Human Prostate Pathology

الموضوع ده بنتكلم فية عن مرض البروستاتا
an Prostate Pathology
Dr. Scott Shappell
Vanderbilt University

Inflammation of the prostate (prostatitis) is common clinically, representing a spectrum of acute and chronic disorders. Prostatitis is most typically diagnosed clinically and by laboratory tests. Histologically, inflammation in the prostate is extremely common. Increased lymphocytes in the prostatic stroma likely occurs with age and is common in the TZ and can be seen in clinical pathology material and does not constitute prostatitis. Active prostatitis (e.g., in chronic active prostatitis) is characterized by neutrophils and monocytes within prostatic epithelium and in gland lumens. This may be associated with mild elevations of PSA and can also produce reactive epithelial atypia.

Benign prostatic hyperplasia (BPH) is the most common urologic disease of men and results from androgen dependent proliferation of prostatic glands and stroma in the prostate transition zone (TZ). BPH increases in frequency with age, approximately 50% of men 50-60 years of age and > 90% of men over 80 exhibiting pathological features of BPH. More than one-third of men will require treatment for BPH in their lifetime. BPH occurs exclusively in the TZ and nodular prostatic growth in this region can result in compression of the prostatic urethra. Little correlation exists between the size of the enlarged prostate and/or TZ and clinical symptoms or decreased urinary flow rates, and increased contractile function of the prostatic stroma, bladder neck, or urethral sphincter is a potential contributing factor. Grossly, the prostate with BPH can be markedly enlarged (up to 100-200 gms vs normal weight of 20-30 gm) and the cut surface exposes marked, nodular expansion in the TZ. Histologically, nodules are composed of a variable mixture of benign glands and fibromusular stroma. The relative contribution of each these elements can differ greatly. Often the glandular elements are cystically dilated and impart a "swiss-cheese" appearance at low power. The glandular elements resemble those of normal benign prostate with large, elongate profiles, although the glands may be more densely packed and/or have increased secretory cells (hyperplasia). Foci of basal cell hyperplasia are also common. Cytologica atypia is not present. The stroma of BPH nodules is hypercellular, with spindle cells having appearance otherwise similar to normal prostate stromal cells. Pure stromal nodules are small circumscribed proliferations of bland spindle cells, often within a myxomatous appearing stroma, located in the immediate periurethral region.

Prostate cancer (Pca) is the most common (non-skin) cancer of males in the United States and about 200,000 cases are diagnosed annually in the US. Only lung cancer is responsible for more cancer related deaths than Pca, which causes approximately 35,000-40,000 deaths annually. Autopsy studies demonstrate an extremely high prevalence of Pca, with rates of histologic Pca as high as 30% in 50 year old males increasing progressively with age to between 70 and 80% by age 80. Such tumors are typically small and well to moderately differentiated, which has led to a distinction between these so-called "latent" or "autopsy Pcas" and so-called "clinical Pca", defined as those detected by clinical means such as by abnormal digital rectal examination (DRE) in the past. Pca is now most commonly diagnosed on transrectal biopsy performed because of an abnormal DRE or especially for an elevated serum PSA. Pca occurs commonly in the posterior and lateral regions of the gland in areas that are readily accessible to palpation in a DRE. PSA is a secretory protein synthesized by normal lumenal epithelial cells. Normal PSA values vary between 0-4 ng/ml. Serum PSA is increased in patients with Pca and in a patient with a PSA greater than 4 ng/ml, a biopsy will yield carcinoma in 25-30% of the cases. The percentage of positive cases is even higher when the PSA value is greater than 10 ng/ml. PSA level is also used for preoperative staging/treatment decision, and more recent refinements (e.g., free to bound PSA) have been developed for predicting cancer risk in patients with intermediate values (4-10 ng/ml) of total PSA.

Pca most often arises in the peripheral zone (PZ). Tumors that arise in the TZ may be seen in association with BPH nodules or may overgrow BPH nodules in the TZ. Such tumors may be detected incidentally during transurethral resection of the prostate (TURP) for BPH-related obstructive symptoms or be detected because of biopsy performed for elevated PSA. There more anterior location mandates that they would have to grow to very large size prior to palpation. TZ tumors may also be noted incidentally in radical prostatectomy specimens. Such tumors are often well differentiated, including Gleason patterns 1 and especially 2, being composed of somewhat circumscribed proliferations of larger glands with more ample, somewhat clear cytoplasm compared to usual Gleason pattern 3 Pca. Foci of infiltrating smaller glands (pattern 3) and even fused glands (Gleason pattern 4) can be seen, but even such tumors appear to have a favorable prognosis following treatment, potentially due to the more interior location and hence organ confined stage of the tumor or still undefined biological differences compared to more usual PZ located tumors.

