Neoplastic Diseases of the Prostate

Prostate-Specific Antigen

Prostate-specific antigen is a serine protease secreted by the epithelial cells of prostatic ducts and acini to liquefy the seminal coagulum. Benign and malignant prostatic tissue produces PSA. Only a small percentage of PSA in serum is free; most is complexed with α-1-antichymotrypsin and α-2-macroglobulin. Patients with prostate carcinoma in general have higher serum PSA values than those without the disease. In the recent past, a serum PSA level greater than 4 ng/mL was considered abnormal and a reason for patients to undergo prostate biopsy. However, serum PSA lacks sensitivity and specificity for prostate carcinoma. Approximately 70% to 75% of prostate carcinomas have serum PSA values greater than 4 ng/mL. The positive predictive value of serum PSA is higher when the concentration is greater than 10 ng/mL or accompanied by abnormal DRE findings. In addition, some nonmalignant conditions, including benign prostatic hyperplasia (BPH), inflammation, infarction, instrumentation, and ejaculation, also increase the serum PSA level. The current American Urologic Association (AUA) guidelines for use of PSA emphasize that PSA is one among many factors to be considered when estimating an individual’s risk for prostate cancer. The other factors to be considered are percentage of free PSA, PSA velocity, DRE findings, family history, ethnicity, and biopsy history. The AUA no longer recommends a PSA threshold cutoff value for biopsy as recommended in the past. The National Comprehensive Cancer Network (NCCN) recommends a baseline PSA and DRE at age 40 years. Provided the DRE results are normal, if the baseline PSA is less than 0.6 ng/mL, then annual screening may begin at age 45 years. If the baseline PSA is more than 0.6 ng/mL, then screening should begin annually at age 40 years. The NCCN recommends prostate biopsy if the PSA is more than 2.5 ng/mL.

Other modifications of PSA testing have been introduced to improve the test’s specificity, including the ratio of free to total PSA, which is decreased in prostate carcinoma; the PSA density, which is the ratio of total PSA to prostate glandular volume as measured with transrectal ultrasound scan (TRUS) and is higher in prostate carcinoma; and the PSA velocity, or the rate of PSA change over time, which is increased in prostate carcinoma.

The PCA3 assay is a recently introduced genetic-based diagnostic test that quantitatively detects PCA3 messenger RNA (mRNA) expression in urine and prostatic fluid with transcription mediated amplification. PCA3 is expressed only in prostatic tissue and is significantly overexpressed in malignant prostate tissue. PCA3 mRNA is highly overexpressed in more than 95% of prostate cancer tissue. A PCA3 score is calculated as the ratio: PCA3 mRNA/PSA mRNA × 1000. A PCA3 score of 35 has been adopted as a cutoff for biopsy. The lower the PCA3 score, the lower the risk of a positive repeat biopsy. The sensitivity of PCA3 in urine is 66% (∼62% probability of positive biopsy); the specificity is 76% (versus 47% specificity for serum PSA). PCA3 is independent of prostate volume, number of prior biopsies, and patient age. The test is unaffected by benign prostatic hyperplasia and prostatitis. PCA3 test is not used as the only sufficient screening tool for prostate cancer detection because cancer has been detected in prostate biopsies despite a negative PCA3 result and, on the other hand, excessively high PCA3 score has been reported despite absent detectable tumor on biopsy.

Prostate-specific antigen testing has significantly affected the clinical and pathologic attributes of detected prostate carcinoma. Most prostate carcinomas detected with PSA screening are of intermediate grade and confined to the prostate. In addition, 5% to 27% of prostate carcinomas are considered potentially clinically insignificant.

Preoperative PSA is often used in combination with needle biopsy Gleason score and clinical stage to predict pathologic stage, including the probability for organ-confined disease, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis, and the likelihood of disease recurrence after therapy. These probability estimates are helpful in discussions with patients about risks versus benefits in choice of treatment options.

Prostate-specific antigen levels may also be used to monitor the response to various treatments. After radical prostatectomy, the serum PSA should drop to an undetectable level; elevated PSA levels signal recurrence or residual disease. After radiation therapy, three consecutive increases in PSA level after it initially reaches a nadir indicate a biochemical failure.

