—  SHORT COURSE #13  —

Interpretation of Prostate Needle Biopsies

Case 8 - Benign Mimics of Prostate Cancer and Unusual Cancer Morphologies which Mimic Benign Conditions (continued)

Rajal Shah and Ming Zhou


Case 8:
A 60 year-old man with elevated PSA and family history of prostate cancer. He underwent a sextant prostate biopsy.

Diagnosis:
High grade prostatic intraepithelial neoplasia (HGPIN)

Prostatic Intraepithelial Neoplasia (PIN)

PIN is the preferred diagnostic term for a putative pre-malignant proliferation of atypical epithelial cells within the pre-existing prostatic ducts and acini [1]. In other words, these are architecturally benign glands lined with cytologically dysplastic cells. It can only be diagnosed by histology, as there are no specific clinical or radiological findings. It doesn't elevate serum PSA either.

Histological features of PIN
PIN has several architectural and cytological features (Table 4). Based on the severity of architectural and cytological atypia, PIN is categorized as low-grade and high-grade. The architectural and cytological atypia is more pronounced in the later. Several studies have shown that good distinction between low-grade and high-grade PIN can be achieved. The prominent nucleoli are the best discriminator between the two. Although there is no consensus as to what constitutes prominent nucleoli; however, if distinct nucleoli can be visualized at 40x magnification, even when it only involves a few cells, it qualifies for prominent nucleoli and therefore a diagnosis of high-grade PIN can be established. In contrast, low-grade PIN may have nuclear enlargement and stratification; however, it only has tiny, inconspicuous nucleoli at higher magnification.

Table 4: Diagnostic criteria for PIN

Histological Features Low grade PIN High grade PIN
Architecture Basophilic appearance
Normal glandular architecture
Luminal cell crowding, irregular spacing, multilayering		Similar to LGPIN, but more pronounced
Luminal cell cytology
NucleiEnlarge, marked size variationEnlarge, size and shape variation
ChromatinNormal Coarse and clumped
NucleoliInconspicuous Large and prominent, similar to PCa
CytoplasmAmphophilic Amphophilic
Basal cell layerIntactOften discontinuous, or absent

Modified from Humphrey PA: Prostate Pathology

An algorithm for diagnosing PIN in prostate biopsy is shown in the Figure 2. If one sees basophilic glands of benign architecture at low power, it should prompt one to consider high-grade PIN and go to high power to look for prominent nucleoli. If prominent nucleoli are absent, it is not high-grade PIN. One should consider low-grade PIN, central zone histology or other mimics. On the other hand, if prominent nucleoli are present, a diagnosis of high-grade PIN can be established after one rules out high-grade PIN mimics.


Figure 2. Diagnosis of PIN in prostate needle biopsies

Significance of low grade PIN in prostate needle biopsies
There are two reasons that low-grade PIN should not be diagnosed in prostate biopsy. First, finding low-grade PIN in needle biopsy is not associated with increase risk for detecting cancer in subsequent biopsies. If the first biopsy shows low-grade PIN and patients undergo repeat biopsy, cancer is found in approximately 18% of the patients. On the other hand, if the first biopsy shows benign prostatic tissue and patients undergo repeat biopsy, prostate cancer is found in 20% of the patients. Therefore, finding low-grade PIN is not associated with increased risk for cancer detected in subsequent biopsies [2, 3, 4, 5]. Second, diagnostic reproducibility for low-grade PIN is poor, even among expert uropathologists [6]. For these two reasons low-grade PIN should not be diagnosed in needle biopsies.

Histological features of high grade PIN
There are four major structural patterns [7] and several minor variations for high-grade PIN, including tufting (56%), micropapillary (29%), flat (15%), and cribriform (0-5%). Uncommon to rare variants include inverted PIN, in which nuclei are aligned along the luminal surface rather than the basal aspect, neuroendocrine, signet-ring cell, and other types [8, 9]. These structural patterns are for diagnostic consideration and in general do not have any clinical significance.

High-grade PIN often has discontinuous, patchy basal cell lining on basal cell immunostaining. In addition, it is also positive for AMACR, although the staining may be weaker than the ordinary prostate cancer [10].

The differential diagnosis for high-grade PIN is lengthy and includes benign and malignant conditions (Table 5). It should also be distinguished from intraductal carcinoma, a controversial entity. Similar to high-grade PIN, intraductal carcinoma is characterized by the proliferation of cytologically malignant cells that fill large prostatic ducts or acini with preservation of basal cell layers. However, it is arbituarily distinguished from high-grade PIN by the presence of solid or sense cribriform pattern, or marked nuclear atypia and non-focal comedonecrosis. The significance of intraductal carcinoma is that it is invariably associated with high-grade invasive cancer, although the latter may not be sampled in the biopsy [19].

