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Prostate


Reviewers: Ali Amin, M.D., Komal Arora, M.D., Gladell Paner, M.D. (see Reviewers page)
Revised: 15 May 2012, last major update May 2012 - IN PROGRESS
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

Table of contents

Primary referencesanatomyhistologyPSA

Prostatitis: prostatitisprostatitis with eosinophilsmalakoplakiaother infectionsabscess

Granulomatous lesions: generalnon-specificallergic granulomatous prostatitispost-TURP granulomasTB-bCG granulomas

Benign lesions/conditions: amyloidblue nevuscalculicystadenomaectopic prostateendometriosisextramedullary hematopoiesisganglioneuromainfarctinflammatory pseudotumorleiomyomalipofuscinmelanosisnodular hyperplasiaPaneth cell-like changepostoperative spindle cell nodulespseudosarcomatous fibromyxoid tumorretention cystsrhabdomyomasignet ring noduleurethral polypsutricle cystsvenous thrombosis

Prostatic intraepithelial neoplasia/PIN: low grade PINhigh grade PINwith adjacent small atypical glands

Prostatic carcinoma: generalhistologic treatment effectcore biopsiesadenocarcinoma of peripheral ductsgradingimmunohistochemistryatypical glands suspicious for malignancyvanishing cancer phenomenon

Other carcinomas: adenoid basal cell tumoradenosquamousatrophicatypical cribriform lesionsbasaloid carcinomacarcinoid tumorcarcinosarcomaclear cell adenocarcinomafoamy gland adenocarcinomalymphoepithelioma-like carcinomametastases to prostatemucinous (colloid)mucinous adenocarcinoma-bladder typeneuroendocrineprostatic duct carcinomaspseudohyperplasticsignet ringsmall cellsquamous cellurothelial carcinoma

Microscopic mimics of prostatic carcinoma: adenosis/atypical adenomatous hyperplasiaatrophybasal cell hyperplasiaclear cell cribriform hyperplasiaCowper's glandsmesonephric remnant hyperplasiamucous gland metaplasianephrogenic metaplasia/adenomaparaganglion tissuepartial atrophypost-atrophic hyperplasiaradiation changessclerosing adenosisseminal vesicles / ejaculatory ductsquamous metaplasiaurothelial metaplasiaverumontanum mucosal hyperplasiaxanthoma cells

Other malignancies: angiosarcomaectomesenchymomaembryonal rhabdomyosarcomaleiomyosarcomalymphomamalignant fibrous histiocytomaPEComaphyllodes tumorPNETsolitary fibrous tumorstromal proliferations of uncertain malignant potentialstromal sarcomasynovial sarcomayolk sac

Miscellaneous: stagingfeatures to reportgrossing specimens

Seminal vesicles/Cowper's glands: normalbenigncarcinoma

Primary references

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AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology
Modern Pathology
Eble: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, 2004
Websites: PathoPicWebpathology.com

Please refer to these primary references for more detailed discussions and photographs

Benign or non-neoplastic conditions of prostate and prostatic urethra

Melanosis

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Definition: melanin within prostatic stromal melanocytes and glandular cells

Presence of melanin within glands probably due to stromal cell transfer (Am J Clin Pathol 1988;90:530)

May be an isolated finding, associated with blue nevus (Eur Urol 1992;22:339) or associated with other prostatic pathology such as adenocarcinoma

Case reports: Case of the Week #137

Treatment: none - no clinical significance by itself

Micro images: Case of the Week #137 - #1#2#3#4#5#6 

Positive stains: S100 (melanocytes)

EM: melanosomes

DD: lipofuscin in prostate (chracteristic of ejaculatory ducts and seminal vesicles but also found in prostatic epithelium, golden yellow-brown to gray-brown granules, positive for Fontana-Masson, PAS with diastase, Congo red, Luxol fast blue, Oil-red-O and Ziehl-Neelsen stains; bleached by permanganate, negative for Prussian blue, Am J Surg Pathol 1994;18:446, Mod Pathol 1996;9:791), blue nevus (spindled stromal cells with marked melanin deposition, nevus cells without pigment are usually present)

 

Paneth cell-like change

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Associated with both benign and malignant lesions, Archives 1992;116:1101

Collections of prostatic cells with eosinophilic granules resembling intestinal Paneth cells, AJSP 1992;16:1013

Represents either (a) PAS-positive and diastase-resistant eosinophilic cytoplasmic granular change in benign prostatic epithelium, or (b) endocrine differentiation with neuroendocrine granules in dysplastic and malignant prostatic epithelia, AJSP 1992;16:62

Positive stains: PAS, diastase resistant (benign epithelium), neuroendocrine markers (dysplastic/malignant epithelium)

EM: exocrine-like or lysosomal-like vesicles in benign epithelium, neuroendocrine granules in dysplastic / malignant epithelium

 

Postoperative spindle cell nodules

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Exuberant stromal reaction occurring weeks to months after TURP that resembles a sarcoma and may cause postoperative bleeding

Gross: friable red nodules, resembling granulation tissue or sarcoma

Micro: cellular with high mitotic activity; intersecting fascicles of spindle cells with extravasated red blood cells resembling Kaposi’s sarcoma; minimal nuclear pleomorphism, no atypical mitoses; relatively small size

Positive stains: keratin (strong), actin (variable)

Negative stains: EMA

 

Pseudosarcomatous fibromyxoid tumor

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Rare, resembles sarcoma or sarcomatoid carcinoma

Similar to postoperative spindle cell nodule but without history of TURP

Diploid, low S phase fraction

Benign behavior

Micro: myxoid lesions, proliferation of spindle fibroblastic cells in a background of granulation tissue-type vascularity and inflammatory cells; rare mitoses, no atypical mitoses

Positive stains: vimentin, smooth muscle actin

Negative stains: S-100, desmin, myoglobin, keratin

EM: fibroblastic and myofibroblastic cell features

References: Hum Path 1993;24:1203

 

Retention cysts

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Symptomatic cysts, 1-2 cm, usually unilocular, adjacent to urethra