Prostate Needle Biopsy

The standard method for detection of prostate carcinoma is with TRUS-guided sextant core biopsies that systematically sample the parasagittal midlobe regions of apex, middle, and base. Several modifications of the sextant protocol have been made. More recently, the standard has been to sample the prostate gland with approximately 10 to 12 cores, in particular from the more lateral aspect of the peripheral zone, where most prostate carcinomas arise. In cases with high suspicion for cancer despite negative biopsy results, “saturation biopsy” may be performed, with collection of 10 to 15 biopsies from each side of the prostate. The addition of transition zone biopsies is also used typically only when the initial biopsy results are negative and the clinical suspicion for cancer is high. More needle cores may also be taken for larger prostates.

Information concerning the anatomic locations of needle biopsies should be preserved by either embedding the samples in separate blocks or inking them in different colors. This information is critical for prognostication and therapy planning. It is also important when a diagnosis of “atypical glands suspicious for prostate carcinoma” (ATYP) is made. Rebiopsy strategy entails concentration in the initial atypical region in addition to sampling of the rest of the prostate. At least three levels of each biopsy core should be cut for hematoxylin and eosin (H&E) staining. An option is for one or two intervening sections to be cut on positive charged slides for potential immunohistochemical studies.

Transurethral Resection of the Prostate

Transurethral resection of the prostate mainly detects transition zone prostate carcinoma and bulky peripheral zone prostate carcinoma that extends into the transition zone. Initially, eight cassettes should be submitted in random fashion. In younger patients (<65 years of age), submission of all the tissue is justified to identify all T1a lesions (i.e., those in which tumor occupies <5% of the total specimen). If T1b disease (in which tumor occupies >5% of the total specimen) is found on the initial eight slides, it is not necessary to submit additional tissue. However, if T1a prostate carcinoma is found on the initial eight slides, the remaining tissue should be submitted for review.

Transrectal Ultrasound Scan

The sonographic appearance of prostate carcinoma is not specific, with 70% to 75% of prostate carcinomas being hypoechoic and the remaining being isoechoic and indistinguishable from surrounding tissue. Many significant prostate carcinomas are missed with TRUS. TRUS remains as a means of guidance for prostate needle biopsies. Innovative ultrasound techniques (including ultrasound contrast agents, three dimensional [3-D] and four-dimensional [4-D] sonography, elastography, and harmonic sonography) promise benefits in comparison with standard TRUS to accurately diagnose prostate cancer.

Computed Tomographic Scan and Magnetic Resonance Imaging

Computed tomographic scan does not play a significant role in the diagnosis of primary prostate cancer; however, new scanners improve the accuracy of prostate cancer staging. The combination of conventional and functional magnetic resonance imaging (MRI) techniques (including diffusion-weighted imaging, dynamic contrast-enhanced MRI, and magnetic resonance spectroscopy) can provide information for differentiating prostate cancer from noncancerous tissue and can be used for MRI-guided biopsies, especially in patients with persistent elevation of serum PSA and previous negative TRUS-guided biopsies.

Radioimmunoscintigraphy

A bone scan provides the most sensitive method for detection of bony metastasis. ProstaScint (Cytogen Corporation, Princeton, NJ), a radioisotope-labeled monoclonal antibody against prostate-specific membrane antigen (PSMA), may detect microscopic metastasis. The sensitivity can be improved with use in combination with PSA, biopsy Gleason score, and clinical stage data.

Patterns of Spread and Metastasis

Local extraprostatic extension typically occurs anteriorly for transition zone cancer and posteriorly and posterolaterally for peripheral zone cancer. Prostate carcinoma can also spread superiorly into the bladder neck. Rarely, it can penetrate Denonvilliers’ fascia posteriorly to involve the rectum. Metastatic prostate carcinoma most commonly involves regional lymph nodes and bones of the pelvis and axial skeleton, where a characteristic osteoblastic response is often elicited.

Architecture

Gland-forming prostate carcinomas are more crowded than benign glands and typically exhibit a haphazard growth pattern, with malignant glands oriented perpendicular to each other and irregularly separated by smooth muscle bundles. They also display infiltrative growth pattern, with malignant glands situated between or flanking benign glands ( Fig. 2-8 , A ). When prostate carcinoma becomes less differentiated, it loses glandular differentiation and forms cribriform structures, fused glands, poorly delineated glands, solid sheets or cords, or even single tumor cells.

Cytoplasm

In contrast to benign glands with irregular and undulating luminal borders, prostate carcinoma glands are smaller and have straight luminal borders. They may have amphophilic, or darker, cytoplasm that is evident even at low magnification ( Fig. 2-8 , B ). However, low-grade prostate carcinoma often has pale-clear cytoplasm, indistinct from benign glands. Prostate carcinoma typically lacks lipofuscin pigment.

