29 - Gallbladder and Extrahepatic Biliary System

Editors: Mills, Stacey E.

Title: Histology for Pathologists, 3rd Edition

> Table of Contents > IX - Genitourinary Tract > 36 - Prostate

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Prostate

John E. McNeal

Embryology and Development of the Prostate

The prostate appears in early embryonic development as a condensation of mesenchyme along the course of the pelvic urethra. By 9 weeks of embryonic life, a number of features that are characteristic of adult contour and location are evident (Figure 36.1). The mesenchymal condensation is most dense along the posterior (rectal) aspect of the urethra and distal (apical) to its midpoint. This is the only region where highly condensed mesenchyme is in immediate contact with urethral lining epithelium, and only here is the urethra lined by a tall columnar epithelium (1). Between its midpoint and the bladder neck, the proximal urethral segment shows a sharp anterior angulation. However, the strip of highly condensed mesenchyme continues directly proximally to a dome-shaped base, leaving a gap between condensed prostatic mesenchyme and proximal urethra.

The ejaculatory ducts penetrate the mesenchyme toward the future verumontanum, which is located at the urethral midpoint. This is wolffian duct tissue, but its stroma is indistinguishable from the remaining prostatic mesenchyme, which is mainly derived from the urogenital sinus (2). However, that portion of the mesenchyme that surrounds the ejaculatory ducts and expands proximally to occupy nearly the entire prostate base is distinguishable in the adult as the central zone, which is probably also derived from the wolffian duct, as are the seminal vesicles (1). In this concept, the prostate is of dual embryonic derivation.

At about 10 weeks, epithelial buds begin to branch, mainly posteriorly and laterally from the posterior and lateral walls of the distal urethral segment into the condensed mesenchyme. Recent computer reconstructions of serially sectioned specimens have shown that the branching pattern that is established initially is identical to that described for the adult later in this chapter (3).

This developmental program is activated by androgen secreted by the fetal testes. However, the eventual size of the neonatal prostate less than 1 cm in diameter is predetermined by the stroma as a programmed number of stromal cell divisions, after which the stroma ceases to have further inductive influence on the branching duct system.

Figure 36.1 Embryonic prostate, age 9 weeks, in the sagittal plane of the pelvis. Urethra (narrow central lumen) is angulated to the right at the midpoint, where the ejaculatory duct approaches from above left. A vertical strip of highly condensed prostate mesenchyme contacts the posterior urethral wall only distal to the ejaculatory ducts. The prostate is flanked by the rectum (left) and pubis (right). Duct buds have not yet formed.

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Postnatally the prostate grows at a slow rate, reaching less than 2 cm in diameter by the time of puberty. During this period, the ducts and acini are lined by epithelium, which undergoes little change from the neonatal period. Gland spaces are lined by cells that are crowded with multilayered dark nuclei (Figure 36.2). There is a superficial resemblance to adult postinflammatory atrophy, but the histologic features are quite different.

The pubertal growth acceleration and maturation of the prostate gland appears not to be complete until at least 20 years of age. The average prostate by this time measures about 4.5 cm in width, 3.5 to 4.0 cm in length, and 3 cm in thickness. In most men over 50 years of age, there is focal resumption of growth as benign nodular hyperplasia (BPH). This process increases the thickness of the gland prominently and affects its length the least; in massive BPH, however, the prostate becomes nearly spherical, with a diameter of 6 cm or more. Dissections show that BPH represents enlargement of only a single tiny region of the gland. In fact, the normal mass of the glandular portion of the prostate after subtraction of the BPH-prone region remains at nearly constant mean volume until 70 years of age or more. However, the range about the mean increases in men more than 50 years of age, suggesting that the normal non-BPH glandular prostate may continue enlarging into old age rather than undergoing atrophy.

Figure 36.2 Prepubertal prostatic duct lined by epithelium with multiple layers of nuclei and showing no cytoplasmic differentiation.

General Relationships: The Glandular Prostate

The human prostate gland is a composite organ, made up of several glandular and nonglandular components. These different tissues are tightly fused together within a common capsule so that gross dissections are difficult and unreliable. Anatomic features are best demonstrated by examination of cut sections in carefully selected planes (4,5). The nonglandular tissue of the prostate is concentrated anteromedially and is responsible for much of the anterior convexity of the organ. The contour of the glandular prostate approximates a disk with lateral wings that fold anteriorly to partially encircle the nonglandular tissue. There are four distinct glandular regions, each of which arises from a different segment of the prostatic urethra.

The urethra is a primary reference point for describing anatomic relationships. These relationships are best visualized in a sagittal plane of section (Figure 36.3). The prostatic urethra is divided into proximal and distal segments of approximately equal length by an abrupt anterior angulation of its posterior wall at the midpoint between the prostate apex and bladder neck (1,6). The angle of deviation is roughly 35 degrees, but it is quite variable and is greater in men with nodular hyperplasia. The base of the verumontanum protrudes from the posterior urethral wall at the point of angulation. The verumontanum bulges into the urethral lumen along its posterior wall for about half the length of the distal segment and tapers distally to form the crista urethralis.

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Figure 36.3 Sagittal diagram of distal prostatic urethral segment (UD), proximal urethral segment (UP), and ejaculatory ducts (E) showing their relationships to a sagittal section of the anteromedial nonglandular tissues [bladder neck (bn), anterior fibromuscular stroma (fm), preprostatic sphincter (s), distal striated sphincter (s)]. These structures are shown in relation to a three-dimensional representation of the glandular prostate [central zone (CZ), peripheral zone (PZ), transition zone (TZ)]. Coronal plane (C) of Figure 36.4 and oblique coronal plane (OC) of Figure 36.5 are indicated by arrows.

The distal urethral segment receives the ejaculatory ducts and the ducts of about 95% of the glandular prostate; it is, therefore, the only segment that is primarily involved in ejaculatory function. The ejaculatory ducts extend proximally from the verumontanum to the base of the prostate, following a course that is nearly a direct extension of the long axis of the distal urethral segment, although usually offset a few millimeters posteriorly.

A coronal plane of section along the course of the ejaculatory ducts and distal urethral segment provides the best demonstration of the anatomic relationships between the two major regions of the glandular prostate (7) (Figure 36.4). The peripheral zone comprises about 65% of the mass of the normal glandular prostate. Its ducts exit from the posterolateral recesses of the urethral wall along a double row extending from the base of the verumontanum to the prostate apex. The ducts extend mainly laterally in the coronal plane, with major branches that curve anteriorly and minor branches that curve posteriorly (Figure 36.4). The central zone comprises about 30% of the glandular prostate mass. Its ducts arise in a small focus on the convexity of the verumontanum and immediately surrounding the ejaculatory duct orifices. The ducts branch directly toward the base of the prostate along the course of the ejaculatory ducts, fanning out mainly in the coronal plane to form a conical structure that is flattened in the anteroposterior dimension. The base of the cone comprises almost the entire base of the prostate. The most lateral central zone ducts run parallel to the most proximal peripheral zone ducts, separated only by a narrow band of stroma.

