—  SHORT COURSE #13  —

Interpretation of Prostate Needle Biopsies

Case 9, 10A, 10B - Diagnosis and Understanding the Significance of HGPIN, Atypical Small Acinar Proliferation (ASAP) And Recognition of Morphological Features of Cancer Following Therapy

Rajal Shah and Ming Zhou


Case 9:
A 72 year-old man with a diagnosis of "atypical small acinar proliferation" on previous prostate biopsy. He was re-biopsied.

Diagnosis:
Minute focus of atypical small acinar proliferation, suspicious for adenocarcinoma of the prostate.

Case 10:
A 55 year-old man with family history of prostate cancer had a PSA of 3.5 ng/ml and had a sextant prostate biopsy.

Diagnosis:
Minute focus of atypical small acinar proliferation, suspicious for adenocarcinoma of the prostate.

Case 10B:
A 69 year-old man with elevated serum PSA. He had a sextant prostate biopsy.

Diagnosis:
Minute focus of atypical small acinar proliferation, suspicious for adenocarcinoma of the prostate. Can't rule out the possibility of atrophy.

Atypical Glands Suspicious For Prostate Cancer (ATYP)

"Atypical glands suspicious for cancer" is a diagnostic term used by pathologists to describe a gland or a focus of glands suspicious for prostate cancer, but lack sufficient architectural/cytological atypia to establish a definitive diagnosis. Unlike prostate cancer or high-grade PIN, ATYP is not a diagnostic entity. Rather, pathologists use this term to convey to their clinical colleagues the uncertainty regarding the diagnosis. Many terms have been used in the past, including atypia, atypical hyperplasia, borderline lesion, lesion of uncertain significance, or atypical small acinar proliferation (ASAP). Many of these terms have been used to describe other prostate entities. For example, atypical hyperplasia was used for high grade PIN. ASAP has also been widely used. However, it is not an accurate term. Many atypical glands are not small, and quite large on the contrary. In addition, some urologists mistake ASAP to high grade PIN. For these reasons, we advocate the use of the descriptive terminology "atypical glands suspicious for prostate cancer", or ATYP. In this handout, we will use ATYP.

Histological features of ATYP
There are many reasons why pathologists cannot make a definitive diagnosis; rather they have to refer them as ATYP. When the atypical glands are only few in number, many pathologists will opt for ATYP diagnosis rather than a definitive diagnosis. Prostate biopsies are prone to several procedure related artifacts, including crush and fragmentation of biopsy cores. These artifacts may prevent an accurate evaluation for architectural and cytological features. In the presence of a focus of crowded glands with no or minimal cytological atypia, one has to rule out adenosis. If the atypical glands have atrophic cytoplasm, one needs to rule out benign atrophy as mild cytological atypia can also be seen in benign atrophic glands. Inflammation can cause significant degree of architectural/cytological atypia. One should be cautious in making a cancer diagnosis if significant amount of inflammation is present. A small focus of atypical glands adjacent to high-grade PIN may represent a focus of microinvasive prostate cancer, or out-pouching/tangential sectioning of the adjacent high-grade PIN. Unless atypical glands are too numerous or too far from the adjacent high-grade PIN, a diagnosis of ATYP adjacent to high-grade PIN (PINATYP) is prudent. Recently, immunohistochemistry that was intended to resolve atypical diagnosis in needle biopsies have also contributed to ATYP. For example, I have seen in consultation several cases which contained morphologically benign glands but were strongly positive for AMACR immunostain.

The differential diagnosis of ASAP is long and includes benign and malignant conditions (Table 6).

Clinical significance of ATYP
The incidence of ATYP in prostate biopsies varies depending on patient population and pathologist's experience. With better defined diagnostic criteria for limited cancer in prostate biopsy and immunohistochemical markers, one expects more atypical diagnosis will be resolved and therefore a reduction of the incidence. On average, ATYP is found in 4.4% of the prostate biopsies [14].

Table 6: Differential diagnosis of atypical glands suspicious for cancer.

  • Normal anatomy
    • Seminal vesicle/ejaculatory duct epithelium

  • Benign
    • Atrophy

    • Partial atrophy

    • Basal cell hyperplasia

    • Adenosis

    • Inflammation

    • Radiation atypia

  • HGPIN

  • PCa minimally sampled in prostate biopsy

Like high-grade PIN, the importance of recognizing ATYP in needle biopsies is its association with prostate cancer in repeat biopsies [1, 2, 3]. Unlike high-grade PIN, the cancer risk associated with ATYP has held steadily from early 1990 to present [3]. On average, 40% of men with ATYP in initial biopsy would be found to have cancer in subsequent biopsies. If the subsequent biopsy is negative, this doesn't exclude the presence of prostate cancer since prostate biopsy is associated with high false negative rate, up to 25% [4]. The majority of the PCa following an initial ATYP diagnosis is clinically significant. We recently reviewed 23 patients who initially had an ATYP diagnosis in prostate needle biopsy and later were confirmed to have PCa. One patient had pelvic lymph node dissection only that revealed metastatic PCa, and 22 underwent RP. The final Gleason grades in the 21 radical prostatectomies were 6 in 11/22 (50.0%), 7 in 6/22 (27.2%), > 8 in 3/22 (13.6%), and undetermined due to preoperative hormonal ablation in 2/22 (9.1%). EPE was present in 4/22 (18.2%), and SVI in 2/22 (9.1%). The tumor volume was low (<0.5 ml) in 7/22 (31.8%), medium (0.5-2 ml) in 10/22 (45.5%), and extensive (>2 ml) in 5/22 (22.7%). Only 7/23 (30.4%) had potentially pathologically insignificant PCa (GS<=6, TV< 0.5 ml, organ confined), and 16 (69.6%) had pathologically significant PCa.

