The differential diagnosis of small cell carcinoma of lung includes large cell neuroendocrine carcinoma, typical and atypical carcinoids, Ewing sarcoma/PNET, primary non-small cell lung cancer, and metastases. Small Cell Carcinoma vs Large Cell Neuroendocrine Carcinoma: The distinction is made on H&E-stained slides. Large cell neuroendocrine carcinoma has large cell size, low nuclear-to-cytoplasmic ratio, vesicular, coarse, or fine nuclear chromatin, and usually prominent nucleoli. Small cell carcinoma has small cell size (less than 3 times the diameter of small resting lymphocytes), scant cytoplasm, finely granular chromatin, and inconspicuous/absent nucleoli. Small Cell Carcinoma vs Carcinoids: Typical carcinoids have lower mitotic activity (<2 mitoses per 2 sq.mm) and no necrosis as compared to small cell carcinoma. Atypical carcinoids have 2-10 mitoses/sq.mm and areas of punctate necrosis. Small cell carcinoma has >10 mitoses/sq.mm and a median of 80 mitoses/sq.mm along with large geographic areas of necrosis. Typical carcinoids generally donít express TTF-1 unlike small cell carcinoma and large cell neuroendocrine carcinoma. Small Cell Carcinoma vs Ewing Sarcoma/PNET: Mitotic activity and Ki-67 labeling index in Ewing Sarcoma/PNET group is lower than that seen in small cell carcinoma. Ewing Sarcoma/PNET show diffuse membrane positivity for CD99 and are negative for low molecular weight keratins. Most cases (~ 95%) of Ewing Sarcoma/PNET show a reciprocal translocation t(11;22)(q24;q12) or t(21;22)(q22;q12) resulting in the fusion of EWS gene with FLI1 or ERG gene, respectively. This finding is not present in small cell carcinoma. Small Cell Carcinoma vs Basaloid Squamous Cell Carcinoma: Basaloid squamous cell carcinoma is strongly positive for p40, p63, and high molecular weight cytokeratins. They are negative for TTF-1 and multiple neuroendocrine markers. The immunohistochemical profile in small cell carcinoma is reversed (positivity for TTF-1, neuroendocrine markers; negativity for p40 p63, and high mol. wt. cytokeratins). The image shows small cell carcinoma of lung with tumor cells around blood vessels forming perivascular pseudorosettes. Necrosis of the intervening areas has created a papillary appearance.