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prostatic intraepithelial neoplasia


Saturday 21 January 2012

prostate intraepithelial neoplasia; PIN


Definition: Prostatic intraepithelial neoplasia (PIN) is a neoplastic transformation of the lining epithelium of prostatic ducts and acini. By definition, this process is confined within the epithelium therefore, intraepithelial.

Prostatic intraepithelial neoplasia (PIN) is a dysplasia of the epithelium lining prostate glands and is a probable precursor of prostatic carcinoma. The appearance of PIN may precede carcinoma by 10 or more years.


- Prostatic Intraepithelial Neoplasia

- high grade prostatic intraepithelial neoplasia (PIN), micropapillary type


Prostatic intraepithelial neoplasia (PIN) can be divided into:
- low grade PIN
- high grade PIN


Initially, PIN was divided into three grades based on architectural and cytologic features recognizing that the changes cover a continuum.

Subsequently, it has been recommended that the classification should be simplified into a two-tier system: low (previous grade I) and high (previous grades II and III) grade lesions.

The distinction between low and high grade PIN is based on the degree of architectural complexity and more importantly, on the extent of cytologic abnormalities.

- Low grade PIN

In low grade PIN, there is proliferation and "piling up" of secretory cells of the lining epithelium with irregular spacing. Some nuclei have small, usually inconspicuous nucleoli while a few may contain more prominent nucleoli. The basal cell layer normally rimming ducts and acini is intact in low grade PIN. It is difficult to reproducibly distinguish low grade PIN from normal and hyperplastic epithelium.

- High grade PIN

High grade PIN is characterized by a more uniform morphologic alteration. Cytologically, the acini and ducts are lined by malignant cells with a variety of architectural complexity and patterns. The individual cells are almost uniformly enlarged with increased nuclear/cytoplasmic ratio, therefore showing less variation in nuclear size than that seen in low grade PIN. Many cells of HGPIN contain prominent nucleoli and most show coarse clumping of the chromatin that is often present along the nuclear membrane.

HGPIN can be readily appreciated at low power microscopic examination by virtue of the darker "blue" staining of the lining that reflects the expanded nuclear chromatin area.

Low grade PIN

Low grade PIN may be found even in men in middle age. PIN does not routinely increase the serum prostate specific antigen (PSA).

PIN usually involves an acinus or a small cluster of acini, but it can be more extensive on occasion. The acini are usually medium-sized to large, with rounded borders. The partial involvement of an acinus is a helpful feature to distinguish PIN from adenocarcinoma.

PIN is characterized histologically by progressive basal cell layer disruption, loss of markers of secretory differentiation, nuclear and nucleolar abnormalities, increasing proliferative potential, increasing microvessel density, variation in DNA content, and allelic loss.

Unlike adenocarcinoma, with which it may coexist, glands with PIN retain an intact or fragmented basal cell layer. (Ayala and Ro, 2007)

Low grade PIN has epithelial cells that are crowded and irregularly spaced, with nuclei that are hyperchromatic and pleomorphic, with small nucleoli.

High grade PIN

High grade PIN has even more hyperchromatism and pleomorphism, the cells are more crowded and heaped up, and nucleoli can be prominent.

Immunohistochemical staining with antibody to low molecular weight keratin can help to identify the fragmented basal cell layer.

Anti-androgenic drug therapy may cause regression of PIN. (Ayala and Ro, 2007)

The appearance of PIN warrants increased surveillance of the prostate for development of an invasive carcinoma because the presence of PIN that is high grade suggests an increased risk for subsequent appearance of adenocarcinoma.

PIN itself is not an indication for aggressive treatment. (Lipski et al, 1996)

Architectural patterns of HGPIN

Four patterns of HGPIN have been described, which are flat, tufting,
micropapillary, and cribrifrom:
- nuclear atypia without significant architectural changes (flat pattern);
- nuclei become more piled up, resulting in undulating mounds of cells (tufting pattern);
- columns of atypical epithelium that typically lack fibrovascular cores (micropapillary pattern);
- more complex architectural patterns appear such as Roman
bridge and cribriform formation (cribriform pattern).

The distinction between cribriform high grade PIN and ductal carcinoma in-situ is controversial (see duct carcinoma in-situ). In high grade PIN, nuclei towards the centre of the gland tend to have blander cytology, as compared to peripherally located nuclei.