Figure 36.4 Coronal section diagram of prostate showing location of central zone (CZ) and peripheral zone (PZ) in relation to the distal urethral segment (UD), verumontanum (V), and ejaculatory ducts (E). The branching pattern of prostatic ducts is indicated; subsidiary ducts provide uniform density of acini along entire main duct course.

The proximal segment of the prostatic urethra is best visualized in an oblique coronal-plane section running along its long axis from the base of the verumontanum to the bladder neck (Figure 36.5). Normally, the proximal urethral segment is related to only about 5% of the prostatic glandular tissue, and almost all of this is represented by the transition zone (8). This zone consists of two independent small lobes whose ducts leave the posterolateral recesses

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of the urethral wall at a single point, just proximal to the point of urethral angulation and at the lower border of the preprostatic sphincter. The sphincter is a sleeve of smooth muscle fibers surrounding the proximal urethral segment (6,8) (Figure 36.6). The main ducts of the transition zone extend laterally around the distal border of the sphincter and curve sharply anteriorly, arborizing toward the bladder neck immediately external to the preprostatic sphincter. Main duct branches fan out laterally and ventrally toward the apex but not dorsally above the plane of the urethra. The most medial ducts and acini of the transition zone curve medially to penetrate into the sphincter (Figure 36.6).

Figure 36.5 Oblique coronal section diagram of prostate showing location of peripheral zone (PZ) and transition zone (TZ) in relation to proximal urethral segment (UP), verumontanum (V), preprostatic sphincter (s), bladder neck (bn), anterior fibromuscular stroma (fm), and periurethral region with periurethral glands. Branching pattern of prostatic ducts is indicated: the medial transition zone ducts penetrate into the sphincter.

Figure 36.6 Preprostatic sphincter in section transverse to long axis of proximal urethral segment. The sphincter is most compact dorsal to the urethra (below) and separates periurethral tissue (dark central area) from central zone glands (bottom, right, and left). Laterally, transition zone glands are embedded in the sphincter. They show cystic change (right) and nodule formation (left).

The periurethral gland region is only a fraction of the size of the transition zone. It consists of tiny ducts and abortive acinar systems scattered along the length of the proximal urethral segment and arborizing exclusively inside the confines of the preprostatic sphincter. These glands lie within the longitudinal periurethral smooth muscle stroma.

The peripheral zone is the most susceptible region to inflammation (7) and is the site of origin of most carcinomas (9). Some cancers arise in the transition zone, and mosttumors found incidentally at transurethral resection (TUR) represent this site of origin (10,11).

The transition zone and periurethral region are the exclusive sites of origin of BPH (8). Most cases consist almost entirely of transition zone enlargement, so-called lateral lobe hyperplasia. Benign nodular hyperplasia in the periurethral region seldom attains significant mass, except as the occasional midline dorsal nodule at the bladder neck that protrudes into the bladder lumen. The above anatomic descriptions have gained acceptance over the past 10 years, replacing a number of previous anatomic models that suffered from less accurate descriptions of morphologic detail (12,13).

General Relationships: Nonglandular Tissue

The nonglandular tissues of the prostate are the preprostatic sphincter, striated sphincter, anterior fibromuscular stroma, and prostatic capsule. The nerves and vascular supply are also included in this section.

The preprostatic sphincter consists of precisely parallel, compact ring fibers forming a cylinder whose proximal end abuts against the detrusor muscle surrounding the urethra at the bladder neck. The coarsely interwoven, somewhat randomly arranged smooth muscle bundles of the detrusor contrast sharply with the uniform arrangement of the sphincter fibers, but there is no boundary between the two structures.

The preprostatic sphincter is thought to function during ejaculation to prevent retrograde flow of seminal fluid from the distal urethral segment. It also may have resting tone that maintains closure of the proximal urethral segment (6). Dorsal to the urethra, the sphincter is compact, but laterally its fibers spread apart and mingle with the small ducts and acini of the medial transition zone (Figure 36.6) (8). Anterior and ventral to the urethra, its fibers do not form identifiable complete rings but blend with the tissue of the anterior fibromuscular stroma. The anterior fibromuscular stroma is an apron of tissue that extends downward from the bladder neck over the anteromedial surface of the prostate, narrowing to join the urethra at the prostate apex (8) (Figures 36.3, 36.7). Its

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lateral margins blend with the prostate capsule along the line where the capsule covers the most anteriorly projecting border of the peripheral zone (Figure 36.5). Its deep surface is in contact with the preprostatic sphincter and transition zone proximally and with the striated sphincter distally. It is composed of large compact bundles of smooth muscle cells that are similar to those of the bladder neck and blend with them at its proximal extent. The smooth muscle fibers are more random in orientation than those of the bladder neck, but they tend to be aligned more or less vertically. They are often separated by bands of dense fibrous tissue.

Figure 36.7 Texture of anterior fibromuscular stroma in an area with little fibrous component. Muscle bundles are coarse and interwoven (trichrome stain).

The anterior fibromuscular stroma is distinguished from the capsule of the prostate by its thickness, its coarse interwoven muscle bundles, and its rough external surface. Microscopically its external aspect shows interdigitation of the muscle bundles along its surface with the adipose tissue of the space of Retzius.

Between the verumontanum and the prostate apex, there is a striated sphincter of small, uniform, compactly arranged striated muscle fibers. It is best developed near the apex and is continuous with the external sphincter below the prostate apex (6,14). The sphincter is incomplete posterolaterally, where its semicircular fibers anchor into the anterior glandular tissue of the peripheral zone rather than encircling the posterior aspect of the urethra. Its degree of development and precise anatomic relationships are variable between prostates. Near the apex in some prostates, individual striated fibers may penetrate deeply into the glandular tissue of the peripheral zone. Consequently, most of the length of the prostatic urethra is provided with sphincteric muscle. The distal striated sphincter is incomplete posteriorly, and the proximal smooth muscle sphincter is probably incomplete anteriorly.

The prostatic capsule envelopes most of the external surface of the prostate, and the terminal acini of the central zone and peripheral zone abut on the capsule. The terminal acini of the transition zone abut on the anterior fibromuscular stroma, and the periurethral glands never reach the prostate surface (8,11). At the prostate apex, there is a defect in the capsule anteriorly and anterolaterally. Here the most distal fibers of the anterior fibromuscular stroma and the striated sphincter together often mingle with the prostatic glandular tissue anterolateral to the urethra, and the relative extent of these three tissue components may vary considerably between prostates. Hence, if carcinoma at the prostate apex invades anteriorly, it may occasionally be difficult to determine whether it has invaded beyond the boundary of the gland. However, around most of the circumference of the apex, the capsule is complete up to the border of the periurethral stroma, where the urethra penetrates the prostate surface. Even with extensive BPH, a thin compressed rim of peripheral zone tissue enclosed by capsule usually still forms the apical prostate boundary except anterior and anterolateral to the urethra.

