Advances in the Biology of Lung Cancer: Clinical Significance of Neuroendocrine Differentiation

Abstract

fixed specimens can be used, but they are less satisfactory. Any pathologist who frequently handles lung specimens should have an immediately accessible supply of a suitable fixative solution for electron microscopy (2% buffered glu- taraldehyde) and should place in the fixative a thin slice of the tissue (<1 mm thick) from any lung tumor that is known to present a problem by light microscopy. The tissue can remain in the fixative solution indefinitely. The categories in the revised WHO classificationthat may be appropriate for poorly differentiated and undifferen- tiated lung carcinomas are undifferentiated large cell carci- noma, small cell undifferentiated and carcinoid tumor. Pathologists frequently resort to calling a tumor with doubtful evidence of differentiation a poorly differentiated but the term has no clinical relevance beyond connoting a non-small cell carcinoma: if neither glandular nor squamous differentiation is clearly present, the tumor should be classified as an undifferentiated large cell carci- noma. Electron microscopy will detect the presence of even the most minor degrees of differentiation, and may therefore serve to reveal that the tumor is a poorly differentiated adenocarcinoma or squamous carcinoma. There is no evi- dence that minimal differentiation influences the biologic behavior, and it is not uncommon to find a mixture of squamous and glandular characteristics at the ultrastructural level. A common difficulty encountered in attempting to classify a lung carcinoma that appears undifferentiated by light microscopy is determining whether it is of large cell or small cell type. Pathologists may take refuge in the term inter- mediate variant of small cell carcinoma, but there is no convincing clinical or ultrastructural evidence to prove that subtyping is justified.� Morphometric studies have shown that the cell and nuclear dimensions of undifferentiated large cell and small cell carcinomas overlap,#{176} but electron microscopy can separate them in most instances.78 When mixtures of small cell with non-small cell carcinoma occur, the large cell component is usually differentiated indicating the combined variant of small cell carcinoma.6 Convincing small cell-large cell carcinomas6 are difficult to document by electron microscopy. While small cell lung carcinomas and carcinoid tumors are distinct entities, each displays a range of morphology and functional properties, and the two overlap, forming a broad group of neuroendocrine neoplasms. A small number of atypical endocrine tumors with intermediate character- istics occupy the ill-defined mid-zone of this spectrum. Morphologic criteria for their identification are not clearly defined, and the nomenclature used to designate them is confusing.2 Consequently, these tumors are difficult to classify by light microscopy, and to provide a better under- standing of their nature and behavior, further studies by immunostaining and electron microscopy, with clinical cor- relation, are required.