Lined by flattened prostatic glandular epithelium or urothelium

 

Rhabdomyoma

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Case report, Archives 2000;124:1518

More common in vulva of young women

3 cases reported in men, one from prostate, one from testis, one from epididymis

Gross/micro images: image1

 

Signet ring nodule

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Micro: stromal nodule with short spindly cells with bland nuclear features, but also large, clear cytoplasmic vacuoles in many cells resembling signet-ring carcinoma cells but non-infiltrative

Positive stains: vimentin, desmin (weak)

Negative stains: mucin

References: AJSP 2002;26:1066

 

Urethral polyps

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Common cause of hematuria in young adults

Benign

Treatment: transurethral fulguration

Gross: single, villous, polypoid lesions in verumontanum and posterior-lateral urethra

Micro: tall columnar cells of prostatic origin, may have nephrogenic (adenomatoid) appearance; may coexist with carcinoma; papillary projections often contain prostatic stroma and glands; broad fingerlike projections differ from delicate fibrovascular cores of papillary urothelial carcinoma

Micro images: image1, image2, image3

Positive stains: PSA, PAP

Cytology: bland columnar cells with uniform oval nuclei, Archives 2000;124:1047; prostatic adenocarcinoma can also present as a urethral polyp

DD: villous polyps (dysplastic epithelium resembles colonic adenomas, are actually papillary prostatic duct adenocarcinomas)

References: AJCP 1975;63:343, AJSP 1983;7:351

 

Utricle cysts

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Usually between bladder and rectum, with cyst orifice at prostatic utricle

Mean age 26 years (range 2 months to 75 years)

Associated with abnormal external genitalia in 25%, unilateral renal agenesis/dysgenesis in 10%

Cysts contain calculi in 10%; epithelial lining is variable or missing

 

Venous thrombosis

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Mast cells are present in increased numbers in adventitia of thrombosed veins; may have a role in endogenous fibrinolysis, AJCP 2001;116:97

 

 

Prostatic intraepithelial neoplasia (PIN)

Low grade PIN

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Common finding in young men

Recommended to NOT put on surgical pathology report since variability in diagnosis exists even between experts, AJSP 1995;19:873

Micro: more architectural complexity than hyperplasia, occasional enlarged nuclei, rare nucleoli, usually diploid

 

High grade PIN

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Present in 14% of patients in a community hospital study

Indicates 33% risk of carcinoma in subsequent biopsies

Low risk for cancer (13%) if two subsequent biopsies are negative

Number of cores with high grade PIN predicts risk of subsequent cancer (1 core-30%, 3 cores-40%, 4+ cores-75%), predominantly cribriform/micropapillary patterns also predict higher risk, AJSP 2001;25:1079

In Americans less than 60 years old, more common in blacks vs. whites

Does not cause elevated PSA

If found on TURP specimen, should examine all submitted tissue for invasive adenocarcinoma

50% are aneuploid

Micro: low power diagnosis; usual patterns are micropapillary / cribriform (70%), flat / tufted (20%); basophilic appearance at low power due to enlarged hyperchromatic nuclei and amphophilic cytoplasm; may develop tall papillary tufts; frequently multicentric in prostatectomy specimens

Identifiable on low power as glands with (a) papillary projections into lumina, (b) hyperchromasia, (c) enlarged nuclei, (d) pleomorphism, (e) stratification/crowding, (f) prominent nucleoli

Cells may contain pigment, may have intraluminal mucin staining similar to invasive carcinoma

Micro images: image1, image2, image3, image4, high MW keratin

Positive stains: basal cells - CK903, p63, CD10 (Hum Path 2003;34:450), secretory cells - P504S/AMACR (AJSP 2003;27:772)

DD: seminal vesicle glands with cribriform epithelium and no atypia (normal findings);

clear cell cribriform hyperplasia (clear cytoplasm, benign nuclei, no/small nucleoli, prominent basal cell layer),

central zone glands (base of prostate adjacent to seminal vesicles; usually cribriform or Roman arch formation at end of core biopsy; tall columnar cells with eosinophilic cytoplasm, prominent basal cell layer; associated thick muscle bundles of bladder neck, no cytologic atypia, Hum Path 2002;33:518)

 

High grade PIN patterns

Apocrine, cribriform, flat, foamy gland, inverted (hobnail), micropapillary, mucinous, Paneth cell-like, pleomorphic, signet-ring cell, small cell neuroendocrine, tufting

 

Cribriform pattern

Micro images: image1, image2

 

Flat pattern

Micro images: image1

 

Foamy gland pattern

Micro: pale/foamy cells with voluminous xanthomatous cytoplasm, forming solid and cribriform patterns

 

Inverted (hobnail) pattern

Localized to peripheral zone, AJSP 2001;25:1534

Associated with concurrent prostatic adenocarcinoma in 50% of cases

Micro: polarization of enlarged secretory cell nuclei toward the glandular lumen; merges with typical micropapillary–tufted HGPIN; often less prominent nucleoli than adjacent noninverted secretory cell nuclei

Reference: AJSP 2003;27:772

 

Micropapillary pattern

Micro images: image1

contributed by Dr. John Irlam, University of Toledo, Ohio - low powerhigh power

Reference: AJSP 2001;25:1079

 

Mucinous

Micro: mucinous distension of glands with flat epithelial lining, blue mucinous secretions

Positive stains: PAS, Alcian blue, AJSP 1997;21:1215

 

Pleomorphic pattern

Micro: pleomorphic nuclei, although nucleoli may not be prominent

Reference: AJSP 2001;25:1079

 

Signet ring pattern

Micro: associated with primary signet ring cell carcinoma

Positive stains: PSA

Negative stains: mucin negative, AJSP 1997;21:1215

 

Small cell pattern

Associated with primary small cell carcinoma

Positive stains: chromogranin, synaptophysin, neuron-specific enolase, AJSP 1997;21:1215

 

