Answer: Bizarre epithelial atypia following chemotherapy

Histology: The most striking alteration is seen in the surface epithelium. The epithelial alterations are characterized by marked enlargement, hyperchromasia and pleomorphism of the nuclei. The enlarged nuclei measured up to 25 micrometers in diameter and are 5 to 8 times their normal size. The atypical nuclei also are irregular with misshapen contours.

The distribution of the atypical cells is variable. In some areas, single atypical cells are unevenly dispersed throughout the respiratory epithelium. In other areas, the atypical cells were more densely distributed and occupy the full thickness of the epithelium. The atypical changes occasionally extend into excretory ducts. On the frozen section material, the epithelial atypia occurs within areas of squamous metaplasia. The constellation of cytologic atypia, full-thickness mucosal involvement and squamous metaplasia is reminiscent a neoplastic process (i.e. keratinizing dysplasia). Unlike true dysplasia, however, the aypia is not associated with appreciable mitotic activity, and the atypical cells are not associated with hyperplasia of the basal cell layer. Immunohistochemical stains for Herpes virus and Cytomegalovirus are negative. Fungal organisms are not appreciated.

Discussion: Various cytotoxic drugs induce bizarre epithelial alterations including nuclear enlargement, hyperchromasia and pleomorphism. These alarming epithelial alterations can be widespread and have been noted in diverse organs and tissues. Although the respiratory epithelium of the lower respiratory tract is a prime target, chemotherapy-induced atypia is not always recognized when it occurs in the upper respiratory tract including the sinonasal tract.

The morphologic changes induced by chemotherapeutic agents can mimic a neoplastic process. Indeed, many studies have cautioned against misinterpreting chemotherapy-induced epithelial atypia as carcinoma. There are several factors that may render the sinonasal tract particularly susceptible to erroneous interpretation of chemotherapy-induced atypia. First, the sinonasal tract has not drawn much attention as a target of such cytotoxic effects, and few pathologists anticipate such alterations at this particular site. Second, when these changes do come across the microscope of an unwary pathologist, first time encounters tend to inopportunely occur during an intraoperative frozen section. At our institution, intraoperative frozen section is often requested to evaluate infiltrative processes involving the paranasal sinuses of oncology patients. In this setting, frozen section artifact tends to accentuate structural distortion and cytologic atypia while obscuring subtle differences between chemotherapy-related atypia and true dysplasia. This diagnostic pitfall can be avoided by recognizing the sinonasal tract as a relatively common site of chemotherapy-related atypia, and by duly noting the clinical context of the biopsy. The diagnosis of squamous dysplasia should be made with extreme caution in any sinonasal biopsy from a patient exposed to chemotherapeutic agents, especially patients with hematologic malignancies who have been recently treated with cyclophosphamide.