Male Genitourinary System





Prostate Gland


Acute and Chronic Prostatitis


Clinical Features


Clinical classification of acute and chronic prostatitis




  • Acute bacterial prostatitis



  • Chronic bacterial prostatitis



  • Chronic abacterial prostatitis



  • Prostate is swollen and tender on palpation



  • Often refractory to antibiotic therapy because the prostate is a “safe haven” for bacteria



  • Patients may present with recurrent urinary tract infections



  • Cultured organisms are the same as those seen in urinary tract infections (i.e., Escherichia coli , other gram-negative rods, and Enterococcus and Staphylococcus species)



  • Same as acute prostatitis, but symptoms are of longer duration



  • Most common form of clinical prostatitis



  • Presents similar to acute and chronic bacterial prostatitis



  • By definition, no organisms are cultured (idiopathic); however, infection by Chlamydia, Ureaplasma , or Mycoplasma species has been suggested



  • Nonspecific (idiopathic) granulomatous type



  • Patients are between 20 and 70 years of age (mean age, 60 years)



  • Patients present with obstructive symptoms, dysuria, fever, and chills; may have a history of urinary tract infection



  • Prostate on palpitation can be firm and indurated (may clinically mimic carcinoma)



  • After bacillus Calmette-Guérin (BCG) therapy: history of intracystic BCG therapy for transitional cell carcinoma (TCC) may be remote ( Figure 11.1B )




    Figure 11.1


    A, Chronic, focally acute prostatitis. Note the presence of reactive atypicality of the acinar epithelium in the form of conspicuous nucleoli. B, Iatrogenic granulomatous prostatitis. Noncaseating epithelioid granulomas and associated lymphocytic infiltrate in a patient receiving bacillus Calmette-Guérin therapy for urothelial cancer. C, Iatrogenic granulomatous prostatitis. Low-power view of palisading histiocytes after transurethral resection. Note the atrophic-appearing prostatic gland (top left) .



  • Post-transurethral or postbiopsy granulomatous type: history of procedure up to 5 years ago



  • Infectious granulomatous type: history of infection by any one of the following




    • Bacteria (tuberculosis, syphilis, or brucella)



    • Fungi (cryptococcosis, blastomycosis, or coccidioidomycosis)



    • Viruses (herpes)



    • Parasites (schistosomiasis, echinococcosis)




  • Primarily affects men older than 50 years



  • Symptoms include fever, frequency, dysuria, and hematuria



  • Urine culture is often positive for E. coli



Gross Pathology





  • Acute and chronic bacterial and chronic abacterial prostatitis




    • Prostatic enlargement; may be soft and swollen




  • Granulomatous prostatitis




    • Enlarged with firm, nodular parenchyma



    • Areas of infarction and necrosis with infectious granulomas are often seen




Histopathology





  • Acute and chronic bacterial prostatitis




    • Prominent neutrophilic infiltrate with abscess formation



    • Neutrophils and necrotic debris may fill prostatic ducts and acini



    • Reactive glandular epithelium showing mild cytologic atypia; nuclei with prominent nucleoli may be seen ( Figure 11.1A )



    • Glands may appear atrophic and have a pseudocribriform architecture owing to little glands budding off within lumen



    • Stroma is edematous and hyperemic




  • Chronic abacterial prostatitis




    • Presence of neutrophils and lymphocytes in prostatic ducts and epithelium



    • Reactive glandular epithelium showing mild cytologic atypia; nuclei with prominent nucleoli may be seen



    • May be associated with glandular atrophy




  • Granulomatous prostatitis



  • Nonspecific (idiopathic) granulomatous type




    • Admixture of histiocytes, plasma cells, eosinophils, neutrophils, lymphocytes, and giant cells



    • Cells arranged in sheets around ruptured ducts and acini




  • Post-BCG therapy




    • Mostly histiocytes and giant cells associated with ducts or acini ( Figure 11.1B )




  • Posttransurethral or postbiopsy granulomatous type




    • Central zone of fibrinoid necrosis surrounded by palisading histiocytes and some multinucleated giant cells ( Figure 11.1C )



    • Minimal chronic inflammatory infiltrate



    • Eosinophilic infiltrate typically presents after recent prostate surgery (1 month after resection)




  • Infectious granulomatous type




    • Granulomatous inflammation, with or without necrosis



    • Eosinophils often present with parasitic infection




  • Malakoplakia




    • Hansemann cells: histiocytes with clear or eosinophilic cytoplasm arranged in sheets with surrounding mixed chronic inflammatory infiltrate



    • Michaelis-Gutmann bodies: round, target-shaped structures found intracellularly and extracellularly




Special Stains and Immunohistochemistry





  • Granulomatous prostatitis




    • Nonspecific granulomatous type




      • Stains positively for histiocytic markers, negative for epithelial markers




    • Infectious granulomatous type




      • May identify causative organism with special stains (Gomori methenamine silver, periodic acid-Schiff [PAS], acid-fast bacillus stains)




    • Malakoplakia




      • Von Kossa calcium, iron, and PAS highlight Michaelis-Gutmann bodies





Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Non-Hodgkin Lymphoma





  • Rare in the prostate gland



  • Proliferation of neoplastic lymphoid cells that typically infiltrate the prostatic stroma in diffuse sheets while sparing the ducts and acini



  • Infiltration into surrounding periprostatic tissues is common



  • Monoclonal lymphoid population seen with flow cytometry and immunohistochemistry



  • Most common tumor subtype is diffuse large cell lymphoma, B-cell type



Poorly Differentiated Adenocarcinoma (Gleason Grades 8 to 10)





  • Infiltrating tumor composed of a diffuse and focally glandular proliferation



  • Malignant cells have pleomorphic nuclei and prominent nucleoli



  • Neoplastic glands lack basal cell layer (negative high-molecular-weight cytokeratin [HMWCK] staining)



  • Inflammatory cell infiltrate is unusual in adenocarcinoma



Sarcoidosis





  • Patients typically have evidence of systemic disease; rare to have isolated prostate involvement



  • Characterized by noncaseating granulomas composed of epithelioid histiocytes and giant cells



  • Special stains for organisms are negative



Pearls





  • Preferable to diagnose inflamed prostate specimens as having acute or chronic inflammation than as acute or chronic prostatitis (i.e., the latter are clinical diagnoses)



  • Biopsy is not required because most prostatitis cases are effectively treated with antibiotics



  • Patients with chronic prostatitis often have frequent recurrences, and histology correlates poorly with clinical findings (e.g., stromal and periglandular mononuclear cell infiltrates are normal in older men)



  • All forms of prostatic disease may cause mild elevation of prostate-specific antigen (PSA)





Selected Reference




  • Ho D.R.: Prostate inflammation: a brief review. Urol Sci 2017; 28: pp. 113-118.


Infarction


Clinical Features





  • Patients may be asymptomatic or present with urinary retention and hematuria



  • Typically occurs in a background of nodular hyperplasia



Gross Pathology





  • In general, the greater the degree of nodular hyperplasia, the greater the likelihood of infarction



  • Central pale-yellow zone surrounded by hyperemic tissue



Histopathology





  • Acute infarction




    • Central coagulative necrosis with surrounding hemorrhage ( Figure 11.2 )




      Figure 11.2


      Prostatic infarct.

      Coagulative necrosis with hemorrhage (right) and early squamous metaplasia of prostatic glandular epithelium (left) .



    • Adjacent glands show reactive and metaplastic changes; typically squamous metaplasia



    • Reactive glandular epithelium is characterized by cells with enlarged nuclei, prominent nucleoli, and mitotic figures




  • Remote infarction




    • Central fibrous scar with hemosiderin admixed with small glands often showing squamous metaplasia




Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Squamous Cell Carcinoma





  • Rare in the prostate gland



  • Infiltrative architecture composed of irregular nests or cords of malignant cells with squamous differentiation; areas of keratinization often seen



  • Will typically have prominent desmoplastic changes in the surrounding stroma



Prostatic Adenocarcinoma, Low Grade





  • Low-power magnification reveals uniform proliferation of small glands with irregular contours and irregular stromal spacing



  • Neoplastic glands are lined by a single layer of epithelium (basal cell layer is absent)



  • Higher-power magnification demonstrates cuboidal or columnar cells with abundant cytoplasm, enlarged nuclei, and prominent nucleoli



  • Perineural infiltration is often present



Pearls





  • Commonly seen at autopsy in men with marked hypotension who had a urethral catheter in place





Selected Reference




  • Bostwick D.: Non-neoplastic diseases of the prostate.Cheng L.MacLennan G.T.Bostwick D.G.Urologic Surgical Pathology.2020.Elsevier, IncPhiladelphia:pp. 358-414.


