Histopathological Evaluation of Prostate Lesions: A Comprehensive Approach

Abstract

This chapter encompasses the spectrum of prostatic diseases seen routinely in the evaluation of prostate biopsy or resection specimens. It covers the basic anatomy and histology, along with tissue examination and processing. The common benign conditions such as benign prostatic hyperplasia (BPH), various kinds of prostatitis, etc., are addressed briefly and prostate adenocarcinoma is discussed in a structured pattern, including the morphological variants, IHC, molecular profiling, microscopic variants, grading, mimickers, etc. Other rare tumors of the prostate are also discussed in brief. This chapter provides a comprehensive update on the 2022 WHO classification of urinary and male genital tumors.

1. Introduction

The prostate is a retroperitoneal organ that surrounds the bladder neck and prostatic urethra. In adults, it is funnel-shaped, weighs about 20 grams [1], and has its base beneath the bladder neck and apex above the urogenital diaphragm. Posteriorly, it is separated from the rectum by Denon Villiers fascia. It is divided into the anterior fibromuscular stroma and three distinct glandular zones, as proposed by Mc Neal (Figure 1) [2].

• The transition zone––envelopes the proximal prostatic urethra and comprises 5% of glandular tissue.

• The central zone––lies toward the base and contains the ejaculatory duct, which opens into the prostatic urethra at the verumontanum; comprises 20% of glandular tissue.

• The peripheral zone––envelopes the central and peripheral zones, and comprises most of the apex; it comprises approximately 70% of glandular tissue.

Figure 1.

Zones of the prostate gland.

These zones are at risk for different types of lesions; benign prostatic hyperplasia (BPH) primarily affects the transition zone, whereas carcinomas involve the peripheral zone. The prostate gland is partially surrounded by a fibrous capsule. The neurovascular bundles run posterolateral to the capsule bilaterally at 5 and 7 o’clock positions. Histologically, the prostate is comprised of glands separated by fibromuscular stroma. The glandular system consists of ducts and acini with little or no morphological difference. The glands often have papillary infoldings and undulating contour. The glands are lined by three types of cells:

• Secretory cells: They are located along the glandular lumen, columnar cells with relatively pale cytoplasm. They stain positively with prostate-specific antigen (PSA); prostate-specific acid phosphatase (PSAP); NKX3.1, some keratins but are negative for high molecular weight types like 34beta E12 [2, 3].

• Basal cells: They represent the stem cells and are located between the secretory cells and basement membrane; they are low cuboidal or cigar-shaped and may have prominent nucleoli. They express high molecular weight keratins like 34beta E12 and CK5/6; p63, p40 [2, 3]. Their presence helps to distinguish between benign conditions and well-differentiated carcinomas.

• Neuroendocrine cells: These cells are sparse and irregularly distributed with no proper known function.

The fibromuscular stroma consists of collagenous fibrous tissue and smooth muscle fibers. Inspissated secretions of the prostate may accumulate in some glands, forming spherical concretions known as corpora amylacea, which increase in number with age.

2. Tissue examination and processing

Prostate specimens received are mainly of three types: transrectal ultrasound (TRUS) biopsy; transurethral resection of prostate (TURP); resection specimens, that is, radical prostatectomy for tumors or suprapubic prostatectomy for benign hyperplasia.

2.1 TRUS needle biopsy

The number of cores is counted and measured (mm). Each core is submitted separately if labeled accordingly and processed. A minimum of three levels is to be examined.

2.2 TURP

Weigh and measure the dimensions of the prostatic chips received. Describe the chips, including color, consistency, and any abnormal area (hemorrhage or necrosis) if seen. As per College of American Pathologists (CAP) guidelines, specimens weighing 12 grams or less are entirely processed. For specimens weighing more than 12 grams, an additional 2 grams are required for every 5 grams of tissue beyond the initial 12 grams for processing [4, 5]. If carcinoma is detected and involves <5% of tissue, the remaining tissue should be entirely processed. In a previously diagnosed case of carcinoma, only a small amount of tissue can be processed.

2.3 Suprapubic prostatectomy

Weigh and measure (three dimensions, mm) the specimen. Serially section at 3–4 mm, carefully examine and describe, including color, consistency, any abnormal area, and areas of hemorrhage or necrosis. Submit at least eight sections from different areas.

2.4 Radical prostatectomy

Weigh the specimen and note the dimensions of the prostate and length of the attached seminal vesicle. Orient the specimen placing a probe through the urethra will help and paint the anterior, posterior, right lateral, left lateral, and superior and inferior surfaces using different colored inks. Cut the seminal vesicles and submit a section including the base of the vesicle with the prostate on both sides. The bladder neck margin (proximal) and apex (distal) are submitted. The remaining prostate is to be serially sectioned at 3–4 mm intervals and carefully examined. Note the color, consistency, any tumor nodule, area of hemorrhage, or necrosis. Sections are submitted from apex to base, and each slice can be bisected or quadrisected to fit the cassettes. All lymph nodes should be submitted after noting their number, size, and cut section appearance.

3. Benign prostatic hyperplasia

BPH is a nodular enlargement of prostate due to hyperplasia of both epithelial and stromal components. Incidence increases with increasing age, with >50% prevalence in males above 50 years of age, and is the most common benign prostatic disease in males above 50 years [1]. It is not a premalignant lesion. The precise etiology remains unclear, and no predisposing or protective factors have been identified other than castration [2, 3]. It is known to be an androgen-dependent disorder. Dihydrotestosterone (DHT), estrogens, and growth factors like fibroblast growth factor (FGF) and transforming growth factor (TGF) beta play an important role [2, 3]. The main symptoms include obstructive symptoms like hesitancy, weak urine stream, and post-micturition dribbling; irritative symptoms like frequency, urgency, and nocturia. Patient can also present with acute urinary retention requiring emergency catheterization for relief [1].

Grossly, the prostate gland is enlarged three to five times of normal or even more. On the cut section, it is seen to involve mainly the transition zone and thus encroach on the urethra, compressing it to a slit-like orifice. It has a multinodular appearance consisting of variable-sized nodules with a gray to yellow color. Microscopically, the earliest change is stromal proliferation, which is followed by glandular hyperplasia. The glandular component comprises variably sized acini and ducts lined by basal and secretory cells (Figure 2). The glands are dilated with papillary infoldings or cystic, and often contain corpora amylacea, which may be calcified. The epithelium is lined by flat to columnar cells. The stromal component comprises bland spindle cells with round to ovoid nuclei. Many morphologic variations exist, including clear cell cribiform hyperplasia, basal cell hyperplasia, adenosis, leiomyomatous nodules, fibroadenomatous, and phyllodes-type hyperplasia. Within areas of BPH, occasional lymphocytes are commonly seen, and a diagnosis of chronic prostatitis is not indicated due to its mere presence [2, 3].