Figure 36.8 The prostate capsule consists of a layer of mainly transverse smooth muscle bundles (red), which is of variable thickness and blends with periacinar smooth muscle bundles at the capsule's poorly defined inner aspect (left). Collagen fibers (blue) are always present and usually concentrated in a thin compact membrane at the external capsular border (right) (trichrome stain).

The capsule of the prostate ideally consists of an inner layer of smooth muscle fibers, mainly oriented transversely, and an outer collagenous membrane. However, the relative and absolute amounts of fibrous and muscle tissue and their arrangement vary considerably from area to area (Figure 36.8) (15,16). At the inner capsular border, transverse smooth muscle blends with periacinar smooth muscle, and clear separation between them cannot be identified either microscopically or by gross dissection. The distance from terminal acinus to prostate surface is variable even between different regions within a single prostate, and the proportion and arrangement of collagenous tissue is inconstant except for the most superficial layer, which appears to form a thin continuous collagenous membrane over the prostate surface. Consequently, except for its external surface, the prostate capsule cannot be regarded as a well-defined anatomic structure with constant features. In contrast to the kidney, there is no inner membrane surface that can be stripped in evaluating capsule penetration by prostatic carcinoma; there are no reliable landmarks for determining the depth of capsule invasion. However, it has been proposed that only complete penetration with perforation through the capsule surface may be related to prognosis in prostatic carcinoma (16,17). Hence, penetration of cancer into the capsule without perforation is not of clinical importance.

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Over the medial half of the posterior (rectal) surface of the prostate, the thickness of the capsule is increased by its fusion to Denonvilliers' fascia (Figures 36.9,36.10). This is a thin, compact collagenous membrane whose smooth posterior surface rests directly against the muscle of the rectal wall (18). The capsule is typically fused to the inner aspect of the fascia, obliterating any trace of its original surface except for occasional remnants of an interposed adipose layer that embryonically covered the anterior aspect of the fascia. In the adult, there remain only scattered microscopic islands of fat, usually forming a layer that is only one adipose cell thick.

Smooth muscle fibers are found to a variable extent in Denonvilliers' fascia, but they usually course vertically, in contrast to the predominant transverse muscle fibers of the adherent capsule. In some prostates, the smooth muscle of Denonvilliers' fascia is gathered into a thick, flattened vertical band at the midline, where it easily may be mistaken in a radical prostatectomy specimen for muscle of the rectal wall. This is an important distinction because carcinoma invading such a longitudinal muscle bundle may still be confined within the prostate and should not be considered to have invaded the rectum. Wherever the capsule and fascia are fused, it is the surface of the fascia rather than the capsule surface that presents a barrier to the spread of carcinoma.

Figure 36.9 Distribution of nerve branches to the prostate, right posterolateral view. Nerves within the neurovascular bundle (NB) (red) branch to supply the prostate (brown) in a large superior pedicle (SP) at the prostate base and a small inferior pedicle (IP) at the prostate apex. Nerve branches (orange) leave the lateral pelvic fascia (not shown) to travel in Denonvilliers' fascia (DF), which has been cut away from the right half of the prostate. Nerve branches from the superior pedicle fan out over a large pedicle area. A small horizontal subdivision (H-N) crosses the base to midline; a large vertical subdivision (V-N) fans out extensively over the prostate surface as far distally as midprostate. Branches continue their course within the prostate after penetration into the capsule within a large nerve penetration area (green). A small inferior pedicle has a limited ramification and nerve penetration area (green). (LPF, lateral pelvic fascia)

Figure 36.10 Relationships of Denonvilliers' fascia (narrow red band) to sagittal plane of prostate (yellow and orange; right) and to rectal smooth muscle (brown; left). (CZ, central zone; PZ, peripheral zone; AFM, anterior fibromuscular fascia)

Superiorly, Denonvilliers' fascia extends above the prostate to cover the posterior surface of the seminal vesicles, but it is only loosely adherent to them (Figure 36.9,36.10). Laterally, the fascia leaves the posterior capsule where the prostate surface begins to deviate anteriorly, and it continues in a coronal plane to anchor against the pelvic sidewalls. So the prostate and seminal vesicles are suspended along the anterior aspect of this fascial membrane as the uterus is suspended from the broad ligament in the female. This can be demonstrated in the radical prostatectomy specimen after surgery for carcinoma. If the specimen is picked up at the right and left superior margins, its posterior aspect is a smooth-surfaced triangular membrane whose apex coincides with the prostate apex and whose base is a transverse line above the seminal vesicles. Any surgical defect in the fascia potentially compromises the complete resection of the tumor because tears in the fascia tend to extend through the adherent capsule and into the gland.

Where Denonvilliers' fascia separates from the prostate capsule posterolaterally, the space between them is filled with adipose tissue in a thick layer between the anterior aspect of the fascia and the posterolateral capsular surface of the prostate. The autonomic nerves, from the pelvic plexus

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to the seminal vesicles, prostate, and corpora cavernosa of the penis, travel in this fatty layer. The nerves, along with the blood vessels to the prostate, originate from the paired neurovascular bundles that course vertically along the pelvic sidewalls just anterior to the junction of Denonvilliers' fascia with the pelvis (Figure 36.9) (19). Most of the nerve branches to the prostate leave the neurovascular bundle at a single level just above the prostate base and course medially as the superior pedicle. These nerve branches fan out to penetrate the superior pedicle insertion area of the capsule, which is centered at the lateral aspect of the prostate base posteriorly (19,20). The insertion area does not usually extend far onto the rectal surface but extends toward the prostate apex as far as the midprostate. Some nerve trunks travel medially across the prostate base, sending branches into the central zone, but the majority of nerve branches fan out distally and penetrate the capsule at an oblique angle.

Most examples of capsule penetration by cancer represent tumor extension through the capsule along perineural spaces (20). Because of the oblique retrograde nerve pathway toward the prostate base, perforation though the full capsule thickness most commonly occurs near or even above the superior border of the cancer within the gland. Because of the boundaries of the superior pedicle insertion area plus the additional thickness of Denonvilliers' fascia overlying the capsule posteromedially, penetration of cancer directly through the rectal surface of the prostate is uncommon.

Before supplying the corpora cavernosa, nerve branches leave the neurovascular bundle at the prostate apex in the very small inferior pedicle and penetrate the capsule directly in a small apical insertion area located laterally and posterolaterally (20). Here the distance from neurovascular bundle to prostate capsule is narrowed to only a few millimeters. The prostate apex is the most common location for positive surgical margins at radical prostatectomy. This may result from capsule penetration along inferior pedicle nerves by cancers that are located near the apex, but it most commonly results from inadvertent surgical incision into the prostate. In this area, the surgeon is most concerned to stay close to the prostate capsule in order to spare the nerves involved in erectile function (21,22).