Tufting pattern

Micro images: image1, image2


Prostatic carcinoma

Core biopsies

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“Six pack”, 6 samples from selected portions of prostate via a spring-loaded 18-gauge biopsy, has false negative rate of 12% due to sampling error

25% of tumor bearing specimens contain only a small focus of carcinoma

Transrectal biopsies more accurate than transperineal biopsies

Gleason score in biopsy correlates with that in prostatectomy (same: 58%, +/- 1 unit: 92%); more errors occur with Gleason scores  5 or 6, which tend to underestimate prostatectomy Gleason score, AJSP 1997;21:566

Tumor seeding of needle tract is rare complication of perineal needle biopsy, more likely with poorly differentiated carcinomas, less common with transrectal biopsy

 

Core biopsy processing

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Three levels recommended, Archives 1998;122:833, AJCP 1997;107:26, AJSP 1999;23:257; additional levels if atypical glands, suspicious for malignancy, AJCP 1998;109:416

Should be reviewed before radical prostatectomy is performed, AJSP 1996;20:851

Biopsy is unsatisfactory if no prostatic glands or stroma; stroma only may indicate a stromal hyperplastic nodule and is satisfactory

Average of 23% of total length of a core is missed by a single histologic level; preembedding cores using "stretch" method may yield more tumor/core, more cores with tumor, more cases with tumor, fewer atypical small acinar diagnoses, fewer cases with 3mm or less of Gleason 6 or less cancer, Hum Path 2000;31:1102

Epstein recommends assigning a Gleason score of at least 5 for adenocarcinoma diagnosed on core biopsies (as opposed to TURP) since 2-4 in this setting usually represent undergrading, are not reproducible and may adversely impact patient care, AJSP 2000;24:477

 

Microscopic features of core biopsies

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Micro: features suggestive of malignancy in a core are (malignant vs. benign specimens): prominent nucleoli (94% vs. 25%), marginated nucleoli (88% vs. 7%), multiple nucleoli (64% vs. 0%), blue-tinged mucinous secretions (52% vs. 0%), intraluminal crystalloids (41% vs. 1%), intraluminal amorphous eosinophilic material (87% vs. 2%), collagenous micronodules (2% vs. 0%), glomerulations (15% vs. 0%), perineural invasion (22% vs. 0%), retraction clefting (39% vs. 7%), and invasion of fat (1% vs. 0%), Archives 2002;126:554

Notes: in assessing intraluminal, amorphous eosinophilic material, must exclude decapitation secretions or fractured corpora amylacea

Collagenous micronodules are nodular masses of paucicellular, eosinophilic, fibrillar stroma which impinge on acinar lumens, Archives 1995;119:444

Glomerulations consist of rounded epithelial tufts within glands reminiscent of renal glomeruli; present in 5% of radical prostatectomy specimens (5-20% of each tumor) and 3% of needle biopsies with cancer (5-10% of each cancer); not observed in benign lesions, Hum Path 1998;29:543

Micro images: image1, image2

 

Basal cell stains on core biopsies

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High molecular weight cytokeratin (34 beta E12) and p63 detect basal cells, which are lacking in adenocarcinoma, and don’t stain secretory cells

Diagnosis of prostatic adenocarcinoma with positive 34betaE12 basal cell staining should be made with extreme caution, only if unequivocal cancer on H&E; if present, is usually patchy, may indicate outpouchings of high grade PIN, AJSP 2002;26:1151

Should save intervening levels for stains; can also destain / restain needle biopsies and put original sections on coated slides, Hum Path 2000;31:1155

Recommended to use cocktail of 34betaE12 and p63, AJSP 2003;27:365

Note: a negative high molecular weight keratin is only diagnostic of adenocarcinoma if there is a high (90%) pre-test suspicion of carcinoma; must also see staining of obviously benign glands.

Positive staining can identify benign mimickers of cancer including benign crowded glands, adenosis and atrophy, and occasionally differentiate high grade PIN vs. cancer

Micro images: image1, H&E of image1, image2, H&E of image2, p63-#1, #2

 

P504S/AMACR stains on core biopsies

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Sensitive and specific for prostate carcinoma on needle biopsies; recommended to use a combination of P504S and 34betaE12 to diagnose limited prostatic adenocarcinoma, AJSP 2002;26:1169

Stains some hyperplastic nodules and benign glands adjacent to transition zone carcinomas, Hum Path 2003;34:228

 

Minimal prostatic adenocarcinoma on core biopsy

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Less than 1 mm on biopsy

Usually is pathologically significant tumor at prostatectomy

Common features are nucleomegaly (96%), infiltrative growth pattern (88%), intraluminal secretions (78%), prominent nucleoli (64%), associated high grade PIN (40%), amphophilic cytoplasm (36%), hyperchromatic nuclei (30%), intraluminal crystalloids (22%); uncommon features are perineural invasion (2%), collagenous micronodules (2%), mitotic figures (2%), Mod Path 1998;11:543

Micro images: image1

DD: adenosis, atrophy, high grade PIN, AJCP 2000;114:896

 

Adenocarcinoma of peripheral ducts and acini

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Tumor distribution: 70% arise from peripheral zone (posterior, lateral, anterior), usually spares periurethral zone except in late stages

radical prostatectomy specimens usually have tumor posteriorly (>90%) and anteriorly (65%); anterior tumor associated with higher tumor volume and extraprostatic extension, AJCP 1999;112:373

Tumor extension: local invasion via seminal vesicles (if infiltrates muscular wall) and bladder base, rarely into prostatic urethra; rectal invasion rare due to tough Denonvillier’s fascia; may present as anterior rectal mass, stricture or serosal implants

Seminal vesicle invasion: via (a) direct spread along ejaculatory duct complex, (b) spread outside prostate, through capsule, then into seminal vesicle, (c) patients with better prognosis who had isolated deposits in seminal vesicle with no contiguous prostatic primary, AJSP 1993;17:1252

Metastases: usually skeletal system, lung/pleura, liver, adrenals and lymph nodes; also testes, breast if estrogen therapy (metastases to male papillary breast cancer - image), dura at autopsy, Archives 2001;125:880