Figure 2.

BPH: Variable-sized ducts and acini lined by basal and secretory cells, H&E, 200x.

4. Prostatitis

4.1 Bacterial prostatitis

Acute prostatitis is characterized by severe lower urinary tract symptoms (LUTS) including irritative and obstructive voiding symptoms with generalized urosepsis. Usually a self-limiting disease, acute prostatitis responds promptly to antibiotics. Chronic bacterial prostatitis is usually associated with mild to moderate pelvic pain and episodes of recurrent urinary tract infections (UTIs). As these infections are usually amenable to antimicrobial therapy, histologic examination of specimens removed for symptomatic prostatitis is thus uncommon. However, on histology, acute bacterial prostatitis is characterized by sheets of neutrophils within and around acini, intraductal desquamated cellular debris, and stromal edema and hyperemia.

4.2 Mycotic prostatitis

Fungal prostatic infections are relatively uncommon; however, the most common causes include blastomycesdermatitidis, Coccidioidesimmitis, and Cryptococcus neoformans. Aspergillus fumigatus, Histoplasma capsulatum, and Candida albicans, and Candida glabrata are among the other rarer causes (Figure 3) [2, 6]. Most fungal prostatitis occurs in the setting of urinary catheterization and use of broad-spectrum antibiotics, leading to systemic hematogenous dissemination in immunocompromised and elderly hosts with comorbidities [2, 6].

Figure 3.

Hyphae and budding yeast forms of candida, H&E stain, 400x, Inset: PAS stain, 400x.

4.3 Tuberculous prostatitis

Systemic tuberculous prostatitis is rare (incidence: 3–12%) due to timely diagnosis and treatment of disease for non-prostatic signs and symptoms of infection, as more than 90% of cases also show lung involvement [2]. However, infection might spread via hematogenous route or may directly invade from the urethra. Confluent areas of caseation, along with cavitation, may result in a grossly enlarged prostate with multiple cavities. Infection might spread to the urinary bladder and further to the rectum, perineum, and peritoneal cavity. The serum PSA levels may be increased. Bacillus Calmette-Guérin (BCG) immunotherapy for superficial urothelial cancer of the bladder may also result in the development of granulomas, which may vary from small, noncaseating and superficial to large, caseating, and throughout the prostate.

4.4 Nonspecific granulomatous prostatitis

Nonspecific granulomatous prostatitis is a rare disorder resulting from a localized immune-mediated reaction to ruptured prostatic secretions and contents. Mostly occurs in glands with preexisting nodular hyperplasia. High-grade fever, urinary obstruction, and hard prostate on palpation constitute the clinical symptoms. The cut surface shows yellow granular nodularity. Microscopically, these nodules show aggregates of dense inflammatory infiltrate chiefly composed of lymphocytes, plasma cells, epithelioid cells, and histiocytes, which often obscure and efface ductal and acinar elements (Figure 4). The early lesions show a tubercle-like reaction with multinucleated giant cells, neutrophils, eosinophils, and detritus within the dilated ducts and acini, which may as well rupture focally, resulting in localized granulomatous and chronic inflammatory reactions; however, microorganisms and caseous necrosis are absent. In contrast, the granulomas in early infectious noncaseating prostatitis surround intact acini. There is dense fibrosis in older lesions, leading to a firm to stony-hard prostate on palpation, simulating carcinoma in about 30% of cases [3]. Serum PSA levels may also be elevated. Immunohistochemical (IHC) stains for histiocytes and T cells surrounding the damaged ducts may help to differentiate from carcinoma.

Figure 4.

Granulomatous prostatitis: nodules composed of dense inflammatory infiltrate chiefly comprising of lymphocytes, plasma cells, epithelioid cells, and histiocytes, with effacement of ductal and acinar elements, H&E, 40x.

4.5 Malakoplakia

Malakoplakia can rarely involve prostate, usually associated with primary bladder disease. It is believed to be caused by an impaired host response to bacterial infection, most commonly to Escherichia coli [2]. It is frequently seen in patients with either a primary or acquired immunodeficiency, such as diabetes, malignancy, or HIV/AIDS; a history of UTI strongly supports the diagnosis. In the prostate, malakoplakia can mimic carcinoma both clinically and radiologically. In needle core biopsy, there is periductal dense inflammatory infiltrate consisting mainly of histiocytes and scattered, atrophic prostatic glands along with basophilic cytoplasmic inclusions that have a targetoid appearance also known as Michaelis-Gutmann bodies.

5. Prostatic infarct

Prostatic infarcts remain mostly asymptomatic or sometimes may cause acute urinary retention due to edema. Serum PSAP and PSA may be elevated. Moore reported the incidence of infarcts to be 18–25% in carefully examined prostates [3]. They are usually associated with nodular hyperplasia, and the size and number of infarcts are directly proportional to the degree of hyperplasia. Other causes include trauma or infection due to cystitis, prostatitis, or a urinary catheter resulting in thrombosis of prostatic vessels. Grossly, they appear gray yellow, speckled, and size may vary from a few millimeters up to 5 cm. Microscopic sections show sharp areas of coagulative necrosis affecting glands and stroma; the latter may be spared sometimes in cases of nodular hyperplasia.

6. Calculi

The prostatic calculi are observed in about 7% cases of nodular hyperplasia and are composed of inorganic salts, namely phosphate salts of calcium, magnesium along with calcium carbonate and calcium oxalate [3]. The corpora amylacea, blood clots, bacteria, and dead epithelial cells act as nuclei for stone formation. They may get extremely hard, leading to suspicion of carcinoma on palpation. Their radiopaque nature makes them easily detectable on X rays.

7. Tumors of prostate

Table 1 describes the latest World Health Organization (WHO) classification of prostate tumors 2022.

1.	Epithelial tumors of the prostate
	A.	Glandular neoplasms of the prostate
		Prostatic cystadenoma High-grade prostatic intraepithelial neoplasia Intraductal carcinoma of the prostate Prostatic acinar adenocarcinoma Prostatic ductal adenocarcinoma Treatment-related neuroendocrine prostatic carcinoma
	B.	Squamous neoplasms of the prostate
		Adenosquamous carcinoma of the prostate Squamous cell carcinoma of the prostate Adenoid cystic (basal cell) carcinoma of the prostate
2.	Mesenchymal tumors unique to the prostate
	Stromal tumors of the prostate
		Prostatic stromal tumor of uncertain malignant potential Prostatic stromal sarcoma

Table 1.

