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
A 60 year-old man with elevated PSA and family history of
prostate cancer. He underwent a sextant prostate biopsy.
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 . 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|
|Nuclei||Enlarge, marked size variation||Enlarge, size and shape variation|
|Chromatin||Normal ||Coarse and clumped|
|Nucleoli||Inconspicuous ||Large and prominent, similar to PCa|
|Basal cell layer||Intact||Often 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
Second, diagnostic reproducibility for low-grade PIN is poor, even among expert uropathologists . 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  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
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
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
Table 5: Differential diagnosis of high grade PIN
- 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)
- 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
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% .
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 . In
contemporary series, the cancer risk associated with high-grade PIN is around 25%, only slightly higher
than that associated with benign diagnosis . 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
. 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 . As for now, we continue to diagnose and report high-grade PIN in prostate
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
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 .
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.
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