Macroscopic identification of prostatic carcinoma in needle biopsy tissue and transurethral resection of prostate (TURP) chips is generally not possible.

Grossly it can be difficult or impossible to recognize prostatic carcinoma, even with the whole gland available for evaluation (15). Palpation of the excised, intact prostate gland can be helpful in a minority of cases in delineating the site(s) of nodularity, but in this era when most carcinomas are clinically impalpable, they are also impalpable at the surgical pathology cutting bench (15). When visible on cut sections, carcinoma can appear nodular and white (Fig. 4A.4) to irregular gray or white-yellow compared with adjacent benign prostatic tissue, which is tan, spongy, and often cystic. Macroscopically recognizable carcinoma tends to be, not surprisingly, of higher grade, stage, and size (15). The lower limit of size detection of gross carcinoma is about 0.5 cm. More often, no gross lesion is evident or a lesion only suggestive of carcinoma is visualized (15). Subtle gross changes in cut sections are best appreciated by comparing right and left halves of the prostate with each other. These subtle alterations include ill-defined, asymmetric, firm, yellow-white areas in the peripheral zone. The more centrally located transition zone carcinomas are characteristically nodular, solid, and bright yellow to white (16), but BPH nodules can precisely simulate this appearance. Attempts to recognize gross extension of carcinoma into extraprostatic tissues and surgical margins in radical prostatectomy specimens can also be a futile exercise.

Most adenocarcinomas arise in the peripheral zone, where posterolateral or posterior positions are typical, with anterior peripheral zone carcinomas seen in only about 7% of cases (17). The predominant carcinoma is in the peripheral zone in about 70% of cases, in the transition zone in about 20% of cases (18,19), and in the central zone in about 5% of cases (20). In roughly one quarter of cases, cancer foci are identified in both the transition and peripheral zones (19).

There are clinical and histopathological differences between transition zone and peripheral zone carcinomas (19,21). Transition zone cancers are more likely to be detected as an incidental finding in TURP chips since TUR selectively samples the transition zone. Transition zone carcinomas tend to lower Gleason grade (with a mean score of 5) compared to peripheral zone carcinomas (with a mean score of 6-7), and transition zone carcinomas less often exhibit extraprostatic extension and seminal vesicle invasion. However, a subset of transition zone carcinoma is high-grade with Gleason grade 4 or 5, with high rates of extraprostatic extension (22). Because of their location transition zone carcinomas often invade into anterior fibromuscular stroma and BPH nodules, while those peripheral zone carcinomas that exhibit extraprostatic extension often invade into posterolateral periprostatic soft tissue. Some transition zone carcinomas can be high-volume, and low-grade with a high preoperative PSA and still organ-confined (23). Histologically, it has been previously proposed that transition zone carcinomas have a distinctive histologic appearance, with columnar cells lining glands of variable shape and contour (18), but these features are not specific and can be seen in a substantial percentage of peripheral zone carcinomas (24). There are some differences between transition zone and peripheral zone carcinomas in DNA ploidy, proliferation index, microvessel density, and p53, bcl2, and matrix metalloproteinase expression as well as molecular genetic differences (19), but these could be related to Gleason grade differences. The outcome data after radical prostatectomy are mixed: some studies show a better outcome for transition zone compared to peripheral zone cancers (21,25), whereas others show no difference (26). It does not appear that transition zone versus peripheral zone location of prostate cancer is an independent prognosticator. Moreover, it is difficult to sample transition zone carcinoma by needle biopsy. Needle biopsies directed toward the transition zone do not adequately sample clinically relevant transition zone carcinomas, since the biopsies often did not sample the transition zone or the dominant transition zone carcinoma (27).

Central zone carcinomas are uncommon, representing 3% to 8% of all prostate cancers (20,28). In one series, these carcinomas were of high grade (with a mean Gleason score of 8) with high rates of extraprostatic extension, seminal vesicle invasion, and biochemical failure after radical prostatectomy (28). Central zone location is not an independent predictor of clinical failure.

It has been recommended, despite lack of independent prognostic significance, that zonal location of the index tumor be reported (29). Note that there is no consensus, however, on how to define an index tumor. The most popular definitions use tumor size, size and grade, or stage and grade (29).

Prostatic adenocarcinomas are multifocal in 50% to 97% of cases (28,30). There is histologic (Gleason grade) and molecular heterogeneity of multifocal adenocarcinoma within the same prostate gland (30,31,32,33). Comparative genomic hybridization and TMPRSS2 gene rearrangement studies suggest that multifocal prostatic carcinomas arise from multiple, independent clonal expansions (32,33).

