Mills Ch35 Prostate

Prostate SamsonW. Fine  ■  Jesse K. McKenney 35

EMBRYOLOGY AND DEVELOPMENT OF THE PROSTATE  964

ARCHITECTURAL AND CYTOLOGIC FEATURES OF THE GLANDULAR PROSTATE  973 Architectural Patterns  973 Cytologic Features  974 DEVIATIONS FROM NORMAL HISTOLOGY  976 CONSIDERATIONS IN TRANSURETHRAL RESECTION AND NEEDLE BIOPSY SPECIMENS  978

GENERAL TOPOGRAPHIC RELATIONSHIPS: McNEAL’S ZONAL ANATOMY  965

SECTIONING OF RADICAL PROSTATECTOMY SPECIMENS  966

ANATOMY OF THE PROSTATE GLAND IN SURGICAL PATHOLOGY SPECIMENS  967 Gross Anatomy  967 Histologic Variation by Anatomic Region  967 Nonglandular Components of Prostatic and Extraprostatic Tissues  969

ACKNOWLEDGMENT  979

REFERENCES  979

wolffian duct (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 walls of the distal (apex to mid) urethral segment into the condensed mesenchyme in a pattern that is essentially identical to that seen in the adult. Postnatally, the prostate grows at a slow rate, reaching less than 2 cm in diameter by the time of puberty. Dur- ing 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 mul- tilayered dark nuclei (Fig. 35.2). 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 older than 50 years of age, there is focal resumption of growth as benign prostatic hyperplasia (BPH). This process increases the thickness of the gland prominently. BPH typically represents enlargement of only a single region of the gland, identifiable in the adult as the transition zone. In fact, the normal mass of the glandu- lar portion of the prostate after subtraction of the BPH- prone region remains at nearly constant mean volume until 70 years of age or more.

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, the mesenchymal condensation is most dense along the posterior (rectal) and distal (apical) aspects of the urethra (Fig. 35.1), where it is in contact with the urethral lining epithelium (1). Between its midpoint and the bladder neck, the proximal urethral segment shows a sharp anterior angulation. However, the highly condensed mesenchyme continues directly proximal to a dome-shaped prostatic base, leaving a gap between con- densed prostatic mesenchyme and proximal urethra. The ejaculatory ducts penetrate this mesenchyme toward the future verumontanum, which is located at the urethral mid- point. The ejaculatory ducts are wolffian duct structures, but in the embryo their surrounding stroma is indistinguish- able from the remaining prostatic mesenchyme, which is mainly derived from the urogenital sinus (2). The portion of 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 like the seminal vesicles, is probably also derived from the

964

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GENERAL TOPOGRAPHIC RELATIONSHIPS: McNEAL’S ZONAL ANATOMY

The human prostate gland is a composite organ, comprised of several glandular and nonglandular components. These different “zones” are tightly fused together within a com- mon sheath of fibromuscular tissue—the “capsule”—such that gross dissection is not possible. In a series of elegant dissections in postmortem specimens, Dr. McNeal showed that anatomic relationships are best demonstrated by exam- ination of cut sections in the sagittal, coronal, and oblique coronal planes (3,4). From these studies, it is evident that: (a) there are three distinct glandular regions: the peripheral, central, and transition zones; and (b) the main nonglandu- lar tissue of the prostate, termed the anterior fibromuscular stroma, is concentrated anteromedially and is responsible for much of the anterior convexity of the organ. The urethra is a primary reference point for describing anatomic relationships. Visualized in a sagittal plane of sec- tion (Fig. 35.3), the prostatic urethra is divided into proxi- mal and distal segments of approximately equal length by an anterior angulation at the midpoint between the prostate apex (distal) and the bladder neck (proximal) (1,5). The

FIGURE 35.1  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.

FIGURE 35.3  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 ]; prepro- static sphincter [ s ]; distal semicircular [“striated”] sphincter [ s ]). These structures are shown in relation to a three-dimensional representation of the glandular prostate (central zone [ CZ ]; peripheral zone [ PZ ]; tran- sition zone [ TZ ]). Coronal plane ( C ) of Figure 35.4 and oblique coronal plane ( OC ) of Figure 35.5 are indicated by arrows .

FIGURE 35.2  Prepubertal prostatic duct lined by epithelium with multiple layers of nuclei and showing no cytoplasmic differentiation.