Nuclei

Typically, prostate carcinoma displays nuclear characteristics distinct from surrounding benign glands, including enlarged nuclei and prominent nucleoli ( Fig. 2-8 , C and D ). Some prostate carcinomas lack prominent nucleoli yet have enlarged and hyperchromatic nuclei. Mitoses and apoptotic bodies are more common in prostate carcinoma, although they are rarely found in benign glands and are still not frequently seen in malignant glands. Cancer nuclei, even in poorly differentiated glands, show little variation in size and shape.

Intraluminal Content

Crystalloids (dense eosinophilic, crystal-like structures within the glandular lumina; Fig. 2-8 , D ) are found more commonly in cancer than in benign glands. However, they are also frequently found in adenosis, a benign condition that mimics low-grade prostate carcinoma. Intraluminal pink, acellular, dense secretions ( Fig. 2-8 , C ) and blue-tinged mucin ( Fig. 2-8 , E ) are additional findings seen preferentially in prostate carcinoma. In contrast, corpora amylacea are common in benign glands and are only rarely seen in prostate carcinoma.

Stroma

Ordinary prostate carcinoma does not elicit a stromal inflammatory or desmoplastic response. Ductal adenocarcinoma of the prostate, however, may induce such stromal reactions with fibrosis-containing hemosiderin-laden macrophages.

Cancer-Specific Features

Three histologic features are diagnostic of prostate carcinoma because they have not been described in benign glands. Mucinous fibroplasia, or collagenous micronodules, occurs as a delicate fibrous tissue with ingrowth of fibroblasts within or adjacent to cancer glands ( Fig. 2-8 , F ). Glomeruloid formation is created by intraluminal proliferation of malignant cells and is often surrounded by a crescentic space that resembles a renal glomerulus ( Fig. 2-8 , G ). Perineural invasion with cancer glands completely or nearly completely encircling the nerve is pathognomonic of prostate carcinoma ( Fig. 2-8 , H ). Benign glands can occasionally be found to abut a nerve; however, circumferential extension of benign glands entirely around a nerve has not been described.

Atrophic Carcinoma

The cancer glands have scant cytoplasm ( Fig. 2-9 , A ) and may be confused with benign atrophy. The diagnosis is based on several features. First, atrophic prostate carcinoma displays an infiltrative growth pattern, with atrophic cancer glands intermingling with larger benign glands. In contrast, benign atrophy usually has a lobulated configuration. Atrophic prostate carcinoma has significant cytologic atypia, namely, nuclear enlargement and prominent nuclei ( Fig. 2-9 , B ). Finally, atrophic prostate carcinoma is often intermixed with nonatrophic ordinary prostate carcinoma.

Pseudohyperplastic Carcinoma

Resembling benign prostatic glands, pseudohyperplastic prostate carcinoma glands are large with branching and papillary infoldings ( Fig. 2-10 , A ). However, the malignant glands are much more closely packed than benign glands, and they display malignant nuclear features typical of prostate carcinoma ( Fig. 2-10 , B ). The diagnosis of pseudohyperplastic prostate carcinoma in needle biopsy is often difficult and necessitates immunohistochemistry to verify the absence of basal cells ( Fig. 2-10 , C ). Despite its benign appearance, pseudohyperplastic prostate carcinoma may be associated with typical intermediate-grade cancer and can exhibit aggressive behavior.

Microcystic Adenocarcinoma

Microcystic adenocarcinoma represents a form of atrophic or pseudohyperplastic variants. It is characterized by cystic dilation and rounded expansion of glands, with a flat luminal lining. Microscopically, the mean glandular size is 10-fold greater than that of usual acinar adenocarcinoma. Intraluminal crystalloids and intraluminal blue mucin are commonly seen ( Fig. 2-11 ). It should be assigned a Gleason score 6.

Foamy Gland Carcinoma

Cancer cells have abundant foamy or xanthoma-like cytoplasm with a very low nuclear/cytoplasmic ratio ( Fig. 2-12 , A ). Although the cytoplasm is xanthomatous in appearance, it contains empty vacuoles rather than lipid. The nuclei of foamy gland prostate carcinoma cells are typically small and hyperchromatic and lack the cytologic features of ordinary prostate carcinoma ( Fig. 2-12 , B ). The diagnosis of foamy gland prostate carcinoma is based on its architectural pattern of crowded or infiltrative glands, abundant foamy cytoplasm, and frequent intraluminal, dense, pink, acellular secretions. Basal cells are absent with immunohistochemistry. Despite the bland cytology, most of the cases that include an associated nonfoamy cancer are Gleason score 6 or greater.