The definitive diagnosis of prostatic carcinoma is most often established by light microscopic interpretation of hematoxylin and eosin-stained sections of needle core biopsy tissue procured
from the peripheral zone. The histologic diagnosis of prostatic carcinoma requires a synthesis of a constellation of features that allows for a definitive diagnosis. A conceptual framework for a rationale approach to this diagnosis entails application of major and minor criteria (34). The criteria are utilized in all prostatic tissue samples. To follow is a description of this approach in needle biopsy.

The major criteria are an infiltrative growth pattern, absence of basal cells, and nuclear atypia. The first of the major criteria, an infiltrative growth pattern, frequently presents as the presence of small crowded malignant glands extending between and/or around larger, more complex, (and often paler) benign glands. These Gleason pattern 3 adenocarcinomas represent the most common pattern recognized in needle biopsy either in pure form as Gleason score 6 (3 + 3) (Fig. 4A.5) or as Gleason score 7, admixed with Gleason pattern 4 (Fig. 4A.6) (35,36,37). (See below section on Gleason grading). Gleason pattern 3 shows haphazardly arranged and variably sized individual, discrete glands (37). The infiltrative character of high-grade (Gleason patterns 4 or 5 and score 7-10) prostatic carcinoma in needle biopsy is typified by ragged invasion of fused microacinar, cribriform, or papillary masses (Fig. 4A.7). Linkage of carcinoma cells into chains and cords also indicates poorly differentiated Gleason pattern 4 adenocarcinoma. Another descriptor of Gleason pattern 4 is ill-defined glands with poorly formed glandular lumina (37). High-grade carcinoma can also invade as sheets, with destruction and effacement of benign prostatic tissue (Fig. 4A.8), or be manifested as comedocarcinoma. These arrangements represent Gleason pattern 5, which is uncommon in needle biopsy (36).

Uncommonly, invasion by carcinoma into extraprostatic tissues sampled by needle biopsy can be appreciated. As incidental findings, periprostatic tissue can be found in up to 77% of needle biopsies (38) and seminal vesicle or ejaculatory duct tissue can be seen in up to 20% of needle biopsies (39). Periprostatic adipose tissue is most often seen at the tips of the needle cores and the presence of carcinoma in this fat can be a useful diagnostic finding. However, this is rarely an isolated finding, and is generally associated with extensive carcinoma in the rest of the needle biopsy tissue. Prostatic carcinoma infiltration into seminal vesicle/ejaculatory duct tissue is an uncommon, incidental discovery, which tends to be more common in extensive, higher grade carcinoma in needle biopsy. Thus, in prostatic needle biopsy, carcinoma of the prostate can present a range of images of infiltration, with invasion into prostatic as well as extraprostatic tissues.

In a small minority of needle biopsy cases, an infiltrative pattern is not evident. These appear to be well-differentiated, Gleason score 3 to 4, adenocarcinomas that are, by definition, well-circumscribed small gland proliferations, with smooth, pushing edges (35,37). However, an entire Gleason score 3 to 4 nodule is not captured by needle biopsy and also, well-differentiated Gleason score 3 and 4 nodules are characteristically found in the transition zone of the prostate, whereas it is the peripheral zone that is typically targeted for needle biopsy. Most apparently well-differentiated adenocarcinomas in needle biopsy tissue actually represent intermediate-grade carcinomas at follow-up radical prostatectomy (35), such that Gleason score 3 to 4 should be rarely, if ever, assigned to adenocarcinoma in needle biopsy tissue (37).

The second of the major criteria for diagnosis of adenocarcinoma is absence of basal cells in the atypical glands. A historic challenge for the surgical pathologist has been the distinction of periglandular stromal fibroblasts from basal cells. Another common difficulty is that distorted, crushed, or poorly preserved carcinoma cells in minimal cancer foci can mimic basal cells. In cases such as these, application of a basal cell-specific immunohistochemical stain for high-molecular-weight
cytokeratin and/or p63 can be diagnostically advantageous. (See below section on immunohistochemistry). However, these immunostains are not “malignant stains,” and basal cells can be lost, usually in fragmented fashion, in benign glands. Specifically, basal cells may be completely absent in scattered benign and especially atrophic glands and a fragmented basal cell layer is characteristic of atypical adenomatous hyperplasia (adenosis) where, on average, 50% of glands lack a basal cell layer (40). Additional but rare benign mimickers of prostatic carcinoma that can lack basal cells include mesonephric hyperplasia and nephrogenic adenoma. Loss of basal cells in a few glands of partial atrophy or crowded benign glands is a common problem that leads to diagnostic difficulty (41). To emphasize, absence of basal cells is a central finding in an atypical gland proliferation, but by itself, it is not fully diagnostic of adenocarcinoma (42).