Arterial branches follow the nerve branches from the neurovascular bundle; they spread over the prostate surface and penetrate the capsule to extend directly inward toward the distal urethral segment between the radiating duct systems of the central and peripheral zones (23,24). A major arterial branch enters the prostate at each side of the bladder neck and runs toward the verumontanum parallel to the course of the proximal urethral segment. It supplies the periurethral region and medial transition zone. Transurethral resection regularly obliterates this arterial branch and all the tissue supplied by it (23).

Architectural Patterns of the Glandular Prostate

The biologic role of the prostate calls for the slow accumulation and occasional rapid expulsion of small volumes of fluid. These requirements are optimally met by a muscular organ having a large storage capacity and low secretory capacity. In such an organ, the different morphology of ducts and acini found in organs of high secretory capacity, such as the pancreas, would appear to be of limited value. Accordingly, the prostatic ducts are morphologically identical to the acini except for their geometry, and both appear to function as distensible secretory reservoirs. Within each prostate zone, the entire duct acinar system, except for the main ducts near the urethra, is lined by columnar secretory cells of identical appearance between ducts and acini. Immunohistochemical staining for prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) shows uniform granular staining of all ductal and acinar cells (Figure 36.11). In view of these considerations, there is probably no functional duct acinar distinction in the prostate, and it is unlikely that there is any morphologic or biologic distinction between carcinomas of ductal versus acinar origin.

Except for the main transition zone ducts, which terminate at the anterior fibromuscular stroma, the main ducts of the prostate originate at the urethra and terminate near the capsule (4,7,8) (Figures 36.4,36.5). Because ducts and acini within each zone have comparable caliber, spacing,

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and histologic appearance, ducts, ductules, and acini cannot reliably be distinguished microscopically except in sections cut along the ductal long axis. Hence, abnormalities of architectural pattern are identified in routine sections mainly by deviations from normal size and spacing of glandular units.

Figure 36.11 Ducts and acini of peripheral zone, immunostained with anti-PSA and showing uniform distribution of protein throughout the cytoplasm of all ducts and acini.

Figure 36.12 Subsidiary duct and branches in peripheral zone, terminating in small rounded acini with undulating borders. Ducts and acini have similar calibers and histologic appearances.

The main excretory duct orifices of the peripheral zone arise from the urethral wall about every 2 mm along a double lateral line extending the full 1.5 cm length of the distal urethral segment. A cluster of three or four subsidiary ducts arise about every 2 mm along the course of each main excretory duct from urethra to capsule. They branch at angles of about 15 degrees and extend only a short distance, rebranching and giving rise to groups of acini (Figure 36.12). Hence, acini tend to be distributed with nearly uniform density along the course of the main duct between urethra and capsule, except that no acini are found immediately adjacent to the urethra. Conversely, beneath the capsule all glands are acinar. The architecture in the transition zone is similar to the peripheral zone. However, there is more extensive arborization because the main ducts arise from the urethra in a small focus.

The duct origins of the transition zone and periurethral glands from the proximal urethral segment represent a proximal continuation of the double lateral line of the peripheral zone duct origins along the distal urethral segment. However, periurethral ducts also originate anteriorly and posteriorly. This accounts for the presentation of periurethral gland BPH as a dorsal midline bladder neck mass, whereas the lateral locations of transition zone BPH masses reflect the constant location of their main ducts (8).

In the peripheral zone and transition zone, ducts and acini are usually 0.15 to 0.3 mm in diameter and have simple rounded contours that are not perfectly circular because of prominent undulations of the epithelial border (5,7). The undulations mainly reflect the presence of corrugations of the wall, which presumably allow expansion of the lumina as secretory reservoirs. An important criterion for the diagnosis of many highly differentiated prostatic carcinomas is their tendency toward precisely round or oval glandular contours (25,26), reflecting a loss of reservoir function.

Central zone ducts and acini are distinctively larger than those of the peripheral zone and transition zone and may be up to 0.6 mm in diameter or larger (Figure 36.13). Unlike the peripheral zone, both ducts and acini of the central zone become progressively larger toward the capsule at the prostate base, where they often exceed 1 mm in diameter. There is also a gradient of increasing density of acini toward the base. Both of these gradients reflect the great expansion of central zone cross-sectional area from a small focus on the verumontanum to almost the entire prostate base. Near the urethra, the central zone ducts have few branches and lack distinctive histologic features. Hence, they may not be recognizable in transverse planes of section near the base of the verumontanum. Acini are clustered into lobules around a central subsidiary duct,

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which is distinguishable from the acini in cross section only by its central location. Ducts and acini are polygonal in contour. Many of the corrugations in their walls are exaggerated into distinctive intraluminal ridges with stromal cores, which partially subdivide acini.

Figure 36.13 Subsidiary ducts and acini in the central zone form a compact lobule with flattened gland borders and prominent intraluminal ridges.

Glandular subdivisions within a given duct branch in the central zone are separated by narrow bands of distinctively compact smooth muscle fibers, whereas broader bands separate different branches. The normal overall ratio of epithelium to stroma here (lumens excluded) is roughly 2:1. The epithelial to stromal ratio of the peripheral zone and transition zone is close to 1:1. In the peripheral zone, the more abundant stroma is loosely woven, with randomly arranged muscle bundles separated by indistinct spaces containing loose, finely fibrillar collagenous tissue. Between the glandular spaces in a given duct branch, stroma is as abundant as between different branches.

There is an abrupt contrast in stromal morphology that delineates the boundary between central zone and peripheral zone and a similar contrast between peripheral zone and transition zone (11) (Figures 36.14,36.15,36.16). The transition zone stroma is composed of compact interlacing smooth muscle bundles (Figures 36.14, 36.16). This stromal density contrasts sharply with the adjacent loose peripheral zone stroma, but it blends with the stromas of the preprostatic sphincter and anterior fibromuscular stroma. Stromal distinctions are less evident in older prostates and may be obliterated by disease (27,28).

Figure 36.14 Border between the peripheral zone (above) and transition zone shows contrast in stromal texture and a band of smooth muscle at the zone boundary. Glandular histology is similar between zones.

Figure 36.15 Peripheral zone acini set in loosely woven fibromuscular stroma. Secretory cells are more regular than in central zone, with smaller basal nuclei and pale cytoplasm. Basal cells are visible.

Figure 36.16 Transition zone acini set in a compact stroma composed of interlacing, coarse, smooth muscle bundles. Acinar histology is identical to that in the peripheral zone. Basal cells are visible.

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Cytologic Features of the Glandular Prostate

As with other glandular organs, the secretory cells throughout the prostate are separated from the basement membrane and stroma by a layer of basal cells. These cells are markedly elongated and flattened parallel to the basement membrane and have slender, filiform dark nuclei and usually little or no discernible cytoplasm (29) (Figures 36.15,36.16). They are typically quite inconspicuous; and, in routine preparations, the basal cell envelope may appear incomplete or even absent around individual ducts or acini. However, immunohistochemical staining for basal cell specific keratin or for p63 antibody shows the envelope to be complete, even where no basal cells are identified with routine stains (30). These stains are consistently negative in the cells of invasive malignant glands (31) because basal cells are absent.

