FLASHPATHH a z e m A l i

SMALL CELL CARCINOMA

H a z e m A l i

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

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

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

CLINICAL

Paraneoplastic syndrome due to abnormal production of:• Hormones:

– ACTH (Cushing's syndrome)– ADH (hyponatremia)

• Auto-antibodies:– Encephalomyelitis– Lambert-Eaton syndrome– Subacute sensory neuropathy

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

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

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

MICROSCOPICCrushed 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 getdeposited in the walls of vessels and connective tissue

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

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 showsdot-like and diffuse staining in the cytoplasm of a pulmonary small cell carcinoma.

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• 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

SPECIAL STUDIESIn 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

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

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

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%

CYTOLOGY• Cellular smears• Dimorphic population

– large cohesive sheets in a background of small blue cellswith discohesion.– The background contains single cells, doublets, andshort cords.

• Small cells with scant cytoplasm (N/C ratio is very high)– The nuclei do not exceed 3 times the size of a restinglymphocyte.

• 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

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

DIFFERENTIAL DIAGNOSISCarcinoid 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

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

DIFFERENTIAL DIAGNOSIS

Typical Carcinoid

Atypical Carcinoid

Large Cell Neuroendocrin

eCarcinoma

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.

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%

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%)

DIFFERENTIAL DIAGNOSIS

Small Round Blue Cells in

adult

Lymphoma Small cell carcinoma

Merkel cell carcinoma

Desmoplastic small round

celltumor

Mesenchymal chondrosarco

ma

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

WWW.

DO NOT FORGET TO SEARCH FOR MORE PICS AND VIRTUAL SLIDES

THANK YOU

H a z e m A l i