Introduction
Over the past few years, pathologists have taken on several important roles in the assessment of adenocarcinomas of the prostate. First, the availability of postoperative serum prostate-specific antigen (PSA) levels and their establishment as a sensitive indicator of progression following surgery have provided the impetus to correlate pathologic findings with progression following radical prostatectomy. The second major role pathologists play is in the diagnosis of adenocarcinoma of the prostate. With the advent of the thin needle biopsy gun and screening with serum PSA, there has been a dramatic increase in the number of needle biopsies performed to rule out adenocarcinoma of the prostate. Pathologists are challenged to make diagnoses on these very limited tissue specimens, as well as to accurately grade and quantify the tumor.
This article covers some of the more topical issues in the pathology of prostatic adenocarcinoma, from its precursor lesions to invasive carcinomas, from needle biopsies to radical prostatectomies. In particular, the discussion focuses on practical aspects of pathology that are critical for oncologists to know for the management of their patients.
Prostatic Intraepithelial Neoplasia
Prostatic intraepithelial neoplasia (PIN) consists of architecturally benign prostatic acini or ducts lined by cytologically atypical cells. Initially, this lesion was termed "intraductal dysplasia," and was classified into three grades: PIN1 (mild dysplasia), PIN2 (moderate dysplasia), and PIN3 (severe dysplasia) [1]. Most authorities today use the term "high-grade PIN" to encompass both PIN2 and PIN3 and "low-grade PIN" to denote PIN1.
Low-Grade PIN
Low-grade PIN should not be commented on in diagnostic reports. First, pathologists cannot reproducibly distinguish low-grade PIN from benign prostate tissue [2]. Second, when low-grade PIN is diagnosed on needle biopsy, patients are at no greater risk of having carcinoma on repeat biopsy [3].
High-Grade PIN
There are several reasons why PIN2 and PIN3 should be combined as high- grade PIN. First, there is much interobserver variability in the distinction between PIN2 and PIN3 [2]. Second, the finding of either PIN2 or PIN3 on needle biopsy is associated with the same risk of carcinoma on subsequent biopsy.
In prostates with carcinoma, there is an increase in the size and number of high-grade PIN foci, as compared with prostates without carcinoma. Also, with increasing amounts of high-grade PIN, there are a greater number of multifocal carcinomas [1]. Several studies have noted an increase in high- grade PIN in the peripheral zone of the prostate, corresponding to the site of origin for most prostate adenocarcinomas. A growing body of data has demonstrated that the expression of various biomarkers in high-grade PIN is either: (1) the same as in carcinoma, as opposed to benign prostate tissue; or (2) intermediate between benign tissue and carcinoma. All of the above findings are to be expected if high-grade PIN is a precursor lesion to prostate carcinoma [4].
High-grade PIN is most critical when found on needle biopsy. In a consecutive series of sextant biopsies performed at Johns Hopkins Hospital, the incidence of high-grade PIN without carcinoma on needle biopsy material was 2%. However, other studies have reported that up to 16% of needle biopsies show high-grade PIN. When high-grade PIN is found on needle biopsy, there is between a 30% and 50% risk of finding carcinoma on subsequent biopsies [3].
The presence of an abnormal rectal examination or an abnormal ultrasound scan does not identify which patients are more likely to have carcinoma on follow-up biopsies; on ultrasound, high-grade PIN may appear indistinguishable from cancer as a hypoechoic lesion [5]. In men with high-grade PIN on needle biopsy, the one finding that increases the likelihood that there is an unsampled carcinoma is an elevated serum PSA density; PIN, by itself, does not give rise to elevated serum PSA values [6].
A repeat biopsy should be performed when high-grade PIN is found on needle biopsy. The significance of the finding of high-grade PIN on transurethral resection of the prostate is more controversial, as there are no follow-up studies in the literature. Some pathologists recommend that needle biopsies be performed on patients who have high-grade PIN on transurethral resection, although others recommended needle biopsies only in younger men [2].
Histologically, PIN can be confused with several benign entities, as well as ductal and acinar (ordinary) adenocarcinoma of the prostate. Also, there are some histologic patterns that are diagnostic of high-grade PIN to some pathologists and yet represent high-grade PIN and associated adenocarcinoma to others [2]. Ploidy does not distinguish high-grade PIN from infiltrating cancer.
Lack of Data on Natural History
Unlike premalignant lesions in other organs, data are lacking on the natural history of high-grade PIN. At present, there is no way to monitor a PIN focus in the prostate to determine: (1) whether or not there already is an infiltrating carcinoma at that site; or (2) when infiltrating carcinoma evolves, whether it has done so in the immediate vicinity of the PIN focus. Because we do not know what percentage of patients with the biopsy finding of high-grade PIN develop infiltrating carcinoma over a given follow-up interval, most authorities do not use the term "carcinoma in-situ of the prostate."
In addition, some data have raised questions about the relationship of PIN to carcinoma. The majority of prostates with early carcinomas lack any high-grade PIN. Also, when PIN is present in glands with an early carcinoma, the intraepithelial neoplasia often is not adjacent to the carcinoma [7]. It appears that high-grade PIN is a precursor lesion to many peripheral intermediate- to high-grade prostatic adenocarcinomas. However, PIN need not be present for carcinoma to arise. Low-grade carcinomas, especially those present within the transition zone, are not closely related to high-grade PIN [2].
Despite this lack of information on the natural history of PIN, it is hoped that suppression of PIN will lead to a long-term decrease in prostate cancer. Based on the observation that potent antiandrogen therapy (luteinizing hormone-releasing hormone [LHRH] agonists and flutamide(Drug information on flutamide) [Eulexin]) can decrease the extent of PIN, a large chemoprevention trial sponsored by the National Institutes of Health is currently attempting to determine whether use of a weaker, less toxic hormonal therapy (ie, 5-alpha-reductase inhibitors) will also have an impact on PIN and carcinoma [8].
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
