neuroendocrine%20tumors
NEUROENDOCRINE TUMORS
Neuroendocrine tumors are rare, small, slow-growing epithelial neoplasms with predominant neuroendocrine differentiation found in most organs of the body.
They arise from cells throughout the diffuse endocrine system.
Carcinoid tumors and pancreatic neuroendocrine tumors are the most common.
Carcinoid tumors arise from the lungs & bronchi, stomach, small intestine, appendix, rectum or thymus.
Majority of the neuroendocrine tumors are sporadic but some tumors are caused by inherited genetic syndromes such as multiple endocrine neoplasia, Von-Hippel Lindau disease, tuberous sclerosis complex and neurofibromatosis.
They have the ability to store and secrete various peptides and neuroamines.

Diagnosis

  • Confirmation of neuroendocrine tumors (NETs) diagnosis should be made by histopathology
  • All tumors are classified according to site, differentiation, marker of cell proliferation (eg Ki67), grade, stage, & hormones
  • Some of the clinical & 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 & stage NETs
    • Most grading systems rely on proliferative rate to separate low, intermediate, & high-grade NETs
    • In general, well-differentiated NETs are considered low or intermediate-grade tumors & 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, & TNM stage
Differentiation
  • Refers to the extent to which the neoplastic cells & non-neoplastic cells resemble each other
  • Well-differentiated
    • They have “organoid” arrangements of tumor cells w/ nesting, trabecular, or gyriform patterns
    • The cells are relatively uniform & produce abundant neurosecretory granules as reflected in the strong & diffuse immunoexpression of neuroendocrine markers
  • Poorly differentiated
    • Less closely resemble nonneoplastic neuroendocrine cells & have more sheet-like or diffuse architecture, irregular nuclei, & less cytoplasmic granularity
    • More limited immunoexpression of neuroendocrine markers
Grade
  • Refers to the inherent biologic aggressiveness of the neoplasm
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

Staging

WHO Grading System
Gastrointestinal & Pancreatic NETs1,2
  • Low grade (G1)
    • Indolent or slow growing
    • < 2 mitoses/10 hpf
    • < 3% Ki67 index
  • Intermediate grade (G2)
    • Less predictable & moderately aggressive
    • 2-20 mitoses/10 hpf
    • 3-20% Ki67 index
  • High grade (G3)
    • Extremely aggressive
    • >20 mitoses/10 hpf
    • >20% Ki67 index

Lung & Thymus NETs2

  • Low grade (G1)
    • Indolent or slow growing
    • < 2 mitoses/10 hpf &
    • Necrosis absent
  • Intermediate grade (G2)
    • Less predictable & moderately aggressive
    • 2-10 mitoses/10 hpf &/or
    • Foci of necrosis present
  • High grade (G3)
    • Extremely aggressive
    • >10 mitoses/10 hpf
    • Poorly differentiated
Staging
  • The American Joint Committee on Cancer (AJCC) & European Neuroendocrine Tumor Society (ENETS) developed the Tumor, Nodes & Metastases (TNM) System for NETs of all anatomical sites
    • There are some differences between these systems, particularly for primary tumors of the pancreas & appendix, but there is also a considerable overlap
    • Staging criteria for both systems depend on the tumor size & extent of invasion into similar landmarks as used for the staging of non-neuroendocrine carcinomas of the same sites
AJCC & ENETS Staging of NETs of the Stomach2,3
Stage 0
  • Carcinoma in situ/dysplasia w/ tumor size <0.5 mm that is confined to mucosa
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage I
  • Tumor invades lamina propria or submucosa & ≥1 cm in size
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor invades muscularis propria or >1 cm in size
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Tumor penetrates subserosa
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIA
  • Tumor invades visceral peritoneum (serosal) or other organs or adjacent structures
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIB
  • Presence of regional lymph node metastasis w/ no distant metastasis
Stage IV
  • Presence of distant metastasis

1Modified from: Kunz PL, Reidy-Lagunes D, Anthony LB, et al; North American Neuroendocrine Tumor Society. Consensus guidelinesfor the management and treatment of neuroendocrine tumors. Pancreas. 2013 May;42(4):559-562.
2Modified from: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumorsversion 1.2015.
3Modified from: Kulke MH, Anthony, LB, Bushnell DL, et al. NANETS Guidelines. NANETS treatment guidelines: well-diff erentiatedneuroendocrine tumors of the stomach and pancreas. Pancreas 2010;39(6):739.