Hyperplasia


Clinical Features





  • Common in males after 60 years of age



  • Patients may have symptoms of urinary obstruction (inability to initiate or terminate urinary flow) or may be asymptomatic



Gross Pathology


Benign (Nodular) Prostatic Hyperplasia





  • Multilobulated surface



  • Variably sized nodules typically located around the prostatic urethra



  • Peripheral zone appears compressed and atrophic



  • Small foci of infarction may be seen



Histopathology


Benign (Nodular) Prostatic Hyperplasia





  • Well-circumscribed, nonencapsulated nodules



  • Composed of hyperplastic epithelial and stromal components ( Figure 11.3A )




    • Epithelial component




      • Large, irregularly shaped glands



      • Glands with a double cell layer and some with pseudostratification of secretory cells



      • Columnar cells with pale-staining granular cytoplasm



      • Papillae with fibrovascular cores



      • Chronic inflammatory infiltrate that surrounds glands




    • Stromal component




      • Composed of fibroblasts and smooth muscle cells





    Figure 11.3


    A, Benign (nodular) prostatic hyperplasia. Low-power view of a gland-rich hyperplastic nodule. Other nodules (not shown) may be stroma rich. B, Basal cell hyperplasia (BCH). Subluminal cell proliferation of basal cells characterized by elongated nuclei, longitudinal nuclear grooves, conspicuous nucleoli, and amphophilic cytoplasm. BCH showing enlarged nucleoli (atypical BCH) should not be confused with high-grade prostatic intraepithelial neoplasia.



Basal Cell Proliferations





  • Basal cell hyperplasia (BCH)




    • Typically an incidental finding



    • Forms well-defined, small solid nests of basal cells or glandular structures; may have an infiltrative architecture



    • Hyperplastic glands with proliferation of uniform basaloid cells that may occlude the glandular lumens ( Figure 11.3B )



    • Glands showing peripheral nuclear palisading



    • Hypercellular, fibroblastic stroma



    • Often seen together with typical benign (nodular) prostatic hyperplasia




  • BCH with nucleolomegaly (“atypical BCH”)




    • Architecture is similar to that of BCH



    • Differentiating feature is basaloid cells with prominent nucleoli




Clear Cell Cribriform Hyperplasia





  • Almost always associated with benign (nodular) hyperplasia



  • Characterized by acini distended by a proliferation of cells with clear cytoplasm forming uniform round spaces



  • Cells are cuboidal to columnar and have small hyperchromatic nuclei, indistinct nucleoli, and clear cytoplasm



  • Basal cell layer is intact



Sclerosing Adenosis





  • Lobular or focally infiltrative glandular proliferation



  • Glands may be round or compressed and have an angulated, slitlike appearance



  • Glands have a double cell layer (may be difficult to appreciate) and a thickened basement membrane



  • Cells contain medium-to-large nuclei with fine chromatin and typically indistinct nucleoli



  • Stromal component contains plump spindle cells arranged randomly or in fascicles



Adenosis/Atypical Adenomatous Hyperplasia





  • Architecturally similar to Gleason grade 1 or 2 adenocarcinoma



  • Circumscribed proliferation of variably sized acini that may show focal infiltration at the periphery



  • Tightly packed small glands intermixed with larger glands



  • Basal cell layer may be discontinuous and indistinct but is usually focally present in at least some glands



  • Glandular cells typically have pale to clear cytoplasm, small nuclei, and inconspicuous nucleoli; prominent nucleoli may occasionally be seen; however, macronucleoli (>3 μm) should not be present



  • Corpora amylacea is often present (much less common in adenocarcinoma)



Special Stains and Immunohistochemistry





  • HMWCK: highlights basal cell layer in benign (nodular) prostatic hyperplasia, BCH, clear cell cribriform hyperplasia, and sclerosing adenosis



  • (MSA) and S-100 protein positive in some basal and spindle cells in sclerosing adenosis (indicates myoepithelial differentiation)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Prostatic Intraepithelial Neoplasia





  • Glands are large and branched with intraluminal papillary projections



  • Nuclei are elongated, pseudostratified, and perpendicular to the basement membrane



Prostatic Adenocarcinoma, Low Grade





  • Low-power microscopy reveals uniform proliferation of small glands with irregular contours and irregular stromal spacing



  • Neoplastic glands are lined by a single layer of epithelium (basal cell layer is absent)



  • Higher-power microscopy demonstrates cuboidal or columnar cells with abundant cytoplasm, enlarged nuclei, and prominent nucleoli



Clear Cell Cribriform Hyperplasia versus Cribriform Adenocarcinoma





  • Cells in clear cell cribriform hyperplasia have distinct clear cytoplasm, small nuclei with indistinct nucleoli, and a prominent basal cell layer



Pearls





  • Treatment for persistent, symptomatic hyperplasia is often transurethral resection; occasionally treated with suprapubic prostatectomy



  • May be treated with various drugs, including




    • Finasteride (androgen-converting enzyme inhibitor)



    • α 1 -Adrenergic blockers




  • Medically treated benign (nodular) prostatic hyperplasia often shows stromal and glandular involution with luminal cell dropout and BCH





Selected Reference




  • Trpkov K.: Benign mimics of prostate cancer. Mod Pathol 2018; 31: pp. 22-46.


Epithelial Metaplasia


Clinical Features


Urothelial and Transitional Cell Metaplasia





  • Describes a condition in which transitional epithelium is within the prostatic ducts and acini



  • Often seen in infants and neonates



  • Generally no clinical symptoms



Squamous Metaplasia





  • May be associated with infarction, estrogen therapy, androgen ablation, or radiation therapy



  • Common in neonates



  • Generally no clinical symptoms



Gross Pathology





  • Nonspecific



Histopathology


Urothelial and Transitional Cell Metaplasia





  • Localized to peripheral prostatic ducts and acini



  • Urothelium admixed with alternating areas of cuboidal and columnar epithelium



  • Cells are spindle to ovoid to polygonal and have ovoid nuclei overlapping in a streaming manner; nuclei are uniform and have prominent nuclear grooves



  • May completely fill gland lumen forming a solid nest



  • Differs from normal urothelium by lack of umbrella cells and presence of eosinophilic secretory lining cells



Squamous Metaplasia





  • Squamous differentiation (polygonal cells with eosinophilic cytoplasm) with variable keratin formation and intercellular bridging



  • May be associated with infarcts and nodular prostatic hyperplasia; if associated with prostatic infarction, mild nuclear atypia may be seen



Mucinous Metaplasia





  • Haphazardly scattered or small groups of tall, mucin-filled goblet cells



  • Cells have small, dark, basally oriented nuclei and abundant mucin-filled cytoplasm



  • Can be found in association with normal and hyperplastic prostate glands, as well as in areas of urothelial metaplasia, BCH, or atrophy



Special Stains and Immunohistochemistry





  • HMWCK positive in urothelial and transitional cells and squamous metaplasia



  • Alcian blue and mucicarmine positive for intracytoplasmic acid mucin in mucinous metaplasia



  • PAS positive for neutral mucin in mucinous metaplasia (diastase resistant)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Transitional Cell Carcinoma





  • Carcinoma in situ (intraductal TCC) is typically present adjacent to the invasive component



  • Infiltrative component consists of single or small groups of cells showing hyperchromatic, pleomorphic nuclei with chromatin clumping, multiple nucleoli, and angulated nuclear borders



  • Mitotic figures and tumor necrosis are common



  • Desmoplasia is typically associated with the invasive stromal component



Squamous and Adenosquamous Cell Carcinoma





  • Rare in prostate gland



  • Infiltrative growth pattern composed of malignant cells with squamous features (keratin formation and intercellular bridging)



  • Must exclude secondary involvement from extraprostatic sites (e.g., urinary bladder)



  • Adenosquamous carcinoma composed of typical squamous cell carcinoma admixed with adenocarcinoma (patients usually have a history of radiation or hormonal therapy)



Mucinous Adenocarcinoma





  • At least 25% of tumor consists of extracellular mucin lakes



  • Neoplastic cells and glands float within lakes of extracellular mucin



  • Cribriform pattern is most common, with mucin within the gland lumina and dissecting between the stroma



  • Neoplastic cells have variable degree of cytologic atypia



Pearls





  • None of the metaplastic cell types are associated with subsequent development of prostatic adenocarcinoma





Selected Reference




  • Evans A.J.: Treatment effects in prostate cancer. Mod Pathol 2018; 31: pp. 110-121.