Work up of ATYP
Immunohistochemistry, including the basal cell markers and AMACR, has played a significant role in the work-up of ATYP cases [5, 6, 7, 8]. We recently conducted a study on how often AMACR contributed to resolving an atypical diagnosis on prostate biopsy beyond that provided by histology and negative basal cell markers [8]. Of 115 initial cases called atypical based on H&E histology and basal cell markers, 76 were positive for AMACR; of these 76 cases, 34 (44.7%) were changed to a final diagnosis of cancer after reviewing positive AMACR staining in conjunction with H&E histology and negative basal cell markers. The cases whose diagnosis was changed from ATYP to cancer were all highly suspicious for cancer based on H&E histology and negative basal cell markers, yet a definitive cancer diagnosis could not be established due to small size, insufficient cytological atypia or biopsy artifact. However, a positive AMACR staining is less useful if the differential diagnosis also includes high-grade PIN, adenosis, nephrogenic adenoma, urothelial carcinoma, or metastatic colorectal adenocarcinoma as these conditions have all been shown to express AMACR to various levels [9, 10, 11, 12, 13]. Negative AMACR staining should not be used to contradict any diagnosis especially a cancer or atypical diagnosis.

Re-biopsy Techniques Following an ASAP Diagnosis
Allen et al, [1] studied men with ATYP diagnosis in sextant biopsies and follow-up sextant biopsies in which cancer was detected. Cancer was found on re-biopsy in the same sight as initial ASAP diagnosis in 48% of cases. 85% of all cases could be detected when the biopsy cores were taken from the same sight as ATYP diagnosis, the adjacent ipsilateral, and adjacent contralateral sides. Based on these data, a rational approach for the re-biopsy following initial ATYP diagnosis should include collection of 3 cores from the site of the initial ATYP biopsy, 2 cores each from adjacent sites, and 1 core each elsewhere.

References:
  1. Allen, E.A., H. Kahane, and J.I. Epstein, Repeat biopsy strategies for men with atypical diagnoses on initial prostate needle biopsy. Urology, 1998. 52(5): p. 803-7.

  2. Chan, T.Y. and J.I. Epstein, Follow-up of atypical prostate needle biopsies suspicious for cancer. Urology, 1999. 53(2): p. 351-5.

  3. Schlesinger, C., D.G. Bostwick, and K.A. Iczkowski, High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol, 2005. 29(9): p. 1201-7.

  4. Keetch, D.W., W.J. Catalona, and D.S. Smith, Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol, 1994. 151(6): p. 1571-4.

  5. Kunju, L.P., et al., Diagnostic usefulness of monoclonal antibody P504S in the workup of atypical prostatic glandular proliferations. Am J Clin Pathol, 2003. 120(5): p. 737-45.

  6. Kahane, H., et al., Utilization of high molecular weight cytokeratin on prostate needle biopsies in an independent laboratory. Urology, 1995. 45(6): p. 981-6.

  7. Wojno, K.J. and J.I. Epstein, The utility of basal cell-specific anti-cytokeratin antibody (34 beta E12) in the diagnosis of prostate cancer. A review of 228 cases. Am J Surg Pathol, 1995. 19(3): p. 251-60.

  8. Zhou, M., et al., How often does alpha-methylacyl-CoA-racemase contribute to resolving an atypical diagnosis on prostate needle biopsy beyond that provided by basal cell markers? Am J Surg Pathol, 2004. 28(2): p. 239-43.

  9. Yang, X.J., et al., Expression of alpha-Methylacyl-CoA racemase (P504S) in atypical adenomatous hyperplasia of the prostate. Am J Surg Pathol, 2002. 26(7): p. 921-5.

  10. Wu, C.L., et al., Analysis of alpha-methylacyl-CoA racemase (P504S) expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol, 2004. 35(8): p. 1008-13.

  11. Skinnider, B.F., et al., Expression of alpha-methylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol, 2004. 28(6): p. 701-5.

  12. Gupta, A., et al., Expression of alpha-methylacyl-coenzyme A racemase in nephrogenic adenoma. Am J Surg Pathol, 2004. 28(9): p. 1224-9.

  13. Zhou, M., et al., Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions. Am J Surg Pathol, 2002. 26(7): p. 926-31.

  14. Epstein, J.I., and M. Herawi, Prostate needle biopsies containing prostatic intraepithelial neoplasia or atpical foci suspicious for carcinoma: implications for patient care. J Urol, 2006. 175: p.820-34