—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 1 - High-Grade Prostatic Intraepithelial Neoplasia

Alberto G. Ayala
University of Texas
M. D. Anderson Cancer Center
Houston, TX


Click on each slide thumbnail image for an enlarged view
Clinical History
This is a 52 year-old man who presents with urinary obstruction, a soft and enlarged prostate at palpation, no localizing ultrasound lesions and a PSA of 11.79. Eight core biopsies are done.


Case 1 - Figure 1 - Low-power view of high-grade PIN. Note the marked contrast between the normal glands and the glands in the center that have increased cellularity.
Case 1 - Figure 2 - Low-power view of high-grade PIN. In this additional view, the glands located in the center of the illustration show definitively increased cellularity.
Case 1 - Figure 3 - Medium-power view of high-grade PIN. Nuclear stratification and hyperchromasia is seen in this view.


Case 1 - Figure 4 - Medium-power view of high-grade PIN. Cellular detail is beginning to be appreciated as well as some nucleoli.
Case 1 - Figure 5 - High-power view of high-grade PIN. Note nuclear stratification and prominent nucleoli; some of these exhibit distinct clear halos.
Case 1 - Figure 6 - High-power view of high-grade PIN. In this view, there is hyperchromasia of many nuclei contrasting with fine nuclear chromatin features of other cells, which exhibit prominent nucleoli.

Diagnosis
High-Grade Prostatic Intraepithelial Neoplasia

Discussion Although dysplasia of the prostate was initially described in the early sixties, it was until 1986 when McNeal and Bostwick clearly gave an account of its morphologic criteria, and established a grading system that closely predicted the association of invasive carcinoma. [1]

Other terms that have been used in the past include: large acinar atypical hyperplasia, [2] hyperplasia with malignant change, [3] and duct-acinar dysplasia. [4] The term prostatic intraepithelial neoplasia or PIN was first proposed by Bostwick and Brawer in 1987. [5] This term was accepted at the 1989 Workshop on Prostatic Dysplasia (Bethesda, MD; March, 1989) as the preferred nomenclature for this pre-neoplastic change. [6, 7] Since then this term has gained wide spread acceptance and is the term used in this discussion.

Histology Characteristics of Prostatic Intraepithelial Neoplasia
PIN is readily identified at low magnification because glandular structures involved by PIN appear darker than the surrounding normal ducts and acini. At high magnification, the epithelium of PIN is thickened and there are varying degrees of nuclear enlargement, nuclear stratification, hyperchromasia, and nucleolar prominence. PIN is usually multifocal and involves clusters of glandular structures; however, PIN occasionally involves only a single gland either partially or completely.

At the 1989 Workshop on Prostatic Dysplasia, [6, 7] it was agreed to designate PIN 1 as low-grade PIN and to combine PIN 2 and PIN 3 together as high-grade PIN. [7] In the remainder of this discussion, we will use grades 1-3 when referring to previous publications in which this classification was used.

Grading of PIN is done at high magnification (40X). The hallmark of PIN 1 is the presence of variable nuclear enlargement and irregular cell spacing resulting in nuclear stratification and crowding. Nucleoli may be seen but are rare and small. PIN 2 and 3 are easily recognized by the additional presence of nuclear enlargement, fine nuclear chromatin pattern which may be heavy, somewhat hyperchromatic, and the presence of large nucleoli. In PIN 2, prominent nucleoli are observed only in some cells, whereas in PIN 3 nearly every cell exhibits a prominent nucleolus usually attended by perinucleolar clearing. Cytologically, the cells of PIN 3 are identical to those of invasive carcinoma, i.e., nucleomegaly, large prominent nucleoli, fine nuclear chromatin pattern, etc. Mitotic figures are rare in high-grade PIN and are not included in the grading criteria of PIN. [1] In a study of high-grade PIN in radical prostatectomy specimens the authors reported mitotic figures in only 3% of the cases. [8] In general, there is good distinction between low-grade PIN (PIN 1) and high-grade PIN (PIN 2 and 3). However, among the lesions showing high-grade PIN, there is greater interobserver variability as to whether the lesion represents PIN 2 or PIN 3. Therefore, classifying PIN 2 and 3 as "high-grade PIN" is recommended. [9]