Prostatic Intraepithelial Neoplasia


Clinical Features





  • High-grade prostatic intraepithelial neoplasia (PIN) is considered to be a premalignant condition based on morphologic, epidemiologic, and genetic features



  • In autopsy series, high-grade PIN precedes carcinoma by 10 years and is common in the fourth decade of life



  • Currently, high-grade PIN is associated with adenocarcinoma on rebiopsy in 25% of patients, significantly less than the 50% association reported in patients biopsied in the late 1980s (see “Pearls”)



  • Presence of high-grade PIN mandates rebiopsy; however, it is unclear that chasing PIN has any benefit (i.e., it simply results in the detection of clinically insignificant prostate cancers)



  • Clinical significance of low-grade PIN is unclear; should not be diagnosed



Gross Pathology





  • Nonspecific



Histopathology





  • Low-grade PIN




    • Morphologic features not rigorously defined and subjective; should not be diagnosed




  • High-grade PIN




    • Four patterns include tufted, cribriform, micropapillary, or flat



    • Cells have enlarged nuclei with prominent nucleoli ( Figure 11.4 )




      Figure 11.4


      Prostatic intraepithelial neoplasia, high grade, flat type. Back-to-back glands lined by a single layer of epithelial cells with prominent nucleoli. Note the presence of attenuated basal cells ( inset ; high-molecular-weight cytokeratin immunohistochemical stain).



    • Basal cells are present but may be attenuated




Special Stains and Immunohistochemistry





  • HMWCK and p63: basal cell layer is immunopositive but may be thin and attenuated



  • α-Methylacyl coenzyme A racemase (AMACR): high-grade PIN may be positive but more apical and granular and less intense than carcinoma



Other Techniques for Diagnosis





  • Morphometric studies: high-grade PIN and adenocarcinoma have similar cytologic features (i.e., nuclear area, nuclear perimeter size, nuclear shape, amount and distribution of chromatin, and nucleolar changes)



Differential Diagnosis


Prostatic Adenocarcinoma, Low Grade





  • Low-power magnification reveals a uniform compact proliferation of small glands with irregular contours and irregular stromal spacing



  • Neoplastic glands are lined by a single layer of epithelium (basal cell layer is absent)



  • Higher magnification demonstrates cuboidal or columnar cells with abundant cytoplasm, enlarged nuclei, and prominent nucleoli



  • Perineural infiltration is often present



  • Negative staining for HMWCK (no basal cell layer)



Pearls





  • The decreasing association between high-grade PIN and carcinoma is due to the following:




    • Increased number of cores performed per biopsy procedure with better targeting of peripheral zone



    • Changing patient population (younger, PSA screened) with lower prevalence or lower volume of adenocarcinoma; Bayesian reasoning dictates that the positive predictive value of any test result (high-grade PIN on biopsy) is a function of the prevalence of disease (carcinoma) in the population being tested




  • Diagnosis of high-grade PIN should be made conservatively (cells must show both nucleomegaly and nucleolomegaly)





Selected References




  • Dickinson S.I.: Premalignant and malignant prostate lesions: pathologic review. Cancer Control 2010; 17: pp. 214-222.



  • Iczkowski K.A.: Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med 2006; 130: pp. 835-843.



  • Zynger D.L., Yang X.: High-grade prostatic intraepithelial neoplasia of the prostate: the precursor lesion of prostate cancer. Int J Clin Exp Pathol 2009; 2: pp. 327-338.


Adenocarcinoma: Acinar (Conventional) And Distinct Subtypes (Microcystic, Pleomorphic Giant Cell, Colloid [Mucinous], Signet Ring Cell, Foamy Gland, Sarcomatoid Carcinoma, Atrophic Type, Pseudohyperplastic)


Clinical Features





  • Most common cause of cancer in men; second most common cause of cancer death after lung cancer



  • One in five American men will be diagnosed with prostate cancer



  • Occurs predominantly in men older than 50 years



  • More prevalent in black men and rare in Asians



  • Familial predisposition exists



  • Because of the typical location of prostatic carcinoma (posterior aspects of the peripheral zone), urinary symptoms occur late; asymptomatic tumors are often detected by digital rectal examination or after routine examination that detects elevated PSA



  • Advanced disease may cause obstructive symptoms (difficulty initiating or terminating urination, frequency, or dysuria)



  • Metastases to bone may cause osteoblastic or osteolytic lesions; however, in men, the demonstration of osteoblastic bone metastases is virtually diagnostic of metastatic prostate carcinoma



  • Back pain is a common finding in patients with metastatic disease



  • Screening methods




    • Digital rectal examination: cancer focus may be nonpalpable or indurated



    • PSA levels greater than 4 ng/mL (some advocate 2 ng/mL) prompt biopsy



    • Random bilateral biopsies now standard of care in select patients with nonpalpable disease



    • Transrectal ultrasound with biopsy




  • Elevated PSA is not sensitive or specific for prostatic cancer; other benign conditions, including inflammatory processes or nodular hyperplasia, may cause slight PSA elevation



  • PSA levels do not distinguish between significant and insignificant cancers; identification of such biomarkers (e.g., EPCA-2, PCAs, TMPRSS2-ERG) is an active area of research



  • Elevated PSA in patients after treatment for prostatic carcinoma is a useful indicator of recurrent or progressive disease



Sarcomatoid Carcinoma





  • Associated with a previous or current high-grade prostatic adenocarcinoma



  • May have a history of radiation therapy for prior adenocarcinoma of prostate



  • Serum PSA may be normal or only slightly elevated



  • Carcinosarcoma and sarcomatoid carcinoma are often used interchangeably; however, by convention




    • Carcinosarcoma should be reserved for tumors that have distinct carcinomatous and sarcomatous elements by histology and immunohistochemistry



    • Sarcomatoid carcinoma should be used for tumors that show a transition between the two elements




Gross Pathology


Acinar (Conventional) Adenocarcinoma





  • Often multifocal



  • Preference for the posterior aspects of the peripheral zone (about 75% of tumors); this location renders tumor more likely to be palpable on digital rectal examination



  • Small tumors typically show no gross abnormalities



  • Neoplastic tissue is firm, gritty, and less spongy than the surrounding non-neoplastic prostate parenchyma; may show focal yellow discoloration



Colloid (Mucinous) Adenocarcinoma





  • Cut surface may be glistening or mucinous



Histopathology ( Figure 11.5 )


Acinar (Conventional) Adenocarcinoma





  • Constitutes more than 95% of prostate cancer



  • Low-power magnification




    • Majority show haphazard proliferation of fairly uniform acini infiltrating between benign elements



    • Occasionally the acini are intermediate-sized (“microcystic”) or dilated and filled with complex, branching epithelial cells (“pseudohyperplastic”)



    • High-grade tumors tend to grow in cords, nests, or sheets;



    • See Gleason grading system ( Figure 11.6 )




      Figure 11.6


      The Gleason grading system has evolved (see above) and continues to evolve with ongoing debate over nuances. The system remains primarily based on architecture with tumors able to form glands (well differentiated) and tumors unable to form glands (poorly differentiated) at the low and high ends of the Gleason grade spectrum, respectively. A, Original Gleason. B, International Society of Urological Pathology (ISUP) 2005 Gleason. C, ISUP 2014 Gleason.

      A from Gleason DF. Histologic grading of prostate cancer: a perspective. Hum Pathol . 1992;23:273–279, with permission from Elsevier. B and C from Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol . 2016;40[2]:244–252.