Autopsy study: 35% had metastases, most common sites were bone (90%), lung (46%), liver (25%), pleura (21%), adrenals (13%); spine involvement common even in small tumors; tends to be upward spread from lumbar to cervical level), Hum Path 2000;31:578

Bony metastases: multiple, usually osteoblastic not osteolytic, may radiographically simulate Paget’s disease or osteosarcoma; usually lumbar spine, sacrum or pelvis due to tumor spread via Batson’s vertebral venous plexus; see clusters of malignant glands surrounded by new bone formation, may cause hypocalcemia, hypophosphatemia, increased alkaline phosphatase; positive for PAP/PSA even after decalcification

Lung metastases: small acinar or cribriform growth, frequent lymphangitic permeation, no stromal response, uniform round nuclei with prominent nucleoli, intraluminal blue mucin, prominent cell borders; usually PSA and PAP positive; may have carcinoid-like architectural features but without fine chromatin pattern, AJCP 2002;117:552; may resemble bronchogenic carcinoma, AJCP 1990;94:641

Nodal metastases: pelvic chains, then retroperitoneum; rarely skips pelvis and goes to lungs/liver

Latent prostate cancers detected at autopsy almost never have nodal metastases

Poorly differentiated carcinomas may metastasize to left supraclavicular or mediastinal nodes (detect with PSA/PAP)

Recurrence after radical prostatectomy: median interval 40 months; mean tumor size 3.2 mm; cancers often lack overt histologic features of malignancy; however, need lower threshold for diagnosis because atypical prostate glands should not be present after radical prostatectomy, Mod Path 2000;13:521; micro images: image1, image2, image3, image4, image5, image6, image7

Prognostic factors: independently important variables are stage, Gleason score, surgical margins, preoperative PSA, Archives 2000;124:995; also perineurial invasion (RR=2), MIB-1 by image analysis on core biopsy (for progression after radical retropubic prostatectomy), AJSP 2002;26:431; angiolymphatic invasion on pT3N0 radical prostatectomy specimens, AJSP 2000;24:859, size of nodal metastasis for 5 year progression free survival after radical prostatectomy, AJSP 1998;22:1491

Urinary cytology: difficult to identify well differentiated tumors; easier for poor/moderately differentiated tumors

Not useful for screening since 10% false negatives; largely replaced by automated spring-loaded 18 gauge biopsy

High grade prostate vs. high grade urothelial carcinoma: prostate has oval nuclei with smooth borders; fine, powdery, evenly distributed chromatin; large nucleolus if present; no significant pleomorphism, AJCP 2000;113:29

Note: atypical cells normally present in seminal vesicle also resemble carcinoma

Tumor in TURP specimen: either extensive spread by conventional carcinoma or central carcinoma

Related to amount of sampling; 5 blocks/12 grams will detect 90% of carcinomas; 8 blocks detects 98% of carcinomas; if <5% carcinoma (T1a/stage A1), sample more chips (T1b/stage A2 if > 5%); if high grade PIN only, embed all tissue and obtain deeper levels

Frozen section diagnosis: look for architectural disarray or perineurial invasion

Lymph node frozen section/imprints: 10% false negatives

Treatment: radical prostatectomy (not warranted if positive pelvic nodes), brachytherapy (radioactive seeds), external beam radiation therapy, watchful waiting (for low grade tumors, localized tumor or limited life expectancy), chemotherapy or hormonal therapy (LHRH analogs, antiandrogens, orchiectomy) for metastastic disease

Most tumors are androgen sensitive, at least initially

Use PSA to monitor tumor response

Patients < age 20: carcinoma rare, usually obstructive symptoms, advanced stage, high grade, poor response to treatment, survival < 1 year

 

Gross: Gritty and firm, gray-yellow, poorly delimited, more easily felt than seen; often undetectable if tumor small

Gross images: image1

Micro: pattern depends on Gleason grade (below); small glands, medium-sized glands, cribriform glands or diffuse single cell infiltration with necrosis; nuclear enlargement, hyperchromasia, prominent nucleoli (>3 microns is specific for malignancy, >1 micron is suggestive); mitotic figures extremely rare except in high grade tumors

Malignant transformation is accompanied by loss of basal cells, first reported by Totten in 1953

Glands are “too many, too small, too crowded” (need not be clustered)

Most common pattern is infiltrative medium sized glands (Gleason 3) - detect on low power as closely packed glands with irregular outline, smooth inner surface, scanty stroma

Less common, usually in transition zone or central zone is a Gleason 1 or 2 pattern of small sized glands forming expansive nodules on low power, regular round glands, small size, usually not multifocal

Cribriform pattern may appear intraductal with preserved basal cell layer, but is usually invasive (Gleason 3 if smooth borders, Gleason 4 if uneven borders)

Single cell infiltration (Gleason 5 pattern) may resemble lobular carcinoma of breast

Note: only diagnose if stringent criteria met, otherwise “focus of small atypical glands suspicious for malignancy”

 

Angiolymphatic invasion

Not commonly seen

 

Calcifications

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More common in benign than malignant prostate, but present in Gleason pattern 5 with comedo-type necrosis (dystrophic calcification) and within lumina of Gleason pattern 3 cribriform and small acinar types and within collagenous micronodules, Archives 1998;122:152

 

Cellularity of vessels

In radical prostatectomy specimens, increased vessel cellularity may be associated with higher grade tumors, Mod Path 2000;13:717 Micro images: image1, image2, image3, image4

 

Corpora amylacea

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Don’t confuse with crystalloids; benign but may be found in tumor; may arise from release of prostate secretory granules; remnants condense to form eosinophilic bodies, which adsorb and layer onto surface of prostatic corpora amylacea, causing them to enlarge, Hum Path 2000;31:94

 

Crystalloids

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Resemble Bence-Jones crystals (Ig kappa/lambda)

Seen in lumina of 10-23% of carcinomas, usually Gleason 3

Rarely in benign glands or metastatic foci (AJCP 1994;101:266)

