Minimal Adenocarcinoma in Prostate Needle Biopsy Tissue

Phataraporn Thorson, MD; Peter A. Humphrey, MD, PhD


Am J Clin Pathol. 2000;114(6) 

In This Article

Differential Diagnosis of Minimal Prostatic Carcinoma

Numerous entities should be considered in the differential diagnosis of minimal prostatic adenocarcinoma. Recent reviews have highlighted these benign lesions, or pseudoneoplasms Table 5 , that may mimic prostatic adenocarcinoma.[27,28,29,30] In-depth discussion of these benign entities is beyond the scope of this review. It is important to note that atypical adenomatous hyperplasia (adenosis) and atrophy are the benign conditions that are most likely to be misdiagnosed as prostatic carcinoma.[6,29,30,31] Atypical adenomatous hyperplasia (or adenosis) is an atypical small acinar proliferation that can masquerade as minimal well-differentiated adenocarcinoma in needle biopsy tissue.[32] While both proliferations are characterized by a circumscribed, high-density collections of small acini, atypical adenomatous hyperplasia is often in continuity with larger, more complex glands;
atypical adenomatous hyperplasia exhibits a fragmented basal cell layer, and the luminal cells typically have bland nuclei.[32,33] Atrophy, on the other hand, is more likely to be confused with a moderately differentiated adenocarcinoma. Atrophy is separated from minimal prostatic carcinoma by the presence of basal cells, cytoplasmic volume loss, and, typically, a lesser degree of nuclear atypia.[34,35,36] However, nuclear enlargement and prominent nucleoli can be observed in atrophy, especially when there is accompanying inflammation.[36] A lobular architecture sometimes can be seen in atrophy, but background fibrosis can simulate a fibrogenic response in sclerotic atrophy, with a resultant infiltrative-like picture. Foci of postatrophic hyperplasia,[37] with its crowded acini, and partial atrophy[38] also can be mistaken for minimal prostatic adenocarcinoma. One should also be aware that adenocarcinoma of the prostate can have atrophic features, with significant cytoplasmic volume loss.[39,40,41] We have seen rare examples of minimal prostatic adenocarcinoma with atrophic features in needle biopsy specimens Image 11. In these cases, continuity with usual adenocarcinoma, in which the cells had a moderate amount of cytoplasm, and substantiation of basal cell absence by a 34betaE12 immunostain were instrumental in diagnosing malignant neoplasm.

Image 11.

Adenocarcinoma with atrophic features. Atrophic prostatic carcinoma (left) is admixed with more typical small acinar adenocarcinoma (right) (H&E, x 400).

Two additional proliferations that figure prominently in the differential diagnosis of minimal prostatic adenocarcinoma are high-grade PIN and a descriptive diagnosis of atypia. It can be exceedingly difficult to differentiate small foci of cribriform high-grade PIN from cribriform invasive carcinoma in needle biopsy tissue. Cribriform high-grade PIN is, however, in pure form, quite rare in prostate needle biopsy tissue,[42] and the uncommon cases (7/300) of minimal carcinoma with cribriform architecture also had a small acinar component.[8] If any basal cells are identified in a pure cribriform proliferation of neoplastic cells on H&E-stained sections or by 34betaE12 immunostain (see "Ancillary Studies"), caution is advised, and a diagnosis of high-grade PIN should be given. Focal, flat, high-grade PIN also can be problematic as it can closely resemble small acinar, minimal carcinoma, but it also is uncommon in pure form in needle biopsy tissue,[42,43] and, again, basal cell presence will exclude invasive carcinoma. Finally, a striking conundrum can be the diagnostic distinction of high-grade PIN with out-pouching vs high-grade PIN with adjacent invasive glands.[44] One should exercise caution if confronted with a few atypical small acini immediately adjacent to high-grade PIN since these could represent protrusions from the high-grade PIN. Basal cells should be sought specifically in these glands. If there are more than a few atypical small acini, and these exhibit a degree of stromal separation from the high-grade PIN, and if these small glands lack basal cells, a diagnosis of carcinoma should be considered Image 12. No quantitative criteria exist for number of glands or amount of stromal distance separation required to definitely diagnose invasion. In borderline cases, we have used the descriptive diagnosis of "high-grade prostatic intraepithelial neoplasia with associated atypical small acinar proliferation" with a description of the differential diagnoses in a comment.

