FLASHPATHH a z e m A l i

LARGE CELL NEUROENDOC

RINE CARCINOMA

H a z e m A l i

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

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.

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.

GROSS

• Can extensively replace lung

• Can be central or peripheral

• Can be multinodular

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

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%

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)

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

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

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

DIFFERENTIAL DIAGNOSIS

• Other neuroendocrine tumors:– Carcinoid tumor– Small cell carcinoma

• Other tumors:– Adenocarcinoma– Large cell undifferentiated carcinoma– Mesothelioma– Lymphoma– Melanoma

DIFFERENTIAL DIAGNOSISCarcinoid 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

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

DIFFERENTIAL DIAGNOSIS

Other Tumors:• No evidence of neuroendocrine differentiation by light microscopy or IHC

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