Nuclear atypia in the form of nuclear enlargement and nucleolar enlargement is the third of the major criteria for diagnosis of adenocarcinoma. Nuclear atypia in malignant glands most often manifests itself as nuclear enlargement and prominent nucleoli. Prominent nucleoli, however, are neither absolutely specific nor sensitive in detection of adenocarcinoma nuclei. For example, nuclei in inflamed benign prostatic epithelial luminal cells or basal cells can harbor large nucleoli. Some prostate cancers do not harbor macronucleoli. Examples include foamy gland carcinoma, which can have shrunken nuclei, prostatic carcinoma with androgen deprivation therapy effect, and some well-differentiated Gleason score 2 to 4 adenocarcinomas (the so-called nucleolus-poor adenocarcinomas). The latter two examples are usually not seen in needle biopsy tissue. One essential point is that when macronucleoli are absent, there should be significant nucleomegaly with or without nuclear hyperchromasia to definitively diagnose carcinoma.

The minor diagnostic criteria include intraluminal mucin, pink amorphous secretions, mitotic figures, intraluminal crystalloids, and amphophilic cytoplasm. These minor or “soft” diagnostic findings are not specific for carcinoma but are useful for prompting in-depth study of the glands harboring these changes, with a view toward assessment of the aforementioned major diagnostic criteria.

There are several histologic features that have been forwarded as specific for malignancy (43)—perineural invasion, collagenous micronodules (also known as mucinous fibroplasia), and glomeruloid intraglandular projections. True perineural invasion, which is characteristic of adenocarcinoma of the prostate, needs to be distinguished from benign glands abutting prostatic peripheral nerve. Collagenous micronodules are a distinctive, but uncommon, type of stromal response to invasive prostatic carcinoma, which often exhibits mucinous differentiation. Adenocarcinomas of the prostate with glomeruloid features are remarkable for intraglandular tufts of malignant cells that resemble (somewhat) renal glomeruli in their low-power appearance. Another finding specific for carcinoma—lymphvascular space invasion—is vanishingly rare in prostate needle biopsy tissue.

One of the major diagnostic challenges confronting the histopathologist in prostate needle biopsy interpretation is the definite establishment of a malignant diagnosis based on a minimal or limited amount of carcinoma in needle biopsy, where there are just a few malignant glands present (44,45). Minimal carcinoma in prostate needle core tissue is often defined as carcinoma of <1 mm in length or involving <5% of needle core tissue (Fig. 4A.9). The major and minor diagnostic criteria should be applied here, just as for more extensive carcinoma. The presence of a few small malignant glands located between larger, more complex, paler benign glands is the most common pattern of invasion in minimal carcinoma, accounting for fully 80% of cases in one series (45). The second most common pattern of infiltration of limited carcinoma is a haphazard growth in stroma, without adjacent benign glands. Uncommon patterns of growth that typically accompany the common patterns are cords of cells, single cells, and cribriform glands. Perineural invasion is distinctly uncommon (at 2%) in cases of minimal carcinoma (44).

The major criteria do not include a quantitative threshold for the number of glands required to establish a diagnosis of malignancy. In one series (44), 80% of minimal carcinoma foci contained more than 10 glands, and in a second series (45), the median number of malignant glands was 20. It is possible to diagnose invasive carcinoma based on just a few glands. For most urologic pathologists, the smallest number of atypical glands, which formed the basis for a definitive diagnosis of malignancy, was three to four (34). In these cases, there should be excellent preservation of cellular detail, without tangential sectioning, such that it is clear on the H&E sections that basal cells are absent and that significant nuclear atypia is present. Both of these major criteria are of immense importance for these most minimal of the minimal carcinomas, where architectural
abnormalities are difficult to impossible to discern. Finally, in this era, there is a trend to confirm the diagnosis of minimal adenocarcinoma with immunohistochemical stains (42).

A small or minimal amount of cancer in prostate needle core tissue does not always equate with a small amount of carcinoma in the whole gland (46). The correlation of amount of cancer in needle core tissue with amount of cancer in the whole gland is not high. One can have greater confidence of the presence of a larger cancer in the whole gland if there is extensive core involvement compared to attempts to predict small cancers in the whole gland based on a small or minimal amount of cancer in needle core tissue. Of importance, minimal or limited carcinoma in needle core tissue does not equate with well-differentiated Gleason score 2 to 4 adenocarcinoma. Most minimal adenocarcinomas are Gleason score 6, but minimal high-grade Gleason score 7 to 10 adenocarcinomas can also be diagnosed in a minority of patients (44,45).

Numerous entities, both benign and malignant, should be considered in the histologic differential diagnosis of prostatic adenocarcinoma. In-depth discussion of all these entities is beyond the scope of this chapter. The next sections highlight the differential diagnostic considerations of focal glandular atypia, also known as atypical small acinar proliferation (ASAP), false-positive diagnoses, false-negative diagnoses, and urothelial carcinoma in the prostate.