Composed of inorganic sulfur; deeply eosinophilic, rhomboid

In benign specimens, not a significant risk factor for subsequent diagnosis of cancer, AJSP 1998;22:446, AJSP 1997;21:725

Same sulfur content as prostate secretory granules and corpora amylacea, Hum Path 2000;31:94

Micro images: image1, image2, in benign glands

 

Cytoplasm

Usually finely granular, may be clear/foamy due to intracellular lipid

 

High grade PIN

Present in 80% of carcinomas

 

Mucin

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Acidic mucin found in lumina in 2/3

Looks basophilic or deeply eosinophilic, confirm with Alcian blue or colloidal iron stains

Normal prostate secretes neutral mucins, although acid mucins also seen in adenosis and post-radiation therapy

Micro images: acidic mucin

 

Perineural invasion (PNI)

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Common (85% of all tumors); when present in needle core biopsy, suggests extraprostatic extension , AJCP 1999;111:223 but see AJSP 2003;27:432

Diameter of perineural invasion may be prognostic factor (Hum Path 2001;32:828)

May mediate local tumor spread via tumor expression of nerve cell adhesion molecule, Hum Path 2003;34:457

Outdated theories are: spread via perineurial lymphatics (they don’t exist), that perineurial space represents tissue plane of least resistance (AJSP 1980;4:143, doesn’t explain why morphologically similar tumors have varying neurotropism), different nerve distribution in malignant vs. benign specimens (actually is similar, S100 not useful for identifying PNI, AJCP 2001;115:39)

Micro images: image1

Reference: AJSP 2000;24:1634, AJSP 2003;27:519

 

Prostatic secretory granules

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Identifiable with strong glutaraldehyde fixation

1 micron, brightly eosinophilic granules (PSA+, PAP+) that fill cytoplasm of secretory cells

Reduced in carcinoma and high grade PIN, Hum Path 2000;31:1515

Formaldehyde causes granules to appear empty, Hum Path 1998; 29:1488

 

Features diagnostic of adenocarcinoma: perineural invasion (benign glands appear benign, and are present only at one edge of nerve), glomerulation, mucinous fibroplasia (collagenous micronodules); PNI may be the only diagnostic feature of malignancy, AJSP 1999;23:918

 

Features favoring diagnosis of adenocarcinoma: small glands between larger glands, crowded glands that stand out from adjacent benign glands, prominent nucleoli, nuclear enlargement, hyperchromatic nuclei, amphophilic cytoplasm, mitotic figures, blue luminal mucin, pink luminal mucin, crystalloids, adjacent high grade PIN

 

Warning features: atrophic cytoplasm, atypical glands associated with inflammation, small crowded glands merging with larger benign glands (adenosis), small crowded glands with corpora amylacea (adenosis), high grade PIN, small atypical crowded glands adjacent to high grade PIN (may be tangential sectioning of PIN)


Other prostate carcinomas

Urothelial carcinoma (primary)

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< 2% of primary tumors

Arises from urothelium in periurethral ducts

Looks identical to bladder tumors

Usually invades bladder neck and surrounding soft tissue

20% have distant metastases, commonly to bone, lung, liver; bone metastases usually osteolytic, not osteoblastic

Often in patients with bladder carcinoma in situ treated with intravesical chemotherapy, because although chemotherapy kills bladder tumor, it doesn’t reach prostatic urethra, prostatic ducts and acini

Poor prognosis even with in-situ disease only

Treatment: cystoprostatectomy, possibly chemotherapy, radiation therapy

Note: 50% with cystoprostatectomy for urothelial carcinoma also have prostate adenocarcinoma, although not necessarily high grade

Micro: in situ component usually present, consisting of nests of neoplastic cells filling prostatic ducts, often with central comedonecrosis; stromal invasion almost always present and characterized by small nests of tumor cells with marked anaplasia and frequent mitotic figures, even compared to poorly differentiated prostatic adenocarcinoma

In prostate needle biopsies, often see in-situ only or in-situ plus invasion; invasive urothelial carcinoma only is rare (9%);

Note: it is important to identify prostatic stromal invasion in cases with intraductal urothelial carcinoma, especially in patients with low grade bladder tumors, since prognosis is poor

Micro images: in situ disease, lymph node metastases from high grade urothelial carcinoma and Gleason 7 prostatic adenocarcinoma, Leu7/CD57

Positive stains: urothelial carcinoma in prostatic ducts may have confusing PSA/PAP staining, since residual ducts are immunoreactive; however, PSA/PAP does not stain urothelial carcinoma cells

Invasive urothelial carcinoma vs. high grade prostatic adenocarcinoma: 34betaE12: 65% vs 6%; CK7: 83% vs 12%; Leu7/CD57: 17% vs. 94%; p53: 33% vs. 3% [positive is any staining for all but p53; p53 required 20% of cells staining], uroplakin/thrombomodulin: 49-60% vs. 0%, Mod Path 2000;13:1186, Hum Path 2002;33:1136

In AJCP 2000;113:383, high grade urothelial carcinomas (varying grade) always PSA negative; positivity of both CK7 and CK20 is predictive of urothelial vs. prostate,

DD: bladder extension of urethral carcinoma

DD: high grade urothelial carcinoma vs high grade prostate: urothelial has more nuclear pleomorphism, variable nucleoli, clumped chromatin; increased mitoses, necrosis, pagetoid spread (rare in prostate adenocarcinoma), AJSP 2001;25:794


Sarcoma/lymphoma/other malignancies

Angiosarcoma

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Rare in prostate, < 10 cases reported

Case report 10 years after radiotherapy for prostatic adenocarcinoma, Archives 2003;127:876

Criteria for radiation-induced sarcoma: the sarcoma should arise in the area previously subjected to irradiation, a latent period (in years) must exist between the time of irradiation and development of the sarcoma, and the sarcoma must be confirmed histologically, Cancer 1948;1:3–29

Gross: extensive necrosis

Micro: proliferative vascular channels lined by atypical, multilayered or solid endothelial cells; tumor cells pleomorphic, varying from spindled to large/plump; large pleomorphic nuclei with clumped chromatin and prominent nucleoli; frequent mitotic figures, some atypical