PIN may display a spectrum of architectural patterns, from a simple flat epithelium to a complex cribriform pattern that may be difficult to distinguish from cribriform carcinoma. The four most common patterns of high-grade PIN are the tufting pattern (87%), the micropapillary pattern (85%), the cribriform pattern (32%), and the flat pattern (28%). Although it is important for diagnostic purposes to recognize these different patterns, it has been shown that there is no significant relationship between the pattern of high-grade PIN and the Gleason grade of carcinomas arising in the same specimen. Moreover, all patterns are frequently observed in the same radical prostatectomy specimen. [8, 9]

Differential Diagnosis of Prostatic Intraepithelial Neoplasia (PIN)
Normal prostatic structures, metaplasias, benign epithelial proliferations, and malignant tumors may be confused with PIN. The differential diagnosis of high-grade PIN is very important when evaluating needle biopsy specimens where PIN may be very focal. It has been recommended that only high-grade PIN (PIN 2 and PIN 3) be reported in these specimens.

The two normal prostatic structures that are frequently interpreted as PIN are normal central zone glands and ejaculatory duct/seminal vesicle epithelium. The central zone glands are architecturally more complex than the peripheral and transition zone glands and exhibit a certain degree of nuclear stratification that may be interpreted as low-grade PIN. Bridging, papillary formation, and focal tubular or cribriform pattern may be present. [10, 11, 12] The central zone is frequently encountered in biopsies from the base of the prostate. The site of the biopsy as well as the presence of the other histologic features of the central zone, including the presence of abundant stroma, should aid in the recognition that the "epithelial atypia" is a normal finding in this location. On the other hand, one should keep in mind that PIN may occur in the central zone. Thirteen percent of the PIN foci in our study of cystoprostatectomy specimens occurred in the central zone. [13] If diagnosis of high-grade PIN is made in the central zone, current information indicates that it has no clinical significance. [14]

Seminal vesicle or ejaculatory duct epithelium may be encountered in TURP specimens or needle biopsies. The seminal vesicle and ejaculatory duct epithelium may be confused with high-grade PIN. Helpful features in distinguishing these normal structures from PIN include the presence of variably sized nuclei (round to oval), often with large "monstrous" cells containing intranuclear inclusions, and the presence of cytoplasmic pigment (lipofuchsin). It should be noted that lipofuchsin is also present in prostatic cells. In case of doubt, the ejaculatory duct/seminal vesicle epithelium is not immunoreactive to PSA or prostatic acid phosphatase (PAP).

PIN 1 can be very subtle, and sometimes other epithelial proliferations frequently encountered in the prostate may be initially misinterpreted as PIN 1. As well, normal tissue may be confused with PIN 1. When sections of tissue cores are in the order of 4 microns or less in thickness, it is not unusual to find a small nucleolus in normal or hyperplastic glandular epithelium. Other lesions that may be confused with low-grade PIN include epithelial hyperplasia of the usual type and transitional metaplasia. The usual hyperplasia does not show nuclear enlargement, but shows uniform nuclei that are evenly spaced without marked nuclear overlap. Transitional metaplasia is characterized by elongate oval shaped nuclei that often contain longitudinal nuclear grooves. A residual luminal (secretory cell) layer is generally present. When transitional metaplasia is more immature than usual, some nucleoli may be present; so, it may also be confused with PIN of a higher grade. In general, there is no nuclear enlargement.

PIN 1 may be confused with high-grade PIN. One must remember that PIN 1 may have prominent nucleoli and some degree of nuclear enlargement, but the number of cells with large nucleoli is minimal. Similarly, only a few cells should have nuclear enlargement.

Other benign epithelial proliferations that should be included in the differential diagnosis of high-grade PIN include basal cell hyperplasia and clear cell cribriform hyperplasia, which are usually not difficult to differentiate from high-grade PIN.

The carcinomas most likely to be confused with high-grade PIN include cribriform carcinoma, adenocarcinoma of ductal origin (especially retrograde filling of ductal structures), and transitional cell carcinoma involving ducts/acini. Features helpful in distinguishing TCC from high-grade PIN include the occasional presence of a residual luminal layer and cytologic characteristics. The cells of transitional cell carcinoma usually vary significantly in size and shape, have a very coarse chromatin pattern, and have significant mitotic activity. In lower grade TCC the cells may show longitudinal nuclear grooves. Because TCC in situ of the bladder frequently shows pagetoid spread, prostatic ducts/acini involved by TCC frequently demonstrate a basal cell layer, as in high-grade PIN.