  • High-power magnification




    • Acini are lined by a single layer of epithelial cells; basal cell layer is absent



    • Epithelial cells are cuboidal or columnar and have abundant amphophilic cytoplasm and enlarged, variably pleomorphic nuclei with one or more prominent macronucleoli



    • Mitotic figures are a helpful feature of malignancy but are uncommon, especially in low-grade tumors



    • Features pathognomonic for carcinoma include glomeruloid structures, mucinous fibroplasias (collagenous micronodules), circumferential perineural invasion, and extraprostatic extension



    • Blue-tinged mucinous material, amorphous eosinophilic material, and crystalloid within lumina of neoplastic glands (less common in benign glands) may be seen




  • Corpora amylacea is rare (much more common in benign conditions)




Figure 11.5


A, Prostatic adenocarcinoma on needle core. Gleason score 3 + 2: pattern 3 based on variability in the size of the acini, and pattern 2 based on good circumscription. B, Histopathologic findings pathognomonic for prostatic adenocarcinoma. Circumferential perineural invasion (top left) , extraprostatic invasion (top right) , glomeruloid bodies (bottom left) , and mucinous fibroplasia and collagenolysis (bottom right) . C, Variants of prostatic adenocarcinoma. Ductal type showing tall columnar cells with marked nucleomegaly and nucleolomegaly (top left) , neuroendocrine carcinoma in a patient with a history of treated acinar-type adenocarcinoma (top right) , signet ring cell type with individual cells diffusely infiltrating (bottom left) , and mucinous type with intraluminal and interstitial mucin (bottom right) .




Colloid (Mucinous) Adenocarcinoma





  • Uncommon variant



  • At least 25% of tumor consists of extracellular mucin lakes



  • Neoplastic cells and glands float within lakes of extracellular mucin



  • Cribriform pattern is most common, with mucin within the gland lumina and dissecting between stromal muscle fibers



  • Neoplastic cells have variable degrees of cytologic atypia



  • Typically associated with an acinar-type adenocarcinoma



  • Considered Gleason grade 4 and is associated with aggressive biologic behavior



Signet Ring Cell Adenocarcinoma





  • At least 25% of tumor consists of cells with a cytoplasmic vacuole that displaces the nucleus to the side



  • Cells diffusely infiltrate the stroma and invade perineural and vascular spaces as well as the prostatic capsule



  • Other patterns of prostatic adenocarcinoma in the same tumor are typically seen



Foamy Gland Adenocarcinoma





  • Histologically characterized by cells with abundant foamy cytoplasm and bland nuclei



  • May be underdiagnosed on needle core because of lack of nucleomegaly and nucleolomegaly



  • Usually associated with higher-Gleason-score acinar-type adenocarcinoma; therefore, prognostic significance per se unclear



Pseudohyperplastic Adenocarcinoma





  • Two patterns on low-power microscopy




    • Crowded glands lined by pseudostratified epithelium (truly pseudohyperplastic)



    • Large acini




  • High-power microscopy shows nucleomegaly and nucleolomegaly



  • May be underdiagnosed on needle core biopsy because the pseudostratified epithelium looks like hyperplasia or high-grade PIN on low-power microscopy and the large acinar pattern deviates from the more typical small acinar pattern



Sarcomatoid Carcinoma





  • Biphasic tumor: admixture of carcinoma and sarcoma components



  • Sarcoma component consists of spindle cells with pleomorphic nuclei and high mitotic rate



  • Common sarcoma patterns




    • High-grade sarcoma (not otherwise specified), fibrosarcoma, leiomyosarcoma, osteosarcoma, rhabdomyosarcoma, chondrosarcoma




  • Should not be confused with the very rare carcinoma that shows giant, pleomorphic cells (“pleomorphic giant cell adenocarcinoma”)



  • Carcinoma component is usually high grade



Atrophic-Type Adenocarcinoma





  • Glandular proliferation with an infiltrative growth pattern



  • Neoplastic cells have large nuclei with prominent nucleoli



  • Glands lack a basal cell layer



  • Generally associated with an adjacent acinar adenocarcinoma



Treated Adenocarcinoma





  • Androgen deprivation therapy




    • Smaller acini or single cells with loss of nucleolomegaly and cytoplasmic clearing (special stains may be required); residual carcinoma showing treatment effect should not be Gleason graded



    • Adjacent benign tissue shows stromal hyperplasia and gland involution with BCH and squamous metaplasia




  • Radiation therapy




    • Smaller acini or single cells with cytoplasmic vacuolization (special stains may be required); residual carcinoma showing treatment effect should not be Gleason graded



    • Adjacent benign tissue shows glandular atrophy, nucleomegaly, nucleolomegaly, and BCH




Special Stains and Immunohistochemistry





  • AMACR




    • Sensitive and specific marker for conventional (acinar) prostate cancer; positive in 82% to 100% of cases



    • Less sensitive in low-grade and hormone-treated conventional prostate cancer and prostate cancer variants, such as foamy gland, pseudohyperplastic, atrophic-type, and ductal-type prostate cancers



    • Positive but less intense, noncircumferential or only focal in high-grade PIN, atypical adenomatous hyperplasia, atrophy, nephrogenic adenoma, and benign glands adjacent to cancer



    • AMACR is less useful in evaluating metastases because many tumors in other organs are immunopositive




  • HMWCK and p63




    • Stains basal cell cytoplasm (HMWCK) and nuclei (p63); therefore, negative in adenocarcinoma because basal cells are absent




  • PSA and prostatic acid phosphatase (PAP) positive for tumor cells of mucinous, signet ring cell, and ductal-type variants of adenocarcinoma; also positive in epithelial component of sarcomatoid carcinoma



  • Carcinoembryonic antigen (CEA) positive in some ductal-type variants of carcinoma



  • Vimentin: spindle cell component of sarcomatoid carcinoma positive



  • Desmin, smooth muscle actin (SMA), and S-100 protein: variable positivity in spindle cell component of sarcomatoid carcinoma



Other Techniques for Diagnosis





  • Genetic studies of clinical relevance: Familial studies have demonstrated an 8q24 ( MYC oncogene) genetic variant that may be associated with prostate cancer risk; men with germline BRCA2 mutations have a 20-fold increased risk of prostate cancer; rearrangements of ETS family genes (most commonly ERG or ETV1 ) next to the androgen-regulated TMPRSS2 promoter has been identified as an early molecular event in the development of prostate cancer, illustrating the role of androgen stimulation in the pathogenesis of prostate cancer; testing for homologous recombination deficiency, particularly somatic or germline mutations of the homologous recombination repair genes ( BRCA1 , BRCA2 , and ATM ) predict response to poly(ADP-ribose) polymerase inhibitors in hormone refractory prostate cancer.



Differential Diagnosis


Sclerosing Adenosis





  • Lobular or focally infiltrative glandular proliferation composed of glands with a double cell layer (may be difficult to appreciate) and a thickened basement membrane



  • Cells contain medium-sized to large nuclei with fine chromatin and indistinct nucleoli



  • Stromal component contains plump spindle cells arranged randomly or in fascicles



  • Cellular spindle cell component is positive for actin and S-100 protein (indicates myoepithelial differentiation)



Atypical Adenomatous Hyperplasia (Adenosis)





  • Architecturally similar to Gleason grade 1 or 2 adenocarcinoma



  • Circumscribed proliferation of variably sized acini that may show focal infiltration at the periphery



  • Tightly packed small glands intermixed with larger glands



  • Basal cell layer may be discontinuous and indistinct but is usually focally present in at least some glands (positive staining for HMWCK)



  • Glandular cells typically have pale to clear cytoplasm, small nuclei, and inconspicuous nucleoli; distinct nucleoli may occasionally be seen; however, macronucleoli (>3 μm) should not be present



  • Corpora amylacea is often present (much less common in adenocarcinoma)



  • Often seen adjacent to unequivocal adenocarcinoma



High-Grade Prostatic Intraepithelial Neoplasia





  • Usually large acini lined by hyperplastic, pseudostratified epithelial cells with elongated, large nuclei with prominent nucleoli