AJCC Staging of NETs of the Pancreas1
Stage 0
  • Carcinoma in situ
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IA
  • Tumor limited to the pancreas, ≥2 cm in size
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IB
  • Tumor limited to the pancreas, >2 cm in size
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor extends beyond the pancreas but w/o celiac axis or superior mesenteric artery involvement
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Presence of regional lymph node metastasis in the pancreas w/o involvement of the celiac axis or superior mesenteric artery
  • Absence of distant metastases
Stage III
  • Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
  • W/ regional lymph node metastasis
  • Absence of distant metastases
Stage IV
  • Presence of distant metastasis
ENETS Staging of NETs of the Endocrine Pancreas2
Stage I
  • Tumor size is <2 cm & limited to the pancreas
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIa
  • Tumor size is 2-4 cm & limited to the pancreas
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIb
  • Tumor size is >4 cm & limited to the pancreas of invading the duodenum or bile duct
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIa
  • Tumor invading the adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of the large vessels (celiac axis or superior mesenteric artery)
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIb
  • Presence of regional lymph node metastasis w/ no distant metastasis
Stage IV
  • Presence of distant metastasis

1Modified from: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors version 1.2015.
2Modified from: Kulke MH, Anthony, LB, Bushnell DL, et al. NANETS Guidelines. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010;39(6):741.

AJCC Staging of NETs of the Appendix1
Stage I
  • Tumor size is ≥2 cm
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage II
  • Tumor size is 2-4 cm or w/ extension to cecum; tumor >4 cm or w/ extension to ileum
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage III
  • Tumor directly invades other adjacent organs or structures (eg abdominal wall & skeletal muscle)
  • W/ or w/o regional lymph node metastasis
  • Absence of distant metastases
Stage IV
  • Presence of distant metastasis
ENETS Staging of NETs of the Appendix2
Stage I
  • Tumor size is ≥1 cm & invades the submucosa & muscularis propria
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor size is ≥2 cm & invades the submucosa, muscularis propria &/or minimally (up to 3 mm) the subserosa/mesoappendix
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Tumor invades the subserosa/pericolic/perirectal fat
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIA
  • Tumor invades the peritoneum/other organs
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIB
  • Presence of regional lymph node metastasis w/ no distant metastasis
Stage IV
  • Presence of distant metastasis
AJCC & ENETs Staging of NETs of the Small Intestine1,2
Stage 0 (AJCC only)
  • Carcinoma in situ
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage I
  • Tumor size is ≥1 cm & invades lamina propria or submucosa
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor size is >1 cm & invades muscularis propria
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Tumor invades through the muscularis propria into subserosal tissue w/o penetration of overlying serosa (jejunal or ileal tumors) or invades pancreas or retroperitoneum (ampullary or duodenal tumors) or into non-peritonealized tissues
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIA
  • Tumor invades visceral peritoneum (serosa) or invades other organs
  • Regional lymph node metastasis is absent
  • Absence of distant metastases

1Modified from: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumors version 1.2015.
2Modified from: Boudreaux JP, Klimstra DS, Hassan MM, et al. NANETS Guidelines. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39(6):756-757

Stage IIIB
  • Presence of regional lymph node metastasis w/ no distant metastases
Stage IV
  • Presence of distant metastasis
AJCC Staging of the NETs of Colon or Rectum1
Stage 0
  • Carcinoma in situ
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage I
  • Tumor size is ≥2 cm & invades lamina propria or submucosa
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor size is >2 cm & invades lamina propria or submucosa or tumor invades muscularis propria
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Tumor invades through the muscularis propria into subserosal tissue or into non-peritonealized pericolic or perirectal tissues
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIA
  • Tumor invades peritoneum or other organs
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIB
  • Presence of regional lymph node metastasis w/ no distant metastases
Stage IV
  • Presence of distant metastasis
ENETS Staging of the NETs of Colon & Rectum3
Stage IA
  • Tumor size is <1 cm
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IB
  • Tumor size is 1-2 cm
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIA
  • Tumor size is >2 cm & invades the muscularis propria
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIB
  • Tumor invades the subserosa/pericolic/perirectal fat
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIA
  • Tumor directly invades other organs/structures &/or perforates the visceral peritoneum
  • Regional lymph node metastasis is absent
  • Absence of distant metastases
Stage IIIB
  • Presence of regional lymph node metastasis w/ no distant metastases
Stage IV
  • Presence of distant metastasis

