Clinicopathologic analyses including immunohistochemical, morphometric, virologic, and DNA ploidy studies were performed on seven cases of small cell (undifferentiated) carcinoma (SCC) and 13 cases of small cell squamous carcinoma (SCSC) of the uterine cervix in an attempt to evaluate which criteria are the most useful in identifying aggressive cervical carcinomas composed of small cells. Highly malignant behavior was found to correlate most closely with the histologic pattern of the tumor. Diffuse infiltration by round to spindle-shaped cells with hyperchromatic nuclei similar to small cell carcinoma in other organs correlated with a high frequency of lymph node metastasis and tumor recurrence. In contrast, tumors with well-defined nests similar to large cell nonkeratinizing squamous cell carcinoma were associated with low rates of lymph node metastasis and recurrence. Although there were trends in the distribution of neuroendocrine and cytokeratin immunohistochemical markers, frequency of detection of HPV 16 and 18 DNA sequences, and ploidy patterns, these features showed considerable overlap and none assisted in consistently separating these two types of neoplasms. Consideration of several features, however, could assist in the differential diagnosis. Women with SCC tended to be younger (mean age 36 yr) compared to women with SCSC (mean age 50 yr). A squamous intraepithelial lesion, i.e., cervical intraepithelial neoplasia, was present in association with 60% of SCSC but was not found in any case of SCC. Tumors positive for keratin and negative for neuroendocrine markers were invariably SCSC, whereas those negative for keratin and positive for neuroendocrine markers were always SCC.(ABSTRACT TRUNCATED AT 250 WORDS)