Pca is difficult to recognize grossly in a radical prostatectomy specimen and areas that appear normal grossly are often infiltrated by adenocarcinoma. Prostatic intraepithelial neoplasia (PIN), particularly high grade PIN (HGPIN) appears to be a precursor lesion for many or most Pcas in the PZ. Recent studies have also begun drawing attention to post-inflammatory atrophy (PIA) as a possible Pca precursor, but further work needs to be done in this area. PIN is histologically defined as cytologically atypical cells (similar to those of cancer) occuring in architecturally benign glands (i.e., normal sized glands with undulating, tufting or papillary projections) similar to normal or hyperplastic glandular epithelium. PIN is now most usefully divided into low and high-grade with progressive nuclear stratification and nuclear enlargement. Macronucleoli, similar to those found in adenocarcinoma, are characteristic of HGPIN. HGPIN is often seen spatially associated with invasive Pca, shares similar molecular alterations at Pca, or has molecular alterations intermediate between benign prostate glands and Pca. The identification of PIN on a prostate biopsy has important implications because it is associated with a high frequency of invasive carcinoma in other biopsy portions or additional sections. There is an increased risk (30-40%) of finding invasive carcinoma on subsequent biopsies, especially in patients with persistent elevation of their serum PSA. Pca seen in association with HGPIN is typically Gleason pattern 3. With tumor growth, "dedifferentiation" to Gleason pattern 4 or higher may be seen, or alternatively, some high grade tumors may arise as such or quickly progress to such, and the relationship between tumor grade and volume may also reflect a growth advantage of higher grade tumors.

Pca is diagnosed by a combination of architectural and cytological features. Pca is generally composed of small, infiltrative glands or sometimes large, irregular glands ( that are too large for cribriform PIN) as well as nuclear and nucleolar enlargement. Nucleoli in malignant glands often reach 3-4 microns or more in diameter. Additionally, normal prostate glands have a tufted epithelial lining composed of 2 cell layers including apical secretory cells as well as a basal cell layer. In progressively higher grade PIN, the basal cell layer may focally be lost while in malignant prostate glands the basal cell layer is totally absent and malignant glands are usually lined by a single layer of cuboidal cells. The basal cell layer can be selectively stained using antibodies to high molecular weight keratin (e.g., CK-903), and the absence of a basal cell layer can be a useful adjunct in the recognition of Pca in a sufficiently large suspicious focus on biopsy. Other histologic features that support the diagnosis of cancer include certain types of intraluminal secretions including blue-tinged mucin, dense pink secretions and eosinophilic crystalloids. Perineural invasion (circumferential growth by atypical cells), present in most radical prostatectomy specimens, is also highly specific for Pca when seen on biopsy. Tumor grade in biopsies is an important factor in treatment decisions and tumor grade in prostatectomy specimens is a major determinate of prognosis and patient management.

Tumor grading is generally accomplished by applying a Gleason grade which is based solely on the histologic or architecture pattern of the neoplasm. The tumor is assigned a primary and a secondary Gleason pattern (1 through 5) based on the predominant and second most predominant patterns for a combined Gleason grade (or Gleason score) of 2-10. Gleason pattern 1 tumors are well circumscribed and composed of fairly uniform, round closely spaced back-to-back glands. Pattern 2 tumors are similar but show a little more irregularity and glands are less uniform in shape and more widely spaced. These patterns (i.e., combined Gleason grade 2-4) are most often found in TZ cancers. Grade 3 patterns show smaller glands that infiltrate between histologically benign glands. Glandular formation begins to become lost in grade 4 patterns with fusion of glands or large, irregularly outlined cribriform nests with minimal luminal differentiation. Gleason 5 patterns include solid nests, including with comedo-type ncrosis and infiltration in small nests without glandular lumens, irregular cords or single cells. Larger volume, higher grade tumors also often contain cribriform and solid proliferations of tumor within pre-existing ducts, sometimes with necrosis. These high grade patterns may represent the spread of invasive tumor within ducts (a "post-invasive" phenomenon in contrast to pre-invasive HGPIN lesions).

In radical prostatectomy specimens, in addition to tumor grade, it is important to determine tumor stage. Stage includes whether the tumor is organ confined or whether it has extended beyond the prostate capsule (pT3a), commonly occurring in the superior posteriolateral aspect, facilitated by large nerve bundles there. Tumors can grow into the ejaculatory ducts within the prostate and ascend to involve the seminal vesicles, or grow directly into the seminal vesicles by extension from the prostate base or from periprostatic soft tissue up at the base, pT3b. Seminal vesicle invasion imparts a markedly worse prognosis. The status of pelvic lymph nodes is also routinely assessed, with lymph node metastases markedly worsening prognosis. Independent of stage at present, the status of surgical margins (e.g., apical, bladder neck, anterior, posterior, lateral, and posterolateral) is also assessed. In general, positive surgical margins ( particularly posterolateral in association with T3 disease and bladder neck) increases risk for disease progression following treatment.