Large cell carcinoma of lung: On the verge of extinction?
Introduction
Non-small cell lung carcinoma has historically been divided into 3 broad categories: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Large cell carcinoma is the least common among these tumors and accounts for 3–9% of all primary pulmonary lung cancers.1, 2 The 2004 World Health Organization (WHO) classification of lung tumors defines large cell carcinoma as an “undifferentiated non-small cell carcinoma that lacks the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation.”1 For practical purposes this includes any tumor in which the line of differentiation cannot be established by light microscopy. At the same time, this definition implies that the term is reserved for resection specimens that contrary to surgical biopsies or cytology preparations are not limited by incomplete sampling or poor cell preservation. In addition to the classic form of large cell carcinoma, the WHO currently recognizes 5 further variants: large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype.
In the last few years, there has been increasing controversy about whether large cell carcinoma of the lung represents a unique clinicopathological entity or as a group combines the most poorly differentiated form of various non-small cell lung carcinomas. The latter theory has received increasing support in the last decade with the advent of specific and sensitive immunohistochemical antibodies that can be used to distinguish between different types of lung cancer and molecular techniques that allow to search for gene expression patterns that are specific for either squamous cell or adenocarcinoma.3, 4, 5 Using these approaches, it has been shown that the majority of large cell carcinomas can be subtyped more accurately.6, 7, 8, 9, 10 This is of particular interest since recent advances in cancer treatment have moved away from standardized cytotoxic chemotherapy and are increasingly directed towards personalized or targeted medical therapies. These novel therapies directed against specific molecular alterations require more precise histologic diagnosis, especially distinction between adenocarcinoma and squamous cell carcinoma, in order to identify the correct approach to molecular testing and to select the appropriate targeted agent. The use of specific therapies for large cell carcinoma has not been investigated sufficiently, which is largely to blame on the relative rarity of this diagnosis, although the latest recommendations suggest to include large cell carcinoma with the adenocarcinoma group for the purpose of treatment and molecular testing.11
Section snippets
Historical aspects of large cell carcinoma classification
The history of pulmonary large cell carcinoma dates back to the middle of the 20th century when Liebow12 used the term “anaplastic carcinoma” to encompass small and large cell carcinomas of the lung. These tumors were separated in the subsequent WHO nomenclature of lung tumors of 1958 into small cell carcinoma and large cell undifferentiated carcinoma; the latter designating a carcinoma without any differentiation precluding inclusion into any of the other categories of lung tumors13 (Table 1).
Histology
Classic large cell carcinoma of the lung by definition is a poorly differentiated carcinoma without the presence of any defining features such as keratinization or intercellular bridges seen in squamous cell carcinomas, any gland or mucin formation that would classify the tumor as an adenocarcinoma or small cells with scant cytoplasm and salt-and-pepper-type chromatin characteristic of small cell carcinoma. Classic large cell carcinoma is a tumor arranged in cellular aggregates or sheets of
Discussion
In the current WHO lung cancer classification schema,1 large cell carcinoma represents a heterogenous group of tumors the definition of which is somewhat vague and which not only includes the classic “undifferentiated” large cell carcinoma but also tumors that clinically, morphologically, or immunohistochemically have a more distinct appearance. The inclusion of the latter group of tumors into the category of pulmonary large cell carcinoma has long been the subject of debate and with the
Comment
Collectively, there is overwhelming evidence that large cell carcinoma of the lung—as defined today—represents a heterogenous group of tumors. As more and more sophisticated adjunct techniques become available, the proportion of cases that cannot be further subclassified and therefore represents the true (“null phenotype”) large cell carcinoma becomes smaller and smaller. From the data presented in the literature, it also appears that the other variants of large cell carcinoma either represent
Recommendation
The diagnosis of pulmonary large cell carcinoma remains a diagnosis of exclusion and one that can only be rendered on resection material. The diagnostic approach therefore depends on the type of surgical material one is dealing with.
For biopsies the term “non-small cell carcinoma” is proposed for tumors showing no clear glandular or squamous differentiation by light microscopy. If a panel of immunohistochemical markers is able to subclassify the tumor, this should be stated and the tumor
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