A normal gland weighs approximately 20 grams in young adults, 20-40 years The urethra passes through center of gland with a sharp 35-degree angle at the halfway point to form proximal and distal urethral segments Verumontanum arises from the posterior aspect of distal urethra and is associated with the openings of the majority of ducts The utricle is a small mullerian remnant located proximal to the verumontanum Most of the gland is surrounded by a dense fibromuscular capsule which is best defined posteriorly and laterally The capsule is poorly defined anteriorly and at the apex making assessment of "extracapsular spread" difficult The major nerve supply to the gland comes via the paired neurovascular bundles which enter the gland laterally near the base This is one reason that most carcinomas which extend beyond the gland do so at this location The paired seminal vesicles are embedded in a dense fibromuscular stroma attached to the posterior bladder wall and drain into the ejaculatory ducts The capsule is also poorly defined at this region Historically the gland was divided into lobes but currently is thought of more in terms of "zones" that have distinctive clinicopathologic correlations.

Accounts for 25% of normal prostate Roughly triangular shaped region with apex at orifice of the ejaculatory ducts in the verumontanum and its base along posterior bladder base It surrounds the ejaculatory ducts About 5% of carcinomas thought to arise here.

Accounts for 5% of normal gland Comprises 2 small lobes which for practical purposes surround the proximal urethra extending from the bladder neck to near the angle of the urethra Nodular hyperplasia (BPH) almost exclusively arises in this zone Approximately 10-20% of carcinomas arise here

Accounts for 70% of the normal gland Surrounds the distal urethra making up the entire apical portion of the gland and extends proximally to near the bladder base peripherally at the posterior and lateral aspects 80% of carcinomas arise here

Gland-free zone consisting of dense fibromuscular connective tissue Blends imperceptibly into bladder neck musculature and apical connective tissue Mostly thick bands of smooth muscle but skeletal muscle also may be present

The gland is essentially made up of numerous tubuloalveolar glands embedded in a fibromuscular stroma The prostatic acini and ducts are all lined by a double layered epithelium made up of basal and secretory cells The basal cells are located between the secretory cells and the basement membrane and likely represent the normal proliferative compartment of the gland The basal cells do not stain for PSA or PAP but can be highlighted with stains for high molecular weight cytokeratin The secretory cells are tall and columnar with clear to pale pink (eosinophilic) cytoplasm The secretory cells stain for PSA and PAP Central zone glands differ from peripheral zone glands in that they have more complex architecture often with micropapillary structures and Roman arch formation. The secretory cells commonly display cytoplasmic lipochrome pigment and the surrounding stroma is dense and compact in comparison to the looser stroma which is characteristically around peripheral zone glands Normal transition zone glands are similar to peripheral zone glands. However, in the aging male, evidence of glandular and stromal hyperplasia is commonly found The prostatic urethra is lined by transitional epithelium which extends for short segments into some ducts The seminal vesicle also has a double layered epithelium characterized by the presence of a golden-brown pigment (lipofuscin) and large pleomorphic (monster) nuclei.

RADICAL PROSTATECTOMY SPECIMENS
Radical prostatectomy specimens are commonly encountered in a modern surgical pathology practice. The information derived from such specimens is used in planning for adjuvant therapy such as radiation and is also used for general prognostic purposes. It is important that the radical prostatectomy specimens are handled in a standardized fashion that allows derivation of the relevant prognostic information.

Handling a Radical Prostatectomy Specimen
There are a variety of methods of handling a radical prostatectomy specimen. In my laboratory, we process the complete gland in the following fashion:

Specimens are generally received fixed in 10% neutral buffered formalin, recommended fixation time 18-24 hours. Weigh specimen (grams) and measure in three dimensions; also include measurements of seminal vesicles. Outer aspect is painted with ink (green on right, blue on left; Davidson marking inks); some authors use additional colors to indicate other areas such as apex and base. The distal 1-1.5 cm apical segment is transected and sectioned in a radial fashion (analogous to cone biopsy). The basal (bladder neck) transverse slice is removed and sectioned perpendicular to the bladder neck surface (inked). Radial/perpendicular sections are used for the apical and bladder neck margins rather than "shave" or enface sections. The latter can result in spurious positivity if the block face is not flat at the time of sectioning. Remainder of gland transversely sectioned perpendicular to the rectal surface at 3-5 mm intervals. Seminal vesicles transversely sectioned from base to tip at 3-5 mm intervals. All sectioned tissue including apical and bladder neck (basal) sections are laid out on a plexiglass orientation board that includes markers for left, right, apex and base. A photocopy of plexiglass orientation board obtained. Block legend indicating cassette numbers written on photocopied sheet. In general, transverse sections are quadrisected, however, in large glands, sometimes six blocks are required. Photocopied sheets may be used during histological assessment for documentation of presence and extent of tumor and to indicate other observations such as extraprostatic extension and margin positivity.