The most valuable adjunctive study for the diagnosis of adenocarcinoma of the prostate, particularly minimal adenocarcinoma, is immunohistochemistry with antibodies directed against basal cells (34βE12 and p63) and AMACR (also known as P504S or racemase) (42). Currently, immunostains are employed in 10% to 20% of all prostate needle core cases (42,59).

Basal cell immunostains can be useful as a confirmatory measure in specific circumstances. Basal cell stains are most often ordered in selected cases in which the differential diagnosis is centered on atypia (ASAP), radiation atypia, atypical adenomatous hyperplasia (adenosis), PIN, basal cell hyperplasia, and atrophy. Minimal residual carcinoma after hormonal therapy also can pose diagnostic challenges, and positive immunostains for PSA and pan-cytokeratin, with a negative 34βE12 immunostain, sometimes can be helpful. The p63 immunostain appears to be more sensitive in basal cell detection than the immunostain using the 34βE12 antibody (60). Some have combined p63 and 34βE12 antibodies in a cocktail. While basal cell antibody or antibodies may still be used alone in immunohistochemistry, a trend is for their inclusion in a cocktail with an AMACR antibody.

It would be desirable in diagnosing adenocarcinoma to have a positive marker that is relatively specific for malignant prostatic epithelial cells, in addition to the negative basal cell markers. One such marker, AMACR, is selective and very sensitive for carcinoma, based upon immunohistochemical studies (42,61). About 80% to 100% of prostatic adenocarcinomas stain. Up to 21% of benign prostatic glands also stain, including atrophy, but the staining signal is usually more focal and weaker compared to carcinoma. A misleading result can be obtained with partial atrophy, where many cases have been reported to be AMACR-positive. This finding, combined with focal basal loss and nuclear atypia that may be seen in atrophy, could result in a misdiagnosis of partial atrophy as adenocarcinoma. Most high-grade PIN foci stain, a minority of atypical adenomatous hyperplasia cases stain, and nephrogenic adenoma, which rarely involves the prostate, can also be positive. This AMACR immunostain can be quite helpful, as a confirmatory tool, in cases of minimal carcinoma. It is best interpreted only in histologic context and in conjunction with 34βE12 and/or p63 immunostaining. Cocktails comprised of AMACR and a basal cell marker such as p63 or AMACR/p63/34βE12, with single or two chromogens, are useful for simultaneous assessment of these markers in the same glands (42).

Currently, no therapeutic targets in prostatic carcinoma are identified by immunohistochemical staining. Specifically, immunostains for the androgen receptor, HER2/neu, CD117 (c-kit), and the epidermal growth factor receptor are not routinely employed since they are not markers that are predictive of response to treatment directed against these proteins.

Currently, there are no molecular genetic tests that are utilized in tissue to diagnose adenocarcinoma of the prostate.

The most widely used histologic grading scheme in the United States and worldwide is the Gleason system (37,62). The Gleason grading system is recommended for use by the 2004 World Health Organization classification book and the 2010 AJCC/UICC cancer staging manual (63). It should be applied to all adenocarcinomas primary in the prostate without a history of treatment effect (see below on treatment effect).

Gleason grade of prostatic adenocarcinoma is one of the most important characteristics of prostate cancer in that it provides an indication of aggressiveness of the cancer. Gleason grade is a measure of differentiation of the cancer and is highly correlated with all important pathological and clinical endpoints such as pathological stage, response to therapy, metastasis, and cancer-specific survival. It is a major component of the Partin Tables, D’Amico risk groups, and Kattan nomograms, in prediction of pathologic stage and response to treatment. It is also critical in selection of patients for active surveillance.

The Gleason grading system is based entirely on the histologic pattern of arrangement of carcinoma cells in H&E-stained prostatic tissue sections. Specifically, the method is one of categorization of histologic patterns at relatively low magnification by the extent of glandular differentiation and the pattern of growth of the tumor in the prostatic stroma. There have been two revisions of the original drawing to reflect new evidence on linkage of Gleason patterns to outcome (37,64). The most current drawing (from Ref. 64) is shown in Fig. 4A.10.

Gleason pattern 1 is a circumscribed nodule of closely packed but separate, uniform, rounded to oval, medium-sized acini (37) (Fig. 4A.10). Most cases of Gleason grade 1 + 1 = score of 2 probably represent adenosis and so this score is rarely used. Gleason pattern 2 is a fairly circumscribed nodule of more loosely arranged glands that are not as uniform as pattern 1. It is most often seen in the context of Gleason score 4 (Fig. 4A.11) or 5. Gleason pattern 3 is comprised of discrete small glands that infiltrate in and around benign glands (Fig. 4A.5). It is most often diagnosed in Gleason score 6 and 7 adenocarcinomas. High-grade Gleason pattern 4 is characterized by fused microacinar glands, ill-defined glands with poorly formed glandular lumina, and cribriform glands (Figs. 4A.6 and 4A.7). It is most often found in Gleason score 7 to 9 carcinomas.

