Pathology of Atypical Small Acinar Proliferation

Atypical small acinar proliferation (ASAP) that is suspicious for malignancy is not a specific pathologic entity; instead, it is a diagnosis that incorporates a continuum ranging from benign, histologically atypical mimics of cancer to marginally sampled cancer. A pathologist may also refer to atypical small acinar proliferation as a proliferation of usually small acini with features highly suggestive of, but not diagnostic for, carcinoma. (See the image below.) ^{[1, 2]}

A prostatic core biopsy showing a focus of atypical small acinar proliferation (ASAP) suspicious for, but not diagnostic of, cancer (arrow, A). A repeat biopsy in the proximity of the same site shows another focus of crowded small-caliber glands (arrow, B), which, on immunohistochemistry with the basal cell marker 34βE12, reveals absence of basal cells, thereby confirming a diagnosis of adenocarcinoma Gleason 3+3 (arrow, C).

Such foci are found in approximately 2-5% of prostate needle biopsy specimens. ASAPs are located most often in the peripheral zone of the prostate; they are rarely located in the transition zone.

ASAP suspicious for malignancy discovered after prostatic core biopsy is highly predictive of subsequent prostatic adenocarcinoma on repeat biopsy, with a reported range of 17-60% of cases. ^{[1, 2]} Schlesinger et al found prostatic adenocarcinoma in subsequent biopsies in 23% of cases after prior diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN) alone; in 37% after diagnosis of ASAP alone; and in 33% after prior diagnosis of HGPIN with contiguous or noncontiguous ASAP. ^[3] Although the predictive value of HGPIN for cancer fell from 36% in older series to 21% in newer series, the predictive value of atypical small acinar proliferation was nearly constant.

Etiology

The etiology of ASAP suspicious for malignancy reflects that of prostatic acinar adenocarcinoma. The implication is that some of these foci really represent underlying adenocarcinomas that are not diagnosable with confidence on core biopsies because of qualitative or quantitative criteria falling below a threshold for malignancy.

No specific genetic information exists for ASAP per se, although those cases of ASAP that represent underdiagnosable cancer would indicate a similar molecular genetic profile as acinar adenocarcinoma.

Epidemiology

All ASAPs are either marginally sampled cancer or benign acini with reactive atypia or atrophy. Thus, the epidemiology of ASAP overlaps that of prostatic acinar adenocarcinoma.

Atypical small acinar proliferation (ASAP) was found to differ significantly from minimal cancer in several respects. Among architectural findings, ASAP foci averaged 0.4mm, versus 0.8mm for minimal cancer. In addition, ASAP was found to have a mean of 11 acini, versus 17 acini for minimal cancer. ^[4] ASAP was more frequently diagnosed if the cytology was confounded by excessive nuclear hyperchromasia (44% vs 9%) and demonstrated less nuclear enlargement than minimal cancer.

According to Iczkowski et al, enlarged nuclei (88% of cases) with prominent nucleoli were found in at least 10% of cells (55% of cases), luminal mucin in 6% of cases, proteinaceous secretions in 33% of cases, adjacent atrophy in 59% of cases, stromal fibrosis in 21% of cases, and amphophilic cytoplasm in 18% of cases. Adjacent high-grade prostatic intraepithelial neoplasia (HGPIN) was noted in 42% of cases. Chronic inflammation was more commonly found (64% of cases) than acute inflammation (21% of cases).

Essentially, microscopic findings are similar to those of adenocarcinoma, with absence of basal cells in the atypical glands. However, the suspicious focus of ASAP reveals a limitation that is either qualitative (degree of atypia) or quantitative (too few atypical glands), precluding a conclusive diagnosis of cancer. ^[5]

Immunohistochemistry can assist in reducing the incidence and ambiguity of atypical small acinar proliferation (ASAP) diagnoses.

A high-molecular-weight keratin (34βE12) and the equivalent cytokeratin 5/6 stain the basal cell layer of prostatic acini. A nuclear marker of basal cells, p63, has the same ability to decorate basal cells. Their presence, as confirmed on immunohistochemistry with these antibodies, almost definitely rules out carcinoma. However, absence of basal cells does not always indicate carcinoma, as benign acinar proliferations that mimic carcinoma (for example, adenosis and partial atrophy) can demonstrate patchy basal cells that result in some glands in these conditions being devoid of a basal cell lining.