The grade of PIN is assigned based on assessment of the nuclei located up against the basement membrane.

Histologic variants

- signet-ring cell PIN
- mucinous cell PIN
- foamy cell PIN
- inverted PIN
- small cell neuroendocrine PIN

Differential diagnosis

Intraductal carcinoma is controversial as it has overlapping features with cribriform high grade PIN and can not be separated from intraductal spread of adenocarcinoma of the prostate.

All three entities consist of neoplastic cells spanning prostatic glands, which are surrounded by basal cells. The most salient morphologic feature distinguishing "intraductal carcinoma" from high-grade cribriform PIN is the presence of multiple cribriform glands with prominent cytological atypia containing comedo necrosis.

In practice, this distinction rarely poses a problem in the evaluation of a prostatectomy specimen as invasive cancer is always concurrently present.

In prostate needle biopsies and TURP, this process may rarely be present without small glands of adenocarcinoma, where some experts consider it prudent to refer to the lesion as high grade cribriform PIN with a strong recommendation for repeat biopsy.

Other experts will use the term "intraductal carcinoma" on biopsy with the recognition that definitive therapy may be undertaken, recognizing that infiltrating cancer will be identified upon further prostatic sampling.

Prognosis and predictive factors

Needle biopsy

High-grade PIN in needle biopsy tissue is, in most studies, a risk factor for the subsequent detection of carcinoma, while low-grade PIN is not.

The mean incidence of carcinoma detection on rebiopsy after a diagnosis of high-grade PIN in needle biopsy tissue is about 30%.

In comparison, the rebiopsy cancer detection frequency is about 20% after a diagnosis of benign prostatic tissue, and 16% after a diagnosis of low-grade PIN.

The large majority (80-90%) of cases of carcinoma are detected on the first re-biopsy after a high-grade PIN diagnosis.

Re-biopsy may also detect persistent high-grade PIN in 5-43% of cases.

High-grade PIN with adjacent atypical glands seems to confer a higher risk for subsequent diagnosis of carcinoma compared to high-grade PIN alone, averaging 53%.

Due to the magnitude of the risk, all men with this finding should undergo re-biopsy. It is not settled whether serum PSA and digital rectal examination findings provide further information beyond PIN presence on risk for subsequent detection of carcinoma.

There are inconsistent data as to whether the extent of HGPIN and its architectural pattern predict risk of subsequent carcinoma. Genetic abnormalities and/or immunophenotype of highgrade PIN are not currently utilized to stratify risk for subsequent detection of carcinoma.

Current standards of care recommend that patients with isolated high-grade PIN be re-biopsied in 0-6 months, irrespective of the serum PSA level and DRE findings.

However, this recommendation may change with emerging data indicating a lower risk of prostate carcinoma following a needle biopsy showing HGPIN.

The rebiopsy technique should entail at least systematic sextant re-biopsy of the entire gland, since high-grade PIN is a general risk factor for carcinoma throughout the gland.

For example, in one study fully 35% of carcinomas would have been missed if only the side with the highgrade PIN had been re-biopsied.

Radical prostatectomy specimens removed for carcinoma detected after a diagnosis of high-grade PIN contain mostly organ-confined cancer, with a mean Gleason score of 6 (range 5-7).

Treatment is currently not indicated after a needle biopsy diagnosis of high-grade PIN.

Patients with isolated highgrade PIN in needle biopsy may be considered for enrollment into clinical trials with chemoprevention agents.


Several studies have found that high grade PIN on TURP places an individual at higher risk for the subsequent detection of cancer, whereas a long-term study from Norway demonstrated no association between the presence of high grade PIN on TURP and the incidence of subsequent cancer.

In a younger man with high grade PIN on TURP, it may be recommended that needle biopsies be performed to rule out a peripheral zone cancer.

In an older man without elevated serum PSA levels, clinical follow-up is probably sufficient.

When high grade PIN is found on TURP, some pathologists recommend sectioning deeper into the corresponding block and most pathologists recommend processing the entire specimen.

Differential diagnosis

- See: Mimickers of prostatic intraepithelial neoplasia. PubMed: 20484280.


- Mimickers of prostatic intraepithelial neoplasia. Epstein JI. Int J Surg Pathol. 2010 Jun;18(3 Suppl):142S-148S. PMID: 20484280