966

SECTION IX : GenitourinaryTract

An oblique coronal section (Fig. 35.5) along the proximal (mid to base) segment of the prostatic urethra from verumon- tanum to the bladder neck best defines its glandular relation- ships. Normally, the proximal urethral segment is intimately related to about only 5% of the prostatic glandular tissue, and almost all of this is the transition zone (7). This zone is formed by two small lobes whose ducts leave the posterolat- eral recesses of the urethral wall at a single point. The main ducts of the transition zone extend laterally and curve sharply anteriorly, arborizing toward the bladder neck. The main nonglandular tissue of the prostate is the ante- rior fibromuscular stroma which overlies the urethra in the anteromedial prostate. Its bulk and consistency vary consider- ably from apex to base, as described further in this chapter. Radical prostatectomy, including removal of the seminal vesicles, is the definitive surgical procedure for patients with prostatic carcinoma. Current convention calls for inking the intact prostate gland and seminal vesicles in two colors in the fresh state to allow assessment of laterality. The most apical region of the gland (approximately 5 mm) is amputated in a transverse plane to include the opening of the distal ure- thra, and then subsequently sectioned parasagittally, perpen- dicular to the inked surface (Fig. 35.6) for embedding. This allows for visualization of apical prostatic tissue in planes that are near perpendicular to the true apical surface and hence, more accurate evaluation of cancer penetration and margin status. Handling of the bladder neck margin may be FIGURE 35.5  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. SECTIONING OF RADICAL PROSTATECTOMY SPECIMENS

verumontanum protrudes from the posterior urethral wall at the point of angulation and is the point at which the ejacu- latory ducts empty into the prostatic urethra. The ejacula- tory ducts then extend proximally from the verumontanum (mid) to the base of the prostate, following a course that is nearly a direct extension of the long axis of the distal (apex to mid) urethral segment, although usually offset posteriorly by a few millimeters. A coronal plane of section (Fig. 35.4) along the course of the ejaculatory ducts and distal (apex to mid) urethral segment provides the best demonstration of the anatomic relationships between the two major regions of glandular prostate, the peripheral and central zones (6). The periph- eral zone comprises about 65% of the mass of the normal glandular prostate. Its ducts exit posterolaterally from the urethral wall along a double row extending from the veru- montanum to the prostate apex. The ducts extend mainly laterally in the coronal plane, with branches that curve anteriorly and posteriorly. The central zone comprises about 30% of the glandular prostate mass. Its ducts arise in a small focus on the veru- montanum and immediately surround the ejaculatory duct orifices. The ducts branch directly toward the base of the prostate along the course of the ejaculatory ducts, fanning out to form an inverted conical structure that is flattened in the anterior–posterior plane. The base of this cone comprises almost the entire base of the prostate. The most lateral central zone ducts run parallel to the most proximal (base) peripheral zone ducts, separated only by a narrow band of stroma, which is usually imperceptible in clinical specimens. FIGURE 35.4  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 the entire main duct course.

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CHAPTER 35:  Prostate

accomplished in a similar fashion to the prostatic apex; how- ever, some institutions shave a thin section of the most super- ficial muscle fragment(s) surrounding the proximal prostatic urethra and submit this tissue as an en face margin (8). While there is consensus that the junction of the seminal vesicles and the prostate should be sampled, the extent to which the remainder of the seminal vesicle should be submitted is not standardized (9). A reasonable approach may be to take two sections of each seminal vesicle, one at the prostatic junc- tion, as well as a mid-seminal vesicle section to account for both contiguous spread of tumor from the prostatic base, as well as seminal vesicle invasion that occurs in the context of extraprostatic tumor extension. The remaining bulk of the gland is sectioned from apex to base in the anterior–posterior plane at approximately 3-mm intervals (10,11). The resulting complete transverse macrosections are submitted as either full whole mount sections or divided into half or quadrant sections using conventional tissue cassettes. Although there is debate as to the appropriate extent of sampling (8), a mini- mum submission of every other intervening macrosection is often recommended. FIGURE 35.6  Apex of prostate seen grossly after 5-mm thick apical block has been subsectioned parasagittally at 3-mm intervals. Orienta- tion of sections and localization of lesions are easily demonstrated, and cuts through the tissue are nearly perpendicular to the apical surface.

and tissue processing (12,13) is also typical, resulting in arti- factual shortening of the distance from prostatic apex to veru- montanum and everting the posterior periurethral tissue into the urethral space. These effects create an artificial “promon- tory” in the apical portions of the gland (Fig. 35.7) (14). FIGURE 35.7  Distal urethra near the apex. Note the “promontory” or eversion of posterior periurethral tissue into the urethral space. The posterior portion of the semicircular sphincter (see Fig. 35.8) is present as a central muscular column.