  • The “flat type” of PIN may show small acini with a single cell layer



  • Basal cell markers (HMWCK or p63) often show attenuated basal cells



  • AMACR often shows granular, apical cytoplasmic positivity in contrast to more diffuse staining seen in carcinoma



Glandular Atrophy and Partial Atrophy/Postatrophic Hyperplasia





  • Atrophic glands may have a focally infiltrative architecture and thus may mimic atrophic-type adenocarcinoma



  • Atrophic glands have open lumens and are lined by cells with an increased nuclear-to-cytoplasmic ratio and inconspicuous nucleoli



  • Atrophic-type adenocarcinoma is associated with an adjacent acinar adenocarcinoma



Clear Cell Cribriform Hyperplasia versus Cribriform Adenocarcinoma





  • Cells in clear cell cribriform hyperplasia have distinct clear cytoplasm, small nuclei with indistinct nucleoli, and a prominent basal cell layer



Transitional Cell Carcinoma





  • Typically, TCC involves the urethra or prostatic ducts in patients with a history of carcinoma in situ of the urinary bladder who have been treated conservatively



  • Carcinoma in situ (intraductal TCC) is typically present adjacent to the invasive component



  • Lacks glandular differentiation



  • Mitotic figures and tumor necrosis are common



  • Stains negative for PSA and PAP



Additional Microscopic Mimics of Prostatic Adenocarcinoma:





  • BCH, Cowper’s glands, mesonephric remnant hyperplasia, mucous gland metaplasia, nephrogenic adenoma, paraganglion tissue, radiation changes, seminal vesicles/ejaculatory duct, squamous metaplasia, urothelial metaplasia, verumontanum mucosal hyperplasia, and xanthoma cells



Pearls





  • Prostatic carcinoma is typically multifocal, and gross examination usually underestimates the extent of disease



  • Tumors of the transitional zone are less aggressive than tumors of the peripheral zone



  • Metastases typically involve the pelvic or para-aortic lymph nodes and axial skeleton (most commonly lumbar vertebrae)



  • Only in recent years has a survival advantage been demonstrated with the onset of widespread PSA screening; however, this same advantage has also been observed in Europe, where PSA screening is less common



  • AMACR staining quality may be affected by technologist expertise, run-to-run variability, and the use of monoclonal (P504S) versus polyclonal antibodies, with the latter showing more background staining



  • Endocrine therapy is used to deprive tumor cells of testosterone and is typically used in patients with widespread metastatic disease (orchiectomy or estrogen administration decreases or eliminates testicular production of testosterone)



  • Cryotherapy and radiation implants are being used more frequently as alternatives to radical prostatectomy



  • In general, the presence of lymph node metastases precludes radical prostatectomy



  • Small prostatectomies should be completely submitted for histopathologic examination, but larger prostatectomies may be partially submitted as long as all of the posterior aspect, apex, and base are submitted (see Iremashvili et al., 2013); the 2018 AJCC TNM guidelines require documentation of the following:



  • Pathologic stage of primary tumor (“T”):




    • pT2: (Organ confined) Document volume (%), and laterality of tumor (one half or both sides)



    • pT3: (Extraprostatic extension) Includes complete invasion through prostatic pseudocapsule, invasion into bladder neck, and seminal vesicle invasion



    • pT4: (Invasion of surrounding structures) Includes invasion into rectum, levator muscles, or pelvic wall




  • Pathologic stage of regional lymph nodes (“N”):




    • N1: Spread to regional lymph nodes, defined as nodes in the true pelvis below the bifurcation of the common iliac arteries




  • Pathologic stage of distant metastasis (“M”):




    • M1a: Spread to lymph nodes beyond regional lymph nodes



    • M2b: Spread to bone



    • M1c: Spread to other sites (regardless of bone involvement)




  • Overall clinical stage takes into account clinical stage, pathologic stage, grade group assigned to the prostate cancer and PSA level ( Figure 11.7 )




    Figure 11.7


    Biochemical recurrence-free survival after radical prostatectomy according to grade group with definitions of each grade group in the right column. Modified from Kryvenko ON, Epstein JI. Prostate cancer grading: a decade after the 2005

    modified Gleason Grading System. Arch Pathol Lab Med . 2016:140[10]:1140–1152.





Selected References




  • Amin M.B.Edge S.Greene F. et. al.AJCC Cancer Staging Manual.2018.Springer VerlagNew York:pp. 723-734.



  • Berney D.M., Fisher G., Kattan M.W., et. al.: Pitfalls in the diagnosis of prostate cancer: retrospective review of 1791 cases with clinical outcome. Histopathology 2007; 51: pp. 452-457.



  • Delahunt B., Egevad L., Samaratunga H., et. al.: UICC drops the ball in the 8th edition TNM staging of urological cancers. Histopathology 2017; 71: pp. 5-11.



  • Kweldam C.F., van Leenders G.J., van der Kwast T.: Grading of prostate cancer: a work in progress. Arch Pathol Lab Med 2019; 74: pp. 146-160.



  • Iremashvili V., Lokeshwar S.D., Soloway M.S., et. al.: Partial sampling of radical prostatectomy specimens: detection of positive margins and extraprostatic extension. Am J Surg Pathol 2013; 37: pp. 219-225.



  • Lotan T.L., Tomlins S.A., Bismar T.A., et. al.: Report from the International Society of Urological Pathology (ISUP) consultation conference on molecular pathology of urogenital cancers. I. Molecular biomarkers in prostate cancer. Am J Surg Pathol 2020;


Ductal Adenocarcinoma


Clinical Features





  • Patients may present with obstructive symptoms and hematuria



  • Cystoscopy may show papillary proliferation distending prostatic urethra



Gross Pathology





  • Prostatic ducts and prostatic urethra may be distended by tumor



Histopathology





  • Invasive adenocarcinoma showing growth along prostatic ducts



  • Papillary and cribriform architecture composed of pseudostratified (endometrioid-like) columnar cells with elongated nuclei



  • Gleason pattern 4. Presence of comedonecrosis should be classified as Gleason pattern 5



Special Stains and Immunohistochemistry





  • Basal cell markers negative



Other Techniques





  • None



Differential Diagnosis





  • PIN




    • Glandular proliferation less complex, glands less dilated, and basal cells may be attenuated but still present




  • Acinar adenocarcinoma with cribriform architecture




    • Cuboidal (noncolumnar) cells with rounded nuclei creating rounded (nonelongated) cribriform spaces




Pearls





  • Usually associated with conventional, acinar adenocarcinoma; pure ductal adenocarcinoma very rare





Selected Reference




  • Egevad L., Epstein J.I., Hameed O., et. al.: Ductal adenocarcinoma.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 166-167.


Intraductal Carcinoma


Clinical Features





  • Nothing specific



Gross Pathology





  • Nothing specific



Histopathology





  • Noninvasive carcinoma distending acini and/or ducts



  • Architecturally may be solid, cribriform or micropapillary. Comedonecrosis may be present



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques





  • Noncontributory



Differential Diagnosis


Prostatic intraepithelial neoplasia





  • Glandular proliferation architecturally much less complex, ducts and acini much less dilated, and much less cytologic atypicality



Pearls





  • The term “intraductal” is a misnomer as the tumor may be intra-acinar



  • Does not impact upon the Gleason score





Selected References




  • Epstein J.I., Oxley J., Ro J.Y., et. al.: Intraductal adenocarcinoma.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 164-165.



  • Paner G.P., Gandhi J., Choy B., et. al.: Essential updates in grading, morphotyping, reporting, and staging of prostate carcinoma for general surgical pathologists. Arch Pathol Lab Med 2019; 143: pp. 550-564.