1Modified from: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: neuroendocrine tumorsversion 1.2015.
2Modified from: Boudreaux JP, Klimstra DS, Hassan MM, et al. NANETS Guidelines. NANETS consensus guideline for the diagnosis andmanagement of neuroendocrine tumors: well-diff erentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum.Pancreas 2010;39(6):756.
3Modified from: Anthony LB, Strosberg JR, Klimstra DS, et al. NANETS Guidelines. e NANETS consensus guideline for the diagnosisand management of gastrointestinal neuroendocrine tumors (NETs): well-diff erentiated NETs of the distal colon and rectum. Pancreas2010;39(6):770.

Laboratory Tests

Biochemical Markers
  • Hormones or amines secreted by the neuroendocrine cells from which the NETs are derived
  • Detection of these substances can provide a more accurate diagnosis & 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 w/o tissue confirmation
  • Also used for surveillance & prognosis of NETs
Chromogranin A (CgA)
  • A 49-kd acidic polypeptide widely present in the neuroendocrine cells secretory granules
  • It is elevated in most patients w/ either functional or non-functional NETs
  • Has high sensitivity & specificity for the detection of NETs
  • Useful marker to detect the progression & metastasis of NETs because it correlates w/ tumor volume
    • However, care should be taken into consideration when measuring & interpreting results
5-Hydroxyindoleacetic acid levels (5-HIAA)
  • A metabolite serotonin found in a 24-hour urine collection that is a useful marker for carcinoid tumors particularly in patients w/ 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) & medications (eg Acetaminophen, Ephedrine, Diazepam, Nicotine, Phenobarbital) can affect the result & should be avoided 48 hours prior to collection of samples
Neuron-Specific Enolase (NSE)
  • A dimer of the glycolytic enzyme enolase
  • Present in the cytoplasmic compartment of the cells of neuronal & neuroectodermal origin
  • Useful marker for follow-up of patients w/ NETs but less specific than CgA
Other Tests
  • Calcitonin, PTH-rp, & 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

Imaging

  • Assist in:
    • Localizing the tumor
    • Assessing the extent of the disease & 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 & evaluating the need for additional treatment
  • Standard of care includes imaging of somatostatin receptor aside from the standard imaging studies (eg MRI & CT)
Computed Tomography (CT) scan
  • 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 & its widely available
    • Can also be done to evaluate tumors before radiofrequency ablation & 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 & pelvic imaging
    • Thin sections & 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, & thoracic lesions

Ultrasonography

  • An adjunct to CT scan in assessing tumor volume before radiofrequency ablation & hepatic arterial embolization, differentiating lesions w/ uncertain CT imaging characteristics
  • Pre-operative endoscopic ultrasound should be considered for rectal NETs 1-2 cm in size

Magnetic Resonance Imaging (MRI)

  • T1-weighted, T2-weighted imaging, & multiphasic (arterial, portal venous, & 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 & 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 & 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 & pregnant or lactating women to avoid radiation exposure
Indium-111-DTPA Octreotide Scintigraphy
  • Shares the receptor binding profile of octreotide making it a good radiopharmaceutical for imaging of somatostatin receptors 2 & 5-positive tumors
  • Important imaging study for identifying & 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 & help in disease staging, preoperative evaluation, surveillance, & monitoring treatment response
    • Extremely useful in confirming the diagnosis & evaluating tumor distribution & 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
Meta-iodobenzylguanidine (MIBG) Scintigraphy
  • Used for staging, monitoring, & performing preoperative evaluation, especially when there is negative or uncertain In-pentetreotide scan results
  • Utilized for identifying patients for radiolabeled MIBG therapy
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