Flash path - Lung - Small Cell Carcinoma
Transcript of Flash path - Lung - Small Cell Carcinoma
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