WHO classification of prostate tumors [7].

7.1 High-grade prostatic intraepithelial neoplasia

Prostatic intraepithelial neoplasia (PIN) is considered to be the end of the spectrum of preinvasive proliferation of prostatic ducts and acini. The term PIN is now used interchangeably with high-grade PIN (HGPIN) as low-grade PIN are not routinely reported due to high inter-observer variability, poor reproducibility, and lack of definite association with prostatic carcinoma [8, 9, 10, 11, 12].

The only proven method to diagnose HGPIN is biopsy, as these lesions do not significantly raise the serum PSA level nor are easily detected on ultrasonography. The incidence of isolated HGPIN in the prostatic biopsy is about 9% in United States, with prevalence and volume of HGPIN rising proportionately with advancing age [10, 13, 14]. Hirori et al. [15] stated that African-American men have higher prevalence than whites in 50–60 age bracket, while Japanese have a lower incidence than men in the United States. This is in contrast to the study by Kilnk et al. [16] which showed that incidence of HGPIN is comparable in Asian and western men [16, 17].

Apart from HGPIN, which affects the peripheral zone, other precursors for prostate cancer include adenosis (atypical adenomatous hyperplasia), affecting the transition zone and less likely for malignant transformation, and proliferative inflammatory atypia (PIA) [16, 18], which occurs frequently in the peripheral zone and has been shown to be in continuum with HGPIN and progress to a small adenocarcinoma lesion [19].

PIN mimics malignancy, cytologically exhibiting nuclear and nucleolar enlargement and cellular proliferations within preexisting ducts and acini. There is increased microvascular density in the stroma, which is intermediate between benign and malignant, along with loss of polarity (Figure 5) [8]. Tufting (most common), micropapillary, cribriform, and flat are the four primary histologic patterns of HGPIN that have been reported [18, 20]. Rarer patterns include signet ring cell, small cell neuroendocrine, mucinous, micro-vacuolated, and hobnail (inverted) pattern. The architectural patterns do not appear to differ in any way that is clinically significant, and identifying them seems to be only useful for diagnostic purposes.

Figure 5.

Micropapillary pattern of HGPIN. Large duct with amphophilic cytoplasm, enlarged hyperchromatic nuclei and prominent nucleoli, H&E, 200x.

The first signs of carcinoma, known as early stromal invasion, appear at the locations of basal cell breakdown and acinar outpouching in acini with HGPIN. About 2% of PIN’s high-power tiny fields have this kind of microinvasion, which occurs equally frequently in all architectural forms. In concordance with cancer, HGPIN is typically multicentric and primarily located in the peripheral zone of the prostate. With an increase in pathologic stage, Gleason grade, positive surgical margins, and perineural invasion (PNI) in prostate cancer, the amount of HGPIN also increases, highlighting the association between PIN and cancer [14].

Basal cell markers such as p63 and high molecular weight keratins (HMWK) have shown promising results to rule out HGPIN from its mimickers, such as basal cell hyperplasia, inflammatory acini, atypical adenomatous hyperplasia, post-atrophic hyperplasia, and alteration in radiation therapy [21, 22].

HGPIN has been associated with more than 50 genetic and molecular disorders. Both HGPIN and prostate cancer have been linked to at least 10 of these alterations. Up to 79% cases of prostate cancer exhibit TMPRSS2-ERG gene fusion [23]. Up to 19% of HGPIN display the same fusion too, which has helped establish that HGPIN is the precursor state of cancer [24, 25]. A regulatory protein for mTOR, 14–3-3σ is over expressed in both HGPIN and prostate cancer [26]. Micro-satellite instability (MSI) and a positive Replication error phenotype (RER+) was seen to be present more in prostate cancer than PIN lesions [27]. FAS (fatty acid synthetase) and p53 expression was also seen more in PIN and Prostate cancers than in normal tissues [28]. Bcl2 has been reported to be expressed in both low- and high-grade PIN [29].

Chromosomal anomalies such as gain of chromosome––8,10,7,12 and Y or loss of heterozygosity of chromosome 8p12–21, telomerase activation in some foci and epigenetic events such as hypermethylation has been seen in HGPIN [30, 31, 32, 33]. Other markers include HER2/neu, c-erb-3 oncoproteins, c-met-proto-oncogene, inducible nitric oxide synthase, alpha-methylacyl-CoA racemase, glycoprotein A-80, apolipoprotein-D, and p16INK4A [34, 35, 36, 37]. The finding of PIN in biopsy warrants further search for synchronous invasive carcinoma. A follow-up biopsy should be done at 3–6 months for 2 years and thereafter yearly for the rest of life.

7.2 Prostatic adenocarcinoma

The prostatic adenocarcinomas are usually present in males older than 65 years of age but may be seen in younger men as well. Clinical presentation includes dysuria, weak or interrupted flow of urine, nocturia, bladder or fecal incontinence, hematuria or hematospermia, painful ejaculation, erectile dysfunction, pain in the back, hips, or pelvis along with nonspecific symptoms of malignancy such as cancer cachexia [1, 38].

7.2.1 Prostatic acinar adenocarcinoma (conventional adenocarcinoma)

This cancer accounts for nearly all prostatic adenocarcinomas. The acini cells line the prostate’s fluid-secreting glands. The cancer starts growing in the periphery of the prostate near the rectum, resulting in the late occurrence of urinary symptoms. It remains relatively indolent, and patients survive a long time after the diagnosis. Asymptomatic tumors are detected by digital rectal examination or by increased PSA levels. Local spread of adenocarcinoma occurs through extra-prostatic extension or seminal vesicle invasion. Distant metastasis occurs when carcinoma invades the lymphovascular spaces. The most common sites of metastasis are regional pelvic lymph nodes, bones, and lungs. Rare sites include the liver and the testis [1, 39].