Micro images: image1

Positive stains: CD34, Factor 8, vimentin

Negative stains: PSA, S100, keratin

 

Embryonal rhabdomyosarcoma

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Most common malignant tumor in children/infants

Firm, smooth enlargement of prostate

Nodal metastases less common than in this tumor in head and neck

Usually present with stage 3 disease, sometimes with distant metastases

80% are cured; most stage 4 patients die of disease

Prognosis:  better if leiomyosarcoma-like appearance

Treatment: multiple agent chemotherapy, surgery and radiation

Micro: cellular, particularly around blood vessels, alternating with myxoid/edematous areas and necrosis; small round / oval / spindly tumor cells; may have bizarre forms with abundant, eosinophilic cytoplasm, variable cross striations; usually extraprostatic extension

DD: bladder rhabdomyosarcoma (may be difficult to distinguish if tumor is large)

 

Leiomyosarcoma

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Causes obstruction, involves adjacent organs

Most common sarcoma in adults

Mean survival 3-4 years; tend to recur; metastases to liver and lung

Gross image: image1

DD: nodular hyperplasia with atypical changes, postoperative spindle cell nodules

 

Lymphoma

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10% of non-Hodgkin’s lymphomas and 10% of leukemias (20% of CLL) involve the prostate

Approximately 1% of pelvic lymph nodes removed at prostatectomy demonstrate malignancy, usually SLL; often no other signs/symptoms

Associated with acute urinary obstruction

Rarely is initial site for Hodgkin’s lymphoma or angiotropic lymphoma

SLL may be incidentally identified in pelvic lymph nodes, Archives 2003;127:567

Treatment (SLL): radiation therapy for symptoms

Gross (SLL): enlarged nodes (mean 3.2 cm)

Micro (SLL): diffuse architectural effacement, replacement of sinuses by tumor cells, pseudofollicles usually present, lack of cortical follicles

Micro images: SLL

 

Malignant fibrous histiocytoma

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Micro images: image1

 

PEComa

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Perivascular epithelioid cell tumors (PEComas) include clear cell “sugar” tumor of lung, lymphangiomyomatosis, angiomyolipoma

Case report of malignant PEComa in 46 year old man involving prostate and seminal vesicle, Archives 2003;127:E96

Micro: epithelioid cells with clear/granular cytoplasm in perivascular distribution

Micro images: image1

Positive stains: HMB45, variable MelanA/MART1

Negative stains: keratin, S100

EM: may have premelanosomes

DD: clear cell sarcoma of soft parts (no vascular stroma, no perivascular arrangement of tumor cells, S100+)

 

Phyllodes tumor

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Rare

Cellular or sarcomatoid stroma and hyperplastic glands; resembles breast tumor

Case report of malignant tumor, Archives 1992;116:296

Case report of large benign tumor, Archives 1992;116:195

 

Primitive peripheral neuroectodermal tumor / PNET

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First case report in 31 year old man at Archives 2003;127:e190

Micro: solid nests and sheets of small round cells

Micro images: image1

Positive stains: CD99/MIC2, vimentin, neuron-specific enolase, synaptophysin

Molecular: EWS/FLI1 type 2 chimeric transcript

DD: small cell carcinoma (solid growth, variable rosettes, CD99-), rhabdomyosarcoma (muscle markers+, 20% are CD99+), lymphoma (90% of lymphoblastic lymphoma are CD99+ but also TdT+ and EWS/FLI1 negative), desmoplastic small round cell tumor (keratin+, desmin+, WT1+)

 

Solitary fibrous tumor

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Rare (< 10 cases reported); often misdiagnosed

Some cases have malignant behavior

Micro: collagenization, hemangiopericytoma-like foci, spindled cells between strips of collagen; two cases described were (a) well circumscribed, minimal mitotic activity or pleomorphism and (b) cellular, less collagenous, more diffuse growth pattern, cytologic atypia, high mitotic activity

Gross/micro images: image1

References: Archives 2001;125:274, Hum Path 2000;31:63

 

Stromal proliferation of uncertain malignant potential

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May resemble breast phyllodes tumors

May recur rapidly after resection and progress to stromal sarcoma

Four patterns: (1) hypercellular stroma with scattered cytologically atypical cells associated with benign glands, (2) hypercellular stroma with minimal cytological atypia associated with benign glands, (3) hypercellular stroma with or without cytologically atypical cells, associated with benign glands in a "leaf like" growth pattern that resembled phyllodes tumors of the mammary gland, and (4) hypercellular stroma without cytologically atypical stromal cells and without glands, AJSP 1998;22:148

DD: stromal sarcomas, phyllodes tumors

 

Stromal sarcomas

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Mean age 54, peak incidence in 50’s and 60’s

Usually present with urinary retention; also abnormal digital rectal examination, hematuria or hematospermia, palpable rectal mass

Includes phyllodes tumors (see above)

Micro: greater cellularity, mitoses, necrosis, and stromal overgrowth than tumors of “uncertain malignant potential”; either pure stromal elements or stromal elements with benign glands resembling malignant breast phyllodes tumors

Positive stains: vimentin (100%), CD34 (100%), progesterone receptor (85%), desmin (50%), smooth muscle actin (33%), HHF-35 (25%)

Negative stains: S100 (100%), ER (usually)

DD: stromal proliferation of uncertain malignant potential

References: AJSP 1998;22:148

 

Synovial sarcoma

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Case report of monophasic synovial sarcoma in 37 year old man, AJSP 1999;23:220

Micro: uniform spindle and oval cells forming interlacing fascicles resembling fibrosarcoma; focally the compact fascicles of tumor cells alternate with hypocellular myxoid tissue resembling peripheral nerve sheath tumors, focal pericytomatous pattern of polygonal cells arranged around dilated, thin-walled blood vessels

Positive stains: vimentin (most cells), EMA (focal)

