Neuroendocrine%20tumors Diagnosis

• Confirmation of NET diagnosis should be made by histopathology
• All tumors are classified according to site, 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
• Required information for reporting of NETs are 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

• Refers to the extent to which the neoplastic cells and non-neoplastic cells resemble each other

Well-differentiated

• They 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

• Less closely resemble nonneoplastic neuroendocrine cells and have more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity
• More limited immunoexpression of neuroendocrine markers

• Refers to the inherent biologic aggressiveness of the neoplasm
• Generally defined by mitotic count and/or Ki67 index

• 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

Genetic Risk Assessment

• Generic risk evaluation is recommended in patients with any of the following:
  • Adrenal cortical carcinoma
  • Paraganglioma/pheochromocytoma
  • Gastrinoma (duodenal/pancreatic or type 2 gastric NET)
  • Multifocal pancreatic neuroendocrine tumors
  • Parathyroid adenoma or primary hyperparathyroidism <30 years old, multiple parathyroid adenoma, 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
  • 1st-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 NET, pituitary adenoma, or foregut carcinoid (bronchial, thymic or gastric)
• Considered in patients with duodenal/pancreatic NET at any age

 

2019 WHO Classification and Grading Criteria for Neuroendocrine Neoplasms of the Gastrointestinal Tract and Hepatopancreatobiliary Organs¹

*Expressed as number of mitoses/2 mm^2
1Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors and adrenal tumors. Version 4.2021.

2015 WHO Criteria for the Diagnosis of Pulmonary NET¹

¹Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors and adrenal tumors. Version 4.2021.

Staging

• The American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) developed the Tumor, Nodes and Metastases (TNM) System for NETs of all anatomical sites
  • There are some differences between these systems, particularly for primary tumors of the pancreas and appendix, but there is also a considerable overlap
  • Staging criteria for both systems depend on the tumor size and extent of invasion into similar landmarks as used for the staging of non-neuroendocrine carcinomas of the same sites

¹Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors and adrenal tumors. Version 4.2021.

¹Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors and adrenal tumors. Version 4.2021.

¹Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors and adrenal tumors. Version 4.2021.

• Hormones or amines secreted by the neuroendocrine cells from which the NETs are derived
• Detection of these substances can provide a more accurate diagnosis and earlier detection of the presence of tumor which leads to improved control of symptoms related to hormone oversecretion
  • However, isolated elevation of these markers is generally not sufficient for diagnosis without tissue confirmation
• Also used for surveillance and prognosis of NETs

• A 49-kd acidic polypeptide widely present in the neuroendocrine cells' secretory granules
• It is elevated in most patients with either functional or non-functional NETs
• Has high sensitivity for the detection of NETs
• Useful marker to detect the progression and metastasis of NETs because it correlates with tumor volume
  • However, care should be taken into consideration when measuring and interpreting results

• A metabolite serotonin found in a 24-hour urine collection or plasma that is a useful marker for carcinoid tumors particularly in patients with small intestinal carcinoid tumors
• Surrogate measure of serotonin (5-HT) metabolism that excess secretion is linked to the presence of carcinoid syndrome
• Has high specificity
  • Decreasing levels indicate a response to treatment while increasing levels mean unsuccessful treatment
• Certain foods (eg avocado, kiwi, banana, tomato, walnut) and medications (eg Acetaminophen, Ephedrine, Diazepam, Nicotine, Phenobarbital) can affect the result and should be avoided 48 hours prior to collection of samples

• A dimer of the glycolytic enzyme enolase
• Present in the cytoplasmic compartment of the cells of neuronal and neuroectodermal origin
• Useful marker for follow-up of patients with NETs but less specific than CgA

• Calcitonin, parathyroid hormone-related peptide (PTHrp), and growth hormone-releasing hormone (GHRH) may be obtained for the detection of pancreatic NETs
• Serum insulin, pro-insulin, C-peptide for insulinomas
• Serum VIP for VIPomas; serum glucagon for glucagonomas; serum gastrin for gastrinoma

• Assist in:
  
  • Localizing the tumor
  • Assessing the extent of the disease and identifying the sites of metastases
  • Planning treatment by:
    
