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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 references, anatomy, histology, PSA
Prostatitis: prostatitis, prostatitis with eosinophils, malakoplakia, other infections, abscess
Granulomatous lesions: general, non-specific, allergic granulomatous prostatitis, post-TURP granulomas, TB-bCG granulomas
Benign lesions/conditions: amyloid, blue nevus, calculi, cystadenoma, ectopic prostate, endometriosis, extramedullary hematopoiesis, ganglioneuroma, infarct, inflammatory pseudotumor, leiomyoma, lipofuscin, melanosis, nodular hyperplasia, Paneth cell-like change, postoperative spindle cell nodules, pseudosarcomatous fibromyxoid tumor, retention cysts, rhabdomyoma, signet ring nodule, urethral polyps, utricle cysts, venous thrombosis
Prostatic intraepithelial neoplasia/PIN: low grade PIN, high grade PIN, with adjacent small atypical glands
Prostatic carcinoma: general, histologic treatment effect, core biopsies, adenocarcinoma of peripheral ducts, grading, immunohistochemistry, atypical glands suspicious for malignancy, vanishing cancer phenomenon
Other carcinomas: adenoid basal cell tumor, adenosquamous, atrophic, atypical cribriform lesions, basaloid carcinoma, carcinoid tumor, carcinosarcoma, clear cell adenocarcinoma, foamy gland adenocarcinoma, lymphoepithelioma-like carcinoma, metastases to prostate, mucinous (colloid), mucinous adenocarcinoma-bladder type, neuroendocrine, prostatic duct carcinomas, pseudohyperplastic, signet ring, small cell, squamous cell, urothelial carcinoma
Microscopic mimics of prostatic carcinoma: adenosis/atypical adenomatous hyperplasia, atrophy, basal cell hyperplasia, clear cell cribriform hyperplasia, Cowper's glands, mesonephric remnant hyperplasia, mucous gland metaplasia, nephrogenic metaplasia/adenoma, paraganglion tissue, partial atrophy, post-atrophic hyperplasia, radiation changes, sclerosing adenosis, seminal vesicles / ejaculatory duct, squamous metaplasia, urothelial metaplasia, verumontanum mucosal hyperplasia, xanthoma cells
Other malignancies: angiosarcoma, ectomesenchymoma, embryonal rhabdomyosarcoma, leiomyosarcoma, lymphoma, malignant fibrous histiocytoma, PEComa, phyllodes tumor, PNET, solitary fibrous tumor, stromal proliferations of uncertain malignant potential, stromal sarcoma, synovial sarcoma, yolk sac
Miscellaneous: staging, features to report, grossing specimens
Seminal vesicles/Cowper's glands: normal, benign, carcinoma
top
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: PathoPic, Webpathology.com
Please refer to these primary references for more detailed discussions and photographs
Benign or non-neoplastic conditions of prostate and prostatic urethra
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)
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
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
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
Symptomatic cysts, 1-2 cm, usually unilocular, adjacent to urethra
Lined by flattened prostatic glandular epithelium or urothelium
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
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
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
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
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)
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
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
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 power; high 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
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
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
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
Basal cell stains on core biopsies
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
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
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
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
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
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
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
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)
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
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)
< 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
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
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)
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
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
Micro images: image1
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+)
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
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+)
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
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
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
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)
Case report with small seminoma, AJSP 2003;27:554
Miscellaneous
Primary tumor (T) – Clinical staging
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
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)
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)
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
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
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
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)
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)
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
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; #4; trichrome #1; #2
Positive stains: trichrome (stains amyloid dusky gray), Congo Red
EM: nonbranching fibrils (Mod Path 1989;2:671)
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
Usually secondary to prostatic infection, in glands adjacent to organ
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
Very rare, must rule out prostate primary
Often mucin producing, ulcerate through skin of scrotum
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
Direct extension or mucosal spread without stromal invasion, AJSP 1987;11:951
End of prostate chapter