Minimal adenocarcinoma, with small acini, adjacent to larger high-grade prostatic intraepithelial neoplasia gland (H&E, x 400).

Diagnoses of atypia have been forwarded as a viable diagnostic category.[5,12,45,46,47,48,49,50] These terms include focal glandular atypia,[12]atypical,[45]atypical suspicious for carcinoma,[46] and atypical small acinar proliferation suspicious for malignancy.[5,47,48,49,50] This category of atypia is undoubtedly a broad diagnostic umbrella and likely encompasses benign and reactive but atypical epithelium to small foci of carcinoma that harbor some but not all features needed for a definitive diagnosis of malignant neoplasm. Some have suggested 3-tiered stratification of the atypia into favor benign, uncertain (or suspicious), and highly suspicious[5,48,50] or favor benign, favor cancer, and undetermined.[46] We have used a 2-tiered scheme of focal glandular atypia and focal glandular atypia, suspicious for malignancy. Thus far, these stratifications have not been proven to be reproducible[51] or clinically significant.[46,48,49]

In our definition of atypia,[12] focal glandular atypia was classified as a gland or groups of glands with architectural atypia, cytologic atypia, or both that are atypical but not diagnostic of atypical adenomatous hyperplasia, high-grade PIN, or carcinoma. Most studies have found that clinical features such as serum PSA level or digital rectal examination findings are not useful in the differential diagnosis of atypia vs minimal carcinoma.[45,46,47,48,49] No set combination of histologic criteria exist to distinguish atypia and, in particular, atypical glands that are suspicious for malignancy from minimal carcinoma. In 1 study, minimal carcinoma foci, in comparison with atypical small acinar proliferation, tended to be larger, more infiltrative, and with greater nuclear atypia, including nucleomegaly and prominent nucleoli.[5] Mitotic figures more often were seen in minimal carcinoma (10% of cases) compared with atypical small acinar proliferation (0%),[5] but in the series of Thorson et al,[4] they were seen in only 2% of minimal carcinomas, which suggests little diagnostic usefulness. Luminal blue mucin, concomitant high-grade PIN, and absence of moderate to severe atrophy also were more common in focal carcinoma vs atypical small acinar proliferation.[5]

However, there is overlap of all of these features in minimal carcinoma vs atypical small acinar proliferation, such that different thresholds exist among histopathologists in the diagnosis of minimal carcinoma vs atypia.[51] Some cases of atypical glands suggestive of malignancy most likely represent prostate cancer that is distorted, poorly preserved, thickly sectioned, poorly stained, and/or clinically or histologically undersampled. In 10% of cases of focal glandular atypia, additional sections from the block reveal definitive carcinoma.[12] So, we recommend obtaining additional sections after an initial diagnosis of atypia in the first 3 slides. This further sampling of tissue in the block can be additional H&E-stained sections, a 34betaE12 immunostain, (see "Ancillary Studies"), or both. Even after additional levels and/or a 34betaE12 immunostain, some cases are borderline, so a descriptive diagnosis of atypia is warranted. The incidence of such an atypical diagnosis varies from 2% to 9%, depending on the series.[12,45,47,52,53,54] The mean incidence in the literature, based on compilation of these data, is about 3% of all prostate needle biopsy specimens. Patients with a focus of atypical glands suspicious for malignancy are at high risk for subsequent detection of cancer, with 34% to 60% of patients given a diagnosis of carcinoma based on repeated biopsy.[45,46,47,48,49,50] So, just as for patients with high-grade PIN, a diagnosis of "atypical, suspicious for malignancy" in a prostate needle biopsy specimen should prompt sextant rebiopsy (usually in 3-6 months).[55]


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