Prostate gland and seminal vesicles
Last revised 6 February 2010
Copyright © 2002-2010 PathologyOutlines.com, Inc.
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Table of Contents
Prostate: normal, histology, prostatitis, prostatitis with eosinophils, malakoplakia, other infections, abscess
Granulomatous lesions: granulomatous prostatitis, 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, melanosis, 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, carcinosarcoma, clear cell adenocarcinoma, foamy gland adenocarcinoma, lymphoepithelial like carcinoma, mucinous (colloid), mucinous adenocarcinoma-bladder type, neuroendocrine, other primaries, 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, Cowpers 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
Sarcoma/lymphoma/other malignancies: angiosarcoma, 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/Cowpers glands: normal, benign, carcinoma
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AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology (AJCP), Dec 1971 to July 2002
American Journal of Surgical Pathology (AJSP), March 1977 to July 2003
Archives of Pathology and Lab Medicine (Archives), January 1976 to July 2003
Human Pathology (Hum Path), Nov 1978 to July 2003
Modern Pathology (Mod Path), Sept 1988 to July 2003
AJCC Cancer Staging Manual (6th Ed)
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
www.Webpathology.com - source of numerous beautiful images
Please refer to these primary references for more detailed discussions and photographs
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Function: conduit for urine, adds nutritional secretions to sperm to form semen during ejaculation
20 g, funnel shaped, 4 x 3 x 2 cm
Within true pelvis between bladder neck (base of prostate) and urogenital diaphragm / levator ani muscle (apex of prostate)
Apex contains some muscle fibers from urogenital diaphragm
Seminal vesicles extend from posterior prostate to posterior surface of bladder
Ampulla of Vas (ductus) deferens and terminal seminal vesicle duct form ejaculatory duct, join prostatic utricle to open into prostatic urethra
Diagrams #1, #2, #3
Denonvillier’s fascia (aka rectovesicle septum): thin layer of connective tissue that separates prostate and seminal vesicles from rectum
Prostatic urethra begins on superior surface, descends almost vertically, with continuous prostatic utricle extending to posterior prostatic wall, exits anteriorly; divided into halves by sharp 35 degree angle midway, at site of verumontanum (bulge along posterior proximal urethra; site of emptying of ejaculatory, central and transition zone ducts)
Peripheral zone ducts empty into distal urethra
Prostatic nervous plexus supplies prostate, seminal vesicles, corpus spongiosum, corpora cavernosum and urethra; nerves distributed evenly in apex, mid gland and base of prostate, AJCP 2001;115:39
Anatomical models
Embryologic model: 5 lobes: 2 lateral plus posterior, middle, anterior lobes
Other model (not used): 2 lateral lobes, small median lobe (contains posterior lobe, forms floor of urethra)
Current model (McNeal): transitional, central, peripheral, periurethral zones
Drawings: McNeal zones
Outer (cortical) zones are termed “peripheral” and “central”; central is towards base
Inner (periurethral) zone is termed “transitional”
PSA
Glycoprotein; kallikrein related serine protease produced by secretory epithelium, drains into ductal system; cleaves and liquefies seminal coagulum formed after ejaculation
PSA > 4 seen in 80% with histologically documented cancer but also in 25-30% with nodular hyperplasia, prostatitis, infarcts, prostatic massage, cystoscopy; elevated in 2 of 18 post-race marathon runners, Archives 2003;127:345
Annual testing recommended for men 50+, men 40+ at increased risk
PSA density (PSA per volume of prostate gland), velocity (changes in PSA with time), %free (unbound to alpha-1-antichymotrypsin), serial measurements important for follow up
Reference: AJCP 1994;102 (4 Supp 1): S31
Transition zone
5% of prostatic volume; 2 pear shaped lobes surrounding proximal urethra
Site of nodular prostatic hyperplasia, may expand to bulk of gland
Site of 10% of prostate cancers (large duct carcinomas)
Contains moderately compact fascicles of smooth muscle
Central zone
25% of prostatic volume; surrounds transition zone to angle of urethra to bladder base
Site of 5% of prostate cancers