Cribriform and ductal-endometrioid carcinomas can be very difficult to distinguish from high-grade PIN with a cribriform pattern. Basal cells are absent in both cribriform and ductal-endometrioid carcinomas, but basal cells may be present when there is retrograde involvement of normal ducts/acini by these tumors. In high-grade PIN, the basal cell layer is retained but in some cases may be only partially retained or "attenuated." The nuclear features of cribriform carcinoma are uniform throughout the duct. In contrast, in high-grade PIN with a cribriform/papillary pattern, the nuclei present at the top of the papillae or in the cribriform areas towards the center of the gland are smaller, rounder, and more hyperchromatic than the nuclei present towards the periphery of the gland. This feature is sometimes referred to as maturation.

Mitotic figures are frequently present in high-grade TCC and in prostate carcinoma of ductal origin and are rare in cribriform carcinoma and in high-grade PIN. While the presence of mitoses in glands considered to be high-grade PIN should call to mind other diagnostic considerations, it should be noted that mitoses are not infrequent in PIN in needle biopsies that have been subjected to rapid fixation. In specimens that have undergone slower and more prolonged fixation (cystoprostatectomy and radical prostatectomy specimens), mitoses are uncommon in PIN.

Basal Cell Layer in Prostatic Intraepithelial Neoplasia (PIN)
The basal cells and luminal cells of the prostatic glands display different keratin immunoreactivity. The high molecular weight cytokeratin monoclonal antibody (clone 34βE12, also referred to as CK-903), recognizes keratin proteins of 49, 51, 57 and 66 kd, and labels the basal cells but not the luminal/secretory cells of the prostatic glands. Other antibodies that also mark basal cells include p63 [15, 16] and cytokeratin 5/6. [17] p63 is a nuclear stain while CK 5/6 stains the cytoplasm. The basal cell layer is present in benign epithelial proliferations, may be disrupted in high-grade PIN, and is absent in carcinoma. [5, 18] Bostwick and Brawer [5]have shown that the frequency and extent of basal cell disruption in PIN is related to the PIN grade and is greatest in high-grade PIN (grade 3).

Clinical Significance of Prostatic Intraepithelial Neoplasia
As high-grade PIN is strongly predictive of the presence of carcinoma (about one third of cases), [1]the identification of high-grade PIN in biopsy specimens has important clinical implications. It has been recommended that only high-grade PIN be included in the pathology report. The pathologist should also indicate its extent in single or multiple core biopsy specimens. When high-grade PIN is present without carcinoma, the diagnosis of high-grade PIN has to be evaluated in conjunction with other clinical parameters, i.e., sextant biopsies versus extended biopsies (more than 10 cores from different sites) in order to determine whether immediate rebiopsy is indicated or whether interval follow-up with serum PSA, digital rectal examination and ultrasound should be recommended. It is also important to specify the number of foci of high-grade PIN and the number of cores involved. Kronz et al, [19] (reported that when three cores are involved with high-grade PIN, there is a 40% chance of finding invasive carcinoma on rebiopsy, but when 4 or more cores are involved, the percentage increases to 75%. [19]

Extended biopsy strategies that include sampling more than 10 biopsy sites of the prostate gland are currently being done in many centers. [20, 21, 22, 23] These biopsies sample areas of the prostate that the sextant biopsy procedure does not sample. Thus, the lateral-anterior aspect of the peripheral zone, the so-called "horns," and the area of the transition zone between the urethra and the pubis are included in addition to the usual areas sampled by the routine sextant biopsy procedure. These areas may harbor small microscopic foci of carcinoma. The current form of management for a patient with a high-grade PIN diagnosed by extended biopsies is to follow the patient on clinical basis. Since the extended biopsies literally map out the major portion of the prostate, if there is a focus of carcinoma, it is probably too small and of no clinical significance, allowing for clinical follow-up.

In summary, high-grade PIN is associated to invasive carcinoma in about one third of patients with this diagnosis. While it has been a routine management to rebiopsy a patient with diagnosis of high-grade PIN, the current practice of obtaining 10 or more core biopsies is changing this philosophy. Thus, patients who had 10 or more core biopsies are being followed with serum determination of PSA and clinical means rebiopsing only when changes become suspicious for invasive carcinoma. [20, 21, 22, 23]

References

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