Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because small cell lung cancer, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with non-small cell carcinoma.[1]

In 1999, the World Health Organization (WHO) classification of lung tumors was updated.[1] Major changes in the revised classification as compared with the previous one (WHO 1981) include the addition of two preinvasive lesions to squamous dysplasia and carcinoma in situ: atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Another significant change is the subclassification of adenocarcinoma: the definition of bronchioalveolar carcinoma has been restricted to noninvasive tumors. A substantial evolution of concepts in neuroendocrine lung tumor classification has occurred. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high-grade non-small cell carcinoma showing histopathological features of neuroendocrine differentiation as well as immunohistochemical neuroendocrine markers. The large-cell carcinoma class now includes several variants, including the LCNEC and the basaloid carcinoma, both with a dismal prognosis. Finally, a new class was defined called carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements that are characterized by a spectrum of epithelial to mesenchymal differentiation. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

Malignant non-small epithelial tumors of the lung are detailed in the following list.

The changes in the WHO classification are described in greater detail in the following sections.

THE NEW WHO/INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER HISTOLOGIC CLASSIFICATION OF NON-SMALL CELL LUNG CARCINOMAS (NSCLC)

1. Squamous cell carcinoma.
   • Papillary.
   • Clear cell.
   • Small cell.
   • Basaloid.



2. Adenocarcinoma.
   • Acinar.
   • Papillary.
   • Bronchioloalveolar carcinoma.
     • Nonmucinous.
     • Mucinous.
     • Mixed mucinous and nonmucinous or indeterminate cell type.
   • Solid adenocarcinoma with mucin.
   • Adenocarcinoma with mixed subtypes.
   • Variants.
     • Well-differentiated fetal adenocarcinoma.
     • Mucinous (colloid) adenocarcinoma.
     • Mucinous cystadenocarcinoma.
     • Signet ring adenocarcinoma.
     • Clear cell adenocarcinoma.



3. Large cell carcinoma.
   • Variants.
     • Large-cell neuroendocrine carcinoma.
     • Combined large-cell neuroendocrine carcinoma.
     • Basaloid carcinoma.
     • Lymphoepithelioma-like carcinoma.
     • Clear cell carcinoma.
     • Large-cell carcinoma with rhabdoid phenotype.



4. Adenosquamous carcinoma.



5. Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
   • Carcinomas with spindle and/or giant cells.
   • Spindle cell carcinoma.
   • Giant cell carcinoma.
   • Carcinosarcoma.
   • Pulmonary blastoma.



6. Carcinoid tumor.
   • Typical carcinoid.
   • Atypical carcinoid.



7. Carcinomas of salivary-gland type.
   • Mucoepidermoid carcinoma.
   • Adenoid cystic carcinoma.
   • Others.



8. Unclassified carcinoma.

Adenocarcinoma

Adenocarcinoma is now the predominant histologic subtype in many countries, and issues relating to subclassification of adenocarcinoma are very important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation. Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/International Association for the Study of Lung Cancer (IASLC) definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors. If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and either a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. Several variants of adenocarcinoma are recognized in the new classification, including well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma.

Neuroendocrine tumors

A substantial evolution of concepts of neuroendocrine lung tumor classification has occurred. LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and the high-grade SCLC and LCNEC. Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLC that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme since the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized, including LCNEC, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype. Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma and, rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle and giant cell carcinomas and carcinosarcomas comprise only 0.4% and 0.1% of all lung malignancies, respectively. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. Biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements based on clinical and molecular data.

References

1. Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. 
   
   

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