Unlike peripheral and transition zones, ducts are large and irregular; glands are complex with tall columnar, pseudostratified, papillary infoldings; striking basal cell layer with eosinophilic cytoplasm
Stroma is densest in central zone, least dense in peripheral zone, in between for transition zone
Reference: Hum Path 2002;33:518
Peripheral zone
70% of prostatic volume, from apex posterior to base, surrounds transition and central zones
Site of 80% of prostate cancers
Has loose fibromuscular stroma with widely spaced smooth muscle bundles, moderate gland complexity
Prostatic non-glandular tissue
“Capsule”: fibromuscular layer most prominent along base and posterior portion of lateral borders; an inseparable component of prostatic stroma, not a distinct capsule, AJSP 1989;13:21
Along lateral borders, fibrous septa traverse periprostatic fat and merges with fibromuscular stroma
Anteriorly, prostatic stroma merges with fibromuscular tissue of urogenital diaphragm
Stroma contains abundant smooth muscle, which duplicates function of myoepithelial cells in breast; i.e. squeezes out secretions
Prostatic glandular tissue
Prostate glands found normally within skeletal muscle at apex, anteriorly, and in distal posterolateral gland
Secrete normal mucins, produce pigment (lipofuscin), are androgen sensitive (castration causes atrophy); differentiation and growth is androgen dependent
Large prostatic ducts have single layer of urothelial-like epithelium without umbrella cells, which is PSA/PAP positive; may undergo squamous metaplasia with estrogen therapy
Benign tissue may contain hyaline globules (degenerative, aka thanatosomes, AJSP 2003;27:700), may be adjacent to skeletal muscle or nerves
Micro images: image1, image2, image3, concretions #1, #2, stroma #1, #2, spermatozoa
Type of cells
secretory cells, basal cells, scattered neuroendocrine cells, urothelium, ejaculatory duct/seminal vesicle type cells
Secretory cells
Located along glandular lumen
Positive stains: prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), vimentin, keratin (some), Leu7/CD57, EMA (80%), CEA (25%)
Negative stains: CK903 (34 beta E12, high molecular weight keratin)
Basal cells
Separate secretory cells from basement membrane; consist of low cuboidal epithelium and columnar mucus secreting cells; may have prominent nuclear groove, prominent nucleoli
May be reserve cells (stem cells), can undergo myoepithelial metaplasia but are NOT myoepithelial cells
Their presence differentiates benign conditions (basal cells are present) from well differentiated adenocarcinoma (not present)
Micro images: 34betaE12
Positive stains: CK903 (34 beta E12 / high molecular weight keratin), p63, androgen receptors
Negative stains: PSA, PAP, S100, actin
Neuroendocrine cells
Irregularly distributed
Micro images: image1
Positive stains: chromogranin A, B, secretogranin II, peptide hormones, PSA
Negatives stains: androgen receptors
Urothelium
In proximal 2 mm of prostatic ducts
Ejaculatory ducts and seminal vesicles
Lined by double cell layer of pseudostratified epithelium, contain lipofuscin (golden-brown pigment), have large, hyperchromatic nuclei (also called "monster" nuclei), may have intranuclear inclusions
Mucins
Normal mucins are neutral; most adenocarcinomas secrete acidic and neutral mucins
Glandular secretions
Can identify with glutaraldehyde based fixatives, fill the normal secretory cell cytoplasm, distinct bright red on H&E staining because of high polyamine content; also present in penile urethra, Hum Path 2002;33:905
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Diagnosis based on quantitative bacterial cultures and microscopic examination of fractionated urine specimens (first 10 ml of urine is urethral, midstream urine is from bladder) and expressed prostatic secretions
Definition: >10 WBC/HPF in prostatic secretions without pyuria; prostatic secretion cultures should have bacterial counts 10x urethral/bladder cultures
Clinical: elevated PSA
Treatment: difficult because antibiotics penetrate poorly into prostate
Micro: macrophages in stroma, neutrophils in ducts/acini are specific for acute prostatitis and usually localized; lymphoid aggregates are common with aging and nodular hyperplasia and not specific for prostatitis
Micro images: image1
DD of lymphoid aggregates: SLL/CLL
Acute bacterial prostatitis: same bacteria types as urinary tract infections (E. coli, gram negative rods, enterococci, staphylococci), usually due to reflux, also following surgical manipulation or sexually transmitted disease; usually localized, may cause obstruction, retention, abscess