Histologic Variation by Anatomic Region Apical One-Third of the Prostate (Apex)

In a surgical pathology specimen sectioned in the anterior–posterior plane, the apical (distal) urethra is located near the center of the section (Fig. 35.8). It is

ANATOMY OF THE PROSTATE GLAND IN SURGICAL PATHOLOGY SPECIMENS

Gross Anatomy In situ operative views of the prostate reveal a cone-shaped organ with its base surrounding the proximal urethral seg- ment and abutting the bladder neck and its apex narrowing around the distal urethral segment as it approaches the uro- genital diaphragm. Surgical manipulation and subsequent detachment of the prostate from native connective tissue leads to superior retraction of the distal (apical) urethra and yields a roughly spherical specimen at the gross dissection bench. Significant tissue shrinkage due to formalin fixation

FIGURE 35.8  Whole mount section from apex of prostate. The urethra and promontory ( P ) are central and proceeding anteriorly, the semi- circular sphincter ( SCS ) and anterior fibromuscular stroma ( AFMS ) are visualized. The posterior, lateral, and anterolateral portions of the apex are composed of peripheral zone ( PZ ) tissue. Most anteriorly, the anterior extraprostatic space ( AEPS ) contains vascular and adipose remnants of the dorsal vascular complex.

968

SECTION IX : GenitourinaryTract

Middle One-Third of the Prostate (Mid Gland) McNeal’s studies revealed a 35-degree angulation of the prostatic urethra at mid gland, dividing the urethra into proximal (toward the base) and distal (toward the apex) segments (Fig. 35.9A–B). The key anatomic landmark in the mid gland is the verumontanum, an exaggerated area of glandular–stromal tissue, located subjacent to the posterior urethral wall, into which the ejaculatory ducts insert and from which the glandular zones arise (16). Histologically, the verumontanum consists of a crowded collection of pros- tatic glands, lined by secretory epithelium and often with abundant intraluminal corpora amylacea, directly underly- ing the urothelium of the prostatic urethra. When promi- nent, the term verumontanum gland mucosal hyperplasia is applied (Fig. 35.10) (17). At mid gland, the transition zone becomes evident as bilateral lobes in the anteromedial region of the gland. The ducts of the transition zone appear to arise from the posterior boundary of the periurethral space and course anterolaterally to serve as a boundary between transition and peripheral zones. A stromal bound- ary between these two zones has also been described (7), but may be difficult to identify in individual cases. In the normal mid gland, the peripheral zone still composes the posterior, lateral, and the majority of anterolateral tissues (Fig. 35.9A). In prostates with BPH, this tissue may be sig- nificantly compressed toward the lateral most portions of the gland (Fig. 35.9B). The anterior fibromuscular stroma in this region may be less evident owing to the increased

immediately surrounded by a thin layer of stroma and a variable number of periurethral glands. The latter intermingle anteromedially with a semicircular band of medium-sized, compactly arranged and vertically ori- ented muscle fibers. This band is incomplete posteriorly, appearing consistently as a densely eosinophilic, aglan- dular muscular column which extends posteriorly from the urethra (Fig. 35.7) and is distinct from the glandular verumontanum of the mid gland. This compact morpho- logic appearance led some authors to designate this as the “striated sphincter” (5,10,15), yet careful histopatho- logic evaluation of the region shows that it is composed purely of smooth muscles. This impression is confirmed by the lack of immunohistochemical staining for sarco- meric actin, a marker of mature skeletal muscle, in the muscle cells of this region (14). Anterior to the semicircular muscle, fibers of the anterior fibromuscular stroma traverse horizontally and laterally as they extend to the anterior- and apical-most aspects of the prostate. While heightened intraprostatic pressure may cause bulging of hypertrophic transition zone acini, no normal transition zone tissue is located in the prostatic apex. The bilateral peripheral zone, which composes essentially all of the glandular tissue at the apex, occupies the posterior, lateral, and anterolateral prostates, abutting the anterior fibromuscular stroma medially and forming a nearly complete ring in histologic sections.

A

B

FIGURE 35.9  A: Whole mount section from mid prostate at the level of the verumontanum ( V ). Note the bilobed transition zone ( TZ ) arising from elongated ducts ( D ) which course anterolaterally. The peripheral zone ( PZ ) still occupies the posterior, lateral, and anterolateral portions of the gland, with a cancer nodule ( CA ) evident in the right anterior peripheral zone. In the mid prostate, the anterior fibromuscular stroma ( AFMS ) is much condensed and the anterior extraprostatic space ( AEPS ) largely retains its apical consistency. B: Whole mount section from mid prostate at the level of the verumontanum ( V ) in a gland with extensive benign prostatic hypertrophy ( BPH ). Anterolateral “horns” of the peripheral zone ( PZ ) are compressed laterally by the expanded transition zone tissue and the AFMS is diminished in extent.