Mucinous (Colloid) Carcinoma

Mucinous prostate carcinoma is defined as a cancer in which 25% or more of the tumor consists of lakes of extracellular mucin. Prostate carcinoma with less than 25% mucinous component should be classified as having mucinous features, whereas prostate carcinoma with intraluminal mucin without lakes of extracellular mucin is not considered as mucinous prostate carcinoma. Clinically, the average age for mucinous prostate carcinoma is similar to that for the ordinary acinar prostate carcinoma, although the clinical stage at presentation is often advanced, with locally advanced or metastatic disease. Microscopically, tumor cells float in lakes of extracellular mucin that are sharply demarcated from the stroma ( Fig. 2-13 , A ). Tumor cells are arranged in cribriform configurations, cords, strands, acini, or tubules. Cytologically, the cells appear bland with occasional prominent nucleoli ( Fig. 2-13 , B ). They are positive for PSA and PSAP.

Prostatic Intraepithelial Neoplasia–Like Adenocarcinoma

Prostatic intraepithelial neoplasia–like adenocarcinoma is a recently recognized unusual variant of prostatic adenocarcinoma that cytologically and architecturally resembles high-grade PIN. Microscopically, this variant of adenocarcinoma is characterized by noncribriform stratified epithelium similar to flat, tufted, or micropapillary patterns of PIN ( Fig. 2-14 , A ). Immunohistochemical stains for basal cells are completely negative ( Fig. 2-14 , B ). In addition, a greater degree of glandular crowding or disorder is found than is usually seen in PIN. The term PIN-like ductal adenocarcinoma has been used to describe some cases that display high columnar cells ( Fig. 2-14 , C ), like ductal adenocarcinoma. The assigned Gleason score is 6.

Signet-Ring–Like Carcinoma

Defined as 25% or more of tumor mass consisting of signet-ring–appearing cells, this histologic variant is a rare entity with an aggressive clinical course. Microscopically, the signet-ring–like tumor cells display nuclear displacement and indentation with clear cytoplasmic vacuoles ( Fig. 2-15 ). In most cases, these vacuoles contain lipid rather than mucin, as with true signet cells. The cancer cells grow in sheets, in small clusters, and as single cells. They are invariably mixed with ordinary acinar prostate carcinoma components. Immunostains for PSA and PSAP are positive in most cases, and stains for CK7, CK20, and HMWCK are negative in all cases. Before a diagnosis of prostatic signet-ring carcinoma is established, a metastasis from other anatomic sites, including stomach, lung, colon, and pancreaticobiliary system, must be excluded. On the other hand, a prostatic signet-ring carcinoma should be considered when one encounters a signet-ring–cell carcinoma of unknown primary, especially if mucin stains are negative.

Sarcomatoid Carcinoma (Carcinosarcoma)

Sarcomatoid prostate carcinoma is composed of both malignant epithelial and spindle cell elements. It may be a de novo diagnosis, or patients may have a history of prostate carcinoma treated with radiation or hormonal ablation therapy or both. Serum PSA values are within normal limits in most cases, despite the frequent presence of nodal and distant metastases. The 5-year survival rate is less than 40%. Microscopically, sarcomatoid prostate carcinoma is biphasic, with a glandular component that shows variable Gleason patterns and a sarcomatoid component that often exhibits nondescript malignant spindle cell proliferation ( Fig. 2-16 ). Specific mesenchymal differentiation can also be present, including osteosarcoma, chondrosarcoma, and rhabdomyosarcoma. Immunohistochemically, the epithelial elements are positive for PSA or pancytokeratins, whereas the sarcomatoid elements react with markers of corresponding mesenchymal differentiation and variably express cytokeratins.

Large-Cell Neuroendocrine Carcinoma

This extremely rare variant of prostate cancer has histological features that are indistinguishable from those of large cell carcinoma of the lung. Most of the patients reported had a history of prostatic adenocarcinoma treated with hormonal therapy. Microscopically, the tumor is characterized by sheets and ribbons of cells with large nuclei, coarse chromatin, and prominent nucleoli admixed to acinar adenocarcinoma. The prognosis is dismal. Tumor cells show focal immunoreactivity for PSA and PSAP and diffuse staining for chromogranin, synaptophysin, CD56, and CD57.

