is usually caused by substance P, histamine or serotonin
• Hypoglycemia: It is seen in patients with insulinoma as part of the Whipple triad (hypoglycemic symptoms, blood glucose level of <40 mg/dL and relief of symptoms with glucose)
• Hyperglycemia
• Dementia
• Dermatoses (eg urticaria, pellagra, cafe au lait)
• Obstructive symptoms (eg nausea, vomiting, cholestasis)
• Weight loss

Neuroendocrine Tumors_Initial Assesment

• Vasomotor symptoms (eg facial flushing, telangiectasia, chronic facial cyanosis, rhinitis)
• Increased intestinal motility (eg diarrhea, borborygmi, abdominal pain)
• Heart failure (eg endocardial fibrosis, pulmonary stenosis, tricuspid insufficiency)
• Bronchoconstriction (eg asthma)

Non-functional Neuroendocrine Tumors  

Most non-functional tumors are asymptomatic and not associated with clinical hormonal syndrome. Symptoms such as abdominal discomfort, diarrhea, bowel obstruction, weight loss, and jaundice are due to local growth and metastasis. These may not be diagnosed until they have progressed to advanced disease because they are slow-growing tumors. These are often found incidentally during imaging studies or surgery and their neuroendocrine origin may be noted only after histologic examination. Non-functional neuroendocrine tumors are biologically active even though they do not secrete peptides which cause a clinical syndrome. The peptides that they secrete are used for their diagnosis (eg chromogranins, especially chromogranin A [CgA], pancreatic polypeptide). The presence of a pancreatic mass without hormonal symptoms in a patient who has increased serum pancreatic polypeptide or CgA level is suggestive of non-functional NETs.

Diagnosis or Diagnostic Criteria

Neuroendocrine neoplasms are divided into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Confirmation of neuroendocrine tumor diagnosis should be made by histopathology. All tumors are classified according to site of origin, differentiation, marker of cell proliferation (eg Ki67), grade, stage and hormones. Some of the clinical and pathologic features are based on the anatomic site, but other features are shared by NETs regardless of their organ of origin.  

Different systems exist to classify, grade and stage NETs. Most grading systems rely on proliferative rate to separate low-, intermediate- and high-grade NETs. In general, well-differentiated NETs are considered low- or intermediate-grade tumors and poorly-differentiated NETs are high-grade in all cases. The required information for reporting of NETs is anatomic site of tumor, diagnosis, grade, mitotic rate, tumor size, presence of multicentric disease, vascular invasion, perineural invasion, pathologic components, lymph node metastases, margin status, and Tumor, Nodes and Metastases (TNM) stage.  

Differentiation  

Differentiation refers to the extent to which the neoplastic cells and non-neoplastic cells resemble each other. Neuroendocrine neoplasms are divided into well-differentiated NETs and poorly-differentiated NECs.  

Well Differentiated Neuroendocrine Tumors  

Well differentiated neuroendocrine tumors have “organoid” arrangements of tumor cells with nesting, trabecular, or gyriform patterns. The cells are relatively uniform and produce abundant neurosecretory granules as reflected in the strong and diffuse immunoexpression of neuroendocrine markers.  

Poorly Differentiated Neuroendocrine Tumors  

Poorly differentiated neuroendocrine tumors less closely resemble non-neoplastic neuroendocrine cells and have more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. These have more limited immunoexpression of neuroendocrine markers.  

Grade  

Grade refers to the inherent biologic aggressiveness of the neoplasm. This is generally defined by mitotic count and/or Ki67 index.  

Proliferative Rate  

The proliferative rate can be assessed as the number of mitoses per unit area of tumor or as the percentage of neoplastic cells immunolabeling for the proliferation marker Ki67.

2022 WHO Classification and Diagnostic Criteria for Neuroendocrine Neoplasm

Reference: Rindi G, Mete O, Uccella S, et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol. 2022 Mar;33(1):115-154. PMID: 35294740
*Expressed as number of mitoses/2 mm²

Screening

Genetic Risk Assessment  

Genetic risk evaluation is recommended in patients with any of the following:

• Adrenal cortical carcinoma
• Paraganglioma/pheochromocytoma
• Gastrinoma (duodenal/pancreatic or type 2 gastric NETs)
• Multifocal pancreatic neuroendocrine tumors
• Parathyroid adenoma or primary hyperparathyroidism <30 years old, multiple parathyroid adenomas, multigland hyperplasia or recurrent primary hyperparathyroidism
• Clinical suspicion for MEN2 due to the presence of medullary thyroid cancer
• A mutation identified on tumor genomic testing
• Close blood relative with a known or likely pathogenic variant in cancer susceptibility gene
• First-degree relative meeting one of the above criteria but not available for testing
• Clinical suspicion for MEN1 due to ≥2 of the following or ≥1 of the following and a family history of ≥1 of the following: Primary hyperparathyroidism, duodenal/pancreatic NETs, pituitary adenoma, or foregut carcinoid (lung, thymic or gastric)

Genetic risk assessment is considered in patients with duodenal/pancreatic NETs at any age, multifocal pancreatic NETS, gastrinoma and other combinations of tumors or cancers in the patient and/or their family members.