969

CHAPTER 35:  Prostate

FIGURE 35.10  The verumontanum often contains densely packed prostatic glands lined by benign secretory cells, often with abundant intraluminal corpora amylacea.

ejaculation to prevent retrograde flow of seminal fluid from the distal urethral segment and may have resting tone that maintains closure of the proximal urethral segment (18). At the base, the glands of the transition zone gradually recede and the few remaining peripheral zone acini once again comprise the anterior glandular tissue. In contrast with its apical appearance, however, the peripheral zone rarely extends anteromedially due to the abundant stroma in this region. This stroma appears as an expansive strip of tissue consisting of both preprostatic sphincter and anterior fibro- muscular stroma, with the latter often merging with large smooth muscle bundles located in the anterior extraprostatic space. With increasing angulation, the prostatic urethra is identified further anteriorly in histologic sections, eventually breaching the anterior-most border of tissue sections at the level of the bladder neck. Posteriorly and posterolaterally, the central zone becomes evident surrounding the ejacula- tory ducts which themselves are immediately encircled by a sheath of loose fibrous tissue with abundant lymphovascular spaces (Fig. 35.13). In the most basal portions of the gland, the well-formed muscular coat at the base of the seminal vesicles emerges and separates from the bulk of the pros- tatic tissue creating a fibroadipose tissue septum. The last vestiges of the central zone are present at the most lateral aspects of these emerging seminal vesicles (14). FIGURE 35.12  Preprostatic sphincter investing the proximal urethra in section from the base of prostate. The sphincter is composed of com- pact, short smooth muscle fibers distinct from prostatic smooth muscle and conveying a paler appearance to the periurethral zone as seen in Figure 35.11. Nonglandular Components of Prostatic and Extraprostatic Tissues Prostatic Capsule and Anterior Fibromuscular Stroma The prostatic “capsule” or condensed fibromuscular tissue (Fig. 35.14) ideally consists of an inner layer of smooth mus- cle fibers and an outer collagenous membrane. However, the relative and absolute amounts of fibrous and muscle

density of glandular tissue in the mid gland coupled with effects of organ contraction (14). Basal One-Third of the Prostate (Base) Progressing proximally from mid gland to base, the urethra becomes invested by a thick layer of short smooth muscle fibers, constituting the “preprostatic sphincter” (Figs. 35.11 and 35.12), which at its most lateral point may be in con- tact with the glands and acini of the transition zone (5,7). The preprostatic sphincter is thought to function during

FIGURE 35.11  Whole mount section from base of prostate. The prepro- static sphincter ( PPS ) is evident as a pale area surrounding the proxi- mal urethra. The transition zone ( TZ ) shows abortive small acini and is covered anteriorly by a vast anterior fibromuscular stroma ( AFMS ) which merges with smooth muscle bundles in the anterior extrapros- tatic space ( AEPS ). Posteriorly, the expansive central zone ( CZ ) sur- rounds the ejaculatory duct complex ( EJD ), while some peripheral zone ( PZ ) is still apparent posterolaterally.

970

SECTION IX : GenitourinaryTract

also variable (7,21) and the proportion and arrangement of collagenous tissue is inconsistent. Consequently, the pros- tate capsule cannot be regarded as a well-defined anatomic structure with constant features. While the capsule envelopes most of the external sur- face of the prostate, there is a defect of variable caliber at the prostatic apex anteriorly and anterolaterally such that the most distal (apical) fibers of the anterior fibromuscular stroma often mingle with the prostatic glandular tissue ante- rior and lateral to the urethra. Hence, if carcinoma is pres- ent in the apical third of the prostate anteriorly, it may be quite difficult to determine whether it has invaded beyond the boundary of the gland. Similar difficulty is encountered at the most proximal portion of the urethra in the bladder neck section, in which no clear capsule is evident. 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 (Fig. 35.3) (7). Its lateral mar- gins blend with the prostate capsule along the line where the capsule covers the most anteriorly projecting border of the peripheral zone. Its deep surface is in contact with the preprostatic sphincter and the transition zone proximally (toward the base) and with the “striated” or the semicircu- lar sphincter distally (toward the apex). It is composed of large bundles of smooth muscle cells that may be separated by bands of dense fibrous tissue, and are more randomly oriented than those of the bladder neck and blend with the latter at its proximal (basal) extent. Unlike the posterolateral prostate, in histopathologic sec- tions the anterior-most region of the gland does not exhibit a distinct “capsule” (19). Rather, as one proceeds from apex to base, the anterior fibromuscular stroma is variably inter- twined with skeletal muscle fibers emanating from the uro- genital diaphragm (apical prostate) (Fig. 35.15) or levator ani muscles (mid prostate) and may fuse with detrusor smooth

FIGURE 35.13  Ejaculatory duct encircled by a fibroconnective tissue sheath containing numerous lymphovascular spaces.

tissues and their arrangement vary considerably from region to region (19,20). At the inner capsular border, transverse smooth muscle blends with periglandular prostatic smooth muscle, and a clear separation between them cannot be iden- tified microscopically (19). The distance from terminal acini of the peripheral and central zones to the prostate surface is

FIGURE 35.14  The prostate capsule consists of a layer of mainly trans- verse 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 ).

