Definition/General
Introduction:
Small intestinal carcinoid tumor is a well-differentiated neuroendocrine tumor arising from enterochromaffin cells
Most common primary tumor of the small bowel
Ileum is most frequent location (90%)
Can produce carcinoid syndrome when metastatic.
Origin:
Arises from enterochromaffin (EC) cells in intestinal crypts
These cells produce serotonin (5-HT) and other bioactive amines
Part of the diffuse neuroendocrine system
May arise from pluripotent stem cells with neuroendocrine differentiation.
Classification:
Well-differentiated NET G1 (<2 mitoses/10 HPF, <3% Ki-67)
Well-differentiated NET G2 (2-20 mitoses/10 HPF, 3-20% Ki-67)
Poorly differentiated NEC G3 (>20 mitoses/10 HPF, >20% Ki-67)
Most small bowel carcinoids are G1 or G2.
Epidemiology:
Peak incidence in 6th-7th decades
Slight male predominance
Increasing incidence (better recognition)
Ileal location in 90% of cases
Multiple tumors in 20-30% of cases.
Clinical Features
Presentation:
Asymptomatic in early stages (60-70%)
Abdominal pain (40-50%)
Bowel obstruction (30-40%)
GI bleeding (20-30%)
Carcinoid syndrome (10-15% with liver metastases)
Palpable mass (large tumors).
Symptoms:
Cramping abdominal pain
Intermittent bowel obstruction
Iron deficiency anemia
Carcinoid syndrome: flushing, diarrhea, bronchospasm, heart disease
Weight loss in advanced cases
Pellagra-like symptoms (niacin deficiency).
Risk Factors:
Family history of carcinoid tumors
MEN-1 syndrome
Neurofibromatosis type 1
Atrophic gastritis
Smoking (weak association)
Age >50 years
Previous malignancy.
Screening:
CT/MR enterography for detection
Octreotide scintigraphy (SPECT/CT)
68Ga-DOTATATE PET (most sensitive)
Serum chromogranin A
24-hour urine 5-HIAA
Capsule endoscopy for small lesions.
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Gross Description
Appearance:
Small, yellow-tan nodule (1-2 cm typical)
Well-circumscribed but not encapsulated
Firm consistency
Homogeneous cut surface
Submucosal location with mucosal elevation
Central umbilication possible.
Characteristics:
Smooth external surface
Yellow to tan color
No necrosis or hemorrhage typically
Well-demarcated from surrounding tissue
Desmoplastic reaction in mesentery when metastatic.
Size Location:
Terminal ileum most common (90%)
Size typically 1-3 cm at presentation
Submucosal origin most common
Multiple tumors in 20-30% cases
Appendiceal involvement possible.
Multifocality:
Multifocal in 20-30% of cases
Synchronous appendiceal carcinoids possible
Regional lymph nodes involved in 60-70%
Liver metastases in 50-60% at presentation
Mesenteric desmoplastic reaction characteristic.
Microscopic Description
Histological Features:
Composed of uniform small cells with round nuclei
Organoid, trabecular, or solid growth patterns
Salt-and-pepper chromatin
Minimal nuclear pleomorphism
Low mitotic activity
Rich vascular stroma
Amyloid deposition occasionally.
Cellular Characteristics:
Uniform cells with round to oval nuclei
Moderate eosinophilic cytoplasm
Fine granular chromatin
Inconspicuous nucleoli
Indistinct cell borders
Cytoplasmic neurosecretory granules
Minimal atypia.
Architectural Patterns:
Organoid nests and ribbons
Trabecular pattern
Acinar/rosette formation
Solid sheets less common
Infiltrative growth at periphery
Lymphovascular invasion common
Perineural invasion possible.
Grading Criteria:
WHO 2019 grading: Grade 1 (G1): <2 mitoses/10 HPF and <3% Ki-67
Grade 2 (G2): 2-20 mitoses/10 HPF and/or 3-20% Ki-67
Grade 3 (G3): >20 mitoses/10 HPF and/or >20% Ki-67
Most are G1 or G2.