Basal cells are not myoepithelial cells analogous to those of the breast because, by electron microscopy, they do not contain muscle filaments (29). Logically, myoepithelial cells would appear to be functionally superfluous in a muscular organ (29). Basal cells have been found to be the proliferative compartment of the prostate epithelium, normally dividing and maturing into secretory cells (32,33,34). Using immunostaining for proliferating cell nuclear antigen as a marker for cycling cells, roughly 1% of basal cells and 0.1% of secretory cells were labeled in each zone, and there was no difference between ducts and acini. Eighty-three percent of all labeled cells were basal cells, even though they comprised only 30% of the total epithelial cell population (34).

In all zones of the prostate, the epithelium contains a small population of isolated, randomly scattered endocrine paracrine cells (35) that are rich in serotonin-containing granules and contain neuron-specific enolase. Subpopulations of these cells also contain a variety of peptide hormones, such as somatostatin, calcitonin, and bombesin. They rest on the basal cell layer between secretory cells but do not typically appear to extend to the lumen or may send a narrow apical extension to the lumen. They often have laterally spreading dendritic processes. They are not reliably identifiable microscopically except with immunohistochemical and other special stains. Their specific role in prostate biology is unknown, but they presumably have paracrine function, perhaps in response to neural stimulation. Like similar cells in the lung and other organs, they occasionally give rise to small cell carcinomas, which do not contain PSA or PAP (36). Not infrequently, however, small cell carcinoma arises as a variant morphologic pattern within adenocarcinomas that elsewhere contain PSA and PAP; peptide hormones are found only in the small cell component (36). Hence, the status of these cells as an independent lineage is doubtful in the prostate.

The secretory cells of the prostate contribute a wide variety of products to the seminal plasma. PSA and PAP are produced by the secretory cells of the ducts and acini of all zones. Pepsinogen II (37) and tissue plasminogen activator (38) are normally produced only in the ducts and acini of the central zone. Lactoferrin is also exclusively a secretory product of the central zone, except in areas of inflammation where both the cells and secretions anywhere in the prostate may produce this substance (39). Lectin staining for cell membrane carbohydrates also shows significant differences between the two zones (40). It has been suggested that the central zone may be specialized for the production of enzymes whose substrates are secreted by the peripheral zone (38), but probable substrates have not been identified. In fact, no secretory product has so far been identified that is produced exclusively by the peripheral zone or transition zone.

The cytoplasm of the normal secretory cell in all zones is similar in appearance and is dominated by the universal abundance of uniform small clear secretory vacuoles. Vacuoles in peripheral zone and transition zone cytoplasm are packed at nearly maximum density (41), whereas, in the central zone, a more abundant dense cytoplasm is associated with a somewhat wider vacuole spacing and lower vacuole density. Because the secretory vacuoles appear empty by routine microscopy, peripheral zone and transition zone cells are pale to clear, and central zone cells are typically somewhat darker.

However, the appearance of normal cell cytoplasm on tissue sections is strongly influenced by staining technique and by the type of fixative used. In the peripheral zone and transition zone, light hematoxylin and eosin (H&E) staining after formalin fixation shows that normal cells are clear cells in which a faint network of pale-staining cytoplasmic partitions between vacuoles can be visualized with careful scrutiny under high magnification (Figure 36.17). Only an occasional cell shows complete outlines that define numerous intact vacuoles, but immunostaining with PSA or PAP on the same tissue sharply outlines all the cytoplasmic vacuolar partitions and shows no evidence of protein within the vacuoles. Denser H&E staining not only darkens the partitions but also enhances diffuse staining throughout the cytoplasm, which obscures both the clear cell appearance and the visualization of the vacuoles.

The contents of the apparently empty vacuoles consist partly of lipid, as judged by interpretation of fat stains on fresh frozen sections, but there is also a nonlipid component. With H&E staining after fixation in glutaraldehyde or the commercial fixative Ultrim (American Histology Reagent Co., Stockton, CA), the clear vacuoles are replaced by brightly staining red granules. The nature of the stained product is probably related to spermine, a low-molecular weight alkaline substance. Using these alternate fixatives, immunostaining for protein such as PSA or PAP is still negative within vacuole lumens.

Figure 36.17 Peripheral zone epithelium showing clear cells in which cytoplasm is barely discernible as composed of a sheet of small empty vacuoles with delicate pale partitions.

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Vacuoles are usually reduced or absent in the cytoplasm in dysplasia (prostatic intraepithelial neoplasia) (41) (Figure 36.3) and in most invasive carcinomas of Gleason's grade 3 or higher. In Gleason's grades 1 and 2 cancer, as well as some areas in grade 3 cancer, cytoplasmic vacuoles are retained, and these tumors have been referred to as clear cell carcinomas.

The secretory lining of peripheral zone glands conveys an orderly appearance, with a single layer of columnar cells having basally oriented nuclei. In most glands, however, the epithelial row shows considerable random variation between neighboring cells in the ratio of cell height to width and in apparent cell volume. Nuclear location also varies from the basal cell aspect to the mid-portion of the cell. The luminal cell border is consequently often uneven, and its roughness is accentuated by frequent cells whose luminal aspect is irregular and frayed. Prostate-specific antigen stain shows a reticular pattern diffusely throughout the cytoplasm (Figure 36.18).

These deviations from uniformity and the resulting slightly untidy pattern of the normal epithelial strip appear intimately related to secretory function. Cytokeratin immunostaining of secretory cells shows that the cytoskeleton does not extend as far as the luminal aspect of each cell (Figure 36.19); it usually terminates somewhat above the midportion of the cell level in a sharp transverse line whose level from cell to cell defines a more uniform thickness of

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the epithelial row than the full thickness that is stained by H&E. All of the cell contents toward the lumen from this transverse line appear to represent an isolated apocrine secretion compartment having diminished or absent cytoskeleton. As much as one-third of the total height of some cells may belong to this apocrine compartment. Lumenward from the terminal line of the keratin cytoskeleton, neighboring cells may lose their lateral adhesion and are sometimes separated by a narrow cleft. The indistinct luminal aspect of some cells appears to represent disintegration of this apical portion of the cell in situ. Release of contents of apocrine secretion into the lumen by fragmentation while still attached to the cell is the characteristic mode of peripheral zone and transition zone secretions; release of intact apocrine sacs from the underlying cell is rarely seen.

Figure 36.18 Peripheral zone epithelium immunostained with anti-PSA. Protein is concentrated in a reticulated pattern that spares vacuole lumens and accentuates portions of vacuole partitions.

Figure 36.19 Peripheral zone epithelium immunostained with antibody to secretory cell cytokeratin. Normal epithelial cells appear quite variable in size and shape, and some nuclei are displaced from cell base. Cytokeratin is accentuated toward luminal border, but at lower right and upper middle, clusters of cells have attached apocrine compartments lumenward, which have no cytokeratin staining and accentuate the irregularity of luminal epithelial border.