Alpha-methylacyl-CoA-racemase (AMACR; P504S) has emerged as a positive immunostain to diagnose cancer. However, AMACR is also positive in high-grade prostatic intraepithelial neoplasia (HGPIN).

Immunohistochemical cocktails can overcome the limitations of using 2 or 3 separate immunostains to study small lesions in prostatic needle biopsies. A 3-antibody cocktail (AMACR, 34βE12, p63) and a double-chromogen reaction have been used for detection of limited prostate cancer. In one study, all malignant glands were negative for basal cells on immunostaining, and all benign glands adjacent to malignant glands were recognized easily by basal cell marker positivity with little or no AMACR expression. No benign glands were simultaneously positive for AMACR and negative for basal cell markers (specificity, 100%). ^[6]

Similarly, Ng et al determined a specificity of 100% with the triple cocktail for the diagnosis of prostate cancer. ^[7] Helpap et al used immunohistochemistry for 34βE12 on 114 cases of biopsy-proven ASAP and were able to confirm cancer in 27% of cases that were devoid of basal cells. ^[8] Iczkowski reported that 34βE12 and AMACR/P504S immunostains resolved 76% of ASAP diagnoses, with disappearance on deeper levels of the abnormal focus in question being the main technical limitation. ^[5]

In a study by Strand et al, ASAP workup was confirmed to be a very useful histologic tool for resolving diagnostic problems in prostate needle biopsy specimens. The study assessed the value of an ASAP workup consisting of preparing new recut sections from the paraffin block and performing hematoxylin and eosin–stained sections and immunostains (using p63, cytokeratins 5 and 14, and AMACR). There were 23 specimens (21.9%) in which the preliminary diagnosis was changed to a definitive diagnosis of carcinoma (10 specimens) or a specific benign diagnosis (13 specimens) based solely on the findings of the ASAP workup. ^[9]

Rates of cancer diagnosed on subsequent prostate biopsies vary according to different reports. ^{[1, 2, 3, 10, 11, 12]} However, contemporary studies indicate a mean predictive value for cancer of 39% on repeat biopsy. ^[5] When an atypical small acinar proliferation (ASAP) diagnosis represents undersampled cancer, the cancer is clinicopathologically similar to cancer diagnosed on first biopsy. Cancer detected on the second or third round of biopsies after an ASAP diagnosis is also similar in grade, stage, and size to cancer detected in control patients in the first biopsy set. ^[10]

The high predictive value of ASAP for subsequent adenocarcinoma indicates a need for repeat biopsy. ^{[13, 14]} Cancer is found in a different sextant site from the initial ASAP site in 39% of patients, suggesting that repeat sampling should include multiple sites of the gland. ^[14] However, also concentrating repeat biopsy sampling at the site of ASAP, knowing that such foci often represent marginally sampled cancer, may also be prudent.

Scattoni et al found that the number and the location of biopsy cores have an effect on the rates of cancer detection in repeated biopsy settings. According to the authors, after an initial negative biopsy, cancer was detected at rebiopsy in 95 men (27.9%). Depending on the different combination of sites considered, the cancer detection rates varied significantly. ^[15]

Ploussard et al also found in their study that repeated biopsy is warranted when ASAP is diagnosed, because of a high risk of prostate cancer. They evaluated the incidence of HGPIN and ASAP in a 21-core extended biopsy and determined that the 6-core and 12-core biopsies detecting HGPIN would have missed the diagnosis of cancer in 10% and 3.6% of cases, respectively, compared with a 21-core biopsy protocol. The cancer detection rate on repeated biopsy for HGPIN was 19% and not significantly different compared with the detection rate on repeated biopsy for clinico-biologic indications. Seven prostate cancers were found among the 17 rebiopsies for ASAP, revealing a detection rate of 41.2%. ^[16]

A study by Warlick et al found that the overall rate of intermediate- and high-grade prostate cancer found on repeat biopsy for ASAP is low. ^[17]

Cheville et al found that 83% of men with atypical small acinar proliferation (ASAP) have increased serum prostate-specific antigen (PSA) levels and that 49% have abnormal digital rectal examinations (DRE). ^[13] Brimo et al concluded that the probability of cancer on follow-up biopsy after an initial diagnosis of ASAP depended on PSA, with men with raised PSA levels being more likely to harbor cancer. ^[18] This trend, however, was not noted by Iczkowski et al. ^[4]