What are the histological findings of carcinoid tumors?

Histological Findings of Carcinoid Tumors

Carcinoid tumors demonstrate highly organized neuroendocrine architecture with bland, uniform cytologic features including moderate granular cytoplasm, finely granular "salt and pepper" chromatin, low nuclear-to-cytoplasmic ratio, and round to ovoid nuclei with inconspicuous nucleoli. 1

Cytomorphologic Features

Typical carcinoids (TC) display the following cellular characteristics:

• Uniform, bland tumor cells with moderate amounts of eosinophilic, finely granular cytoplasm 1
• Round to ovoid nuclei with finely granular, evenly distributed "salt and pepper" chromatin pattern 1
• Inconspicuous or absent nucleoli, distinguishing them from large cell neuroendocrine carcinoma 1
• Low nuclear-to-cytoplasmic ratio, contrasting sharply with small cell lung cancer 1
• Minimal nuclear pleomorphism or atypia, though cell atypia alone does not reclassify the tumor 1

Architectural Patterns

The growth patterns are highly characteristic:

• Organoid nesting is the most common architectural pattern 1
• Trabecular (ribbon-like) arrangement of tumor cells 1
• Insular growth pattern with well-defined tumor cell islands 1
• Palisading pattern around blood vessels 1
• Rosette formation may be present 1
• Acinar or glandular profiles can occasionally be seen 2, 3

Mitotic Activity and Necrosis

The mitotic count is the single most critical histologic criterion for classification:

• Typical carcinoid: <2 mitoses per 2 mm² (or <2 per 10 HPF) with rare to absent mitotic figures 1
• Atypical carcinoid: 2-10 mitoses per 2 mm² with greater mitotic activity 1
• Mitoses should be counted in areas of highest activity, and when near cutoffs, at least three 2-mm² fields should be counted with the mean used for classification 1

Necrosis patterns differ significantly:

• Typical carcinoids typically lack necrosis 1
• Atypical carcinoids show punctate (focal, discrete) necrosis only 1
• Confluent or geographic necrosis indicates higher-grade neuroendocrine carcinoma, not carcinoid 1

Immunohistochemical Profile

Both typical and atypical carcinoids demonstrate strong neuroendocrine marker expression:

• Chromogranin A: positive in the majority of cases 1
• Synaptophysin: positive with strong, diffuse staining 1
• CD56/NCAM: positive in most cases 1
• TTF-1: positive in 85-90% of pulmonary carcinoids, though this does not confirm pulmonary origin as it's expressed in extrapulmonary sites 1
• Cytokeratin (AE1/AE3, CAM5.2): positive in nearly all cases 1

Proliferative Index

Ki-67 labeling index is particularly valuable in small biopsies:

• Typical and atypical carcinoids: Ki-67 index 5-15% (generally low) 1
• Small cell lung cancer: Ki-67 index 50-100% (markedly elevated) 1
• Ki-67 cannot reliably distinguish typical from atypical carcinoids but is useful for separating carcinoids from high-grade neuroendocrine carcinomas 1, 4

Distinguishing Features from Other Neuroendocrine Tumors

Critical differences from small cell lung cancer:

• Carcinoids have larger cells with more abundant cytoplasm versus SCLC's scant cytoplasm 1
• Carcinoids lack nuclear molding, a hallmark of SCLC 1
• Carcinoids show organized architecture rather than SCLC's sheet-like growth 1
• Crush artifact and Azzopardi effect (perivascular basophilic condensation) are absent in carcinoids but common in SCLC 1

Critical differences from large cell neuroendocrine carcinoma (LCNEC):

• LCNEC has >10 mitoses per 2 mm² with confluent necrosis 1
• LCNEC shows more cytologic atypia and larger cell size 1
• LCNEC demonstrates more aggressive architectural patterns with less organized structure 1

Special Histologic Variants and Associated Findings

Additional features that may be present:

• Argyrophilic granules can be demonstrated with special stains 5
• Mucin production may be present in some cases 5
• Spindle cell pattern, squamous metaplasia, or pleomorphism can rarely occur 2
• Association with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), tumorlets, or multiple tumors suggests multiple primaries rather than metastases 1

Common Diagnostic Pitfalls

Critical caveats in diagnosis:

• Small biopsy samples cannot reliably distinguish typical from atypical carcinoids because adequate assessment of mitotic rate and necrosis requires surgical specimens 1
• Crush artifact in small biopsies can make accurate mitotic counting difficult, necessitating Ki-67 immunostaining 1, 4
• Tumors with carcinoid morphology but >10 mitoses per 2 mm² represent a diagnostic challenge and may behave more aggressively despite carcinoid-like appearance 3
• Combined tumors exist where carcinoid features coexist with adenocarcinoma or squamous cell carcinoma components 1