My study notes for all pathologists

1. FLASHPATH
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2. LARGE CELL
NEUROENDOCRINE
CARCINOMA
H a z e m A l i

3. CLINICAL
Carcinoid tumors are part of the spectrum of neuroendocrine lung tumors that includes:
• Large cell neuroendocrine carcinoma
• Small cell carcinoma
• Typical carcinoid
• Atypical carcinoid

4. CLINICAL
• High grade neuroendocrine carcinoma
• < 3% of primary lung tumors
• More common in adults
• Strong association with smoking
• Ectopic hormone secretion is NOT a feature.

5. CLINICAL
• More likely to develop recurrent lung cancer (poor prognosis)
– The overall survival at five and 10 years is poor, approximately 20% and 10%, respectively.
– Usually have shorter survival than patients with other histologic types of NSCLC, even in
those with stage I disease
• Surgery has no/limited role and the usual treatment is chemotherapy (similar to small
cell carcinoma)
– Remember that carcinoid tumors usually treated surgically.

6. GROSS
• Can extensively replace lung
• Can be central or peripheral
• Can be multinodular

7. MICROSCOPIC
• Patterns: at least focal
– Organoid
– Trabecular
– Palisading
– Rosettes formation
• Tumors cells:
– Large, polygonal cells with abundant cytoplasm (low N/C ratio)
– Nuclear pleomorphism
– Vesicular, coarse, or fine chromatin
– Visible, prominent nucleoli
• High mitotic rate (>10 mitoses/10 hpf)
• Necrosis is prominent
“Resembles non-small cell carcinoma cytologically, but on closer inspection has a hint of
neuroendocrine architecture confirmed by special stains” - Rosai

8. SPECIAL STUDIES
• Neuroendocrine markers
– Chromogranin, Synaptophysin, Neuron Specific Enolase, and CD56
– May show reduced staining
• Pan-keratin
– Cam 5.2 is better than AE1/AE3 (to be safe, use both)
• TTF-1
• Ki67 (Mib1)
– More than 20%

9. SPECIAL STUDIES
• Chromogranin:
– Acidic glycoprotein in neurosecretory granules
– (Cytoplasm, granular)
• Synaptophysin:
– Transmembrane glycoprotein found in presynaptic vesicles
– (Cytoplasm, granular)
• CD56:
– NCAM “Neural Cell Adhesion Molecule”
– (Membranous)

10. SPECIAL STUDIES
• Overall, SYN and CD56 are more sensitive than CHR but CHR is more specific.
• CD57 can be used as “2nd line” neuroendocrine marker
• NSE is no longer used in neuroendocrine tumors diagnosis (very low specificity)
• Some NE tumors will label for either CHR or SYN but not both
– so to be safe, use both
• SYN and CHR are usually strongly expressed in low-grade NE neoplasms (e.g.
carcinoid), whereas expression may be weak/focal in high-grade NE neoplasms (e.g.
small cell carcinoma)
– Fortunately, CD56 is positive in high-grade NE tumors

11. SPECIAL STUDIES
Electron microscopy: Dense-core secretory granules
– Membrane-limited dense-core granules
– Vary in size (50–400 nm), shape, and density
• depending on the protein contained in the granule
– Usually have a halo between the core and the membrane

12. CYTOLOGY
• Cellular smear
• Large polygonal to oval cells
• Cells tend to focally organize as rosettes or cords with palisaded nuclei
• Nuclei are variable in size and shape, but usually large.
– Should be more than three times the size of a resting lymphocyte
• Chromatin may be:
– Vesicular with prominent nucleoli (mimicking adenocarcinoma)
– Coarse and stippled with occasional nucleoli (mimicking small cell carcinoma)
• Obvious mitotic activity and necrotic debris

13. DIFFERENTIAL DIAGNOSIS
• Other neuroendocrine tumors:
– Carcinoid tumor
– Small cell carcinoma
• Other tumors:
– Adenocarcinoma
– Large cell undifferentiated carcinoma
– Mesothelioma
– Lymphoma
– Melanoma

14. DIFFERENTIAL DIAGNOSIS
Carcinoid Tumor
• Organoid pattern is well-formed
• Higher N/C ratio than LCNEC
• Bland nuclei
– Except atypical cases that may show mild pleomorphism
• Inconspicuous nucleoli
• Low mitosis
– Typical: < 2 mitoses/10 hpf
– Atypical: 2 – 10 mitoses/10 hpf
• Low Ki67 (Mib1)
– Typical: < 2%
– Atypical: 2 – 20%
• No necrosis
– May be seen (but less extensive) in atypical cases

15. DIFFERENTIAL DIAGNOSIS
Small cell lung carcinoma (SCLC):
• Absent organoid pattern
• Small cells with scant cytoplasm (High N/C ratio)
• Nuclear molding
• Nuclear pleomorphism
• Fine granular chromatin
• Absent nucleoli

16. DIFFERENTIAL DIAGNOSIS
Other Tumors:
• No evidence of neuroendocrine differentiation by light microscopy or IHC

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