Pleomorphic Giant Cell Carcinoma

Pleomorphic giant cell carcinoma is a rare (less than 10 cases reported), highly aggressive histologic variant composed of high-grade prostatic adenocarcinoma with prominent bizarre, anaplastic giant cells. In addition to the pleomorphic giant cell component, multiple coexistent histologic components have been reported, including high Gleason score conventional prostate cancer, small cell carcinoma, squamous carcinoma, and ductal adenocarcinoma. Some of the patients present with distant metastases. Both acinar adenocarcinoma and anaplastic giant cell components display immunoreactivity for cytokeratins AE1/AE3 or CAM 5.2; staining for PSA is variable in the giant cell component. Most cases are reported in patients with a history of prostate cancer treated with androgen ablation and radiation. The disease course is aggressive.

Lymphoepithelioma-Like Carcinoma

This uncommon, poorly differentiated carcinoma histologically resembles lymphoepithelioma of the nasopharynx but does not seem to be related to Epstein-Barr virus (EBV) infection. Few cases have been reported in the prostate, with a mean age of 76 years (range, 69 to 82 years). Patients present with obstructive symptoms, elevated PSA values, and locally advanced disease. Tumor has a syncytial growth pattern with indistinct cell border. A dense lymphocytic infiltrate is present admixed with plasma cells, neutrophils, and occasional eosinophils. In all cases, the lymphoepithelioma-like component is admixed with acinar adenocarcinoma. The carcinoma cells are positive for PSA, PSAP, and AMACR. The clinical outcome is poor.

Adenocarcinoma with Diffuse Aberrant p63 Expression

This recently described unusual variant of prostate cancer is characterized by p63 expression of the tumor cells in a nonbasal distribution ( Fig. 2-17 , C ) and lack of basal cell stain for HMWCK and CK5/6 ( Fig. 2-17 , D ). Microscopically, the tumor is composed predominantly of glands, nests, and cords of cells with atrophic cytoplasm, hyperchromatic nuclei ( Fig. 2-17 , A ), and visible nucleoli ( Fig. 2-17 , B ). Cases range from Gleason patterns 3 to 5. Most of the tumors reported so far were organ confined at radical prostatectomy.

Radiation Therapy Effects

Both cancer and benign glands respond variably to radiation, with some glands showing marked radiation effect and others showing no such effect. For benign prostatic tissue, the classic alterations are extensive glandular atrophy with stromal predominance. Glands retain their lobular architecture, although individual glands often assume irregular, angulated contours. Secretory cells are atrophic, and basal cells become hyperplastic and multilayered, with scattered, markedly atypical nuclei that appear degenerated ( Fig. 2-18 ). These cells are positive for basal cell immunohistochemical markers. Radiation-treated prostate carcinoma, on the other hand, has a variable appearance, from no or minimal radiation effect to significant radiation-induced changes. The classic radiation-induced changes in prostate carcinoma are a decrease in number of cancer glands, poorly formed glands, and single cancer cells; abundant vacuolated cytoplasm; nuclear pyknosis; and stromal fibrosis ( Fig. 2-19 ). Architecturally, the key feature for recognition of the radiated cancer is closely packed glands with a haphazard infiltrative growth pattern and the presence of infiltrating individual cancer cells—architectural findings that are inconsistent with a benign process. Up to 30 months may be needed for cancer to clear after radiation therapy. Therefore rebiopsy should be performed no sooner than this time. Findings on rebiopsy predict the prognosis, with positive biopsy results that show no treatment effect having a worse outcome than negative biopsy results and cancer with treatment effect having an intermediate prognosis.

Androgen Deprivation

Androgen deprivation via surgical castration or pharmacologic blockade has become a common treatment modality for patients with locally advanced or metastatic prostate carcinoma. More recently, preoperative (neoadjuvant) hormonal ablation is sometimes used for clinically localized prostate carcinoma, to retard tumor growth before surgery if there is a delay between biopsy and definitive resection. In benign prostate tissue, androgen ablation results in pronounced glandular atrophy and stromal predominance. Luminal secretory cells become atrophic and exhibit nuclear pyknosis and cytoplasmic clearing. Basal cells undergo hyperplasia and squamous metaplasia. The histology of prostate carcinoma may be significantly altered after hormonal therapy. The neoplastic glands tend to be smaller and atrophic, with compressed or obliterated lumina ( Fig. 2-20 , A ). Tumor cells develop pyknotic nuclei and abundant foamy or clear vacuolated cytoplasm ( Fig. 2-20 , B ). Sometimes, single tumor cells are widely scattered within the stroma, resembling histiocytes. Complete dissolution of tumor cells may also be seen, leaving empty clefts or mucin aggregates ( Fig. 2-20 , C and D ). Immunohistochemically, cancer cells after hormonal therapy are positive for pancytokeratins, PSA, and AMACR but negative for HMWCK, although the staining intensity for PSA and AMACR may be reduced.

