Prostatic adenocarcinoma resembling benign hyperplastic glands architecturally is a recently recognized entity. In the only prior study on this entity, 100 needle biopsies were studied and only two contained carcinoma with pseudohyperplastic features, which occupied a small percentage of the cancer. The current study investigates histologic attributes of pseudohyperplastic prostatic adenocarcinoma on needle biopsy and simple prostatectomy in which the pseudohyperplastic regions represent the majority of the cancer. The authors reviewed outside cases received in consultation by one of the authors (J.I.E.) and the surgical pathology files of Johns Hopkins Hospital from January 1991 to August 1998 and identified 20 cases of needle biopsy and simple prostatectomy in which > or =60% of the cancer had benign architectural features. The majority (19 of 20) were consult cases. Of the 20 cases studied, 16 were needle biopsies, two were transurethral resections of the prostate, and two were enucleations. Cancer involved one core in 75% of the needle biopsies. In 13 of the 20 cases (65%), > or =90% of the cancer had pseudohyperplastic features. Benign features included papillary infoldings in all cases, large atypical glands in 95% of cases, branching in 45% of cases, and corpora amylacea in 20% of cases. The extent of pseudohyperplastic cancer ranged from 1.0 to 10.0 mm (average, 3.7 mm). Within the pseudohyperplastic foci, features helpful in establishing a malignant diagnosis were nuclear enlargement in 95% of cases, pink amorphous secretions in 70% of cases, occasional to frequent nucleoli in 45% of cases, and crystalloids in 45% of cases. Other features associated with malignancy (mitoses, blue-tinged mucin, adjacent high-grade prostatic intraepithelial neoplasia, and perineural invasion) were seen infrequently. Immunohistochemical stains for high-molecular weight keratin showed an absence of basal cells in the pseudohyperplastic areas in all 20 cases, confirming the diagnosis of cancer. It is critical to recognize pseudohyperplastic prostatic adenocarcinoma and the features needed to establish a malignant diagnosis so these carcinomas are not misdiagnosed as benign.