Partial Sampling
In my experience, it takes approximately one block per gram of radical prostatectomy specimen. The average number of blocks per radical prostatectomy specimen in my own practice is about 38.

There is data in the literature suggesting that partial submission strategies can provide the required prognostic factor information. In an era of cost containment, such strategies may be prudent. In the situation where there is a dominant palpable nodule involving one side of the gland, the whole involved side may be processed with only selective sampling of the opposite side. In the modern era of PSA screening, dominant palpable nodules are becoming much less common and in these situations a gross tumor is usually not visualized. Partial sampling strategies can involve submission of alternate transverse slices of the gland. In such methods, it is important to include the apical and basal segments in their entirety as described above. In some situations, one has to deal with very large hyperplastic glands (>75 grams) with a prominent nodular transition zone. In these situations, one can remove the transition zone from each transverse slice and only submit the peripheral tissue in its entirely. Selective samples from the right and left transition zones should also be obtained. In this fashion, considerable numbers of blocks can be saved. In situations where no tumor is identified in the first round, the remainder of the tissue would then have to be processed. In most situations, however, tumor is readily identified in the initial partial sampling.

Reporting of Radical Prostatectomy Specimens with Emphasis on Prognostic Factors
The histologic assessment of radical prostatectomy specimens provides important prognostic attributes of prostate cancer that warrant being routinely reported. The College of American Pathologists (CAP) has developed a classification system for prognostic factors in solid tumours and this has been advocated for usage in prostate cancer. Category 1 prognostic factors are those that have been deemed to be of proven prognostic significance and are useful in clinical patient management. In radical prostatectomy specimens, the Gleason score, pathologic stage and margin status fall into category 1 along with preoperative serum PSA. Category 2 prognostic factors are those that "show promise" as predictive or prognostic factors based on evidence from published studies but still require further evaluation. Tumor volume (intraglandular extent) and histologic subtype fit into this category.

There are a large number of category 3 prognostic factors where there is some scientific evidence to support their adoption as diagnostic or prognostic factors but where the data is too preliminary.

Category 3 factors include perineural invasion, lymph-vascular space invasion, proliferation markers and apoptotic markers, microvessel density measurements, neuroendocrine marker status and various other phenotypic and genotypic markers.

Based on literature review and consensus development, it has been recommended by the CAP that the factors listed in table 1 be reported in radical prostatectomy specimens. All of these factors are assessed by microscopic evaluation.

Table 1 - Prognostic Factors Recommended For Reporting In Radical Prostatectomy Specimens

Histologic type Histologic grade: Gleason score with primary and secondary grades Tumor size: Percentage of prostatic tissue involved by carcinoma Pathologic stage: TNM system application Margins: Location and extent of margins involved with tumor

Histologic Type While 95% of prostatic adenocarcinomas are of conventional or acinar type, there are a number of variants that have been identified. These are listed in table 2 using a classification suggested in the AFIP Fascicle on Prostate Tumors.

Table 2 - Histologic Variants Of Prostatic Carcinoma

Prostatic duct adenocarcinoma Mucinous (colloid) adenocarcinoma Signet ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Basaloid and adenoid cystic carcinoma Transitional cell carcinoma Small cell carcinoma Sarcomatoid carcinoma Lymphoepithelioma-like carcinoma Undifferentiated carcinoma, not otherwise specified

The subtypes are uncommon but many of them do have a special prognostic significance. For instance, small cell carcinoma is a particularly aggressive neoplasm which may occur has a pure form or in combination with ordinary adenocarcinoma. There may be a role of adjuvant chemotherapy in the context of metastatic disease.

Histologic Grade (Gleason Score)
The histologic grade of adenocarcinoma in radical prostatectomy specimens is one of the mot powerful predictors of patient outcome after surgery. Both the World Health Organization and the College of American Pathology (1999 Consensus Conference) have recommended routine reporting of Gleason grades (scores) in radical specimens.