FIGURE 35.15  Anterior fibromuscular stroma showing admixture of smooth muscle bundles with skeletal muscle fibers from the urogenital diaphragm at the apex of the prostate.

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muscle (mid to base). Moreover, the anterior fibromuscular stroma also contains blood vessels that supply/drain the ante- rior prostate throughout its extent. Due to the complex tissue composition of the anterior and anterolateral prostates and lack of a definitive border, the task of separating prostatic from extraprostatic tissue can be challenging in this region. Extraprostatic Tissues, Prostatic Innervation, and Vascular Supply In vivo, the tissue immediately anterior to the prostate is the dorsal venous or vascular complex, a series of veins and arter- ies set in fibroadipose tissue that runs over the anterior pros- tate and continues distally to supply/drain the penis (22). At the time of radical prostatectomy, the dorsal vascular complex is ligated and then divided, with a portion of the blood vessels and fibroadipose tissue remaining adherent to the prostate specimen. These may be identified as the anterior extrapros- tatic tissue from apex through mid gland. The most proxi- mal (basal) two to three sections typically reveal medium- to large-sized smooth muscle bundles admixed with adipose tissue (Fig. 35.16). These fibers are morphologically identi- cal to those of the detrusor muscle and possibly represent the inferior border of the bladder neck (23). 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 (Figs. 35.17 and 35.18), a thin, compact collagenous membrane whose smooth

FIGURE 35.16  Prostate at mid to base of the gland—anterior extra- prostatic space displays numerous medium- to large-sized discrete (detrusor-like) muscle bundles ( DLM ) admixed with adipose tissue, which merge with the anterior fibromuscular stroma ( AFMS ).

FIGURE 35.17  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 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 dis- tally as mid prostate. Branches con- tinue 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 penetra- tion area ( green ). LPF , lateral pelvic fascia.

972

SECTION IX : GenitourinaryTract

posterior surface rests directly against the muscle of the rectal wall (24). The capsule is typically fused to the fascia with occasional remnants of an interposed adipose layer. In the adult, there remain only scattered microscopic islands of fat along with a variable number of smooth muscle fibers. Superiorly (toward the base), Denonvilliers’ fascia extends above the prostate to cover the posterior sur- face of the seminal vesicles in a loosely adherent fashion (Fig. 35.17). Laterally, the fascia leaves the posterior cap- sule where the prostate surface begins to deviate anteriorly, and it continues in a coronal plane to anchor against the pelvic sidewalls. Thus, the prostate and seminal vesicles are suspended along the anterior aspect of this fascial mem- brane in a similar fashion to the uterus being suspended from the broad ligament in the female. As the seminal vesicles leave the prostate base, they extend laterally along its basal surface. Often there is no capsule between the two organs, at least for the medial cen- timeter or more of the seminal vesicle. The degree of fusion between the two muscular walls is variable between pros- tates, but there is frequently no boundary between the two organs medially with a minimal amount of common muscu- lar wall separating the most basal central zone gland lumen from the seminal vesicle lumen (Figs. 35.18 and 35.19). 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 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 bilateral FIGURE 35.18  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 ) cov- ers the dome-shaped surface of the anterior central zone ( top center ). All glandular tissues within is central zone. One main duct ( center ) is seen in profile as it flares out toward the base, generating elaborate acinar struc- tures. Behind the seminal vesicle ( SV ), the posterior central zone extends superiorly as a narrow plate. Denonvilliers’ fascia ( D ) is not adherent behind the seminal vesicles but blends with the capsule below.

FIGURE 35.19  Minimal muscular tissue separating the prostatic central zone ( right ) from the seminal vesicles ( left ) at the base of the prostate.

neurovascular bundles that course vertically along the pelvic sidewalls (Fig. 35.17) (25). Most of the nerve branches to the prostate leave the neurovascular bundle just superior to the prostate base and course medially as the superior pedi- cle. These nerve branches fan out to penetrate the “superior pedicle insertion area” of the capsule, centered at the pos- terolateral aspect of the prostate base (25,26) and extend as far as mid gland. 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 pen- etrate the capsule at an oblique angle. Small microscopic paraganglia may also be seen in association with extrapros- tatic nerves and ganglia, reportedly identified in up to 8% of radical prostatectomies (27). They are characterized by small collections of round cells with clear or amphophilic cyto- plasm, often with small cytoplasmic granules and an associ- ated small capillary vasculature (Fig. 35.20). Some variable

FIGURE 35.20  While paraganglia may be seen in extraprostatic tis- sues, often in association with peripheral nerves and ganglia, very rare examples may be intraprostatic.