The morphologic appearance of normal peripheral zone epithelium is closely mimicked by only that minority of clear cell well-differentiated carcinomas that retain abundant cytoplasmic clear vacuoles, often Gleason's grades 1 and 2 (25,26). However, these malignant cells usually differ from normal peripheral zone in having a sharply defined luminal plasma membrane that lies at the same height between epithelial cells and traces an even transverse line around the gland perimeter (Figure 36.20). Thus, the fragmenting apocrine compartment is usually absent; and, correspondingly, the cytoskeleton as visualized by keratin immunostaining the entire cytoplasm. Also, these malignant clear cells are of more nearly equal dimensions and contours than their benign counterparts, and nuclei are more strictly localized at the cell base. In dysplasia and in most grade 3 carcinomas, secretory vacuoles are much reduced or absent; cell cytoplasm is correspondingly dark (41).

Figure 36.20 Clear cell carcinoma immunostained with antibody to secretory cell cytokeratin shows stronger cytokeratin accentuation at a luminal epithelial border, which is more even than in Figure 36.19, and lacks the apocrine secretory compartment. Cells are larger and more uniform than in Figure 36.19, with more basally located nuclei.

Central zone epithelium, by contrast, shows an accentuation of the mild disorder of cell arrangement of the peripheral zone/transition zone (Figure 36.21). Here the epithelium is variably thickened by prominent cell crowding. Nuclei, which are usually larger than in the peripheral zone, are often displaced further from the cell base than in the peripheral zone and may give the illusion of stratification in more crowded areas. Cell height is often quite variable, and because the luminal cell border usually is intact rather than disintegrating, irregular protrusion of cell apices into the lumen is prominent. Apocrine secretion in the central zone may be identical to that in the peripheral zone, but often it is characterized by intact spherical sacs in the gland lumen, containing no vacuoles, and staining more densely than the parent cell. They tend to remain intact after secretion as dense luminal spheres (Figure 36.21).

The dark cytoplasm, thickened variable epithelium, and complex architecture in the central zone may be misinterpreted as atypical hyperplasia or dysplasia on needle

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biopsies. However, the distinctive histologic features plus the absence of nuclear size variability, hyperchromasia, and loss of polarity rule against dysplasia. The central zone is not often sampled by needle biopsies because its maximum extent is mainly restricted close to the prostate base.

Figure 36.21 Central zone epithelium with dark cytoplasmic staining in an area of active apocrine secretion. Clear vacuoles are absent from apocrine secretion. Nuclei appear crowded and disordered, lying at different levels.

Unique specialized secretory structures called lacunae are also common in the central zone (39). These are tiny round lumens that appear to lie entirely within the epithelial cell layer, isolated from the main duct acinar lumen system (Figures 36.22,36.23). A complete layer of flattened epithelial cells is seen to surround each lacuna, but these lacunar cells have no apparent contact with stroma. They only abut onto surrounding secretory cells. Lacunae are a specialized apparatus for lactoferrin production and storage, as demonstrated by immunohistochemical staining.

The central zone appears to represent a separate glandular organ within the prostate capsule. Aside from its unique morphologic features, its ducts arise from the urethra separately from the double lateral line of the remainder of the prostate. In addition, its ducts are in close anatomic proximity to the ejaculatory ducts and seminal vesicles. It has been suggested that the central zone may arise embryonically as an intrusion of wolffian duct stroma around the ejaculatory ducts into an organ that is otherwise of urogenital sinus origin (7). Pepsinogen II (37) and lactoferrin (39) are secreted by both the central zone and seminal vesicles but are not found under normal conditions in the peripheral or transition zones.

Figure 36.22 Central zone with dense muscle bundles, dark basal cells, and opaque cytoplasm.

Figure 36.23 Central zone gland immunostained with anti-lactoferrin. Lacunae on both sides of the lumen are densely stained, but cell cytoplasm is negative.

Deviations from Normal Histology

Beyond the age of 30 years, many prostates begin to show a variety of focal deviations from normal morphology (4,7,27,28). Their prevalence, extent, and severity progressively increase with age so that most prostates by the seventh decade of life are quite heterogeneous in histologic composition. Although these deviant histologic patterns seldom have clinical significance, their distinction from adenocarcinoma or BPH is sometimes difficult.

Early morphologic studies concluded that focal atrophy in the prostate was a manifestation of aging and was seen as early as 40 years of age. In fact, focal atrophy in the prostate is often the consequence of previous inflammation rather than aging (4,7). The number and extent of atrophic foci tend to be greater in older men, but their histologic appearance is identical to that of isolated foci found as early as 30 years of age. The histologic features are identical to those produced by chronic bacterial prostatitis, but no etiologic agent has been identified in the vast majority of cases, most of which appear to be asymptomatic.

Postinflammatory atrophy is an extremely common lesion and is mainly a disease of the peripheral zone, where its distribution is sharply segmental along the ramifications of a duct branch (4,7). It is characterized by a marked shrinkage of ducts and acini with periglandular fibrosis and variable distortion of architecture (Figures 36.24,36.25).

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Glandular units may be drawn together into clusters or spread out into a pattern suggesting invasive carcinoma. In addition to the presence of tiny distorted glands, the resemblance to cancer is further increased by the fact that nuclei may remain relatively large with occasional small nucleoli.

Figure 36.24 Focus of postinflammatory atrophy in peripheral zone. Duct acinar architecture is apparent but distorted by marked gland shrinkage, with reduced luminal area and periglandular fibrosis.

In contrast to carcinoma, cell cytoplasm is usually much reduced in volume, and evidence of the original duct acinar architecture often can be detected. Furthermore, there is usually residual inflammation, with scattered round cells in the adjacent stroma. Finally, there is sometimes an admixture of glands showing the earlier active phase of the process, with prominent periductal and periacinar chronic inflammatory infiltrate and less prominent gland shrinkage.

Cystic atrophy is another common focal lesion that is typically found in the peripheral zone and is segmental in distribution. The markedly enlarged acini with flattened epithelium and the segmental distribution suggest an obstructive cause (Figure 36.26). However, obstruction is not typically demonstrable, and the stroma between glands is usually attenuated rather than compressed by luminal expansion. This suggests that stromal atrophy may be the main pathogenetic event.

The histologic hallmark of BPH is the expansile nodule, produced by the budding and branching of newly formed duct acinar structures (Figure 36.27), by the focal proliferation of stroma, or by a combination of both elements (4,5,8,42). It mainly affects the transition zone, with occasional contribution from the periurethral region. Individual BPH nodules rarely become larger than 1.6 cm in greatest diameter; and, in any prostate, median nodule diameter is almost always less than 8 mm. An exception is produced in massive BPH by secondary nodule enlargement due to cystic dilatation of component glands.

