- Small cell carcinoma is an aggressive neuroendocrine lung tumor that comprises 10-20% of lung cancers. It is strongly associated with smoking. - Microscopically, it is composed of small, round blue cells with scant cytoplasm, molding nuclei, fine chromatin, and high mitotic activity. Necrosis is prominent. - Immunohistochemically, it stains positive for neuroendocrine and pulmonary markers like chromogranin, synaptophysin, CD56, TTF-1 and is typically high grade with a Ki-67 of over 20%. - It must be differentiated from other small blue cell tumors, carcinoid tumors and large cell neuroendocrine

1. FLASHPATH
H a z e m A l i

2. SMALL CELL
CARCINOMA
H a z e m A l i

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

4. CLINICAL
• 10-20% all of lung carcinoma
• Usually adult (male)
• Usually associate smoking
• 95% of patients present with a central mass comprised of hilar and/or mediastinal
adenopathy
– Cough, hemoptysis, chest pain, lobar collapse
– Shortness of breath from pleural effusions
– Hoarseness from recurrent laryngeal nerve invasion
– Superior vena cava syndrome

5. CLINICAL
Lung cancer and smoking:
• Some data suggest that filtered cigarettes, which remove larger tar particles, have
allowed carcinogens to penetrate to more distal parts of the lung and produce
peripheral adenocarcinomas
• While central squamous carcinomas or small cell carcinomas caused mainly by
larger particles

6. CLINICAL
Paraneoplastic syndrome due to abnormal production of:
• Hormones:
– ACTH (Cushing's syndrome)
– ADH (hyponatremia)
• Auto-antibodies:
– Encephalomyelitis
– Lambert-Eaton syndrome
– Subacute sensory neuropathy

7. CLINICAL
• Main line of treatment: chemotherapy, radiation
– SCLC is rarely resected
• Small cell carcinoma is very aggressive tumor with early distant metastasis
– Overall 5-year survival is 5% - 10%.
– Few patients with SCLC survive longer than 12–19 months
– Brain metastasis occurs in >50%
• Therefore prophylactic cranial radiation recommended

8. GROSS
• Since small cell carcinomas are rarely resected, the gross features of the tumor are seldom
seen in the surgical pathology laboratory.
• Mostly present as central/perihilar mass:
– White-tan
– Soft, friable
– Extensive necrosis
– Frequent hilar nodes involvement
• Sometimes massive hilar adenopathy without obvious
lung primary
• In about 5% of cases present as peripheral coin-shaped lesions

9. MICROSCOPIC
• Patterns:
– Mainly: Sheets
– May be (focally): Trabecular, Palisading, Rosettes
– Absent Organoid pattern (Nests)
• Tumor cells:
– Small, round/oval cells with minimal cytoplasm
(High N/C ratio)
– Nuclear molding
• nuclei press together and indent each other due to the
near absence of cytoplasm
– Dark hyperchromatic nuclei
• Fine granular (salt and pepper) chromatin
– Absent nucleoli
• High mitotic rate “>10 mitoses/10 hpf”
• Necrosis is prominent

10. MICROSCOPIC
Crushed Blue Cells “Crush artifact” is common SCLC, especially
in biopsies rather than large specimens.
– “chromatin smearing or streaming”
Azzopardi phenomena:
• basophilic nuclear DNA from necrotic tumor cells get
deposited in the walls of vessels and connective tissue

11. MICROSCOPIC
Combined small cell carcinoma variant:
• Classic SCLC features + additional component consisting of any histologic subtype of
NSCLC
– Non–small cell component is usually squamous cell, adenocarcinoma, or large cell
carcinoma
• less commonly, spindle cell or giant cell carcinoma
– Non–small cell component needs to be specified in the diagnosis

12. SPECIAL STUDIES
• Neuroendocrine markers
– Chromogranin, Synaptophysin, Neuron Specific Enolase, and CD56
– Weak, Focal staining (EXCEPT CD56)
• Pan-keratin
– Cam 5.2 is better than AE1/AE3 (to be safe, use both)
– “Dot-like” peri-nuclear staining pattern
• TTF-1
– > 90% of cases
– Nuclear
• Ki67 (Mib1)
– More than 20%
• Calretinin
– 50% of cases
(A–C) TTF-1 stains the nuclei and pankeratin shows
dot-like and diffuse staining in the cytoplasm of a
pulmonary small cell carcinoma.