Negative stains: S100, keratin, neuron-specific enolase, CD34, desmin, muscle-specific actin, alpha-smooth muscle actin

Molecular: t(X;18)(p11.2;q11.2)

 

Yolk sac tumor

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Case report with small seminoma, AJSP 2003;27:554

 

 

Miscellaneous

Staging

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Primary tumor (T) – Clinical staging

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TX:  Primary tumor cannot be assessed

T0:  No evidence of primary tumor

T1:  Clinically inapparent tumor neither palpable nor visible by imaging

T1a:  Tumor incidental histologic finding in 5% or less of tissue resected

T1b:  Tumor incidental histologic finding in more than 5% of tissue resected

T1c:  Tumor identified by needle biopsy (e.g. because of elevated PSA)

T2: Tumor confined within prostate

T2a:  Tumor involves one half of one lobe or less

T2b:  Tumor involves more than one half of one lobe, but not both lobes

T2c:  Tumor involves both lobes

T3:  Tumor extends through the prostatic capsule

T3a:  Extracapsular extension (unilateral or bilateral)

T3b:  Tumor invades seminal vesicle(s)

T4:  Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles or pelvic wall

 

Notes:

● Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c

● Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2, not T3

 

Primary tumor (T) – Pathologic staging

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pT2:  Organ confined

pT2a:  Unilateral, one half of one side or less

pT2b:  Unilateral, involving more than one half of one side, but not both sides

pT2c:  Bilateral disease

pT3:  Extraprostatic extension

pT3a:  Extraprostatic extension or microscopic invasion of bladder neck

pT3b:  Seminal vesicle invasion

pT4:  Invasion of rectum, levator muscles or pelvic wall

 

Notes:

● Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c

● Invasion into the prostatic apex or into (but not beyond) the prostati9c capsule is classified as T2, not T3

● There is no pathologic T1 classification

● Margins are important, and margin status is independent of T classification.  Classify positive margins as either focal or extensive based on the length of involvement of the inked line of resection.

● Laterality of extraprostatic extension (EPE) is not prognostically important.  EPE should be quantitated as focal (< 1 HPF on 1-2 sections) or nonfocal.  Determine EPE in radical prostatectomy specimens by comparing the presence of tumor to the normal edge of the prostate gland.  Seminal vesicle invasion means tumor invades its muscular coat, seen first at the base of the seminal vesicles.  The amount of tumor in the seminal vesicles is not important.  pT3 can have positive or negative margins.  Patients with clinical T3 disease are usually not surgical candidates - 50% have nodal metastases at diagnosis, 50% develop metastases at 5 years and 75% die of prostate carcinoma within 10 years. 

Micro images: extraprostatic extension

 

Margins: apex is most frequent site of positive margin; positive margins at base usually indicate extensive disease; tumor at anterior region margin usually is considered extraprostatic extension because usually is exterior to prostate.  Close margins (< 1 mm) are considered adequate for prostate.

 

Regional lymph nodes (N)

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NX:  Regional lymph nodes were not assessed

N0:  No regional lymph node metastasis

N1:  Metastasis in regional lymph node(s)

 

Notes:

● pNX, pN0 and pN1 are the same as cNX, cN0 and cN1

● NX, N0, N1 may lack clinical relevance.  Some surgeons proceed with radical prostatectomy even if nodes are positive at frozen section if preoperative Gleason score is 7 or less, since time to onset of distant metastases is long. 

● Metastases to periprostatic or periseminal vesicle lymph nodes suggests poor prognosis, AJSP 2001; 25:1429

 

Distant metastases (M)

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M0:  No distant metastasis

M1:  Distant metastasis

M1a:  Distant metastasis to non-regional lymph node(s)

M1b:  Distant metastasis to bone(s)

M1c:  Distant metastasis to other site(s) with or without bone disease

 

Note: When more than one site of metastasis is present, the most advanced category is used.  pM1c is most advanced.

 

Anatomic stage / Prognostic groups

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Stage I:  T1a-2a N0 M0   PSA<10   Gleason 6 or less  OR

   T1-2a N0 M0   PSA unknown   Gleason unknown

Stage IIA:  T1a-c N0 M0   PSA < 20   Gleason 7   OR

   T1a-c N0 M0   PSA 10-19.9   Gleason 6 or less   OR

   T2a-b N0 M0   PSA < 20   Gleason 7 or less   OR

   T2b N0 M0   PSA unknown   Gleason unknown

Stage IIB:  T2c N0 M0   Any PSA   Any Gleason   OR

   T1-2 N0 M0   PSA 20 or higher   Any Gleason   OR

   T1-2 N0 M0   Any PSA   Gleason 8 or higher

Stage III:  T3a-b N0 M0   Any PSA   Any Gleason score

Stage IV:  T4 or N1 or M1

 

Notes:

When either PSA or Gleason is not available, grouping should be determined by T stage or either PSA or Gleason as available

 

Features to report

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Prostatectomies:

Structures included in specimen (prostate [complete or not], seminal vesicles, vas deferens, bladder neck)

Weight, size in 3 dimensions

Histologic type and location of tumor (if any)

Gleason pattern/grade and score

% of prostate involved by tumor (need not give volume but an indication of minute vs. voluminous)

Presence of perineural invasion (diameter may be prognostic factor, Hum Path 2001;32:828)

Presence of angiolymphatic invasion, AJSP 1996;20:1351

Presence of extraprostatic tissue invasion

Presence of seminal vesicle invasion

Presence of high grade PIN

Margins

Lymph nodes (# involved, # sampled) and diameter of largest metastasis, AJSP 1998;22:1491

Acute or chronic inflammation (often doesn’t correlate with clinical prostatitis)

Granulomatous prostatitis (may elevate PSA, produce suspicious feeling gland)

 

Note: extranodal tumor extension not related to survival, Mod Path 2000;13:113

 

Biopsies (core or transurethral prostate resection)

Histologic type

Gleason primary and secondary grades and total score

Percentage positivity of each core, # cores involved, # cores total

Presence of perineural, angiolymphatic or extraprostatic tissue invasion

Presence of high grade PIN (if no carcinoma, report # of cores involved and pattern of high grade PIN)