Immunohistochemistry
Positive Markers:
Chromogranin A (95-98% positive)
Synaptophysin (90-95% positive)
CD56 (NCAM) (85-90% positive)
Serotonin (80-85% positive)
INSM1 (nuclear, 95% positive)
CDX2 (intestinal origin, 85% positive).
Negative Markers:
TTF-1 (negative, excludes lung primary)
Islet 1 (negative, excludes pancreatic)
CK7 (usually negative)
CK20 (variable)
p63 (negative).
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis
Serotonin positivity supports intestinal origin
INSM1 most sensitive and specific
Ki-67 essential for grading
CDX2 supports intestinal primary.
Molecular Subtypes:
No established molecular subtypes
Serotonin-producing (intestinal carcinoids)
Hormone receptor expression (somatostatin receptors)
Chromosomal alterations (18q loss common).
Molecular/Genetic
Genetic Mutations:
CDKN1B mutations (MEN4 syndrome)
Chromosomal losses: 18q (60-70%), 11q (40-50%), 16q (30-40%)
TP53 mutations rare in low-grade
MEN1 gene in familial cases
Simple karyotype in G1/G2.
Molecular Markers:
Loss of chromosome 18 (SMAD genes)
SSTR expression (somatostatin receptors 2 and 5)
Tryptophan hydroxylase (serotonin synthesis)
VEGF expression
Low Ki-67 in G1/G2 tumors.
Prognostic Significance:
Size >2 cm increases metastatic risk
Grade most important prognostic factor
Ki-67 >3% indicates higher grade
Lymph node metastases common but may have good prognosis
Liver metastases determine carcinoid syndrome risk.
Therapeutic Targets:
Surgical resection primary treatment
Somatostatin analogs (octreotide, lanreotide) for functional tumors
Everolimus (mTOR inhibitor)
Sunitinib (multi-kinase inhibitor)
PRRT (177Lu-DOTATATE) for SSTR-positive tumors.
Differential Diagnosis
Similar Entities:
Adenocarcinoma of small bowel
GIST
Lymphoma
Metastatic neuroendocrine tumor (pancreas, lung)
Small cell carcinoma
Paraganglioma.
Distinguishing Features:
Carcinoid: Well-differentiated, low Ki-67, serotonin+
Adenocarcinoma: Glandular, mucin+, CEA+
GIST: KIT+, DOG1+, neuroendocrine markers-
Small cell carcinoma: High-grade, high Ki-67, TTF-1 may be +
Lymphoma: CD45+, monoclonal.
Diagnostic Challenges:
Distinguishing G1 vs G2 carcinoid tumors
Separating from poorly differentiated NEC
Identifying primary vs metastatic
Mixed adenoneuroendocrine carcinoma (MANEC) recognition.
Rare Variants:
Tubular carcinoid
Insular carcinoid
Goblet cell carcinoid (appendiceal)
Large cell neuroendocrine carcinoma
Mixed adenoneuroendocrine carcinoma (MANEC).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen
[resection type], [size] cm
Diagnosis
Well-differentiated neuroendocrine tumor (carcinoid)
WHO Grade
WHO Grade [G1/G2/G3]: Mitoses [count]/10 HPF, Ki-67: [%]%
Size and Extent
Size: [X] cm, depth: [mucosal/submucosal/muscularis propria/serosa]
Immunohistochemistry
Chromogranin A: +, Synaptophysin: +, Serotonin: +, Ki-67: [%]%
Lymph Nodes
[X] positive out of [X] examined
TNM Stage
pT[X]N[X]M[X], Stage [I-IV]
Prognostic Factors
Size, grade, lymph node status, distant metastases
Final Diagnosis
Small intestinal neuroendocrine tumor (carcinoid), WHO Grade [G1/G2], [size] cm, pT[X]N[X]M[X]