Figure 36.25 Tiny distorted glands of postinflammatory atrophy. Irregular contours and large nuclei mimic carcinoma; however, cytoplasm is scant, and there are periglandular collagenous rings.

Figure 36.26 Cystic atrophy in the peripheral zone.

Figure 36.27 Very small, gland-rich benign nodular hyperplasia nodule arising from dense stroma.

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Grossly BPH is usually recognized as a globular mass replacing each transition zone and composed of numerous individual nodules embedded within a diffusely hyperplastic transition zone tissue (Figure 36.28). Only the nodular component is recognizable histologically as a deviation from normal pattern; internodular tissue, even when increased in amount, is not distinguishable microscopically from normal transition zone.

The enlargement of transition zone BPH produces a characteristic progressive deformity of overall prostate contour (Figure 36.29). The tissue lateral and posterior to the prostatic urethra (central zone and peripheral zone) is relatively unyielding, and expansion is directed anteriorly and toward the apex at the selective expense of stretching and thinning of the anterior fibromuscular stroma. This produces a predominant increase in the thickness (anteroposterior dimension) of the gland. The anterolateral wings of the peripheral zone where they taper to join the anterior fibromuscular stroma (Figure 36.5) are compressed and thinned concomitant with increase of overall prostate width, but posterior and lateral peripheral zones are not significantly thinned except in massive BPH.

The central zone is the least compressed region, but it is pulled forward over the BPH mass, accompanied by characteristic lengthening of the proximal urethral segment. As the urethra lengthens, its angulation at the midpoint increases, sometimes approaching 90 degrees (Figure 36.29). Increased angulation produces a more globular anteroapical compartment, which accommodates a larger BPH mass. The mucosa of the lateral urethral walls is compressed between the two opposed transition zone masses, and its surface area is stretched to a larger expanse as the transition zone masses expand (Figure 36.30).

Figure 36.28 Small BPH nodule with increase of epithelial to stromal ratio to roughly 2:1 and surrounded by normal transition zone with epithelial to stromal ratio far below 1.

Basal cell hyperplasia is most often seen as a secondary change in BPH nodules or inflammatory foci (33). The basal cells of ducts and acini become rounded with oval nuclei, and they form a multilayered lining that stains for

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basal cell specific cytokeratin (Figure 36.31). There is typically a single luminal row of columnar secretory cells that stain positive for PSA.

Figure 36.29 Sagittal diagrams of prostate showing main features of deformity produced by transition zone BPH. Transition zone (TZ) is bounded by the distal urethral segment (ud), proximal urethral segment (up), and anterior fibromuscular stroma (FM) (see Figure 36.3). Only the last leg of this triangular compartment yields easily to the pressure of transition zone expansion. Increased angulation and lengthening of urethra produce a more spherical compartment with increased capacity. Arrows indicate main features of deformity. (CZ, central zone; PZ, peripheral zone; ed, ejaculatory duct)

Figure 36.30 Model of prostate with severe BPH seen in three-quarter frontal view. The transition zone mass on far side (blue) shows growth mainly anteriorly and toward the apex. BPH mass has been removed on the near side, showing concavity in the peripheral zone caused mainly by stretching and thinning of the anterolateral margin. The urethra shows prominent increased angulation, with anterior stretching of lateral walls between BPH masses.

In BPH, basal cell hyperplasia is common at the margin of nodule infarcts, where presumably it represents a reaction to ischemia. Consistent with this proposal is the finding of smooth muscle atrophy and replacement by fibroblastic stroma in these areas. Much more commonly, basal cell hyperplasia is found in BPH nodules without frank infarction, but the almost invariable presence of fibroblastic stroma and smooth muscle atrophy suggest that ischemia may be etiologic here also. Gland shrinkage also usually accompanies these foci and may suggest a superficial resemblance to carcinoma.

Dysplasia is a type of morphologic change seen in any prostate zone and characterized by focal enlargement of individual cells in an area with rounded dark nuclei showing changes characteristic of adenocarcinoma and occasionally showing features intermediate between cancer, dysplasia ducts, and acini (Figures 36.32,36.33).

Evaluation of Radical Prostatectomy Specimens

Normal morphologic features can be difficult to evaluate in the age group in which radical prostatectomy is usually performed. Landmarks are often obscured or distorted by retrogressive changes with aging or inflammation, whereas some prostates retain the normal appearance of the third decade of life, and some show increased glandular epithelial activity with or without atypia. Not infrequently, the morphologic appearance of any zone seems unrelated to the changes in other zones. Difficulties of interpretation are compounded when all sections are cut in the same plane

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rather than different planes designed for optimum visualization of each zone.

Figure 36.31 Prostatic duct with basal cell hyperplasia immunostained with antibody to basal cell specific cytokeratin. Basal cells create multiple layers, but a single luminal layer is secretory and remains unstained.

Figure 36.32 Central zone with right half normal and left half showing mild dysplasia.

Figure 36.33 Central zone with left half showing mild dysplasia and right half showing severe dysplasia.

Transverse planes of section, perpendicular to the rectal surface are the most common type of routine prostate sectioning, partly because they are the easiest to cut. They are also nearly parallel to the plane of many ultrasound and magnetic resonance images. They show much the same relationships as the oblique coronal planes except that the urethra is never seen along its long axis. It is important to review the expected appearance of transverse planes at different levels because of the considerable differences encountered.

Transverse sections distal to the base of the verumontanum demonstrate the transition zone at most levels of section toward the apex in most men over 50 years of age, even when there are few nodules to signify BPH (8,42). Diffuse transition zone enlargement accompanying nodule development is nearly universal with age, and expansion is mainly anterior and toward the apex. The boundary between the transition zone and peripheral zone is often visualized more clearly by ultrasound imaging than by histologic study. Microscopically the difference in texture of the stroma between the two zones is the most important evidence for the location of the boundary between them, but it may not be apparent at all points.

The boundary of the transition zone with the peripheral zone seldom extends closer than 1.0 cm to the posterior (rectal) prostate surface. If there has been a previous TUR, the resection cavity usually extends mainly anteriorly from the posterior urethral wall. Significantly, the TUR often spares the lateral portion of the transition zone, sometimes with residual nodules, and the transition zone boundary remains intact.

Proximal to the base of the verumontanum, only one or two sections still show a transition zone unless there is a large mass of BPH tissue. The ejaculatory ducts now appear on these proximal sections, with the utricle between them. The dorsal, compact transverse portion of the preprostatic sphincter may be seen just anterior to the ejaculatory ducts. The sphincter and urethral lumen progress more anteriorly at each level of section cephalad until they reach the anterior tissue border at the bladder neck.