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CHAPTER 35:  Prostate

cytologic atypia may be present in paraganglia, which could be confused with carcinoma, particularly in rare examples of intraprostatic paraganglia. 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 (26). Here the distance from neurovas- cular bundle to prostate capsule is narrowed to only a few millimeters and hence sparing the nerves involved in erec- tile function requires dissecting very close to the prostatic capsule in this region (28,29). Arterial branches follow the nerve branches from the neurovascular bundle; they spread over the prostate sur- face and penetrate the capsule to extend directly inward toward the distal (apex to mid) urethral segment between the radiating duct systems of the central and peripheral zones (30,31). A major arterial branch enters the prostate at each side of the bladder neck and runs toward the veru- montanum parallel to the course of the proximal (mid to base) urethral segment. It supplies the periurethral region and medial transition zone. Architectural Patterns The biologic role of the prostate calls for the slow accumu- lation and occasional rapid expulsion of small volumes of fluid. These requirements are optimally met by a muscu- lar organ having a large storage capacity and low secretory capacity. It is fitting then that the prostatic ducts are mor- phologically identical to the acini except for their geom- etry, 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 phos- phatase (PAP) shows uniform granular staining of all ductal and acinar cells (Fig. 35.21). Except for the main transition zone ducts, which termi- nate at the anterior fibromuscular stroma, the main ducts of the prostate originate at the urethra and terminate near the capsule (3,6,7) (Figs. 35.4 and 35.5). Since ducts and acini within each zone have a similar caliber, spacing, and histo- logic appearance, ducts, ductules, and acini cannot reliably be distinguished microscopically. Hence, abnormalities of architectural pattern such as those seen in adenosis, pros- tatic intraepithelial neoplasia (PIN), and prostatic carci- noma are identified in routine sections mainly by deviations from normal size and spacing of glandular units. The main excretory duct orifices of the peripheral zone arise every 2 mm from the distal (apex to mid) urethral ARCHITECTURAL AND CYTOLOGIC FEATURES OF THE GLANDULAR PROSTATE

FIGURE 35.21  Ducts and acini of peripheral zone, immunohistochemi- cally stained with anti-PSA and showing uniform distribution of protein throughout the cytoplasm of all ducts and acini.

segment along a double lateral line. A cluster of three or four subsidiary ducts arise about every 2 mm along each main excretory duct from urethra to capsule. These sub- sidiary ducts branch and extend only a short distance, rebranching and giving rise to groups of acini (Fig. 35.22). 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. In the peripheral zone and transition zone, ducts and acini have simple rounded contours that are not perfectly circular because of prominent undulations of the epithelial border (4,6). The undulations presumably allow expansion of the lumina as secretory reservoirs. Central zone ducts and acini are distinctively larger than those of the peripheral zone and transition zone (Fig. 35.23). Both ducts and acini of the central zone become progres- sively larger toward the capsule at the prostate base reflect- ing the great expansion of central zone cross-sectional area from a small focus on the verumontanum to almost the entire prostate base. The corrugations in central zone duct/ acinar walls are often exaggerated into distinctive intraluminal ridges—so-called “Roman arches.” In some specimens, there is an evident contrast in stromal morphology that delineates the boundary between peripheral zone and transition zone (21). The transition zone stroma is composed of compact interlacing smooth muscle bundles. This stromal density differs from the adjacent loose

974

SECTION IX : GenitourinaryTract

FIGURE 35.24  Prostatic acini with basal cells demonstrating little to no cytoplasm and arranged parallel to the basement membrane.

and the stroma by a layer of basal cells. The basal cells are typically elongated and flattened parallel to the basement membrane and have slender dark nuclei and usually little or no discernible cytoplasm (Fig. 35.24) (34). They are typically quite inconspicuous and, in routine preparations may appear incomplete or even absent around individual ducts or acini. Immunohistochemical labeling with high—molecular-weight cytokeratin and/or antibodies to p63 highlights the basal cell population (Fig. 35.25) (35–37). These stains are consistently negative in the cells of invasive malignant glands (36) because basal cells are absent. Basal cells are not myoepithelial cells analogous to those of the breast because, by electron micros- copy, they do not contain muscle filaments (34). In all zones of the prostate, the epithelium con- tains a small population of isolated, randomly scattered endocrine–paracrine cells (38) that are rich in serotonin- containing granules and contain neuron-specific enolase.

FIGURE 35.22  Subsidiary duct and branches in peripheral zone, termi- nating in small rounded acini with undulating borders. Ducts and acini have similar calibers and histologic appearances.

peripheral zone stroma, but 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 (32,33). Cytologic Features As with other glandular organs, the secretory cells through- out the prostate are separated from the basement membrane

FIGURE 35.25  Same acini as in Figure 35.24 labeled with a double immunohistochemical stain for 34 β E12 (cytoplasmic) and p63 (nuclear) in basal cells.

FIGURE 35.23  Low-power view of prostatic central zone architecture; large glands with complex luminal infoldings and distinct intraluminal bridges (“Roman arches”).

