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A 63-year-old man with history of smoking was found to have a 3.0 cm lung mass on imaging. There was no evidence of extrapulmonary disease. CT-guided FNA was inconclusive. A lobectomy specimen revealed a 3.2 x 3.0 x 3.0 cm tumor upon sectioning and the tumor cells were cytokeratin (+), chromogranin (+) and synaptophysin (+).
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, and Case 5 is small cell carcinoma
Criteria for Diagnosis and Comments:
The tumor shows a nested or organoid pattern of growth with peripheral palisading in some areas. The tumor cells are small to intermediate, round to oval, with scant cytoplasm, finely granular chromatin and inconspicuous nucleoli. Areas of necrosis are interspersed throughout the tumor leading to a pseudopapillary pattern in some regions. Occasional large cells are present, some with multinucleation, but comprise <5% of the tumor. The histologic features and the immunohistochemical profile provided are typical of small cell carcinoma (SCLC).
The diagnosis of SCLC is largely based on morphology. The arrangement of tumor cells can be diffuse or can show typical neuroendocrine features like trabeculae, nests, rosette formation and peripheral palisading. Large areas of necrosis are present in majority of the cases. In areas of necrosis, encrustation of DNA can occur around blood vessels (Azzopardi effect) in ~10% of cases. The periphery of the tumor can show extensive crush artifact. Nuclear molding is common and can be identified in most cases. In small biopsies with limited tissue or crush artifact, immunohistochemistry can play an important role in the diagnosis. Cytokeratin is expressed in the majority of tumors with dot-like cytoplasmic reactivity in some cases. Neuroendocrine markers like chromogranin and synaptophysin are expressed in 50-60% of SCLC. The staining can be patchy, especially with chromogranin. More recently, the use of neural cell adhesion molecule CD56 has been advocated due to high sensitivity (>90%). CD56 staining remains intact even in areas of crush artifact. However, caution needs to be exercised while evaluating crushed areas as CD56 expression can occur in seromucinous glands, nerve bundles as well as in some lymphomas and non-small cell carcinomas. The majority of pulmonary SCLCs (60-90%) also express TTF-1. Since SCLC at other sites can also express TTF-1, this is not helpful in the distinction of pulmonary vs. extrapulmonary SCLC.
The distinction of SCLC from non-small cell carcinomas and other neuroendocrine tumors is of paramount importance. SCLCs are usually have high response rates (80-90%) to cisplatin-based chemotherapy and are not amenable to surgery, except for tumors that are limited to the lung. The AJCC staging has been replaced by a different staging system in SCLC that divides the disease into ‘limited’ and ‘extensive’ categories. Stages I, II and III correspond to limited disease, while stage IV is extensive. Staging is the only reliable indicator of outcome in SCLC in the lung.
As defined in the most recent 2004 WHO classification, pure small cell carcinoma includes tumors composed of small lymphocyte-like cells (oat cell), intermediate sized polygonal cells, fusiform cells or mixture of these. Combined small cell carcinoma shows additional non-small elements like adenocarcinoma, squamous cell, large cell, spindle or giant cell carcinoma. When SCLC occurs with squamous or adenocarcinoma component, there is no minimum percentage of the latter component for the designation of combined SCLC. However, the percentage of large cells required for the diagnosis of combined SCLC/large cell neuroendocrine carcinoma is not clear. Since a small number of large cells are present in most SCLC, an arbitrary figure of 10% has been proposed. Since the outcome in SCLC vs. combined SCLC/large cell neuroendocrine carcinoma is likely to be similar, this distinction may not be clinically relevant.
Large cell neuroendocrine carcinoma (LCNEC) is composed of large polygonal cells with moderate to abundant cytoplasm, coarse granular or vesicular chromatin and prominent nucleoli. Infarct-like zones of necrosis and brisk mitoses (>10 per 10 high power field) are common. Histological features like nests, trabeculae, rosettes and/or palisading suggest neuroendocrine differentiation that has to be confirmed by immunohistochemistry or electron microscopy to establish the diagnosis. The clinical behavior of LCNEC is not fully understood. They are thought to be more aggressive than other large cell carcinomas. Based on a small cohort of cases, the chemosensitivity has been shown to be intermediate (~50%) between SCLC (80-90%) and non-small cell carcinomas (15-30%). Since LCNEC is a rare entity, multicenter trials with a large cohort are needed to establish definite guidelines. Despite the morphological similarity between LCNEC and SCLC, these tumors are placed in different categories as LCNEC is presently recognized as part of non-small cell lung cancers. The cell size in SCLC and LCNEC forms a continuum and may defy definite categorization in ~5% of cases even after expert review. Hence it has been suggested that and these entities be lumped together as high grade neuroendocrine carcinoma. However, till the natural history of LCNEC is clarified, it is prudent to continue this distinction.
| ||Small cell carcinoma||Large cell neuroendocrine carcinoma|
|Size of tumor cells||Small to intermediate (<3 resting lymphocytes)||Large|
|Fusiform cells||Often present||Uncommon|
|Nuclear smearing||Often present||Uncommon|
|Cytoplasm||Scant; moderate in some cells||Moderate to ample|
|Nuclear chromatin||Finely granular||Coarsely granular or vesicular|
|Chemosensitivity||Good||Intermediate between SCLC and other nonsmall cell variants|
Atypical carcinoids share many features with typical carcinoid, but are defined in the current WHO classification as having 2-10 mitoses /10HPF and/or necrosis. Hence tumors with less than 2 mitoses/10HPF, but having necrosis, are categorized as atypical carcinoid as are the tumors meeting the mitotic rate criteria. This definition has not been universally accepted. High grade neuroendocrine carcinoma (both SCLC and LCNEC) are distinguished from atypical carcinoids based on high-grade nuclear features, wide areas of necrosis and high mitotic activity (typically >10 per 10 high power fields). The proper classification of pulmonary neuroendocrine neoplasms is imperative due to its profound impact on prognosis. The 5-year survival rates in typical carcinoid, atypical carcinoid and high grade neuroendocrine carcinomas (both SCLC and LCNEC) are in the neighborhood of >95%, 70-80% and 30-40% respectively.
SCLC can have a dyscohesive pattern and mimic lymphoma, while the presence of sheet-like or nested pattern with rosettes can resemble peripheral neuroectodermal tumor. Distinction from lymphoid neoplasms (keratin negative, LCA positive) and peripheral neuroectodermal tumor (keratin negative/focal, CD99 positive) can be facilitated by immunohistochemistry. SCLCs typically do not express LCA or CD99 (MIC2); weak and focal expression of CD99 can occur in a minority of SCLC.
Poorly differentiated or basaloid variant of squamous cell carcinoma can be confused with SCLC, especially in small biopsies. Immunohistochemistry for p63 and TTF-1 can aid in this distinction. Squamous cell carcinomas express p63 in nearly all cases, and are uniformly negative for TTF-1 and neuroendocrine markers. On the other hand, majority of SCLC are positive for TTF-1 and neuroendocrine markers. Variable results have been reported with p63 in SCLC ranging from rare positive to positive staining in nearly 75% of cases.