The bladder neck lies a variable number of sections below (apical to) the highest transverse section cut at the prostate base (Figure 36.34). The central zone may not be apparent histologically until the bladder neck level of section or higher. It usually appears suddenly between two transverse levels of section separated by only 3 mm. This is because the central zone is an inverted flared cone whose apical region near the verumontanum consists predominantly of main duct branches that cannot be readily distinguished from those of other zones. At the transverse level where it is first recognizable, the anterior portion of the central zone may lie directly above the area occupied by the transition zone in the section just one level below, and the transition zone is usually no longer visible. The central zone has a more distinctive histologic appearance in sections toward the base because of the rather abrupt increase in size and number of branches. The most basal section is usually almost entirely composed of central zone and consists mostly of acini that are distinctively large, polygonal, and closely packed (14).

Figure 36.34 Parasagittal section of prostate base located almost at midline. Bladder neck smooth muscle above the level of bladder neck lumen is seen as a small dark patch (B) at far right. A layer of fat (F) covers the dome-shaped surface of the anterior central zone (top center). All glandular tissue within is central zone. One main duct (center) is seen in profile as it flares out toward the base, generating elaborate acinar structures. Behind the seminal vesicle (SV), the posterior central zone extends more celaphad as a narrow plate. Denonvilliers' fascia (D) is not adherent behind the seminal vesicles but blends with the capsule below.

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As the seminal vesicles leave the prostate base, they extend laterally along its basal surface (Figure 36.9). Often there is no capsule between the two organs, at least for the medial centimeter or more of the seminal vesicle. The degree of fusion between the two muscular walls is variable between prostates, but there is frequently no boundary whatever between the two organs medially, and only one millimeter of common muscular wall may separate the most basal central zone gland lumen from the seminal vesicle lumen.

The origin of the ejaculatory ducts at the junction of seminal vesicles and vas deferens is surrounded by central zone glandular tissue and usually situated so that about two-thirds of the central zone mass is anterior to the ejaculatory ducts. However, it is quite common for the ejaculatory ducts to be situated more posteriorly; occasionally they enter the prostate on the rectal surface and entirely posterior to the central zone.

The most basal transverse section of prostate usually has some bladder neck muscular wall at its anterior extent (Figure 36.34). Behind this muscle is a strip of fat that lies between the seminal vesicles and the bladder and rests on top of the most anterior aspect of the central zone. That portion of the central zone anterior to the ejaculatory ducts usually terminates at a lower level than the posterior portion, and the latter extends further cephalad as a thin plate between seminal vesicles and Denonvilliers' fascia (Figure 36.35). The strip of fat contains the large nerve trunks extending medially from the autonomic ganglia of the superior pedicle, which is situated lateral to the central zone at this level. When cancer penetrates the capsule at the prostate base, it is often seen within the fatty strip between bladder neck and central zone. Less often, it is associated with the nerves and ganglia of the superior pedicle lateral to the gland. Occasionally cancer extends above the prostate base posteriorly within the layers of Denonvillier's fascia. In large cancers, these three routes of extension anteriorly, laterally, and posteriorly often fuse with cancer in the seminal vesicle to produce a confluent mass of tumor above the prostate base.

Figure 36.35 High power of central zone showing vertical course of ducts. (SV, seminal vesicle; F, fat)

Figure 36.36 Apex of prostate seen grossly after 6-mm thick apical block has been subsectioned parasagittally at 3-mm intervals. Orientation of sections and localization of lesions are easily demonstrated, and cuts through the capsule are nearly perpendicular to the apical surface.

At the apex of the prostate, sections should be taken as serial parasagittal subsections of a 6-mm thick block (Figure 36.36). This procedural modification sacrifices the transverse sectioning of the last level, which would lie 3 mm above the apex. However, it creates the advantage of showing the apical prostate tissue in planes that are more nearly perpendicular to the apical capsule surfaces, so that penetration of cancer can be more easily evaluated. In this area, where positive surgical margins are relatively common and capsule layers may be indistinct, such an advantage is important. Anterior to the urethra and for a narrow span anterolaterally, there is no capsule but only the distal end of the anterior fibromuscular stroma. Here there is a variable admixture of glands, striated muscle, and smooth muscle, and evaluation of capsule penetration is difficult. This is an area where adequate surgical resection is particularly difficult, and a positive margin may occasionally be created by transection of a small anterior cancer that was incidental, whereas the clinically detected cancer was elsewhere and has been successfully removed.

Considerations in Transurethral Resection and Needle Biopsy Specimens

Tissue distortion by heat coagulation near the edges of TUR chips can create important diagnostic problems that occasionally may be insurmountable. Basal cell hyperplasia,

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adenomatous hyperplasia, inflammatory atrophy, and fragments of BPH nodules with small glands may be indistinguishable from carcinoma. Loss of nuclear detail occurs to a greater depth into the chip than obvious cell distortion. Hence, small foci of cancer may be more difficult to diagnose because of the artifactual absence of nucleoli. Gleason has indicated that the identification of occasional nucleoli larger than 1 m in diameter is an important criterion for distinguishing well-differentiated cancer from adenosis (26).

Figure 36.37 Benign tubular invaginations from the wall of the intraprostatic seminal vesicle showing architectural and cytologic features that suggest carcinoma. Note the characteristic yellow-brown cytoplasmic granules.

The same problems are seen in needle biopsies, where the artifact is presumably due to compression rather than heat. The presence of artifact is usually limited to loss of nuclear detail and is more subtle because areas of severe tissue distortion are not often represented.

The regions of the prostate sampled by TUR and by needle biopsy tend to be quite different. Most needle biopsies represent peripheral zone tissue. Unless a special effort is made, the needle seldom reaches the central zone or the more anterior portions of the transition zone.

In the majority of cases, TUR specimens consist of transition zone tissue, urethral and periurethral tissues, bladder neck fragments, and anterior fibromuscular stroma (42). The preprostatic sphincter is always present but usually not identifiable. Occasionally, fragments of the proximal end of the striated sphincter are present. Our study of radical prostatectomy specimens post-TUR has shown that the resection usually does not extend beyond the transition zone boundary into the central or peripheral zones, and usually not all the transition zone tissue has been removed (42).

Occasionally, peripheral zone or central zone tissue may be sampled at TUR. Central zone fragments show distinctive architectural and cytologic features described above. They are not infrequently accompanied by fragments of ejaculatory duct, intraprostatic vas deferens, and/or seminal vesicle. The tiny tubular outgrowths from the walls of these structures may be misinterpreted as adenocarcinoma when seen in tangential sections that do not reveal the main lumen (Figure 36.37). This impression may be further encouraged by the frequent presence of enlarged dark nuclei of bizarre contour. The presence of golden brown cytoplasmic granules, which may be few and inconspicuous, helps to establish the true diagnosis. Uniform negative staining for PSA and PAP are confirmatory.

Acknowledgment

Dr. McNeal, the author of this chapter, passed away in November 2005. Dr. Ronald Cohen, who worked closely with Dr. McNeal for 10 years and is most familiar with Dr. McNeal's work, was asked to proofread and answer questions associated with this chapter. Dr. Cohen is Associate Professor on the Faculty of Medicine at University of Western Australia as well as Director of Pathology at Uropath both in Perth, Western Australia.

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