Adenoid Cystic/Basal Cell Carcinoma


Clinical Features





  • Serum PSA and PAP levels are typically not elevated



  • Benign and malignant basal cell lesions are relatively uncommon (reported in less than 6% to 9% of cases); benign basal cell proliferations make up most of them



Gross Pathology





  • Nonspecific



Histopathology





  • Basal cell tumors consist of a spectrum of disease ranging from BCH to atypical BCH to basal cell adenoma to basal cell carcinoma (BCC); historically, a basal cell tumor with a cribriform architecture has been referred to as an adenoid basal cell tumor or adenoid cystic carcinoma (ACC); BCC and ACC are now considered parts of a morphologic continuum



Basal Cell Carcinoma





  • Infiltrative clusters of basaloid cells



  • Often have prominent desmoplastic stromal response



  • Must demonstrate one or more of the following features: necrosis, perineural invasion, or infiltration outside prostatic capsule



Basal Cell Carcinoma with Cribriform Spaces (Adenoid Cystic Carcinoma)





  • Histologic features similar to those of ACC of the salivary glands



  • Cells form poorly circumscribed, infiltrative nodules surrounded by a loose or myxoid stroma



  • Nests show peripheral nuclear palisading around adenoid cystlike spaces that contain mucinous, eosinophilic, or hyaline material



  • Focal squamous differentiation with keratin production may be seen



  • Basaloid cells are uniform and have round hyperchromatic nuclei



  • Perineural invasion is rare



  • Low malignant potential; no reports of metastasis (believed by some authors to be part of BCH and adenoma)



Special Stains and Immunohistochemistry





  • PSA and PAP typically positive



  • HMWK: focal weak positivity in basaloid cells



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Basal Cell Hyperplasia





  • Often see other findings of androgen blockade including stromal and glandular involution and squamous metaplasia



  • Lacks cytologic atypicality, infiltrative growth and desmoplasia seen in adenoid cystic/BCC



Sclerosing Adenosis





  • Lobular or focally infiltrative proliferation composed of glands with a double cell layer (may be difficult to appreciate) and a thickened basement membrane



  • Cells contain medium-sized to large nuclei with fine chromatin and indistinct nucleoli



  • Cellular spindle cell stroma with evidence of myoepithelial differentiation demonstrated by positive staining for S-100 protein and MSA



Atypical Adenomatous Hyperplasia





  • Circumscribed proliferation of variably sized acini that may show focal infiltration at the periphery



  • Tightly packed small glands intermixed with larger glands



  • Some glands may show a basal cell layer (positive for HMWCK)



  • Glandular cells typically have pale to clear cytoplasm, small nuclei, and inconspicuous nucleoli; prominent nucleoli may occasionally be seen; however, macronucleoli (>3 μm) should not be present



Adenocarcinoma, Cribriform Type





  • Typical cytologic features of malignancy, including cuboidal or columnar cells with abundant amphophilic cytoplasm, enlarged nuclei, and one or more prominent macronucleoli



  • Absence of basal cell layer (negative for HMWCK)



Pearls





  • Typically treated with transurethral resection; controversy still exists regarding treatment for BCC



  • Basal cell lesions in the prostate form a spectrum of disease behavior that is typically benign



  • Malignant behavior in adenoid basal cell tumor has not been demonstrated





Selected References




  • Fine S.W.: Variants and unusual patterns of prostate cancer: clinicopathologic and differential diagnostic considerations. Adv Anat Pathol 2012; 19: pp. 204-216.



  • Humphry P.A.: Histological variants of prostatic carcinoma and their significance. Histopathology 2012; 60: pp. 59-74.



  • Montironi R.: Epstein JI, Iczkowski KA. Basal cell carcinoma.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 171.


Neuroendocrine Tumors


Clinical Features





  • Rarely occurs de novo; patients usually have a history of treated prostate cancer



  • Most show no evidence of hormonal secretion; however, paraneoplastic syndromes (Cushing syndrome, hypercalcemia, syndrome of inappropriate antidiuretic hormone [SIADH] secretion and Eaton-Lambert syndrome) can occur



  • May have minor elevations of serum PSA



  • Metastasizes through hematogenous (liver, brain) rather than lymphatic channels



Gross Pathology





  • Nonspecific



Histopathology





  • Neuroendocrine differentiation seen in the following circumstances:




    • Conventional prostate adenocarcinoma frequently contains isolated cells positive for neuroendocrine markers only (not apparent on H&E [hematoxylin & eosin] slides)



    • Conventional prostate adenocarcinoma with a neuroendocrine component apparent on H&E slides



    • Conventional prostate adenocarcinoma with intermingled cells showing Paneth cell-like neuroendocrine differentiation



    • Carcinoid-like tumors (“well-differentiated neuroendocrine tumor”)



    • Small cell neuroendocrine carcinoma



    • Large cell neuroendocrine carcinoma



    • Post-therapy neuroendocrine differentiation (which some have designated “treatment-related neuroendocrine prostate cancer” or “Aggressive variant of prostate cancer”)




Special Stains and Immunohistochemistry





  • Neuron-specific enolase (NSE), chromogranin, and cytokeratin typically positive



  • PSA and PAP: often negative or only focally positive



  • AMACR: 50% positive



  • Secretory products may be present within neoplastic cells



  • Adrenocorticotropic hormone (ACTH), serotonin, calcitonin, human chorionic gonadotropin (HCG), thyroid-stimulating hormone (TSH), and bombesin



Other Techniques for Diagnosis





  • Electron microscopy: neuroendocrine cells contain round, regular membrane-bound neurosecretory granules, measuring 100 to 400 nm



Differential Diagnosis


Metastatic Small Cell Carcinoma from Bladder or Lung





  • Clinical history is important



  • Lacks associated acinar adenocarcinoma that is usually seen in primary neuroendocrine carcinoma of the prostate gland



Non-Hodgkin Lymphoma





  • Primary prostatic lymphoma is rare



  • Neoplastic lymphoid population infiltrating around ducts and acini (typically spares prostatic glands)



  • Infiltration into surrounding periprostatic tissue is common



  • Positive for leukocyte common antigen (LCA)



  • Negative for cytokeratin, NSE, chromogranin, and other neuroendocrine markers



Pearls





  • Many acinar-type prostatic adenocarcinomas show immunohistochemical evidence of neuroendocrine differentiation, the significance of which is unknown



  • Neuroendocrine carcinoma of the prostate may respond to small cell carcinoma–directed chemotherapy but is clinically aggressive





Selected References




  • Epstein J.I., Amin M.B., Evans A.J., et. al.: Neuroendocrine tumours.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 172-174.



  • Hu J., Han B., Huang J.: Morphologic spectrum of neuroendocrine tumors of the prostate. An updated review. Arch Pathol Lab Med 2020; 144: pp. 320-325.



  • Manucha V., Henegan J.: Clinicopathologic diagnostic approach to aggressive variant prostate cancer. Arch Pathol Lab Med 2020; 144: pp. 18-23.



  • Paner G.P., Gandhi J., Choy B., et. al.: Essential updates in grading, morphotyping, reporting, and staging of prostate carcinoma for general surgical pathologists. Arch Pathol Lab Med 2019; 143: pp. 550-564.


Transitional Cell Carcinoma


Clinical Features





  • Rare primary prostate gland tumor (represents 1% to 3% of primary prostatic gland malignancies)



  • Common symptoms include hematuria or urinary obstruction



  • PSA not elevated



  • Three modes of prostatic involvement




    • Primary tumor of prostatic urethra, ducts, or acini



    • Secondary mucosal involvement from a prior or currently active bladder cancer



    • Direct invasion from bladder cancer infiltrating through the bladder wall




Gross Pathology





  • Nodular proliferation in prostatic urethra



  • Nonspecific nodular architecture with involvement of prostatic ducts and acini



Histopathology





  • Carcinoma in situ (intraductal TCC) is typically present adjacent to the invasive component; may involve the urethra, the prostatic ducts and acini, and occasionally the ejaculatory ducts and seminal vesicles



  • Infiltrative component consists of small groups or single cells with hyperchromatic, pleomorphic nuclei with chromatin clumping, multiple nucleoli, and angulated nuclear borders



  • Mitotic figures and tumor necrosis are common



  • Elicits a desmoplastic stromal reaction



  • Pagetoid spread and squamous metaplasia may be seen



Special Stains and Immunohistochemistry





  • HMWCK, CK7, and CK20 variably positive



  • PSA and PAP negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Prostatic Adenocarcinoma





  • Gleason grade 5 adenocarcinoma with comedonecrosis may be difficult to distinguish from TCC



  • Focal gland formation can typically be found after careful evaluation of multiple sections



  • Not associated with TCC in situ



  • Positive for PSA, PAP, or AMACR



Pearls





  • Typically urethral or prostatic duct TCC is seen in patients with a history or urothelial carcinoma elsewhere



  • Prostatic stromal involvement by TCC is, by definition, stage T4 disease and carries a poor prognosis





Selected References




  • Fine S.W.: Variants and unusual patterns of prostate cancer: clinicopathologic and differential diagnostic considerations. Adv Anat Pathol 2012; 19: pp. 204-216.