Cryotherapy

Cryoablation of the prostate is a promising technique in the treatment armamentarium for clinically localized prostate cancer and for localized recurrent prostate cancer after radiation therapy. Cryosurgical ablation refers to rapid deep freezing of the prostate. Multiple cryoprobe needles filled with circulating liquid nitrogen transform the prostate gland into an ice ball, which results in tissue destruction and death of benign and malignant cells. Postcryosurgery prostate tissue shows typical features of repair, including marked stromal fibrosis and hyalinization ( Fig. 2-21 , A ), hemosiderin deposition ( Fig. 2-21 , B ), and stromal hemorrhage, inflammation, and squamous metaplasia. Coagulative necrosis ( Fig. 2-21 , C ) may be present between 6 and 30 weeks from therapy, followed by patchy chronic inflammation. Dystrophic calcification is infrequent and usually appears in areas with the greatest reparative response. Biopsies after treatment may reveal no evidence or residual tumor, even in some patients with elevated PSA levels. Ghosts of malignant cells may be appreciated in areas that show coagulative necrosis ( Fig. 2-21 , C ). In some cases, the cancer shows no evidence of treatment effect or immune response, which suggests lack of inclusion of that area in the ablation killing zone.

High-Intensity Focused Ultrasound Scan

High-intensity focused ultrasound scan (HIFU) destroys target tissue through the thermal and mechanical effects of nonionizing, acoustic radiation (i.e., sound waves). As the tissue compresses and expands with exposure to the acoustic waves, gas is extracted, creating bubbles that oscillate violently, collapse, and disrupt cell membranes. The high temperature also induces the creation and release of chemically reactive free radicals, responsible for the induction of apoptosis and activity on nuclear DNA. HIFU-induced acute tissue damage manifests as areas of sharply delineated intraprostatic coagulative necrosis. Vacuolated cytoplasm, ruptured cell membranes, and destroyed cellular organelles as signs of definitive cell death have been routinely observed in treated tissue regardless of their structure. Careful histological examination within the area of coagulative necrosis has revealed no remnant viable cells that could potentially escape the therapeutic effect of HIFU. Recent studies have reported acute and chronic inflammation, glandular atrophy, hemosiderin deposition, focal coagulative necrosis, dense stromal fibrosis, and edema in benign tissue after HIFU treatment. In areas of viable tumor, no post-HIFU histological changes appear to preclude the use of Gleason scoring.

Prostate-Specific Antigen

Prostate-specific antigen is detected in secretory cells of benign prostate glands in all anatomic zones, but not in basal cells, seminal vesicle/ejaculatory duct epithelium, or prostatic urothelial cells. Most prostate carcinomas also express PSA ( Fig. 2-22 , A ), although considerable intratumoral and intertumoral heterogeneity is seen and the expression is decreased in a minority of high-grade prostate carcinoma. After androgen deprivation and radiotherapy, some cancers can lose PSA expression. PSA immunoreactivity can be detected to variable degrees in some nonprostatic tissues and tumors, including urethral and periurethral glands, cystitis cystica and glandularis, urachal remnants, bladder adenocarcinoma, and extramammary Paget disease of the penis.

Prostate-Specific Acid Phosphatase

Prostate-specific acid phosphatase has diagnostic utility similar to that of PSA, although it is in general more sensitive and less specific than the latter ( Fig. 2-22 , B ). Nonprostatic tumors that are reported to be positive for PSAP include some neuroendocrine tumors (pancreatic islet cell tumors and gastrointestinal carcinoids), urothelial carcinoma, and anal cloacogenic carcinoma.

Cytokeratins

Benign prostatic secretory and basal cells are immunoreactive for antibodies to broad-spectrum and low–molecular-weight cytokeratins (CKs). Negative staining for both CK7 and CK20, which is typical of prostate cancer, is useful to differentiate prostate carcinoma from urothelial carcinoma, which is typically positive for both markers.

