Divergent differentiation in neoplasms. Pathologic, biologic, and clinical considerations

In this rather brief review, we have illustrated and discussed selected examples of dual or multiple differentiation within certain neoplasms. In so doing, we have attempted to present those cases which highlight common diagnostic problems and which have important biologic and clinical implications. We have shown how tumors arising in many organs such as the lung, gastrointestinal tract, and thyroid can simultaneously manifest combined endocrine-nonendocrine differentiation, and we have addressed this phenomenon in relation to the "parent cell of origin" theory. We have emphasized that while many tumors do in fact resemble the tissues in which they arise, the possession of a particular phenotype, such as endocrine, does not necessarily imply that the tumor in question was derived from an endocrine progenitor cell. To reinforce the concept that the histomorphologic, biochemical, and functional properties of tumor cells reflect ongoing differentiation events rather than a static situation, we have presented examples of tumors in which changes in phenotype have been observed during the course of disease, e.g., small cell carcinomas of the lung and prostate, as well as tumors in which divergent differentiation reflects similar lines of differentiation occurring in normal tissues, e.g., certain neurogenic tumors. Finally we have considered important clinical implications of mixed differentiation and changing phenotype and their impact on the pathologist.