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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 secre- tory cells and often have laterally spreading dendritic pro- cesses. 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. 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, while pepsinogen II (39), tissue plasminogen activator (40), and lactoferrin are normally produced only in the ducts and acini of the central zone. While PSA and PAP have historically been utilized as immunohistochemical markers of prostatic epithelium (or for prostatic origin in car- cinomas), newer antibodies against the NKX3.1 protein are also frequently employed in routine clinical practice (41). The cytoplasmic appearance of the normal secretory cell in all zones is similar and contains an abundance of small clear secretory vacuoles. Vacuoles in peripheral zone and transition zone cytoplasm are tightly packed (42), whereas in the central zone, a more abundant dense cytoplasm is associated with a somewhat wider vacuole spacing and lower vacuole density. Since the secretory vacuoles appear empty by routine microscopy, peripheral zone and transition zone cells are typically pale to clear, while central zone cells are typically somewhat darker (Figs. 35.26 and 35.27).

FIGURE 35.27  Central zone epithelium with eosinophilic cytoplasm and prominent basal cell layer.

The appearance of normal cell cytoplasmon tissue sections is strongly influenced by staining technique and by the type of fixative used. In the peripheral zone and the transition zone, light hematoxylin & eosin (H&E) staining after formalin fixa- tion shows that normal cells are “clear cells” in which a faint network of pale-staining cytoplasmic partitions between vacu- oles can be visualized with careful scrutiny under high magni- fication. Only an occasional cell shows complete outlines that define numerous intact vacuoles, but immunostaining with PSA (Fig. 35.28) or PAP on the same tissue sharply outlines

FIGURE 35.28  Peripheral zone epithelium immunostained with anti- body to PSA. Protein is concentrated in a reticulated pattern that spares vacuole lumens and accentuates portions of vacuole partitions.

FIGURE 35.26  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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all the cytoplasmic vacuolar partitions and shows no evidence of protein within the vacuoles. Darker 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 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 neighbor- ing 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 con- sequently often uneven, and its irregularity is accentuated by frequent cells whose luminal aspect appears frayed. Central zone epithelium shows an accentuation of the mild disorder of cell arrangement of the peripheral zone/ transition zone (Figs. 35.23 and 35.27). Here the epithe- lium 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 appear pseudostratified. The dark cytoplasm, thickened variable epithelium, and complex architecture in the central zone may be misinter- preted as PIN on needle biopsies. However, the distinctive histologic features coupled with the absence of enlarged nuclei, nucleoli, or hyperchromasia and an often prominent basal cell layer are useful in excluding this diagnosis. DEVIATIONS FROM NORMAL HISTOLOGY Beyond the age of 30 years, many prostates begin to show a variety of deviations from normal morphology (3,6,32,33). Their prevalence and extent of these changes progressively increase with age so that most prostates are quite heteroge- neous in histologic composition by the seventh decade of life. Although these histologic patterns seldom have clini- cal significance, their distinction from adenocarcinoma 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 (3,6). The number and extent of atrophic foci tend to be greater in older men, but their histologic appearance is identi- cal to that of isolated foci found as early as 30 years of age. Atrophy is an extremely common lesion and is mainly seen in the peripheral zone, where its distribution is typically segmental along the ramifications of a duct branch (3,6). Publication of a Working Group classification (43) has high- lighted four patterns of focal atrophy with distinctive histo- logic features. The most common of these is termed simple atrophy , in which irregular or angulated, basophilic acini are seen at low magnification. Some degree of acinar dropout may be present. Individual acini have reduced cytoplasm,

FIGURE 35.29  Simple atrophy demonstrating angulated, basophilic glands with limited to no cytoplasm and dark nuclei; scattered chronic inflammatory cells are also present.

yet nuclei often retain their usual size (Fig. 35.29). Simple atrophy is commonly associated with chronic inflammation that may involve the prostatic stroma or epithelium. Espe- cially in the setting of inflammation, atrophic glands may exhibit small nucleoli. The combination of small angulated glands with variable architectural distortion and nucleoli may mimic cancer and cause diagnostic difficulty. Simple atrophy with cyst formation is characterized by rounded acini of very large diameter which have a sieve-like gross and cyst-like microscopic appearance. Glands show back to back architecture with little intervening stroma (Fig. 35.30). Cytologically, the cyst-like acini have little to no apparent cytoplasm and unlike simple atrophy , are uncommonly associated with chronic inflammation. Postatrophic hyperplasia , like simple atrophy , has a baso- philic appearance at low magnification and is composed of small round acini in a vaguely lobular arrangement. In radical

FIGURE 35.30  Back-to-back large caliber rounded acini with little to no cytoplasm characteristic of cystic atrophy.

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CHAPTER 35:  Prostate

FIGURE 35.33  Prostatic stromal hyperplasia is characterized by a relatively lobular or nodular proliferation of cytologically bland spindle cells associated with prominent small round blood vessels.