Grossly, the tumor is firm, gritty, and less spongy than surrounding non-neoplastic prostate [1]. Microscopically, there is haphazard proliferation of crowded, uniform small acini with irregular contours arranged in back-to-back fashion showcasing an infiltrative pattern. The acini are lined by a single layer of epithelial cells, and the basal cell layer is absent. The epithelial cells are cuboidal or columnar and have abundant amphophilic cytoplasm along with pleomorphic nuclei with the presence of one or more prominent macronucleoli. The presence of mitotic figures is according to the grade of the tumor. Corpora amylacea is rare. Intraluminal crystalloids, blue mucin, glomerulations, collagenous micronodules, and circumferential perineural invasion are some of the other features found in this carcinoma [1, 39, 40]. The unusual histological patterns include:

• Atrophic adenocarcinoma (including aberrant p63 +): There is glandular proliferation with an infiltrative growth pattern; neoplastic cells have large nuclei with prominent nucleoli; glands lack basal cell layer. Many glands have scant cytoplasm, non-lobular, and infiltrative appearances on low power. High power shows some glands with abundant cytoplasm and other glands with scant cytoplasm (atrophic) but with an infiltrative architecture [39, 40, 41].

• Pseudohyperplastic adenocarcinoma: It occurs in the transition zone. Two of the following patterns are observed on low power:

  1. Crowded glands lined by pseudostratified epithelium having rounded nuclei and a prominent nucleolus.

  2. Large acini: Features associated with prostatic neoplasia, such as intraluminal crystalloids, pink amorphous secretions, and wispy blue mucin, are seen in a few cases. Discovery of intraluminal crystalloids at low magnification in hyperplastic-appearing glands may provide a diagnostic clue as to the presence of pseudohyperplastic carcinoma. It may be underdiagnosed because the pseudostratified epithelium looks like hyperplasia or HGPIN [39, 40, 41].

• Microcystic adenocarcinoma: It exhibits gland dilatation with intermediate-sized glands that are 10 times the size of usual small acinar adenocarcinoma glands. The expansion of the luminal spaces generates a rounded profile, and the luminal cell lining layer is flat, with or without atrophic changes. Intraluminal crystalloids and blue mucin are uniformly present. There is always admixture with usual small acinar adenocarcinoma, which most often comprises the majority of the tumor [39, 40, 41].

• Foamy gland adenocarcinoma: There is the presence of small glands with tall and columnar tumor cells, along with the occurrence of abundant foamy cytoplasm, luminal secretions, and bland nuclei. Occasionally, consist of cribriform, fused, or poorly formed glands, cords, single cells, or solid sheets. Gleason pattern 4 or 5. Can be underdiagnosed on a core biopsy [39, 40, 41].

• Mucinous (colloid) adenocarcinoma: Cut surface is mucinous/glistening. Uncommon variant. There is presence of extracellular mucin in at least 25% of tumors. Neoplastic cells having a variable degree of cytological atypia and glands float within lakes of extracellular mucin. The cribriform pattern is the most common, showing mucin within the gland lumina and dissecting between stromal muscle fibers. It is considered Gleason grade 4, showing aggressive biological behavior [39, 40].

7.2.1.1 Subtypes of prostatic acinar adenocarcinoma

1. Signet ring-cell like adenocarcinom: At least 25% of tumors consist of cells with a cytoplasmic vacuole that displaces the nucleus to the side (signet ring cell morphology). The cells, arranged mainly in small nests, diffusely infiltrate the stroma and invade the perineural and vascular spaces as well as the capsule of the prostate [42].

2. Pleomorphic giant cell adenocarcinoma (PGCC): It is an aggressive form of prostatic adenocarcinoma. PGCC is defined by extreme nuclear atypia and pleomorphism, with characteristic bizarre multinucleated and mononuclear giant cells, usually with abundant cytoplasm and often atypical mitoses. Additional clinicopathologic features are perineural and/or lymphovascular invasion, cribriform architecture, and/or intraductal carcinoma or tumor necrosis [43].

3. Sarcomatoid carcinoma: Biphasic tumor with carcinomatous and spindle sarcomatoid components. The sarcomatoid areas are composed of spindle cells with large, pleomorphic, hyperchromatic nuclei and a high mitotic rate [39, 40].

4. PIN-like carcinoma: Rare tumors characterized by crowded, often cystically dilated glands architecturally resembling HGPIN, lined by malignant pseudostratified columnar epithelium. In some cases, the pseudostratified neoplastic epithelial cells are elongated, whereas in other cases the cells are cuboidal and nuclei are rounded with prominent nucleoli that are variably present. The histologic features overlap with pseudohyperplastic subtype [44]. According to WHO 2022, PIN-like carcinoma is classified as a subtype of acinar adenocarcinoma (although it can be related morphologically to ductal adenocarcinoma as well) [7].

7.2.2 Prostatic ductal adenocarcinoma

This cancer is a rarer but more aggressive form of adenocarcinoma. It develops in the cells lining the tubes and ducts of the prostate gland. It frequently develops along with acinar adenocarcinoma. It may not necessarily increase PSA levels, making it harder to detect. It may have papillary or polypoid mass extending into the urethra. Prostatic ductal adenocarcinoma (PDA) consists of large glands composed of tall columnar cells, which often have pseudostratified nuclei. The main patterns include cribriform, papillary, solid, and PIN-like pattern. The cribriform and papillary architecture are composed of pseudostratified columnar cells along with the occasional presence of comedo necrosis. The neoplastic cells have atypically large nuclei with coarse chromatin and large nucleoli. Mitotic figures are persistent. Considered Gleason grade 4 (or 5 if comedo necrosis present). The cribriform pattern in ductal adenocarcinoma has been shown to be more likely to have extraprostatic extension, seminal vesicle invasion, lymphovascular invasion, and advanced pathologic stage [39, 40].

7.2.3 Immunohistochemistry

Immunohistochemistry (IHC) offers limited utility in prostate adenocarcinomas as the diagnosis is based primarily on histomorphological features. Its application is known for enhancing the diagnostic accuracy mainly for prostate biopsies or identifying metastatic prostatic cancers in other organs [45]. During the interpretation of IHC markers, clinical, radiological, and histomorphological details should always be kept in mind. The use of these markers is mainly warranted in certain specific conditions, namely:

7.2.3.1 Diagnosis of minimal adenocarcinoma on needle biopsies

Small adenocarcinomas (measuring <1 mm or involving <5% of needle core tissue) form one of the most common adjunctive studies for use of IHC markers against basal cells [46, 47]. The most widely used immunomarkers for this purpose are high-molecular-weight cytokeratins (HMWCK) such as 34bE12 and p63. p40 which is an isoform of p63 is comparable for identifying basal cells. It is noteworthy that the loss of basal cells is not specific for carcinoma and may also be observed in benign pseudoneoplastic conditions like atrophy and adenosis [47, 48].