High-grade Gleason pattern 5 shows little to no glandular differentiation and is composed of solid sheets (Fig. 4A.8), cords, single cells, and/or comedocarcinoma. This pattern is usually detected in Gleason score 9 and 10 carcinomas. The five basic grade patterns are used to generate a histologic score (sometimes called sum), which can range from 2 to 10, by adding the primary grade pattern and the secondary grade pattern. The primary pattern is the one that is predominant in area, by simple visual inspection. The secondary pattern is the second most common pattern. If only one grade is in the tissue sample, that grade is multiplied by 2 to give the score.

The Gleason grading system allows for two separate grade patterns in an individual tissue sample, but the histomorphological appearance of prostatic carcinoma is more
heterogeneous than this. Indeed, in one study (65), an average of 2.7 Gleason grade patterns (range 1-5) were found in carcinomas in whole prostate glands. The number of grades assigned depends on tumor sample size and size of the tumor in the whole gland. So, more than two grades are more often observed in TURP chips (28% of cases) compared to needle biopsies (4%-7% of cases) (66), and tumors >1 to 2 cm3 in size tend to have more than two grades.

Tertiary high-grade pattern 4 or 5 is important to recognize and report. For needle biopsy tissue where there are more than two patterns present and the worst grade is neither the predominant nor the secondary grade, the predominant and highest grade should be chosen to arrive at a score (67). This approach has been validated in a large clinical series (68). This approach for needle biopsies should also be used for TURP and open prostatectomy cases. In radical prostatectomy tissues, the approach is a bit different: the presence of tertiary high-grade pattern 5 should be noted, but not incorporated into the score. Data from radical prostatectomy cases indicate that a high-grade Gleason pattern 4 or 5 that is a tertiary component occupying <5% of the tumor influences pathological stage and progression rates (69). How to generate an overall score with the tertiary pattern is not established for radical prostatectomy specimens.

Gleason grading should be performed in all prostatic tissue samples, including needle core biopsy specimens. A Gleason grade should be assigned even to needle biopsy cases with minimal prostatic carcinoma, measuring <1 mm in length. Comparisons of Gleason grade in needle biopsy with Gleason grade in the matched whole prostate gland show a 70% to 75% agreement (36). For needle biopsy cases, there are several sources of grading error, including difficulty in appreciation of an infiltrative growth pattern, tissue sampling error (related to the small amount of tissue sampled by needle biopsy and grade heterogeneity), tissue distortion, pathologist experience, and observer variability. Even with extended and saturation needle biopsy protocols, it is difficult to attain perfect agreement between needle biopsy and radical prostatectomy Gleason score.

Assignment of Gleason grade to larger tissue samples, including TURP chips, and open (simple) and radical prostatectomy specimens is often more straightforward than in needle biopsy cases. A distinctive characteristic of carcinoma grade in TURP chips and open (simple) enucleation prostatectomy specimens is that well-differentiated Gleason score 2 to 4 adenocarcinomas are much more common in these tissue specimens compared to needle biopsies and radical prostatectomy specimens. Cautery artifact can generate difficulty in grading carcinoma in TURP chips. The Gleason grade of incidental stage T1a/b carcinoma tends to be somewhat less than the grade in the whole gland since the TURP procedure samples the transition zone where lower grade carcinomas arise.

The Gleason grading system, like all histological grading methods, possesses an inherent degree of subjectivity. Intraobserver and interobserver variability does exist (70). Pathologist training and experience can influence the degree of interobserver agreement. For pathologists, improvement in Gleason grading of carcinoma can be achieved by participation in educational courses at meetings and by use of tutorial programs including Web site programs.

Gleason grading of prostatic carcinoma outside the prostate and in metastatic deposits has been reported, but the Gleason system was not originally designed for this purpose as it is based upon epithelial (carcinoma)-stromal architectural relationships within the prostate.

In general, the Gleason grading system should be applied only to tumor that shows no evidence of treatment effect. For radiation therapy cases, where there is no evidence or minimal evidence of therapy effect, Gleason grading may be utilized. Hormonal therapy can cause pattern alterations resembling high Gleason grades, such that one should not report histologic grade after hormonal therapy, with the exception of finasteride or dustasteride, which are felt to have minimal if any impact on Gleason grade (71).

