Large Cell Carcinoma & Giant Cell Carcinoma

Large cell carcinoma is a type of bronchogenic carcinoma which is extremely undifferentiated and the origin of the cells cannot be established. These tumors may be extremely undifferentiated forms of either squamous or adenocarcinoma. This image demonstrates a diffuse infiltration of large polygonal cells with a pale eosinophilic cytoplasm with pleomorphic, vesicular nuclei with prominent nucleoli. Multinucleated or giant cell forms may occur, occasionally the cytoplasm is pale staining, giving rise to their distinction as "clear cell" type.

This cytologic preparation demonstrates the poorly differentiated large cells with pleomorphic nuclei, variation in cell size, and abundant cytoplasm typical of these tumors. Note also the numerous red cells. These may be due to a traumatic procedure, or due to the highly infiltrative nature of these tumors.

UNDIFFERENTIATED LARGE CELL CARCINOMA

As its name implies, undifferentiated large cell carcinoma shows no evidence of squamous or glandular maturation. Thus these tumors are often diagnosed by default, when all other possibilities have been excluded.

Large cell carcinoma represents 10-20% of bronchogenic tumors. These tumors lack any diagnostic features to suggest their diagnosis prior to biopsy. They tend to grow rapidly, metastasize early, and are strongly associated with smoking.

Because of the small samples obtained in biopsies, larger resection specimens often yield more information and change the diagnosis to adenocarcinoma or squamous cell carcinoma. Glandular differentiation is found more common than squamous in tumors that have previously been diagnosed as large cell undifferentiated on small biopsies. This correlates with the gross observation that these tumors tend to be present peripherally, like adenocarcinomas.

Gross Appearance

Large cell tumors are usually large, bulky, well-circumscribed, pink-gray masses with extensive hemorrhage and necrosis. Although they commonly have central necrosis, they rarely cavitate. They tend to present in the mid to peripheral lung zones. They may extend locally to involve the segmental or subsegmental bronchi.

Microscopic Features

Undifferentiated large cell carcinoma are defined by the WHO as "a malignant epithelial tumor with large nuclei, prominent nucleoli, abundant cytoplasm and usually well defined cell borders, without the characteristic features of squamous cell, small cell or adenocarcinomas." The diagnosis is made when elements of squamous or glandular differentiation cannot be proven.

The cells are generally round to polygonal and present in groups without any higher architectural features. As a rule, the nuclei are large and round with prominent nucleoli. Due to the necrosis that frequently accompanies these tumors, there are zones of dropout within the middle of the specimens, which may suggest a glandular lumen. Sometimes there may be a variable population of the cells that have a clear cytoplasm, however, they stain negatively for mucin with either a mucicarmine or periodic acid-Schiff with diastase stain. For this reason, obtaining a mucin stain is imperative to make the diagnosis. It has been reported that in approximately half of the cases where undifferentiated large cell carcinoma is suspected, a mucin stain will be positive, thus designating the tumor as an adenocarcinoma. For a mucin stain to be considered truly positive, intracytoplasmic mucin must be identified. Extracellular mucin positivity is not significant.

Immunohistochemical stains have shown undifferentiated large cell carcinomas to be a diverse group of tumors including poorly differentiated adenocarcinomas and squamous cell carcinomas. Based on cytokeratin expression, there are type major populations within this category. One group expresses simple epithelial cytokeratins, and is considered to be a poorly differentiated adenocarcinoma. While the other population, suggested to be a poorly differentiated squamous cell carcinoma, expresses cytokeratins more commonly associated with squamous epithelia.

GIANT CELL CARCINOMA

Giant cell carcinoma is categorized by the WHO as a variant of large cell carcinoma.

This subtype is particularly aggressive and carries a very poor prognosis.

Gross Appearance

These tumors generally present as a large peripheral mass with a focal necrotic component.

They do not involve the large airways, unless by direct extension.

Microscopic Features

Giant cell carcinoma is recognized as a large cell carcinoma with a component of highly pleomorphic multinucleated cells. The nuclei are varied in size and shape. Generally, they are large and irregularly shaped with clumped chromatin and one or more nucleoli. However, the range of nuclear features extends to include multiple small nuclei within a cell. It is considered that at least 30-50% of these cells be present before making the diagnosis. These cells generally contain a large amount of finely vacuolated eosinophilic cytoplasm.

Cell cohesion is frequently lost.

There is often a necrotic component to these tumors, resulting in a neutrophilic or monocytic inflammatory cell infiltrate.

Immunohistochemical stains can be useful in differentiating this tumor from a wide variety of other tumors that may be suggested by its histologic appearance.

Negative staining for mucin differentiates it from an adenocarcinoma.

Positive staining for cytokeratins is useful in eliminating sarcomas as a possibility.

The loss of cell cohesion may suggest a lymphoma. However, unlike lymphomas, giant cell tumors are negative for leukocyte common antigen (CD45).

These tumors are sometimes positive for human chorionic gonadotrophin (hCG) and may superficially resemble choriocarcinomas.