AMACR (also called P504S and racemase) is an α-methylacyl-CoA racemase that plays a role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives [49]. It shows positivity in prostatic adenocarcinoma with a high sensitivity and specificity. Of all cases, 80–100% of acinar adenocarcinomas show positivity, with characteristic granular cytoplasmic staining, sometimes with luminal accentuation. It also shows positive staining in most cases of HGPIN and thus cannot distinguish between invasive and noninvasive epithelium. This warrants the need for its use in conjunction with basal cell markers. In an ideal world, a malignant gland should show luminal reactivity for P504S in the luminal cells and absence of staining for the two basal cell markers, whereas the opposite should be true for benign glands. Another antibody named ERG protein expression shows high specificity for neoplastic prostatic glandular epithelium, but its sensitivity is only about 50% and does not add value beyond basal cell markers and AMACR expression for diagnosing minimal adenocarcinoma [50].

7.2.3.2 Distinction between poorly differentiated prostatic carcinoma and urothelial carcinoma

The best immunomarkers to aid in this differential diagnosis are PSA and GATA3 [46]. PSA is positive in 90–95% of high-grade adenocarcinomas of the prostate and negative in urothelial carcinomas whereas GATA3, a zinc finger transcription factor shows positivity in 80% of high-grade urothelial carcinomas and is almost always negative in prostatic adenocarcinoma. Other markers to confirm prostate origin are NKX3.1 (a homeobox-containing transcription factor), p501S, PSAP, and PSMA [46].

7.2.3.3 Differentiation of high-grade adenocarcinoma of the prostate from granulomatous prostatitis/xanthoma

The differential of a xanthoma or granulomatous prostatitis may arise in certain histological variants, such as the foamy gland variant of adenocarcinoma. The use of epithelial markers such as AE1/AE3 and CAM5.2, which show positivity for prostatic adenocarcinoma cells along CD68-staining histiocytes, will help in this distinction.

7.2.3.4 Differentiating between high-grade adenocarcinoma of the prostate and urinary bladder adenocarcinoma

The markers for high-grade prostatic adenocarcinoma are PSA, PSAP, and prostein. PSA and PSAP antibodies show high sensitivities (90–95%) for high-grade prostatic adenocarcinomas (Gleason score 8–10). They generally do not react with bladder adenocarcinoma, but sometimes even these markers may show positive staining. Therefore, the use of CDX2 and carcinoembryonic agent (CEA) which show a sensitivity of 47–65% for bladder adenocarcinomas, along with prostate-specific markers, is recommended [46].

7.2.3.5 Discrimination of high-grade adenocarcinoma of the prostate from colorectal adenocarcinoma

Both prostatic adenocarcinomas and colorectal carcinomas show proclivity for older males, and thus colon carcinoma serves as an important differential diagnosis. CDX2 and villin show positivity for cells of colon carcinoma and should be applied in adjunct to PSA, PSAP, and PSMA [46].

7.2.3.6 Diagnosis of metastatic adenocarcinoma of the prostate

Immunomarkers that help in proving prostatic origin are PSA, PSAP, prostein, and NKX3.1 with each of the markers reproducing a sensitivity of >94% [46, 51]. The use of PSA and PSAP is limited, as their expression may be decreased after androgen deprivation therapy [52]. Also, PSA shows immunoreactivity in some salivary gland neoplasms, while PSAP shows positivity in both salivary gland neoplasms and neuroendocrine carcinomas. It is also interesting to note that some cases of urinary bladder adenocarcinomas have shown positivity for prostein, but the characteristic granular perinuclear staining is not seen [53]. These evidences prove that NKX3.1 is highly specific and thus most reliable for prostatic adenocarcinomas [51]. Prostate-specific markers of limited diagnostic utility are PSMA, ERG, AR, and AMACR due to low sensitivity and specificity.

7.2.4 Molecular profiling

Large-scale genomic studies done in the recent past, including The Cancer Genome Atlas (TCGA) have lended further insights in understanding the molecular landscape of somatic DNA alterations in prostate cancer [54, 55, 56, 57]. The most common molecular alterations associated with the initiation of prostate cancers are MYC overexpression, shortening of telomeres, inactivation of GSTP1 and other genes by CpG island hypermethylation, and gene fusions involving ETS transcription factors (TMPRSS2::ERG). Some genes, such as the PI3K, MYC, and p53 pathways are altered in sporadic prostate cancer, whereas the RAS-MAPK pathway has shown little evidence. Noteworthy oncogenic drivers in 25–50% cases are androgen-driven ETS factors, withTMPRSS2-ERG fusion being most common. Other members of the ETS family that serve as 3′ partners include ETV1, ETV4, ETV5, and FLI1 [58, 59]. The prevalence of these ETS rearrangements ranges from 27–79% [59].

Other cases of acinar adenocarcinoma of the prostate are driven by somatic mutations involving FLU, SPOP, FOXA1, or IDH1 which are mutually exclusive with ETS rearrangements and with each other. Progression of the disease is mitigated by gain of 8q24 (including MYC), loss of PTEN, inactivation of TP53, and additional mutations and hypermethylation events. The association of these genetic alterations is associated with a worse prognosis and goes on to prove that genomic instability is central to the disease progression of prostate cancers [60, 61].

Metastatic prostate cancers initial sensitivity to androgen deprivation or androgen receptors (AR) blockade, yet most cases progress to castration-resistant prostate cancer. This transition is seen to have association with AR gene amplification, mutation, or rearrangement, and/or with the activation of AR splice variants [62, 63]. This concludes that AR remains a key driver of late-stage disease. About 20% of metastatic prostatic carcinomas harbor germline or somatic alterations in DNA repair genes involved in homologous recombination repair (HRR), mismatch repair, and other genes, such as BRCA1, BRCA2, ATM, CHEK2, FANCI, and PALB2 [57, 64, 65]. These findings have prompted the current guideline recommendations for germline and/or somatic testing for DNA repair defects in men with aggressive primary tumors and in men presenting with metastatic prostate cancer [66, 67].

7.2.5 Grading

The Gleason system is widely accepted and preferred grading system throughout the world for prostate adenocarcinoma [68]. It has undergone several modifications over the past 50 years, most recently after the International Society of Urological Pathology (ISUP) consensus conferences in 2005, 2014, and 2019 and the 2019 white paper by the Genitourinary Pathology Society (GUPS) [69, 70, 71, 72]. The major modification happened in its manner of grading going from traditional Gleason grading to the now accepted grade group (GG) system [70].