Experimental grading approaches include quantitation of amount of high-grade (percentage Gleason pattern 4 or 5) carcinoma. Overall, use of the % 4/5 parameter in needle biopsy is limited by a high false-negative rate.

After Gleason grade, the most important parameter in needle biopsy tissue is cancer extent (46). The amount of prostatic carcinoma in needle biopsy tissue is related to pathologic stage, primary tumor size, and response to therapy. The amount of cancer is reported as number of positive needle cores out of total number of cores, and percentage of prostate needle core tissue involved by carcinoma, and/or linear mm of cancer in the needle core (46). The amount of needle core cancer is used, along with other factors, in nomograms to predict recurrence after radical prostatectomy and small indolent cancers (see below), and in some active surveillance protocols, as one of several factors used as enrollment criteria.

Perineural invasion by carcinoma in needle biopsy tissue is associated with increased pathologic stage in most studies in univariate analysis, but, in general, perineural invasion lacks independent ability in multivariate analysis to predict radical prostatectomy stage once Gleason grade and amount of tumor in needle biopsy tissue are known. Perineural invasion is not used in the Partin Tables to predict pathologic stage and it is not used in any nomogram to predict response to surgery. There is a stronger linkage of perineural invasion in needle core tissue and response to radiation therapy, compared to surgery, although the data are conflicting as to significance.

Pathologic T staging, or determination of anatomic extent of carcinoma, is performed based on histopathologic examination of radical prostatectomy tissue sections and applies only to adenocarcinomas of the prostate and not to sarcomas and prostatic carcinoma variants that are not adenocarcinomas. Pathologic N staging is based upon histologic examination of regional lymph nodes. Pathologic M staging occurs with histologic diagnosis of prostatic carcinoma in nonregional lymph nodes, bone, or other metastatic sites. The 2010 TNM AJCC/UICC staging classification should be utilized (63). Staging is performed separately from margin assessment except when there is intraprostatic incision with a positive margin (with ink on both benign glands and carcinoma). Here the pathologic stage should be designated as pT2+ (67), indicating that the stage is a least pT2 and could be pT3.

Important histopathologic T findings that warrant reporting include the determination of pT2 organ-confined versus pT3a extraprostatic extension (EPE) by carcinoma, focal versus nonfocal (established) EPE, and pT3b invasion into seminal vesicle wall (64). For organ-confined adenocarcinomas, subdivision of pT2 into pT2a, b, and c is felt to harbor little if any prognostic significance (72) but is still retained in the 2010 TNM system. Multifocality and zone of index tumor may be reported but do not provide independent prognostic information. Perineural invasion by carcinoma in the prostate is very common, being seen in 85% to 90% of radical prostatectomy cases, and does not provide prognostic information (73). Extraprostatic extension is defined by the presence of carcinoma in periprostatic adipose tissue or carcinoma in the same plane as the fat. At the anterior and apical prostate and bladder neck regions there is a paucity of fat and in these locations EPE is diagnosed when carcinoma extends beyond the normal arc of benign prostatic glands. It is difficult to impossible to diagnose EPE in distal apical margin sections, due to the ill-defined outer edge of the prostate here and so EPE should not be diagnosed in those sections. For pT3 carcinomas, the amount of extraprostatic cancer is of prognostic significance and should be reported as focal versus nonfocal, and the location (apical, bladder neck, anterior, lateral, posterolateral, and posterior) and number of sites of EPE should be given. Focal EPE is defined as either only a few cancer glands beyond the confines of the prostate (74) or tumor outside the prostate involving less than one high-power microscopic field in one or two sections (75). Nonfocal EPE is more extensive than this. Note that a change in the 2010 TNM scheme compared to the 2002 version is that microscopic bladder neck invasion is now pT3a, not pT4 (63). pT3b carcinoma is tumor in the muscular seminal vesicle wall; carcinoma in soft tissue surrounding the prostate should not be considered pT3b, but rather pT3a. There are several mechanisms for spread of intraprostatic carcinoma into the seminal vesicle wall (76). The most common pathway is EPE by carcinoma into periprostatic tissue at the base of the prostate, with penetration into the outside of the seminal vesicle wall. The second most common type is direct tracking along the ejaculatory duct complex into the seminal vesicles. The third form is characterized by isolated deposits of cancer in lymphvascular spaces in the seminal vesicle wall. Seminal vesicle invasion should be specified as unilateral or bilateral, but it is not necessary to report amount of tumor in the seminal vesicle or the pathway of spread. Finally, additional parameters that should be reported in radical prostatectomy cases include lymphvascular space invasion by carcinoma, which is an independent prognostic indicator (77), and amount of intraprostatic carcinoma. Intraglandular extent of carcinoma is a significant prognostic factor in most series in univariate analysis, but its independent value is controversial in multivariate analyses (46). Quantitation of amount of cancer in the prostate is recommended, with reporting as percentage of the prostate involved by carcinoma and/or as greatest linear dimension of a dominant nodule (if present) (67). Determination of tumor volume by image analysis is not practical for routine reporting. Percentage of the prostate involved by carcinoma, as determined by simple visual inspection, has been shown in several studies to be significant in multivariate analysis in predicting PSA failure after surgery (78,79,80), even for pathologically organ-confined pT2 carcinoma (79,80), and in predicting overall survival (81).