  • Grignon D.J.: Urothelial carcinoma.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 168-169.



  • Humphry P.A.: Histological variants of prostatic carcinoma and their significance. Histopathology 2012; 60: pp. 59-74.


Squamous Cell Carcinoma and Adenosquamous Carcinoma


Clinical Features





  • Rare in the prostate gland



  • Typically found in older age group (mean age of about 70 years)



  • Two clinical scenarios




    • Primary, de novo squamous cell carcinoma



    • Associated with treated (radiation or hormone ablation) adenocarcinoma




  • Serum PSA and PAP are usually normal



  • Metastatic bone lesions osteolytic, in contrast to adenocarcinoma, which causes osteoblastic bone lesions



  • Most commonly associated with squamous cell carcinoma of the urinary bladder



  • May be associated with Schistosoma haematobium infection



Gross Pathology ( Figure 11.8A )





  • Nonspecific




Figure 11.8


Primary squamous cell carcinoma of the prostate.

A, Cross sections showing nodular growth replacing the gland. Low-power (B) and high-power (C) photomicrographs showing infiltrative squamous cell carcinoma with keratinization.


Histopathology





  • Similar histologic features to squamous cell carcinoma of other sites



  • Malignant squamous cells arranged in cords and nests with an infiltrative architecture



  • Two forms of carcinoma




    • Pure squamous carcinoma




      • Rare



      • Infiltrative growth pattern composed of malignant cells with squamous features (keratin formation and intercellular bridging) ( Figure 11.8B and C )



      • No gland formation



      • No patient history of radiation or hormonal therapy



      • Must exclude secondary involvement from extraprostatic sites (e.g., bladder)




    • Adenosquamous carcinoma




      • Admixture of adenocarcinoma and squamous cell carcinoma



      • Typically associated with a history of radiation or hormonal therapy





Special Stains and Immunohistochemistry





  • PSA and PAP are positive in glandular component of adenosquamous carcinoma; pure squamous cell carcinoma is typically negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Squamous Metaplasia





  • Commonly associated with prostatic infarction



  • Lacks significant cytologic atypia and tumor necrosis



Prostatic Primary





  • Much more common to have a squamous cell carcinoma in the prostate gland as metastatic disease or direct extension from adjacent organs (i.e., urinary bladder) than as a prostatic primary



Pearls





  • Behaves in an aggressive manner (mean survival of 14 months, regardless of therapy)



  • Unresponsive to androgen-deprivation therapy





Selected References




  • Li J., Wang Z.: The pathology of unusual subtypes of prostate cancer. Chin J Cancer Res 2016; 28: pp. 130-143.



  • Humphry P.A.: Histological variants of prostatic carcinoma and their significance. Histopathology 2012; 60: pp. 59-74.



  • Epstein J.I., Algaba F.: Squamous neoplasms.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 170.


Phyllodes Tumor


Clinical Features





  • Rare neoplasm



  • Wide age range



  • Patients present with symptoms associated with prostatic enlargement, which include urinary obstruction, hematuria, and dysuria



Gross Pathology





  • Multinodular solid, gray-white mass



  • Cut surface may be spongy or cystic



  • Variable size; may be larger than 25 cm in diameter



Histopathology





  • Biphasic tumor composed of epithelial and stromal components



  • Epithelial cells are cuboidal to columnar, arranged in double-layer lining glands, cysts, or slitlike spaces




    • Stellate to spindle stromal cells arranged in a loose, myxoid background




  • Glandular or cystic spaces compressed by cellular stroma into a leaflike configuration ( Figure 11.9 )




    Figure 11.9


    Prostatic phyllodes tumor.

    Proliferation of specialized prostatic stroma bulging into prostatic glands and creating clefted spaces.



  • Likelihood of recurrence and malignant behavior is associated with a high stromal to epithelial ratio (stromal hypercellularity), cellular atypia, and high mitotic rate



Special Stains and Immunohistochemistry





  • Vimentin: stromal component is typically positive



  • PSA and PAP: epithelial cells may be positive



  • SMA negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Stromal Hyperplasia





  • Benign prostatic hyperplasia nodule with stromal overgrowth may be large



  • Lacks epithelial component and leaflike configuration



Giant Multilocular Prostatic Cystadenoma





  • Solitary cystic tumor with a surrounding dense fibrous stroma



  • Numerous, variably sized cystic spaces lined by a benign-appearing prostatic epithelium



  • Lacks leaflike configuration



Postoperative Spindle Cell Proliferation





  • Rare reactive spindle cell proliferation that may occur after transurethral prostate resection (previously resected prostate tissue must show no evidence of a mesenchymal or spindle cell tumor)



  • Benign cytologic features and variable mitotic rate (uniform cells with no nuclear pleomorphism and no atypical mitotic figures)



  • Lacks epithelial component



Solitary Fibrous Tumor of the Prostate





  • Low-power view has variable cellularity and lacks leaflike configuration



  • High-power view has spindled cells insinuating themselves into bands of collagen



Leiomyoma or Leiomyosarcoma





  • Monophasic hypercellular spindle cell neoplasm without epithelial component



  • Positive for SMA and desmin



Sarcomatoid Carcinoma





  • Malignant spindle cell proliferation admixed with a malignant epithelial component



  • Spindle cell component may predominate; cytokeratin positivity, the distinguishing feature, may be weak and focal



Pearls





  • Most are cured by surgical resection and follow a benign clinical course; however, biologic behavior is difficult to predict based on histologic features



  • Tumors with overtly malignant stromal component have given rise to distant metastases (most commonly lung and bone)



  • Diagnosis on needle biopsy may be difficult





Selected References




  • Cheville J., Algaba F., Epstein J.I., et. al.: Mesenchymal tumours.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 175-177.



  • McKenney J.K.: Mesenchymal tumors of the prostate. Mod Pathol 2018; 31: pp. S133-S142.


Rhabdomyosarcoma


Clinical Features





  • Most common sarcoma of the prostate



  • Occurs primarily between birth and 6 years of age



  • Most common in the head and neck, followed by the genitourinary tract



  • About 20% of childhood cases occur in the genitourinary tract



  • Rare cases reported in older men



  • Presents with pelvic mass and urethral obstruction



  • Pelvic mass may cause bladder displacement and rectal compression



Gross Pathology





  • Large, gray-white mass typically measuring 5 to 10 cm



  • Appears grossly circumscribed but is typically infiltrative microscopically



Histopathology


Embryonal Rhabdomyosarcoma





  • Most common subtype



  • Mixture of sheets of primitive, undifferentiated, round to spindle cells admixed with haphazardly arranged rhabdomyoblasts in a myxoid stroma



  • Primitive cells are small and round with dark nuclei and minimal cytoplasm



  • Variable numbers of strap cells, with or without cross-striations



  • Variable mitotic activity



Alveolar, Botryoid, and Pleomorphic Patterns





  • These patterns are rare



  • Botryoid pattern consists of polypoid fragments covered with urothelium that often extends into the urethra or bladder



Special Stains and Immunohistochemistry





  • Vimentin, MSA, desmin, and myoglobin positive



  • Stains negatively for cytokeratin, LCA, NSE, PSA, and PAP



Other Techniques for Diagnosis





  • Electron microscopy: rhabdomyoblasts have cytoplasmic myofilaments and Z bands



  • Flow cytometry: tumor cells are typically aneuploid



Differential Diagnosis





  • Must rule out metastasis from other primitive childhood small round blue cell tumors



  • Non-Hodgkin lymphoma



  • Typically found in older age groups



  • Neoplastic lymphoid cells infiltrating stroma in diffuse sheets or patches; ducts and acini are typically spared



  • Positive for LCA



  • Composed of a monoclonal lymphoid population



Pearls





  • Presence of strap cells or rhabdomyoblasts is diagnostic



  • Treatment typically consists of surgery, chemotherapy, and radiotherapy



  • The prostate and urinary bladder are considered “unfavorable prognosis” sites





Selected Reference




  • McKenney J.K.: Mesenchymal tumors of the prostate. Mod Pathol 2018; 31: pp. S133-S142.