The system is based primarily on the pattern of growth of neoplastic glands on low-power magnification, where 5 patterns are described, with 1 showing maximum differentiation and 5 showing least differentiation (Table 2). Owing to the heterogeneous tumor differentiation, prostate cancers often exhibit more than one pattern. In the traditional grading system, the most common patterns (primary and secondary) were recorded to derive the Gleason score (GS), however, it has now been revised to the primary and worst patterns for biopsy. The sum of these patterns constitutes the Gleason score that ranges from 2 to 10 [73, 74, 75]. This grading does not consider nuclear and cytoplasmic features.

Table 2.

Gleason grade patterns (after the ISUP 2005 and 2014 modifications).

The 2005 ISUP consensus conference introduced a key number of changes, most noteworthy was Patterns 1 and 2 are no longer assigned to core needle biopsy specimens and are rarely used in radical prostatectomy (RP) specimens, leaving an effective range of 6–10 for Gleason scores.

Also, since 2005 it is recommended to derive the GS by adding the primary pattern with the worst pattern for core needle biopsy, unlike radical prostatectomy specimens where the score is derived from the sum of the primary and secondary prevalent patterns [69]. Some radical prostatectomy specimens may show more than 2 patterns, where the worst pattern (pattern 5) represents the smallest volume, being referred to as the tertiary high-grade pattern. In such situations, if the tertiary grade pattern constitutes >5% of the tumor volume, it becomes the secondary pattern in Gleason scoring [71, 72, 76, 77]. Higher tertiary pattern volumes are associated with a worse prognosis and reported despite the 5% cut-off being somewhat arbitrary. If the higher-grade component constitutes <5% of the tumor, it is to be dealt differently in the 2019 ISUP and GUPS systems (Table 3).

Issues		GUPS 2019 Recommendations	ISUP 2019 Recommendations
Minor/tertiary pattern in RP specimen	GP3 (25%), GP4, and GP5 pattern in RP present with GP5 < 5%	GS 3 + 4 = 7 or 4 + 3 = 7 with minor/tertiary pattern 5
	> 95% GP3 with <5% GP4*	GS 3 + 4 = 7	GS 3 + 3 = 6 with minor/tertiary pattern 4
	> 95% GP3 with <5% GP5*	GS 3 + 5 = 8	GS 3 + 3 = 6 with minor/tertiary pattern 5
	> 95% GP4 with <5% GP5*	GS 4 + 5 = 9	GS 4 + 4 = 8 with minor/tertiary pattern 5

Table 3.

Unresolved disagreements between GUPS and ISUP recommendations.

In 2014 ISUP conference, the concept of grade groups (GG1-GG5) was endorsed. It is also referred to as “ISUP grade” or simply “WHO Classification of Tumors grade (WHO grade)” in order to separate it from the other grade grouping systems used before 2013. The most distinctive advantage is with respect to the communication of results to patients, clinicians, and researchers. This advantage can be understood by noting that Gleason score 3 + 3 = 6 cancers are assigned Gleason Grade Group (GG1) which highlights their generally favorable prognosis, whereas 3 + 4 = 7 cancers (GG2) are placed in a separate grade group compared to 4 + 3 = 7 cancers (GG3) highlighting the higher risk of recurrence associated with the latter (Figures 6–8; Table 4) [70, 78].

Figure 6.

Gleason grade 3 pattern showing well-formed glands with infiltration, H&E, 100x.

Figure 7.

Gleason grade 4 pattern showing ill-defined glands in a cribriform pattern, H&E, 100x.

Figure 8.

Gleason grade 5 pattern showing single cell infiltration along with solid sheets, H&E, 40x, 100x (Inset- left) and 400x (Inset- right).

Grade Group	Gleason Score	Definition
1	6	Only individual, discrete, well-formed glands
2	3 + 4 = 7	Predominantly well-formed glands with lesser component of poorly formed/fused/cribriform/glomeruloid glands
3	4 + 3 = 7	Predominantly poorly formed/fused/cribriform/glomeruloid glands with lesser component of well-formed glands
4	4 + 4 = 8,; 3 + 5 = 8,; 5 + 3 = 8	Only poorly formed/fused/cribriform/glomeruloid glands or Predominantly well-formed glands and lesser component lacking glands or Predominantly lacking glands with lesser component of well-formed glands
5	4 + 5 = 9,; 5 + 4 = 9,; 5+ 5 = 10	Lack of gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands

Table 4.

Histologic Definition of the Grade Groups.

7.2.6 Serum prostate-specific antigen levels

PSA is secreted into the seminal fluid, where it is responsible for semen liquefaction. The release of PSA into the bloodstream enables the detection in serum. Serum PSA levels correlate with the risk of prostate cancer in most instances. When combined with patient age, digital rectal examination findings, and additional factors such as race and family history, serum PSA can be used to assess the need for biopsy.

The established normal range is 2–4 ng/ml [79]. The use of PSA for screening is limited as its levels can be raised in BPH and prostatitis, as well as with mechanical manipulation of the prostate gland. These factors, when coupled with the biological variation of PSA concentrations, result in its low specificity and low positive predictive value.

For improving the specificity of PSA testing, several PSA derivatives are now being used. These include PSA density (the ratio of PSA to gland volume), PSA doubling time, PSA velocity (the change of PSA over time), and age- and race specific PSA reference ranges. This step has resulted in modest improvements in the specificities in some studies [80, 81]. While these studies are potentially important, the results will remain underutilized unless they are able to provide information on how to address clinically relevant questions.

7.2.7 Metastasis

Hematogenous route is the most common mode of spread. Higher grade, larger primary and increase in local stage has been associated with increased likelihood of metastasis [82].

Bone (90%): Prostate cancers show predisposition for spread to bone, mainly due to the unique microenvironment and high vascularity (seed and soil hypothesis), although it is not universal [83]. Ten percent of new cases are identified after bony metastasis, while 70–80% of all the relapsed cases post radical prostatectomy also show bony metastasis [82]. Lesions are more osteoblastic than osteolytic. Multifocal small lesions in the axial skeleton, particularly in close proximity to bone marrow, are the most common pattern. Patients present either with cord compression symptoms, or pathological fractures. The spine (lumbar vertebrae particularly), pelvis, and ribs are the most common sites of spread [82, 83].

Viscera: Lungs (45%), liver (25%), and pleura (21%) are the most common visceral organs involved, while others including peritoneum, adrenal, ureters, kidney, meninges, spleen, testis, etc., have been noted [83]. Neuroendocrine tumors have a propensity toward visceral metastasis compared to bone.