Surgical margin status of the distal apex, bladder neck, and peripheral margins of the prostate is important in prognosis and consideration of adjuvant therapy. A positive margin is a significant risk factor for biochemical recurrence after surgery (82,83), particularly for men with intermediate- and high-risk cancer (83). It should be noted that a positive margin does not necessarily mean that there is residual carcinoma left in the patient. Location and extent of any margin positivity should be given in the surgical pathology report (67). Extent may be reported as number of positive sites and as linear mm of carcinoma at the margin. While the number and extent of positive surgical margins significantly influence the risk of biochemical failure, this quantitation did not improve a nomogram model of failure after radical prostatectomy (82). Some view a positive apical margin as a lesser risk factor for biochemical recurrence compared to other locations, although this is not a universal finding (82).

Pathologic N staging is based on histopathologic evaluation of lymph nodes submitted separately at the time of radical prostatectomy. A histopathologic diagnosis of metastatic prostatic carcinoma in pelvic lymph nodes can be established at frozen section or on permanent sections. Frozen section examination of pelvic lymph nodes is now less commonly requested since there is a low incidence of positive nodes in this current era. If a decision is made to perform a frozen section of lymph nodes, one should be aware of several caveats. First, gross examination of lymph nodes, including assessment of lymph node size, is of limited value due to low sensitivity and specificity (84). Secondly, there is a low sensitivity of around 60% to 70% for identifying lymph node metastasis at frozen section (84). This is due to detection of small metastatic deposits in
permanent sections only and in additionally submitted tissue that was not frozen. Permanent section histologic diagnosis of pelvic lympadenectomy specimens should be based on microscopic examination of a single section from paraffin blocks of all lymph node tissue, and, if possible, all perinodal soft tissue. This is so for several reasons. First, the number of lymph nodes examined is directly related to detection of metastatic disease (85). Second, in about 10% of cases, the only microscopically visualized metastatic deposits will be in soft tissue (84) or in small, grossly invisible lymph nodes or soft tissue (86). These soft tissue metastatic deposits probably are plugs of carcinoma in lymphvascular spaces. Microscopically, prostatic carcinoma in lymph nodes usually resembles one of the patterns in the primary tumor and is usually moderately or poorly differentiated. While extent of cancer in pelvic lymph nodes has prognostic value, the 2010 AJCC/UICC staging scheme does not incorporate extent in pN classification. Furthermore, no “micrometastatic” nodal prostate cancer size has been established. Data on extranodal extension by carcinoma as a prognostic indicator are mixed. Experimental diagnostic tools for detecting prostate carcinoma in lymph nodes include immunohistochemical stains for PSA, PSAP, and cytokeratin and RT-PCR for PSA and PSMA. These approaches are not in routine use and are not currently validated for patient management. Reporting of pelvic lymph nodes should include clinically designated anatomic site of pelvic lymph nodes, number of lymph nodes examined, and number involved by carcinoma (67). Reporting of the diameter of the largest metastatic deposit in mm is also recommended (67). Reporting of extranodal extension by carcinoma is optional (67).

Pathologic T and N stage, along with radical prostatectomy Gleason grade and margin status, and preoperative PSA are used in a nomogram to predict recurrence after radical prostatectomy (87).

Latent adenocarcinoma of the prostate is detected at autopsy in a high percentage of cases, with a mean of 25% (range 9%-46%), depending on extent of gland sampling, age of the patient population, and country (88). These clinically unsuspected prostatic carcinomas diagnosed at postmortem examination are of lower grade, stage, and size than clinically detected carcinomas, although there is some overlap in pathologic features between autopsy-detected and clinically detected carcinomas. Most autopsy-detected prostate cancers are well-differentiated Gleason score 2 to 4 acinar adenocarcinomas and organ-confined, with a median tumor volume of 0.24 mL (range 0.01-10 mL) (89). In autopsy cancers high Gleason grade of score 7 or greater is discovered in 16% of men over 60 (90) and up to 16% of men have extraprostatic extension of carcinoma (89). Thus close to about one fifth of autopsy prostate cancers exhibit higher grade and stage characteristics that could have been clinically significant. Similar histopathologic findings have been reported for incidentally detected prostatic adenocarcinomas detected in radical cystoprostatectomy specimens excised for bladder cancer.