    • Determining whether surgical resection for possible cure or cytoreductive surgery is needed
    • Assessing whether treatment for advanced metastatic disease is appropriate
  • Monitoring the response to therapy and evaluating the need for additional treatment
• Standard of care includes imaging of somatostatin receptor (SSR) aside from the standard imaging studies [eg magnetic resonance imaging (MRI) and computed tomography (CT)]
  • Useful in assessing receptor status, distant disease and whether patient may benefit from SSR-directed therapy

• Triphasic CT of the liver should be a standard component of imaging modality of NETs because the liver is the most common site of metastasis and its widely available
  
  • Can also be done to evaluate tumors before radiofrequency ablation and hepatic arterial embolization
  • Should be routinely used preoperatively for evaluation of potentially resectable primary or metastatic tumors
  • Used to monitor response to therapy
• Multiphasic CT is recommended for abdominal and pelvic imaging
  • Thin sections and use of a negative oral contrast agent may be helpful in identifying small primary tumor in the small bowel
• Superior for localizing primary tumor, mesenteric invasion, tumor metastasis, and thoracic lesions
• Chest and mediastinal CT for suspected bronchopulmonary and thymic tumors

Magnetic Resonance Imaging (MRI)

• T1-weighted, T2-weighted imaging, and multiphasic (arterial, portal venous, and delayed) dynamic MRI are recommended for NETs
  
  • Has high sensitivity in detecting pancreatic NETs
  • However, some do not prefer to use it routinely in gastroenterohepatic NETs
• Can be used to characterize hepatic tumors before surgery if the diagnosis is unclear and if CT or ultrasound results are inconclusive
• Also recommended to determine the presence of metastasis
  • Studies have shown that MRI is more sensitive than CT for the detection of small liver metastasis
• Preferred imaging modality in the following cases:
  
  • When CT is contraindicated and it is less sensitive for tumor detection
  • Patients having contrast allergies, hepatic steatosis or renal insufficiency
  • Patients for possible liver resection or tumor-debulking surgery
  • Initial localization of tumor in children and pregnant or lactating women to avoid radiation exposure

Ultrasonography

• An adjunct to CT scan in assessing tumor volume before radiofrequency ablation and hepatic arterial embolization, and differentiating lesions with uncertain CT imaging characteristics
• Pre-operative endoscopic ultrasound should be considered for rectal NETs 1-2 cm in size
• Contrast-enhanced ultrasound may be used to assess liver lesions that are equivocal on CT/MRI

Positron Emission Tomography (PET) Scan/CT or PET/MRI

• Uses radiolabeled somatostatin analog gallium-68 (68Ga) dotatate
• Studies showed high sensitivity and specificity for the diagnosis of NETs
• Useful in tumor staging, pre-operative imaging and restaging
• SSR PET imaging is more sensitive than SSR scintigraphy in assessing SSR status

• Shares the receptor binding profile of Octreotide making it a good radiopharmaceutical for imaging of SSRs 2- and 5-positive tumors
• Important imaging study for identifying and staging gastroenterohepatic NETs
  
  • Most sensitive imaging modality for detecting widespread metastatic disease in NETs
  • However, it is less sensitive for metastatic insulinomas
• Can detect Octreotide-avid lesions in the body and help in disease staging, preoperative evaluation, surveillance, and monitoring treatment response
  • Extremely useful in confirming the diagnosis and evaluating tumor distribution and burden
  • Has high sensitivity
  • Done as whole-body imaging that detects disease at unsuspected sites
  • Provides information on the site but not about the size of the tumor
  • It is advised that octreotide treatment be temporarily discontinued before scintigraphy so as not to alter the results

• Used for staging, monitoring, and performing preoperative evaluation, especially when there is negative or uncertain In-pentetreotide scan results
• Utilized for identifying patients for radiolabeled MIBG therapy

Bronchoscopy

• Used for diagnosing and staging lung and thymic carcinoids
  • May be used as a confirmatory test for suspected central lesions
  • A required procedure prior to surgical resection

Endobronchial Endoscopic Ultrasonography (EBUS)

• Minimally invasive technique used for peripheral lesions and to rule out bulky mediastinal nodes in patients suspected of lung and thymic carcinoids

Mediastinoscopy

• May be used for evaluating mediastinal nodes in patients suspected of lung and thymic carcinoids