Basal Cell Markers

High–molecular-weight cytokeratin, detected with the antibody clone 34βE12 that recognizes CK1, CK5, CK10, and CK14 or with the antibody cocktail that recognizes CK5 and CK6, is expressed only by prostate basal cells, and not by secretory cells ( Fig. 2-22 , C ). Prostate carcinoma uniformly lacks a basal cell layer and consequently is negative for HMWCK ( Fig. 2-22 , C ). Absence of a basal lining is demonstrated by lack of immunostain for HMWCK and supports a diagnosis of prostate carcinoma in the context of suspicious architectural or cytologic features on routine H&E stains. However, prostate carcinoma can occasionally contain sparse tumor cells that are positive for HMWCK yet not in a basal cell distribution, especially after radiation or hormonal therapy. Intraductal spread of prostate carcinoma or entrapped benign glands may also be mistaken as residual basal cells in prostate carcinoma. Conversely, some benign conditions, including adenosis (atypical adenomatous hyperplasia) and partial atrophy, can sometimes have a discontinuous or even absent basal cell lining. p63 is a nuclear protein expressed in basal cells of pseudostratified epithelia, including prostate. It has similar diagnostic utility ( Fig. 2-22 , D ) and pitfalls to HMWCK but with the following advantages: (1) it stains a subset of basal cells that are negative for HMWCK; (2) it is less susceptible to staining variability, particularly in TURP specimens with cautery artifact; and (3) it is easier to interpret because of its strong and sharp nuclear staining. An additional pitfall is that in a rare variant of prostate cancer (adenocarcinoma with diffuse aberrant p63 expression), tumor cells expression p63 in a nonbasal distribution (see Fig. 2-17 , C ).

α-Methylacyl-Coenzyme A Racemase

The AMACR (or P504S) enzyme is involved in the metabolism of branched-chain fatty acids and bile acid intermediates. It is overexpressed in most prostate carcinomas ( Fig. 2-23 , A and B ). Because of its intratumoral heterogenous expression patterns, AMACR is positive in only 80% of prostate carcinomas in prostate needle biopsies. Several histologic variants of prostate carcinoma, such as foamy gland, atrophic, and pseudohyperplastic prostate carcinoma, show lower AMACR expression. AMACR is not entirely specific for prostate carcinoma because it is present in HGPIN (>90%), adenosis (∼20%), partially atrophic glands, and occasionally morphologically benign glands. AMACR can be used as a confirmatory staining for prostate carcinoma, in conjunction with H&E histology and basal cell markers.

Basal cell markers and AMACR can be combined in a single immunostaining reaction ( Fig. 2-24 ). Such “cocktail” staining may be advantageous for working up a small focus of cancer that might be present only in one tissue section.

NKX3.1

NKX3.1 is an androgen-regulated tumor suppressor gene located on chromosome 8p largely specific to prostate. Staining for NKX3.1 protein is positive in most primary prostatic adenocarcinomas, but it may be downregulated in high-grade prostate cancers and lost in some metastatic prostate cancers. The use of NKX3.1 is recommended in the differential diagnosis of poorly differentiated prostate cancer versus urothelial carcinoma ( Fig. 2-25 , A and B ), particularly when tumor exhibits equivocal/weak or negative staining for PSA and negative/focal staining for p63 and HMWCK, and also in the evaluation of metastases from unknown primary site.

Prostein

Prostein (or P501S) is a prostate-specific protein localized to the Golgi complex, uniquely expressed in prostatic tissue (normal and cancerous) and unrelated to Gleason grade. Similar to NKX3.1, the use of prostein is recommended in the differential diagnosis of poorly differentiated prostate cancer versus urothelial carcinoma ( Fig. 2-26 , A and B ) and in the metastatic setting from unknown primary site.

ERG

Immunostaining for ERG is used as a surrogate for TMPRSS2-ERG gene fusion, a specific molecular event seen in 40% to 50% of prostate cancers and in approximately 20% of HGPIN that intermingles with cancer. Given the high specificity of ERG protein expression for prostate cancer, positive ERG staining may help establish a diagnosis of limited prostate cancer on challenging needle biopsies ( Fig. 2-27 , A and B ) in conjunction with other markers (basal cell markers, AMACR) and may be useful in the diagnosis of metastasis from unknown primary site.

Gleason Pattern 1

This pattern is composed of a very well-circumscribed nodule of closely packed but separate glands that do not infiltrate into adjacent tissue ( Fig. 2-29 ). The glands are of intermediate size and are similar in size and shape. This pattern is exceedingly rare and is usually only a minor component of prostate carcinoma when present. It may be seen in transition zone prostate carcinoma.