13. 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)

14. 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

15. SPECIAL STUDIES
• AE1/AE3
– Broad-spectrum CK antibody that detect both LMWCK and HMWCK
– Detect epithelial cells, mesothelial cells
– AE1 detects CKs 10, 15, 16, and 19
– AE3 detects CKs 1 to 8
– (Cytoplasm)
• CAM 5.2 (34βH11):
– CK antibody against only LMWCK
– Detect simple and glandular epithelium (Non-Squamous)
– CKs 8, 18
– (Cytoplasm)
• Remember the Dot-like, perinuclear pattern is seen in both small cell carcinoma & Merkel cell carcinoma
• Note that small cell carcinoma is CK 7 –ve / CK 20 -ve

16. SPECIAL STUDIES
In the recent past, all neuroendocrine cells were erroneously thought to be neural
(neural crest) derived.
However, it appears that neuroendocrine neoplasms actually fall into two groups:
• Truly neural:
– Include: pheochromocytoma, paraganglioma, PNET, neuroblastoma
– CKs Negative
• Endoderm-derived/epithelial:
– Include: carcinoid, pancreatic endocrine neoplasm, small cell carcinoma
– CKs Positive

17. SPECIAL STUDIES
• TTF-1 (Thyroid transcription factor 1):
– Transcription factor that is seen in thyroid gland and lung:
• Thyroid gland: thyroglobulin and thyroid peroxidase
• Lung: Clara cell secretory protein and surfactant proteins
– (Nuclear)
• TTF-1 is used to differentiate between Pulmonary (+ve) from Nonmonary (-ve) small
cell carcinomas

18. SPECIAL STUDIES
Electron microscopy: few dense-core secretory granules can be seen in SCLC
• 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

19. SPECIAL STUDIES
Molecular:
• 3p deletions: consistent finding
• p53 mutations: 75 – 90%
• Rb mutations: close to 100%
• High level of the anti-apoptotic protein BCL2: 90%

20. CYTOLOGY
• Cellular smears
• Dimorphic population
– large cohesive sheets in a background of small blue cells
with discohesion.
– The background contains single cells, doublets, and
short cords.
• Small cells with scant cytoplasm (N/C ratio is very high)
– The nuclei do not exceed 3 times the size of a resting
lymphocyte.
• Nuclear molding is a characteristic feature of small cell carcinoma
• “Salt and pepper” chromatin with No nucleoli.
• Mitotic activity can be very high and necrotic debris is always present

21. DIFFERENTIAL DIAGNOSIS
• Other neuroendocrine tumors:
– Carcinoid tumors
– Large cell Neuroendocrine carcinoma
• Other tumors:
– Adenocarcinoma
– Squamous cell carcinoma
– Mesothelioma
– Lymphomas
– Melanoma
– Other small round blue cells tumors

22. DIFFERENTIAL DIAGNOSIS
Carcinoid Tumor
• Organoid pattern is well-formed
• Smaller N/C ratio than Small cell carcinoma
• Bland nuclei
– Except atypical cases that may show mild pleomorphism
• No nuclear molding
• 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

23. DIFFERENTIAL DIAGNOSIS
Large cell neuroendocrine carcinoma (LCNEC):
• Organoid pattern may be present but less extensive
• Larger cell size with large cytoplasm (lower N/C ratio)
• Vesicular, coarse, or fine chromatin
• Visible nucleoli
• Crush artifact and nuclear molding are NOT usually seen

24. DIFFERENTIAL DIAGNOSIS
Typical Carcinoid Atypical Carcinoid
Large Cell
Neuroendocrine
Carcinoma
Small Cell
Carcinoma
TTF-1 +/– (~30%+, weak) 50%+ 90%+
Cytokeratins +/– (~80%+) + + (dot-like)
CHR, SYN, CD56 + strong diffuse + diffuse to focal + usually weak
focal
Ki67 <2% (mean 1%) <20%
(mean 10%)
>>20%
(mean 50%)
>>20%
(mean 70%)
Ki67 rate is very helpful in evaluating small specimens, particularly if crushed.
Carcinoids can have a crush artifact, and can be over interpreted as small cell carcinoma in the
absence of Ki67.

25. DIFFERENTIAL DIAGNOSIS
Squamous cell carcinoma Small cell carcinoma Adenocarcinoma
TTF-1 0 – 15% 85 – 100% 40 – 85%
Napsin A 0 – 2% 0% 70 – 87%
p63 80 – 100% 0 – 30% 0 – 30%
CK5/6, CK903 80 – 100% 5 – 25% 0 – 20%
P40 100% 0% 3%
Neuroendocrine 0 – 10% 80 – 100% 0 – 10%

26. DIFFERENTIAL DIAGNOSIS
• Melanoma
– Positive for S-100, HMB 45, melan-A, SOX 10
– Negative for pankeratin, chromogranin, synaptophysin, and CD56
• Lymphoma
– Positive for CD45 and CD3 or CD20; some types are positive for CD56
– Negative for pankeratin, chromogranin, synaptophysin
• Mesothelioma
– Positive for pankeratin, CK7, calretinin, h-caldesmon, D2-40, CK5/6, and WT1
– Some cases are positive for chromogranin (10%), synaptophysin (8%), and CD56 (13%)

27. DIFFERENTIAL DIAGNOSIS
Small Round Blue
Cells in adult
Lymphoma
Small cell
carcinoma
Merkel cell
carcinoma
Desmoplastic small
round cell
tumor
Mesenchymal
chondrosarcoma
IHC Panel:
• CK & EMA
• CD45
• CD99
• NE Markers
• TTF-1
• WT1
• Vimentin
• Desmin
• S100, Melan A, HMB 45
Small cell variants
of Carcinomas,
Sarcomas,
Melanomas

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