Node: Nodal metastasis is associated with high risk (10-year survival of 47–86%) and poor outcome. The location of the organ makes excision of the entire drainage network unfeasible. Most commonly, the regional pelvic nodes are involved, followed by paraaotic and mediastinal nodes [2].

7.2.8 Prognostic factors

Prostate cancer has one of the best survival rates, with a 5-year rate of 97% in the United States [87]. Survival time will be determined by multiple factors. Metastatic foci act as a sign of poor prognosis [82]. Others include:

Age: With advancing age (especially more than 65 years), tumors present at a higher stage and also have an increased risk of post-procedural complications [85].

Tumor volume: A study by McNeal et al. [85] correlated increased tumor burden (critical volume 12 cc) with a higher degree of node positivity, capsular breach, loss of differentiation, positive margins, and a higher risk of metastasis [85].

Zone of involvement: According to McNeal’s Zones, cancers arising from the transitional zone have more favorable pathological features than those arising from the peripheral zone [85].

Heterogeneity and multicentricity: Multifocality is associated with a higher grade, stage, and recurrence compared to unifocal prostate cancer [85].

Grading: Gleason grade still is the strongest clinical predictor for cancer progression. A grade more than 7 is associated with higher risk of extra-prostatic extension, recurrence post-therapy, and mortality [85, 86].

PSA: Baseline and rapid rise of PSA levels have been well included in the risk estimations for the survivability of prostate cancer outcomes as well as for follow-up of patients post-therapy. High level of PSA has been a good screening tool to further evaluate patients for cancer. Rapid rise in post-therapy levels is a strong predictor for poor outcome [86].

Perineural invasion (PNI): PNI has been the major mechanism of extra-capsular extension by cancer cells in prostate. However, the amount of prognostic influence is debated upon (Figure 9) [86].

Figure 9.

PNI, H&E, 400x.

PIN: PIN has also been under conflicting reports regarding its influence in prognosis. A low-grade PIN is not reported. A high-grade PIN, in absence of carcinoma, may have an increased risk of detecting malignancy, however, in its presence, may not have any prognostic relevance [84].

Intraductal carcinoma: It is an independent prognostic risk factor for survival and is associated with high Gleason’s Grade, larger tumor burden, and increased risk of metastasis [84].

Extra-prostatic extension: It has an independent poor prognostic outcome resulting in a higher progression rate and decreased survival [84].

Positive margins: It is one of the most significant prognostic factors after grading of the tumor. A positive margin has been associated with biochemical recurrence of the cancer. Combined with Gleason’s grade of the margin, the presence of any Grade 4/5 pattern has doubled the risk of biochemical recurrence than of Grade 3 [84].

Other biochemical prognostic factors: Low E cadherin expression, high IGF expression, p53 mutations, decreased p27 levels, high p21 levels, and high ploidy status are few of the biochemical parameters known to influence prognosis and decrease survivability of the patients. AR mutations have been a major cause of hormone therapy-resistant prostate cancer, decreasing survivability and increasing recurrence [85].

7.2.9 Mimickers of malignancy

1. Prostatic atrophy: Atrophic glands may have open lumina, crowded cells, scant cytoplasm, and an increased N:C ratio [2]. Post-atrophic hyperplasia will have an increased number of similar glands and less stroma. There can be isolated areas of increased proliferation, dilated glands surrounded by fibrosis, etc. Partial atrophy can show focal areas of crowding and disorganization with a mild increase in the N:C ratio. Gland-forming adenocarcinomas have basally situated nuclei and pale to amphophilic abundant cytoplasm, rather than scant. Basal markers are consistently negative; however, atrophy may show patchy negative in some areas. AMACR may be positive in those patchy basal-negative areas.

2. Seminal vesicles/ejaculatory duct: Edge of prostate cores may show the irregular glandular epithelium of seminal vesicle with luminal projection diverticulations and mild nuclear degenerative atypia. The presence of prominent lipofuchsin granules is an aid, although enlarged lysosomes in normal prostate glands may appear similar. Lipofuchsin-like granules are absent in cancer cells. Prostate markers are negative in seminal vesicles. The basal layer is intact in the seminal vesicle.

3. Adenosis: Adenosis, especially atypical adenomatous hyperplasia, can show numerous crowded pale staining glands, with focal conspicuous nucleoli resembling a nodule of low-grade adenocarcinoma. There is an abrupt transition from normal glands to malignant glands in carcinoma compared to the smoother transition in adenosis. Glands of adenocarcinoma are haphazardly arranged and infiltrate the stroma at right angles to each other, compared to the lobular arrangement of adenosis. Associated complexity of glands like branching, irregular shape, and papillary infolding are more features of benign disease than malignant. Basal cell markers are intact, at least focally, in adenosis.

4. Sclerosing adenosis: Small relatively localized foci of glands resembling ordinary adenosis, merging with cords and singly scattered cells with occasional conspicuous nucleoli. Hyalinized basement membrane-like component in a few glands. Prominent stromal component in sclerosing adenosis, absent in malignancy. Myoepithelial cell markers are absent in cancer.

5. Others:

1. Conditions simulating low grade (Gleason score 6): Cowper glands, radiation atypia, basal cell hyperplasia, nephrogenic adenoma, verumontanum hyperplasia, mesonephric hyperplasia.

2. Conditions simulating high grade (Gleason score 7–10): Nonspecific granulomatous prostatitis, paraganglia, clear cell cribriform hyperplasia, xanthoma, signet ring cell lymphocytes (degenerated or artifactual changes in lymphocytes).

7.3 Squamous cell carcinoma prostate

Squamous cell carcinoma prostate (SCC), accounts for less than 1% of all carcinomas of prostate [88]. The age at diagnosis ranges from 52 to 79 years [89]. The patients present with complaints of straining during micturition, weak stream, hesitancy, dysuria, infection, and bone pain due to metastases. Bony lesions in SCC, unlike prostatic adenocarcinoma, are osteolytic [90, 91, 92].

Numerous theories suggesting the neoplastic cell of origin of SCC include either basal or reserve cells of acini of prostate or transitional epithelium of urethra or ducts [93, 94]. Other theories explaining the histogenesis are: (1) adenocarcinoma cells undergoing metaplastic transformation; (2) a collision-type tumor, in which the squamous component develops from metaplastic foci following radiation or hormone therapy; and (3) a potential deviance from pluripotent stem cells with the capacity for multidirectional differentiation [95, 96, 97, 98].