Gleason Pattern 2

This pattern has a less well-circumscribed nodule of medium-sized glands, with some degree of variation in size and shape and looser arrangement. Minimal invasion of cancer glands into surrounding tissue may be found ( Fig. 2-30 ). Although the cytoplasm is not evaluated in the Gleason grading system, in Gleason patterns 1 and 2 cancer glands, it tends to be abundant and pale-clear. Gleason pattern 2 cancer may be seen in the transition zone. The new modified Gleason grading system states that for needle biopsies, patterns 1 and 2 should be diagnosed rarely, if ever. Gleason score 1 + 1 = 2 tumors also were acknowledged to almost always represent adenosis, with basal cell demonstrable after immunohistochemical staining.

Gleason Pattern 3

This pattern is the most common. The cancer glands often infiltrate between the adjacent benign glands. They vary in size and shape and are often angular. Small glands are typical ( Fig. 2-31 , A ), but they may be large with angulations and branching ( Fig. 2-31 , B ). All cribriform glands should be graded as Gleason pattern 4. Poorly formed glands, originally considered Gleason pattern 3, are now considered Gleason pattern 4.

Gleason Pattern 4

Glands appear fused, cribriform, or poorly formed. Fused glands are composed of a group of glands that are no longer separated by stroma. Cribriform glands may be small and have smooth, round, well-circumscribed contours ( Fig. 2-32 , A ) or may be large with irregular contours and jagged edges ( Fig. 2-32 , B ). The intraluminal cellular proliferation spans the entire diameter of the lumen. Poorly formed glands still have glandular configuration, but they have ill-formed glandular lumina ( Fig. 2-32 , C ). The hypernephromatoid pattern is a rare variant composed of fused glands with clear or very pale cytoplasm ( Fig. 2-32 , D ).

Gleason Pattern 5

Cancer cells form solid sheets ( Fig. 2-33 , A ), strands, or single cells ( Fig. 2-33 , B ) that invade the stroma. Comedonecrosis may be present ( Fig. 2-33 , C ).

Tertiary Gleason pattern refers to a minor pattern that occupies less than 5% of the tumor volume. In radical prostatectomy, the presence of a high-grade tertiary pattern adversely affects the prognosis. For example, the presence of a tertiary pattern 5 in a Gleason score 4 + 3 = 7 prostate carcinoma worsens the prognosis, compared with the same tumor without a tertiary high-grade component. However, the prognosis is not as poor as that of a 4 + 5 = 9 cancer. In prostate needle biopsies that harbor three patterns when the worst pattern is the least common, the highest pattern should be incorporated as the secondary pattern.

Morphologic variants of prostate carcinoma are uncommon and often are mixed with ordinary prostate carcinoma. Grading such variants should be based on the underlying cancer glandular architecture. Cancers with pseudohyperplastic, atrophic, and microcystic features are graded as Gleason pattern 3. Ductal adenocarcinoma is graded as Gleason pattern 4 or 5 if comedonecrosis is present. Mucinous (colloid) adenocarcinoma can be graded as Gleason pattern 3, if composed of round discrete glands within mucin pools, or Gleason pattern 4, if composed of irregular, cribriform, or fused glands. Signet-ring–cell and sarcomatoid variants are aggressive tumors, comparable with Gleason score 9 or 10. On the other hand, squamous cell carcinoma, urothelial carcinoma, small cell carcinoma, and basaloid/adenoid cystic carcinoma are not assigned a Gleason grade. Prostate carcinoma treated with hormonal ablation or radiation can appear artifactually to be of higher Gleason grade; therefore Gleason grade should not be assigned to such cases. If no effect of the therapy is evident, a Gleason grade can be assigned. Prostate carcinoma displays remarkable intratumoral grade heterogeneity; therefore the biopsy Gleason grade may in some cases represent undergrading or overgrading compared with the radical prostatectomy. Nevertheless, the concordance between biopsy and prostatectomy Gleason scores is within one Gleason score in most cases. Multiple studies have shown that the Gleason grade is currently the most powerful prognostic indicator for prostate carcinoma. It correlates with all the important pathologic parameters in radical prostatectomies and with prognosis after radical prostatectomy and radiation therapy. The distinction between Gleason scores 6 and 7 is critical. Gleason 7 prostate carcinoma behaves significantly worse than Gleason 6 cancer but better than Gleason score 8 to 10 cancer. The importance of Gleason grade is evidenced by the use of various nomograms to predict pathologic stage and disease progression after surgery and radiotherapy. These nomograms, including Partin tables and Kattan nomograms, use preoperative biopsy Gleason score, tumor extent, clinical stage, and serum PSA to predict the risk of extraprostatic extension, seminal vesicle invasion, and lymph node metastasis and the probability of disease recurrence after treatment.