It is recommended that both the primary and secondary Gleason patterns (grades) should be reported along with a score (sum). There are scant data related to the presence tertiary patterns but any high grade tumors (grade 4,5) should be noted, even if it is a minor or tertiary component.

Some authors have suggested that the quantification of the percent Gleason patterns 4/5 is of prognostic significance, however, the role of this measure needs further study. Reproducibility and interobserver agreement in the quantification of the percent Gleason patterns 4/5 needs to be demonstrated.

Prostatic adenocarcinoma is frequently multifocal in radical prostatectomy specimens. Some pathologists only report the Gleason score of the "dominant nodule". This may be okay in the situation of a pT2 nodule; however, many tumors in the PSA-screening era do not have a dominant nodule but are multifocal. It is recommended that a Gleason score (grade) be based on the entire tumor in radical prostatectomy specimens.

Tumor Size
Tumor size (volume) is an important prognostic factor linked to a variety of pathologic and clinical end points such as histologic grade, TNM Stage, PSA level, outcome and response to therapy. Additionally, definitions of clinically significant versus clinically unimportant prostate cancer generally incorporate tumor size measurement. The percentage of carcinoma in radical prostatectomy specimens has been shown to be an independently important prognostic factor with respect to recurrence after surgery.

A variety of methods of measuring tumor size are available to the pathologist including visual inspection of the percent of tissue involved by tumor which can be expressed in intervals such as <1%, <5%, 5-10%, 10-20%, etc. Other methods include measuring the diameter of the largest tumor nodule visualized microscopically, counting the number of blocks involved by tumor, grid morphometric analysis and computer assisted image analysis. The latter approach is the most rigorous and quantitative method but is impractical for routine surgical pathology practice. The reporting of tumor size is recommended both by the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology. It is generally suggested that the light microscopic visual inspection of percent of prostatic parenchyma involved by carcinoma be reported on radical prostatectomy specimens.

Pathologic Staging (TNM)
The current TNM Classification of Prostatic Adenocarcinoma is shown in table 3. The pathologic pT category should be reported in radical prostatectomy specimens. There is no pathologic pT1 category. pT2 disease is organ confined with subcategories including pT2a - tumor involving one-half of one lobe or less, pT2b - tumor involving more than one-half of one lobe but not both lobes, and pT2c - tumor involving both lobes. pT3 disease is extraprostatic with pT3a being extraprostatic extension and pT3b involving seminal vesicle. pT4 disease is locally aggressive with invasion of local structures such as the urinary bladder, rectum or pelvic wall musculature.

Table 3 - 2002 TNM Classification - Prostatic Adenocarcinoma

Primary Tumor, Clinical (T) TX Primary tumor cannot be assessed TO No evidence of primary tumor T1 Clinically unapparent tumor not palpable or visible by imaging T1a — Tumor incidental histologic finding in 5% or less of tissue resected T1b — Tumor incidental histologic finding in more than 5% of tissue resected T1c — Tumor identified by needle biopsy (e.g. because of elevated PSA) T2 Tumor confined within prostate* T2a — Tumor involves one half of one lobe or less T2b — Tumor involves more than one half of one lobe, but not both lobes T2c — Tumor involves both lobes T3 Tumor extends through the prostatic capsule** T3a — Extracapsular extension (unilateral or bilateral) T3b — Tumor invades seminal vesicle(s) T4 Tumor is fixed or invades adjacent structures other than seminal vesicles, bladder neck, external sphincter, rectum, levator muscles, and /or pelvic wall Primary Tumor, Pathologic (pT) pT2*** Organ confined pT2a — Tumor involves one half of one lobe or less pT2b — Tumor involves more than one half of one lo be, but not both lobes pT2c — Tumor involves both lobes pT3 Extraprostatic extension pT3a — Extraprostatic extension pT3b — Seminal vesicle invasion pT4 Invasion of bladder, rectum Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Metastasis in regional lymph node or nodes Distant Metastasis**** (M) MX Distant metastasis cannot be assessed MO No distant metastasis M1 Distant metastasis M1a — Non-regional lymph node(s) M1b — Bone(s) M1c — Other site(s)

^* Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging is classified as T1c.

^** Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.