FIGURE 35.31  Postatrophic hyperplasia with atrophic acini in a lobular array surrounding a central dilated duct.

prostatectomy sections, these acini often seem to surround a dilated duct (Fig. 35.31), which has led some to use the alternate term “lobular atrophy.” The close packing of multi- ple small acini conveys a histologic impression of hyperplas- tic glands, yet whether this is truly a hyperplastic process or not remains unknown. The atrophic acini are often engulfed in a variable degree of fibrotic or sclerotic stroma. Cytologi- cally, postatrophic hyperplasia shows low cuboidal cells with scant cytoplasm and small- to medium-sized nucleoli. Like simple atrophy , chronic inflammation is often present, and the differential diagnosis of adenocarcinoma is often raised, especially in needle biopsy material. Partial atrophy is distinct from the other forms described here in that cytoplasm is attenuated, but is variably pres- ent, with a nonbasophilic appearance at low magnification. Characteristically, partial atrophy displays more cytoplasm lateral to the nucleus, increasing internuclear distance and imparting a pale low-power impression (Fig. 35.32). Small- to

medium-sized nucleoli, as well as intraluminal dense pink sections/crystalloids may mimic carcinoma. Partial atrophy is frequently seen admixed with foci of simple atrophy suggest- ing that they represent a spectrum of atrophic changes. In contrast to atrophy, the histologic hallmark of BPH is the expansile nodule, produced by the budding and branch- ing of newly formed duct–acinar structures, by the focal proliferation of stroma (Fig. 35.33), or by a combination of both elements (Fig. 35.34) (3,4,7,44). It mainly affects the transition zone.

FIGURE 35.32  Focus of partial atrophy with attenuated pale cytoplasm andwispy eosinophilic intraluminal secretions. The nuclei appear relatively evenly spaced due to retention of the lateral cytoplasm.

FIGURE 35.34  Nodule of glandular benign nodular hyperplasia in the prostatic transition zone.

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FIGURE 35.36  Prominent squamous metaplasia is often present sur- rounding areas of ischemia or frank infarct.

FIGURE 35.35  Focus of basal cell hyperplasia showing multiple layers of rounded basal cells with a central flattened layer of eosinophilic secretory cells. The basal cells commonly contain small prominent nucleoli.

Grossly BPH is usually recognized as a globular mass replacing each transition zone and is composed of numer- ous individual nodules. Only the nodular component is rec- ognizable 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 char- acteristic progressive deformity of overall prostate contour. The expansion is chiefly anterior and toward the apex result- ing in stretching and thinning of the anterior fibromuscular stroma and producing an increase in the thickness (antero- posterior dimension) of the gland. The anterolateral “horns” of the peripheral zone (Fig. 35.9B) are compressed and thinned concomitant with increase of overall prostate width. Basal cell hyperplasia is most often seen as a secondary change in BPH nodules or inflammatory foci (45). The basal cells of ducts and acini become rounded with oval nuclei, and they form a multilayered lining (Fig. 35.35) that stains for basal cell–specific high—molecular-weight cytokeratins. There is typically a single luminal row of columnar secretory cells that stain positive for PSA. When ischemia or frank infarcts are present (often in association with BPH), squamous metaplasia may also become prominent. This benign metaplastic change may closely mimic urothelial carcinoma (Fig. 35.36) (46). Because many men with prostate cancer are treated by radiation therapy, pathologists must be familiar with its effects on benign glands. After radiation, the normal glands typically become atrophic, but with cytoplasmic eosino- philia that imparts a “squamoid” appearance, and scattered nuclei become enlarged and hyperchromatic, albeit with degenerative-appearing, “smudgy,” chromatin (Fig. 35.37). Many of the cells within these glands assume a basal cell phenotype, so the expression with basal cell markers, includ- ing GATA3, is common. Because of the cytologic atypia, the latter immunophenotypic finding may cause confusion with urothelial carcinoma (47,48).

CONSIDERATIONS IN TRANSURETHRAL RESECTION AND NEEDLE BIOPSY SPECIMENS

Tissue distortion by thermal artifact near the edges of trans- urethral resection (TUR) tissue fragments (“chips”) can create important diagnostic problems that occasionally may be insurmountable. Basal cell hyperplasia, adenomatous hyperplasia, atrophy, and fragments of BPH nodules with small glands may be difficult to distinguish from carcinoma without utilizing adjunctive immunohistochemical stains. Loss of nuclear detail occurs more homogeneously across the tissue chips than obvious cell distortion. Hence, small foci of cancer may be more difficult to diagnose because of the artifactual absence of nucleoli.

FIGURE 35.37  Radiation therapy induces atrophic changes in benign prostatic glands, often with associated cytoplasmic eosinophilia and nuclear pleomorphism.