There is a subset of clinically detected carcinomas, particularly T1c carcinomas detected due to serum PSA elevation, that have features similar to latent autopsy and cystoprostatectomy-detected prostatic carcinomas. One pathologic definition for potentially insignificant (also called potentially indolent or harmless) prostatic carcinoma, based on examination of radical prostatectomy tissues, is a small (<0.5 mL) carcinoma that is organ-confined, with no high-grade Gleason pattern 4 or 5 (91). Up to 29% of T1c carcinomas fall into this category (92,93).

Efforts have been made to develop clinical and pathologic needle biopsy criteria to predict potentially indolent prostate cancer (92,94,95,96,97). One model uses percentage free PSA >15, Gleason score <7, and <3 cores involved, with no core having more than >50% tumor involvement (94). One nomogram utilizes pretreatment serum PSA level, clinical stage, primary and secondary Gleason grade, ultrasound volume, and mm cancer and noncancer in needle core tissue (92). The utility of nomograms to predict indolent cancer has been validated (97), although the prediction is not perfect and there is need for improvement. These models and nomograms may help in the decision-making process between definitive therapy versus active surveillance.

The vast majority of primary carcinomas of the prostate are acinar adenocarcinomas. Unusual histologic variants or subtypes account for about 5% to 10% of primary carcinomas (64).

Ductal adenocarcinoma is the second most common subtype of prostatic adenocarcinoma after the acinar subtype. Previously known as endometrioid adenocarcinoma, in pure form it accounts for about 1% of prostatic cancers and when mixed with acinar adenocarcinoma, roughly 5% of prostatic cancers. Microscopically, these are usually papillary and/or cribriform columnar cell adenocarcinomas that can arise centrally (causing urinary obstruction and hematuria), but can also be found peripherally. Most patients present at a more advanced stage and outcome is worse than acinar adenocarcinoma.

Variants of acinar adenocarcinoma include atrophic, pseudohyperplastic, foamy, colloid (mucinous), signet ring, oncocytic, lymphoepithelioma-like, and sarcomatoid carcinoma (carcinosarcoma). Particularly notable for poor outcomes are signet ring carcinoma of the prostate, which is high-grade Gleason pattern 5, and sarcomatoid carcinoma, which may be a homologous spindle cell malignancy or heterologous, with an osteosarcomatous, chondrosarcomatous, or rhabdomyosarcomatous component. In one half of the men with sarcomatoid carcinoma, there is a history of prostatic adenocarcinoma treated by hormonal and/or radiation therapy.

Rare types of prostatic carcinoma include urothelial carcinoma (arising from central prostatic ducts), squamous and adenosquamous carcinoma, basal cell carcinoma, and neuroendocrine carcinomas, including small cell and large cell neuroendocrine carcinomas. It is important to exclude primary urethral and urinary bladder urothelial carcinoma before diagnosing primary prostatic urothelial carcinoma. Squamous cell and adenosquamous carcinomas of the prostate comprise <1% of all prostatic carcinomas and in about two thirds of cases there is a history of hormonal and/or radiation treatment of acinar adenocarcinoma. Average survival is 2 years. Basal cell carcinoma of the prostate includes malignant basaloid proliferations (basaloid or basal cell carcinomas) and also neoplasms that resemble, to a certain degree, adenoid cystic carcinomas of the salivary glands. Small cell carcinoma of the prostate is quite rare and in one half of cases is admixed with adenocarcinoma. The histological appearance is similar to small cell carcinoma of the lung. In one third of cases, there is a history of prostatic adenocarcinoma, followed by hormonal therapy. A similar history is obtained in most cases of large cell neuroendocrine carcinoma of the prostate. Outcome is very poor for neuroendocrine carcinomas of the prostate.

Mesenchymal neoplasms are rare. The most common benign mesenchymal neoplasm is the leiomyoma, and the most common malignant mesenchymal neoplasms are rhabdomyosarcoma in children and leiomyosarcoma in adults.

Hematolymphoid neoplasms may involve the prostate, including leukemia, lymphoma, Hodgkin disease, and multiple myeloma. Leukemic infiltrates almost always indicate secondary spread, and are usually chronic lymphocytic leukemia. About one third of prostatic lymphomas are felt to be primary. The most common histologic type is diffuse large B cell lymphoma.

Miscellaneous neoplasms rarely encountered in the prostate include paragangliomas, melanocytic neoplasms, and germ cell tumors.

Secondary malignancy in the prostate is overall uncommon, but can be seen in a substantial minority of patients with urothelial carcinoma of the urinary bladder, leukemia, and non-Hodgkin lymphoma.