Therapy related changes

 

Reference: Archives 2000;124:1034, AJSP 1997;21:1496 (perineural invasion doesn’t predict extraprostatic extension)

 

Grossing prostate specimens

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Radical prostatectomy: totally embed or systemic sampling

 

Systemic sampling (12-13 blocks)

Ink surface with 2 colors to designate left versus right

Amputate apex and serial section parallel to urethra

For base, thin shave or amputate and serial section parallel to urethra

Submit base of seminal vesicles, margins of right and left vas deferens

Serial section prostate perpendicular to urethra, submit all gross tumor (look in peripheral zone, posterior or posterior-lateral area for asymmetry in size, color, density between left and right sides)

 

Transurethral resection biopsies (prostate chips)

If specimen 12 g or less, submit all

If specimen more than 12g, submit at least 12 g; if unsuspected carcinoma found that involves 5% or less of tissue examined, submit remaining tissue (may increase stage from T1a to T1b)

 

 

Seminal vesicles and Cowper's glands

 

Normal

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Seminal vesicles

Thick muscular wall, complex mucosal folds, columnar and basal cells

Columnar cells associated with atypical appearing “monster” cells and lipofuscin pigment, wall may contain hyaline globules (degenerative), AJSP 1981;5:483

Lipochrome pigment granules may be type 1 (coarse, golden yellow-brown, usually abundant, usually in seminal vesicle/ejaculatory duct epithelium) or type 2 (fine, gray-brown, or dark and scant, present in occasional prostate adenocarcinomas or normal prostate acini)

Crystalloid type secretions common, although usually multiple, curved edges, varied forms (elliptical, cylindrical, rodlike, and rectangular); not associated with malignancy, Archives 2001;125:141

Normal seminal vesicles may be aneuploid, Mod Path 1991;4:687

MUC6 staining (seminal vesicles + vs. adenocarcinoma -) may differentiate from prostatic adenocarcinoma, AJSP 2003;27:519

Micro images: image1, image2, image3

Positive stains: MUC6

 

Cowper's glands-normal

Aka bulbourethral glands

Well demarcated lobules composed of small, compact glands resembling minor salivary glands, radiating from a central excretory duct lined by pseudostratified epithelium, and entrapped within fascicles of muscle

Mucin producing glands in urogenital diaphragm seen occasionally in TURP specimens, rarely in needle biopsies

Micro images: image1, image2, image3, image4

Positive stains: mucin, smooth muscle actin (periphery of acini)

Negative stains: PSA (variable), PAP, S100, CEA, CK903 (usually)

EM: acini lined by secretory cell layer, with myoepithelial cells at periphery of acini

References: AJSP 1997;21:1069, AJSP 1997;21:550

 

Seminal vesicles - benign or non-neoplastic lesions

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Amyloidosis

Commonly occurs in seminal vesicles

Incidence increases with age, reaching 21% in men age 75 years and older (Histopathology 1993;22:173, Am J Pathol 1983;110:64). 

Usually a localized finding

Although immunohistochemistry often detects lactoferrin (Ann Pathol 2004;24:236), amyloid apparently derives from semenogelin I, the major secretory product of the seminal vesicles (J Lab Clin Med 2005;145:187)

Semenogelin I and II are mainly responsible for immediate gel formation of freshly ejaculated semen, and are degraded by the proteolytic action of prostate specific antigen/PSA (J Androl 1996;17:17, free full text)

Case reports: Case of the Week #85

Micro images: image #1#2#3#4trichrome #1#2

Positive stains: trichrome (stains amyloid dusky gray), Congo Red

EM: nonbranching fibrils (Mod Path 1989;2:671)

 

Cystadenomas

Incidental finding in elderly men; multilocular

May have cytologic atypia / low malignant potential and recur, AJSP 1987;11:210

Negative stains: PSA, PAP

 

Cysts

Present as masses between rectum and base of bladder in men in 20’s

Usually unilateral, unilocular and resemble dilated seminal vesicles

Congenital cysts are associated with ipsilateral renal agenesis, ureteral abnormalities, oligospermia

Acquired cysts associated with obstruction secondary to chronic prostatitis

 
Tuberculosis

Usually secondary to prostatic infection, in glands adjacent to organ

 

Seminal vesicles - carcinoma

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Primary carcinoma

Very rare, must confirm microscopically, should be localized primarily to seminal vesicle, must rule out invasion from prostate (do PSA/PAP) or rectum or other site; should preferable be a papillary adenocarcinoma resembling architecture of normal seminal vesicle

Resembles Gleason patterns 3 or 4, prostatic duct adenocarcinoma, mucinous (colloid) carcinoma

Usually unresectable and patients die within 2 years

Micro images: image1, image2, CK7, CA-125

Positive stains: CK7, CA-125

Negative stains: PSA, PAP, CK20

DD: prostatic adenocarcinoma (PSA+, PAP+, CA-125 neg), bladder urothelial carcinoma (CK20+, CA-125 neg), rectal adenocarcinoma (CA-125 neg, CK7 neg, CK20+), bladder adenocarcinoma (CA-125 neg)

References: Hum Path 1987;18:200, Mod Path 2000;13:46

 

Adenocarcinoma of Cowper’s glands

Very rare, must rule out prostate primary

Often mucin producing, ulcerate through skin of scrotum

 

Mullerian adenosarcoma like tumor

Case report in 49 year old man, occupied right sided seminal vesicle and adhered to right side of prostate and rectum; disease free after cystoprostatectomy, Archives 1992;116:1072

Micro: highly cellular stroma with spindle-shaped pleomorphic cells suggestive of low grade sarcoma; also dilated cystic spaces lined by columnar epithelia

Positive stains: vimentin, desmin, muscle-specific actin

EM: smooth muscle differentiation

 

Urothelial carcinoma involvement of seminal vesicle

Direct extension or mucosal spread without stromal invasion, AJSP 1987;11:951

 

End of prostate chapter