^*** There is no pathologic T1 classification

^**** When more than one site of metastasis is present, the most advanced category is used. PM1c is most advanced.

The distinction between pT2 and pT3 is critical and depends on the identification of extraprostatic extension (EPE). The descriptors of EPE are outlined in table 4.

Table 4 - Descriptors of Extraprostatic Extension (EPE)

involvement of fat involvement of perineural space in large neurovascular bundles bulging tumor beyond the normal contours of the prostate gland, sometimes with desmoplastic stromal reaction

Earlier literature emphasized tumor extending beyond the prostatic capsule, the latter representing a condensation of fibromuscular connective tissue that blends imperceptibly into prostatic stroma. The prostatic capsule is present to some extent along the posterior and lateral aspects of the gland but is relatively deficient anteriorly, basally and at the apex. There has been confusion in the literature regarding terms such as invasion to, into and through capsule along with terms such as capsular penetration or perforation. EPE is the preferred terminology when the tumor extends beyond the normal confines of the prostate gland.

In radical prostatectomy specimens, involvement of periprostatic fat indicates EPE. There have been extremely rare instances of intraprostatic fat but for all practical purposes involvement of fat indicates EPE. EPE has been subdivided into focal and established categories where focal EPE = only a few neoplastic glands involving periprostatic fat and established EPE means more extensive involvement often with a tongue of tumor extending well into the fat.

Tumor involving large nerves usually in the region of the neurovascular bundles, even in the absence of fat involvement, is also considered EPE. Bulging tumor beyond the normal contour of the prostatic edge sometimes with a desmoplastic reaction is also an indication of EPE, even in the absence of fat involvement. Identification of EPE anteriorly and basally where fat is relatively deficient can be quite difficult. In the absence of fat involvement, the presence of a bulging nodule, desmoplasia or infiltration of large smooth muscle bundles of the bladder neck indicates EPE. Microscopic involvement of the bladder neck does not indicate pT4 disease. This generally requires gross extension of tumor into bladder muscle.

pT3b disease is defined as involvement of the muscular wall of the seminal vesicle. Care must be taken not to equate ejaculatory duct involvement with seminal vesicle involvement. Ejaculatory ducts are surrounded by loose fibrovascular connective tissue and lack a well developed muscular wall. Seminal vesicle invasion requires involvement of the muscular wall and not just the soft tissue surrounding the seminal vesicle. The latter would still indicate pT3a disease.

Prostatic carcinoma may involve seminal vesicle through a variety of routes:

1. spread along ejaculatory duct
   
   
2. extension directly from base of prostate into seminal vesicle
   
   
3. invasion of periprostatic and periseminal vesicle soft tissue with secondary extension into the muscular wall
   
   
4. rarely metastatic deposits.

1. artifactual positivity created by tissue disruption at surgery or in the pathology lab
   
   
2. destruction of tumor cells at the margin by mechanical factors, ischemia or granulation tissue
   
   
3. lack of aggressiveness of some tumors even when at the margin.

REFERENCES

Anatomy and Histology

1. McNeal JE. Normal histology of the prostate. Am J Surg Pathol 12:619-633, 1988.
   
   
2. McNeal JE, Stamey TA, Hodge KK. The prostate gland: Morphology, pathology and ultrasound anatomy. Monogr Urol 9:36-54, 1988.

Handling a Radical Prostatectomy Specimen

1. Amin MB, Grignon DJ, Bostwick DG, et al. Recommendations for reporting of resected prostatic adenocarcinoma. Am J Clin Pathol 105:667-670, 1996.
   
   
2. Cohen MB, Soloway MS, Murphy WM. Sampling of radical prostatectomy specimens: how much is adequate? Am J Clin Pathol 101:250-252, 1994.
   
   
3. Epstein JI. Pathologic assessment of the surgical specimen. Urol Clin North Am. 28:567-594, 2001.
   
   
4. Smith Sehdev AE, Pan CC, Epstein JI. Comparative analysis of sampling methods for grossing radical prostatectomy specimens performed for nonpalpable (stage T1c) prostatic adenocarcinoma. Hum Pathol 32(5):494-499, 2001.
   
   
5. Hall GS, Kramer CE, Epstein JI. Evaluation of radical prostatectomy specimens: A comparative analysis of sampling methods. Am J Surg Pathol 16:315-324, 1992.
   