Table 5: Differential diagnosis of high grade PIN
  • Benign
    • Prostatic central zone glands

    • Seminal vesicle/ejaculatory duct epithelium

    • Reactive atypia due to inflammation, infarction or radiation

    • Metaplasia (transitional cell, squamous cell)

    • Hyperplasia (clear cell cribriform hyperplasia, basal cell hyperplasia)

  • Malignant
    • Prostate carcinoma with cribriform pattern

    • Ductal adenocarcinoma

    • Urothelial carcinoma

    • Intraductal carcinoma of the prostate

Clinical significance of high grade PIN
The incidence of high-grade PIN in prostate needle biopsies varies from 0% to 24.6% with an mean of 7.7% (median 5.2%). The importance of recognizing high-grade PIN in needle biopsy is its association with prostate cancer in repeat biopsy [11, 12, 13, 20]. Such risk varies widely from studies that were performed in early 1990 and studies that were performed recently. In studies performed in early 1990, the average risk of cancer associated with high-grade PIN is 36%. In studies performed between 1995 and 1999, such risk dropped to 28%. In studies performed after, such risk further decreased to 21% [14]. Several factors may be responsible for such decrease in cancer risk associated with high-grade PIN. The extended biopsy scheme has been used increasingly in recent years and it increases the cancer detection in the initial biopsy, and therefore may reduce cancer detection in subsequent biopsies [15]. In contemporary series, the cancer risk associated with high-grade PIN is around 25%, only slightly higher than that associated with benign diagnosis [20]. The majority of publications that compared the risk of cancer in the same study following a needle biopsy diagnosis of high-grade PINto the risk of cancer following a benign diagnosis on needle biopsy show no difference between the two groups. Since high-grade PIN has been considered as a risk factor for detecting cancer in subsequent prostate biopsies, patients were recommended to undergo repeat biopsies. In a recent review article, the authors recommend that patients do not need a routine biopsy within year one following the diagnosis of high-grade PIN [20]. However, several recent studies, including our own study, suggest that high-grade PIN confer a much higher cancer risk than that published in the literature under certain clinical scenarios. For example, one study found a 39% risk of finding PCa on repeat biopsies obtained after an initial diagnosis of widespread HGPIN that involved >4 biopsy cores, and supported the need for a repeat biopsy in this subset of patients [21]. As for now, we continue to diagnose and report high-grade PIN in prostate biopsies.

Re-biopsy scheme for high grade PIN
The presence of high-grade PIN implies the entire prostate gland is at increased risk of harboring prostate cancer, analogous to LCIS in the breast. Therefore re-biopsy should sample the entire gland [16, 17], rather than the site(s) where the high-grade PIN was initially found.

Reporting of high grade PIN
High-grade PIN should be reported in the prostate biopsy report, while low-grade PIN should not [18]. Reporting of extent and architectural patterns of high-grade PIN is optional. WHO and CAP also recommend the inclusion of a diagnostic comment of repeat biopsy for urologists. Some practicing pathologists believe that the decision of re-biopsy is best made by clinicians, therefore a recommendation of re-biopsy should not be from pathologists.

References:
  1. Bostwick, D.G. and J. Qian, High-grade prostatic intraepithelial neoplasia. Mod Pathol, 2004. 17(3): p. 360-79.

  2. Aboseif, S., et al., The significance of prostatic intra-epithelial neoplasia. Br J Urol, 1995. 76(3): p. 355-9.

  3. Brawer, M.K., et al., Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology, 1991. 38(2): p. 103-7.

  4. Keetch, D.W., et al., Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. J Urol, 1995. 154(2 Pt 1): p. 347-51.

  5. Raviv, G., et al., Prostatic intraepithelial neoplasia: influence of clinical and pathological data on the detection of prostate cancer. J Urol, 1996. 156(3): p. 1050-4; discussion 1054-5.

  6. Epstein, J.I., et al., Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol, 1995. 19(8): p. 873-86.

  7. Bostwick, D.G., et al., Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol, 1993. 24(3): p. 298-310.

  8. Argani, P. and J.I. Epstein, Inverted (Hobnail) high-grade prostatic intraepithelial neoplasia (PIN): report of 15 cases of a previously undescribed pattern of high-grade PIN. Am J Surg Pathol, 2001. 25(12): p. 1534-9.

  9. Reyes, A.O., et al., Unusual histologic types of high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol, 1997. 21(10): p. 1215-22.

  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. Davidson, D., et al., Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies. J Urol, 1995. 154(4): p. 1295-9.

  12. O'Dowd G, J., et al., Analysis of repeated biopsy results within 1 year after a noncancer diagnosis. Urology, 2000. 55(4): p. 553-9.

  13. Kronz, J.D., et al., Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol, 2001. 25(8): p. 1079-85.

  14. 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.

  15. Chen, M.E., et al., Detailed mapping of prostate carcinoma foci: biopsy strategy implications. Cancer, 2000. 89(8): p. 1800-9.

  16. Langer, J.E., et al., Strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy. J Urol, 1996. 155(1): p. 228-31.

  17. Shepherd, D., et al., Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostate needle biopsy. J Urol, 1996. 156(2 Pt 1): p. 460-2; discussion 462-3.

  18. Amin, M., et al., Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol Suppl, 2005(216): p. 20-33.

  19. Guo, C, and J.I. Epstein, Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance. Modern Pathol, 2006. 19: p. 1528-35

  20. 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

  21. Netto, G, and J.I. Epstein, Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol, 2006. 30(9): p.1184-8