Mott et al. described the first approved criterion to determine the histologic characteristics of SCC, which consisted of the following: (1) an invasive disordered growth and cellular anaplasia that clearly indicated the presence of a malignant neoplasm; (2) distinct squamous features, such as keratinization, squamous pearls, and/or multiple distinct intercellular bridges; (3) no glandular or acinar pattern; (4) no history of estrogen therapy; and (5) the absence of SCC elsewhere, especially in the bladder [88]. In order to distinguish between SCC and non-neoplastic squamous metaplasia, which might result from radiation therapy, estrogen therapy, infarct, acute or chronic prostatitis, or granulomatous prostatitis caused by Bacillus-Calmette-Guérin, these parameters are crucial [99].

There is no specific and reliable IHC marker to differentiate between well-differentiated SCC from atypical squamous metaplasia or primary prostatic SCC from metastatic squamous cell carcinoma, as highlighted by Lager et al. [100] Clinically, the serum PSA and PAP levels remain unchanged [91]. SCC is an aggressive tumor with a mean survival of 14 months. Patients present with poorly differentiated grade in 45% cases and metastasis in 32% cases [101, 102].

7.4 Adenosquamous carcinoma

Adenosquamous carcinoma (ASCC) of prostate is a very rare form of prostatic carcinoma, with an incidence of 0.03 cases per million; it is even rarer than squamous cell carcinoma of prostate [103]. Patients present with dysuria, pain in rectum or pelvis, urinary retention, infection, hematuria, or bone pain as a result of metastases.

ASCC are composed of both glandular and squamous components with the squamous component accounting for an average of 40% tumor [5–95%] [104]. In a study conducted by Jue et al., it was seen that the majority of the patients with ASCC had poor or undifferentiated histology. The histogenesis of ASCC of the prostate can be understood by a number of theories: (i) adenocarcinoma cells undergoing metaplastic transformation; (ii) collision-type tumor; (iii) Pluripotent stem cells with the ability to differentiate in several directions represent the source of ASCC; (iv) Clonal evolution or divergence of persistent cancer, related to the selective pressure of therapy, would be a more likely explanation for ASCC occurring after radiation or androgen deprivation therapy [96, 105, 106, 107, 108, 109]. Glandular cells are positive for PSA, PAP, low molecular weight keratin (LMWK), and negative for high molecular weight keratin (HMWK), while the squamous component show positive staining HMWK and negative for LMWK, PAP, and PSA [96]. The molecular mechanism of this neoplasm is poorly understood. DNA analysis of ASCC has shown that the adenocarcinoma component was diploid and the squamous component was aneuploid and tetraploid [107]. The disease typically spreads by metastases, most commonly to lymph nodes and bones. The prognosis is dismal, with the expected median survival time to be only 12–14 months.

7.5 Adenoid cystic carcinoma prostate

Also known as basaloid carcinoma or adenoid cystic-like tumor, adenoid cystic carcinoma prostate (ACC) of prostate is a rare yet unique variant (incidence: 0.01%) that shares similar histomorphology to its salivary gland counterpart. They have insidious onset with recurrent and metastatic potential, as shown by few studies. The patients complain of obstructive symptoms or hematuria [110, 111]. The age bracket extends from 28 to 97 years and a peak between 60 and 75 years. Serum analysis yields a near normal serum PSA level. Patients in whom serum PSA level was raised were invariably found to have foci of prostatic adenocarcinoma. These findings suggest the difference in cell of origin of ACC, which are the non-secretory basal cells, and the importance of histomorphological and immunohistochemical staining in the diagnosis of these cases [113].

ACC can be divided histologically into basaloid type or adenoid cystic type. The basaloid variant shows irregular, variably sized solid nests, cords, and trabeculae exhibiting peripheral palisading of basaloid cells, with individual cells showing pleomorphism, a high N:C ratio, an irregular nucleus, and infiltration of adjacent structures. There is minimal or absent cribriform arrangement in these types of lesions [113]. The adenoid cystic variant is identified by prominent cribriform architecture, hyalinized, eosinophilic, or mucinous stroma with mucoid secretion in the lumen [112].

7.6 Mesenchymal tumors of prostate

Leiomyoma is the most common benign mesenchymal tumor of prostate. However, it lacks the well-organized fascicles and does not show degenerative features such as hyalinization, necrosis, or calcification [114].

Sarcomas of prostate are classified as prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (PSS) based on degree of stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. They typically present with lower urinary tract obstruction and less commonly with a palpable mass, hematuria, hematospermia, or rectal fullness. They typically occur in the transition and peripheral zones of the prostate. The median age of presentation of STUMP is 57.5 years, which is slightly older than that of PSS, which is 51.5 years [115].

STUMP has five histological patterns: (1) hypercellular atypical stromal cells with a degenerative appearance, (2) hypercellular bland fusiform stromal cells, (3) phyllodes pattern, (4) myxoid stroma containing bland stromal cells, (5) epithelioid stromal pattern. It is positive for vimentin and PR, variably positive for CD34, SMA, and desmin, and uncommonly expresses ER. KIT, S100, and STAT6 are negative. It can be differentiated from Florid BPH by an extensive growth of atypical stromal cells and an absence of nodularity and thick-walled vessels [115].

PSS is rare, accounting for <1% of prostatic cancers. It may be circumscribed or may infiltrate surrounding benign prostate glands. It shows diffuse stromal growth in storiform, epithelioid, fibrosarcomatous, or leaf-like patterns or can be patternless also. It often presents with diffuse stromal hypercellularity, cytological atypia, increased or atypical mitosis, and necrosis. It is positive for vimentin and variably positive for CD34, while usually negative for SMA and desmin and uncommonly expresses ER and PR. Epithelial markers like pancytokeratin are rarely positive. It has the potential to act aggressively and can metastasize to distant sites such as bone and lung [115].

8. Conclusion

Prostatic parenchyma is known to show a variety of non-neoplastic and neoplastic pathologies. Being a retroperitoneal organ, a limited prostatic specimen is acquired via various guided methods or via complete organ excision. Much of the benign pathologies like BPH and prostatitis are well managed conservatively and have a good prognosis. Carcinomas of the prostate are the most common type of primary prostatic malignancy, with specific precursor lesions such as PIN. Recent advancements in molecular profiling have shed light on the genomic instability that drives prostatic adenocarcinoma. Key alterations, particularly in the androgen receptor gene, play a critical role in the transition to castration-resistant prostate cancer. The identification of TMPRSS2-ERG gene fusions and other molecular markers has significantly enhanced our understanding of tumor behavior, paving the way for personalized therapeutic strategies.