   
6. Humphrey PA, Walther PJ. Adenocarcinoma of the prostate: Tissue sampling considerations. Am J Clin Pathol 99:746-759, 1993.
   
   
7. Sakr WA, Grignon DJ, Visscher DW, et al. Evaluating the radical prostatectomy specimen: A protocol for establishing prognostic parameters and defining genetic abnormalities. J Urologic Pathol 3:355-364, 1995.
   
   
8. Sakr WA, Wheeler TM, Blute M, et al. Staging and reporting of prostate cancer - sampling of the radical prostatectomy specimen. Cancer 78:366-368, 1996.
   
   
9. Srigley JR, Amin MB, Bostwick DG, Grignon DJ, et al. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland. A basis for checklists. Arch Pathol Lab Med 124:1034-1039, 2000.
   
   
10. True LD. Surgical pathology examination of the prostate gland: practice survey by the American Society of Clinical Pathologists. Am J Clin Pathol 102:572-579, 1994.
    
    
11. Wheeler TM, Lebovitz RM. Fresh tissue harvest for research from prostatectomy specimens. Prostate 25:274-279, 1994.

Reporting Of Radical Prostatectomy Specimens With Emphasis On Prognostic Factors

1. Association of Directors of Anatomic and Surgical Pathology: Recommendations for the Reporting of Resected Prostate Carcinomas. Am J Clin Pathol 105:667-670, 1998.
   
   
2. Bostwick DG, Foster CS: Predictive factors in prostate cancer: Current concepts from the 1999 College of American Pathologists Conference on Solid Tumor Prognostic Factors and the 1999 World Health Organization Second International Consultation on Prostate Cancer. Semin Urol Oncol 17:222-272, 1999
   
   
3. Bostwick DG, Grignon DJ, Hammond EH, et al. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:995-1000, 2000.
   
   
4. Carvalhal GF, Humphrey PA, Thorson P, et al. Visual estimate of the percentage of carcinoma is an independent predictor of prostate carcinoma recurrence after radial prostatectomy. Cancer 89:1328-1314, 2000.
   
   
5. Greene FL, Page DL, Flemming ID, Fritz AG, Balch CM, Haller DG, Morrow M. AJCC Cancer Staging Manual, 6^th Edition, Springer 2002, pp 309-313.
   
   
6. Humphrey PA, Vollmer RT: Percentage carcinoma as a measure of prostatic tumor size in radical prostatectomy tissues. Mod Pathol 10:320-333, 1997.
   
   
7. Humphrey PA, Walther PJ: Adenocarcinoma of the prostate. Part II: Tissue prognosticators. Am J Clin Pathol 100:256-269, 1993.
   
   
8. Iselin CE, Robertson JE, Paulson DF: Radical perineal prostatectomy: Oncological outcome during a 20-year period. J Urol 161:163-168, 1999.
   
   
9. McNeal JE, Villers AA, Redwine EA, et al. Histologic differentiation, cancer volume and pelvic lymph node metastasis in adenocarcinoma of the prostate. Cancer 66:1225-1233, 1998.
   
   
10. Ohori M, Scardino PT, Lapin SL, et al. Teh mechanisms and prognostic significance of seminal vesicle involvement by prostate cancer. Am J Surg Pathol 17:1252-1261, 1993.
    
    
11. Pan CC, Potter SR, Partin AW, Epstein JI: Teh prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: A proposal to modify the Gleason grading system. Am J Surg Pathol 24:563-569, 2000.
    
    
12. Paulson DF: Impact of radical prostatectomy in the management of clinically localized disease. J Urol 152:18286-1830, 1994.
    
    
13. Randolph TL, Amin MB, Ro JY, Ayala AG: Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. Mod Pathol 10:612-629, 1997.
    
    
14. Srigley JR, Amin MB, Bostwick DG, Hammond EH, for Members of the Cancer Committee, College of American Pathologists. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland. A basis for checklists. Arch Pathol Lab Med 124:1034-1039, 2000.
    
    
15. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol 29:856-862, 1998.
    
    
16. Wieder JA, Soloway MS: Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 160:299-315, 1998.
    
    
17. Young RH, Srigley JR, Amin MB, Ulbright TM, Cubilla A: Tumors of the Prostate Gland, Seminal Vesicle, Male Urethra and Penis. Washington DC: Armed Forces Institute of Pathology. Atlas of Tumor Pathology, 3^rd series, 2000.