By Bahram Robert Oliai, M.D.
In this the second in my first series of three reviews on clinicopathologic enigmas in prostate pathology I will tackle the salient issues regarding the diagnosis of atypical acini on prostate biopsy (A.K.A. ASAP) including how we make this diagnosis and what this means for the patient. In addition, I will briefly discuss optimal strategies for follow-up so that if cancer eventually develops it is caught at an early, curable stage.
Atypical Acini (ATYP) A.K.A. ASAP
In approximately 3-5% of prostate needle biopsies atypical foci are identified, that while suspicious for cancer are not diagnostic – these are often referred to as “Atypical Small Acinar Proliferations,” A.K.A. ASAP. I prefer to use the term atypical acini rather than ASAP, as in most cases these do not represent a proliferation or proliferative appearing lesion.
Most often these foci consist of only a handful of acini showing cytologic and/or architectural atypism. Bostwick and Meiers describe these ASAP foci as consisting of no more than 2 dozen acini (2) – in my experience they are often much smaller, often consisting of 5 or fewer acini. If these were truly “proliferations” we could more often make a definitive diagnosis.
Semantics aside, these atypical foci while suspicious for cancer lack sufficient cytologic and/or architectural features to establish a definitive diagnosis of cancer, causing pathologists, urologists, and patients a fair amount of grief (FIGS 1a, 1b). Common reasons for an atypical diagnosis includes a small focus (too few acini to make a definitive diagnosis), an atypical focus at the edge of the core precluding assessment of the entire focus and making it difficult to rule out HGPIN, conflicting immunoperoxidase findings (focal reactivity with basal cell markers in acini suspicious for cancer), histologic artifacts (the best fixative for prostate biopsies is 10% buffered formalin), atypical acini with atrophic features (cannot rule out atrophy), adenosis, and inflammation with reactive acinar changes. Furthermore, both atrophy and adenosis can be patchy to negative with basal cell immunostains complicating matters further.
In their review of ASAP, Bostwick and Meiers describe 3 questions that pathologists need to ask themselves before diagnosing small foci of cancer on needle biopsy (2). I feel that these questions constitute an excellent “acid test” in making this sometimes challenging diagnosis. The questions are as follows: “Would you be absolutely confident of this diagnosis if it were followed by a radical prostatectomy with negative findings?” “Would another colleague pathologist agree with the diagnosis of cancer?” “Can you confidently support the diagnosis of cancer based solely on this biopsy result?” Only when the answer to all three questions is an emphatic yes, should the diagnosis of cancer be made. These are the questions I keep in mind when evaluating these small foci in prostate biopsies and it is for this reason that at PROPATH® all positive prostate biopsies are reviewed by at least two experienced pathologists.
The reported risk of cancer on follow-up biopsy after an atypical diagnosis varies ranging from 17-70% with an average risk of 40% (1, 2, 4). In 40% of cases atypical foci may actually represent under sampled cancer (2). Several studies have shown little benefit in attempting to stratify risk morphologically (i.e. atypical favor carcinoma, atypical indeterminate, atypical favor benign). In a study by Chan et al. 35% of cases initially labeled as “atypical, favor benign,” yielded malignant diagnoses on follow-up biopsy (3). Therefore an atypical diagnosis is a worrisome finding no matter how you “slice it” and carries a much higher risk of subsequent carcinoma than a diagnosis of HGPIN. As such these patients need follow-up.
Generally, patients with an atypical diagnosis should be re-biopsied within 3-6 months. Sampling should focus on the site of the initial atypical diagnosis (i.e. 3 cores) with increased sampling of adjacent ipsilateral and contralateral sites (i.e. 2 cores each) followed by routine sampling of all sextant sites (1 core each). All containers should be clearly labeled as to location so pathologists can correlate the original atypical site to current biopsies (4).
There are no clear guidelines regarding the number of times patients need to be rebiopsied following an initial atypical diagnosis to be considered “out of the woods” so to speak, and this may again ultimately be a decision that is made by the patient in discussion with the treating physician.
HGPIN with Adjacent Atypical Acini (PINATYP)
This refers to the finding of a few small atypical acini in the vicinity of HGPIN (FIGS 2a, 2b). The differential diagnosis in cases such as this would include tangential sections of glands “budding off ” HGPIN vs. early invasive carcinoma. This is an extremely difficult differential and often even Immunohistochemistry for basal cells will not resolve the issue since HGPIN can show patchy negative staining as can its “buds.” Cancer can be confidently diagnosed when the number of atypical glands simply overwhelm the focus of HGPIN, like a pack of hungry wolves encircling and wearing down a large moose, such that they cannot all be attributed to “budding off ” the adjacent HGPIN. PINATYP carries a risk of subsequent cancer higher than that of HGPIN alone (46%, 5) and as such should be followed in the same manner as described above.
References:
1. Allen EA, Kahane H, Epstein JI. Repeat biopsy strategies for men withatypical diagnoses on initial prostate needle biopsy. Urology 1998; 52: 803-807.
2. Bostwick DG, Meiers I. Atypical small acinar proliferation in theprostate clinical significance in 2006. Archives of Pathology and Laboratory Medicine 2006; 130: 952-957.
3. Chan TY, Epstein JI. Follow-up of atypical prostate needle biopsies suspicious for cancer. Urology 1999; 53(2): 351-355.
4. Epstein JI, Herawi M. Prostate needle biopsies containing prostaticintraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of Urology 2006; 175: 820-834
5. Kronz JD, Allan CH, Shaikh AA, Epstein JI. Predicting cancer followinga diagnosis of high-grade prostatic intraepithelial neoplasia on needlebiopsy data on men with more than one follow-up biopsy. The American Journal of Surgical Pathology 2001; 25(8): 1079-1085.
Date of last revision: January 2007.