Lymphoma


Clinical Features





  • Most common in older men (mean age, 60 years)



  • Presents with urinary obstruction symptoms



  • Primary lymphoma involves the prostate gland without extraglandular involvement (i.e., liver, spleen, lymph nodes, peripheral blood)



  • Secondary involvement of the prostate gland by a systemic lymphoma is more common than primary prostate lymphoma



  • Systemic symptoms (fever, chills, night sweats, and weight loss) are infrequent and typically seen only in patients with disseminated disease



Gross Pathology





  • Diffuse enlargement of the prostate gland



  • Tan, homogeneous, rubbery parenchyma



Histopathology





  • Proliferation of neoplastic lymphoid cells that typically infiltrate the prostatic stroma in diffuse sheets while sparing the ducts and acini



  • Infiltration into surrounding periprostatic tissues is common



  • Most common subtype is diffuse large cell lymphoma, B-cell type; small cleaved cell lymphoma is also relatively common



  • Hodgkin disease is rare



Special Stains and Immunohistochemistry





  • LCA positive (non-Hodgkin lymphoma)



  • Refer to Chapter 14 for specific immunohistochemistry profiles



Other Techniques for Diagnosis





  • Flow cytometric immunophenotyping using fresh tissue is useful in documenting clonality and for subtyping lymphomas (refer to Chapter 14 )



Differential Diagnosis


Chronic Prostatitis with Follicular Hyperplasia





  • Mixed inflammatory infiltrate with germinal center formation



  • Inflammation is typically within duct lumina and in the glandular epithelium



  • Nonclonal lymphocytic population



Granulomatous Prostatitis





  • Admixture of histiocytes, plasma cells, eosinophils, neutrophils, lymphocytes, and giant cells



  • Inflammatory cells cause destruction of the prostatic ducts and acini



Neuroendocrine Carcinoma





  • Characteristic prostatic adenocarcinoma associated with a neuroendocrine carcinoma, which may range from a low-grade neuroendocrine carcinoma (carcinoid) to a small cell undifferentiated carcinoma (oat cell carcinoma)



  • Areas of necrosis are typical in small cell carcinoma



  • Positive for cytokeratin, NSE, chromogranin, and other neuroendocrine markers



  • Negative for LCA



Rhabdomyosarcoma





  • Typically found in younger age group



  • Mixture of sheets of primitive, undifferentiated, round to spindle cells admixed with haphazardly arranged rhabdomyoblasts in a myxoid stroma



  • Positive for MSA, desmin, and myoglobin



  • Negative for LCA



Pearls





  • Surgery is used mainly for relief of urinary obstruction symptoms



  • Poor prognosis; death typically results within 2 years of diagnosis





Selected Reference




  • Ferry J.A.: Haematolymphoid tumours.Moch H.Humphry P.A.Ulbright T.M. et. al.World Health Organization Classification of Tumours: WHO Classification of Tumours of the Urinary System and Male Genital Organs.2016.IARC PressLyon:pp. 178.


Testis


Cryptorchidism


Clinical Features





  • Usually unilateral (75%)



  • Occurs in 3% to 4% of term infants and in up to 20% of premature infants



  • Undescended testicles typically descend by 3 months of age (<1% remain undescended at 1 year of age)



  • Associated with an inguinal hernia in 10% to 20% of cases



  • Most cryptorchid testes are found in the inguinal canal



  • Right testicle is more commonly involved



  • Patients with undescended and surgically descended cryptorchid testes have decreased fertility and increased risk for certain germ cell and non–germ cell tumors



  • Normal descent of testes is under hormonal control



Gross Pathology





  • Cryptorchid testes are smaller and softer than normal testes



Histopathology





  • Histologic changes in cryptorchid testis occur by age 2 years



  • Seminiferous tubules may be small or ring shaped and have areas of tubular sclerosis or atrophy ( Figure 11.10 )




    Figure 11.10


    Cryptorchidism.

    Complete tubular sclerosis and mild Leydig cell hyperplasia.



  • Spermatogonia may be decreased in number and irregularly distributed or totally absent



  • Sertoli cells are increased in number; Leydig cell hyperplasia may be prominent



  • Interstitium is typically widened and edematous



  • Normally descended testis contralateral to the cryptorchid testis often shows many of the same histologic features



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Causes of testicular maldescent include anatomic abnormalities of the gubernaculum, hormonal dysfunction, mechanical impairment, and gonadal dysgenesis



Pearls





  • Testicles normally descend from their intra-abdominal location to the scrotum in two phases, both of which are under hormonal control; defects in the transabdominal phase are much less common than defects in the inguinal-scrotal phase



  • Patients with cryptorchidism have a 5 to 10 times higher risk for testicular malignancy than the general population; orchiopexy does not reduce the risk for cancer but does make detection easier



  • Most common consequence is infertility



  • Early orchiopexy (surgical placement of the testis in the scrotum) may have a positive effect on fertility; orchiopexy after 4 years of age does not increase fertility





Selected Reference




  • Niedzielski J.K., Oszukowska E., Slowikowska-Hilczer J.: Undescended testis—current guidelines: a review of the literature. Arch Med Sci 2016; 12: pp. 667-677.


Testicular Cysts


Clinical Features





  • Usually unilateral



  • May be difficult to distinguish from cysts of paratesticular adnexa by ultrasound



Gross Pathology





  • Albugineal cysts are usually uniloculated, centered in the visceral tunica albuginea, and contain clear fluid



  • Epidermoid cysts are usually uniloculated, abut the visceral tunica albuginea; and contain laminated, granular, friable material ( Figure 11.11 )




    Figure 11.11


    Epidermoid cyst.

    Hemisected testis showing sharply circumscribed cyst in testicular parenchyma, abutting tunica albuginea and containing laminated material.



  • Rete testes cysts (cystic dysplasia of the rete testes) are usually multiloculated, retiform, centered in the testicular hilum, and contain clear fluid



Histopathology





  • Albugineal cysts are at least partially lined by low cuboidal serosal epithelium



  • Epidermoid cysts are lined by attenuated squamous epithelium, contain keratinaceous material, and, by definition, lack adnexal structures and germinal elements



  • Rete testes cysts (cystic dysplasia of the rete testes) are lined by attenuated, low cuboidal epithelium



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Dermoid cysts are lined by keratinizing squamous epithelium but also have adnexal structures



  • Teratomas may be mostly cystic lined by keratinizing squamous epithelium but also have teratomatous elements



Pearls





  • Complete submission of epidermoid cysts is required to rule out dermoid cysts and teratoma





Selected Reference




  • Ulbright T.M., Young R.H.: Testicular and paratesticular tumors and tumor-like lesions in the first two decades. Semin Diagn Pathol 2014; 31: pp. 323-381.


Hydrocele


Clinical Features





  • Most are idiopathic; may be associated with inguinal hernia, scrotal trauma, orchitis, or testicular tumors



  • May be secondary to congenital lack of closure of the processus vaginalis, resulting in a communication with the peritoneal cavity



  • Characterized by accumulation of serous fluid between the parietal and visceral tunica vaginalis



  • Occasionally patients present with acute testicular enlargement secondary to hemorrhage; lack of transillumination may necessitate orchiectomy



Gross Pathology





  • Clear serous fluid-filled cavity compresses adjacent testis



  • Hemorrhage or infection may cause fluid to become opaque



  • Tunica may be thickened in long-standing lesions



Histopathology





  • Fluid-filled cavity lined by flattened or cuboidal mesothelial cells



  • Mesothelium may be hyperplastic or cytologically atypical



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Spermatocele





  • Usually located near rete testis or caput epididymis



  • Contains spermatozoa



Mesothelial Cyst





  • Usually located anterior or lateral to testis



  • May arise within the tunica vaginalis, tunica albuginea, epididymis, or rarely the spermatic cord



  • May be multiloculated




Selected Reference

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Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Male Genitourinary System
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