Chronic bacterial prostatitis: symptoms of low back pain, dysuria, perineal and suprapubic discomfort; often have history of urinary tract infection by same organism; may have NO symptoms
Chronic abacterial prostatitis: similar clinically to chronic bacterial prostatitis but negative cultures; may be due to sexually transmitted disease organisms of Ureaplasma urealyticum, Chlamydia trachomatis, Mycoplasma hominis
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DD: nonspecific granulomatous prostatitis, eosinophilic prostatitis, iatrogenic granulomas or parasitic infestation
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May involve prostate, usually associated with bladder disease
Ages 47+
Represents a peculiar form of tissue reaction to bacterial infection
Usually periductal, may resemble carcinoma on ultrasound, may actually coexist with carcinoma
Prostate enlarged on clinical examination, suggestive of carcinoma
Micro images: image1
DD: nodular histiocytic prostatitis - similar but without Michaelis-Gutmann bodies
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Dimorphic fungi associated with AIDS or other immunocompromise, usually with hematogenous dissemination
Chlamydia trachomatis and Trichomonas vaginalis often present (Archives 1986;110:430), but unknown if they are pathogens
AIDS related changes: epithelial cell apoptosis (simple cell shrinkage and exploding glandular cells), intracytoplasmic inclusions (apoptotic bodies) associated with lipofuscin, Archives 1998;122:875; increased numbers of concretions, AJCP 1990;93:196
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Usually due to obstruction and E. coli; historically was often due to gonorrhea
Symptoms: acute urinary retention, perineal pain; prostate fluctuation on digital rectal exam
Diagnosis: transrectal ultrasound
Treatment: incision and drainage and antibiotics
Granulomatous lesions
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Rare (< 1%) immune mediated reaction to prostatic secretions released from obstructed ducts
Usually associated with nodular hyperplasia in men age 50+
Symptoms: 20% have triad of high fever, prostatitis symptoms and hard prostate on digital rectal examination
Gross: stone hard to firm, obliterated architecture, yellow nodules
Micro: granulomas centered in lobules with multinucleated giant cells (30% of cases), epithelioid histiocytes, lymphocytes, plasma cells, fibrosis and eosinophils (may be prominent, Archives 1997;121:724); no organisms, no caseation
Early: mostly neutrophils and desquamated epithelial cells; late: granulomatous and chronic inflammatory cells
Positive stains: histiocytes for lysozyme
Negative stains: PSA/PAP in histiocytes (AJCP 1991;95:330)
DD: carcinoma (primary, metastatic), acid-fast bacilli, fungi, BCG treatment of bladder, post TURP
Allergic granulomatous prostatitis
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Very rare ( <20 reported cases)
Reflects asthma or systemic allergic reaction; often serum eosinophilia, systemic granulomas
Treatment: steroids
Micro: multiple small, necrobiotic granulomas surrounded by numerous eosinophils; diffuse stromal eosinophils
DD: Post-TURP granulomas with eosinophils (more irregular granulomas, eosinophils not diffuse)
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Formerly eosinophilic prostatitis
No systemic symptoms, develop months to year after TURP or rarely after needle biopsy
Occur after cautery in other sites
Hair granuloma: post-TURP, hair probably embedded in prostate by earlier needle biopsy, Hum Path 1996;27:196
Micro: central region of fibrinoid necrosis surrounded by pallisading histiocytes; resembles rheumatoid nodules; long tortuous granulomas may dissect tissue; minimal surrounding inflammation (lymphocytes, plasma cells, rare eosinophils); more eosinophils in first month after TURP, AJSP 1984;8:217
Micro images: image1
Tuberculosis and bCG-related granulomas
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Tuberculosis
Prostate is most common site for tuberculosis in male GU tract (involved in >90% of cases with GU involvement), due to hematogenous spread from lungs or direct invasion from urethra
May perforate into urethra and extend into bladder or rectum
May calcify or become small and fibrotic, resembling carcinoma
Diagnosis: fluctuant, tender zones, usually bilateral, on digital rectal examination
bCG
Due to intravesical treatment with bacillus Calmette-Guerini for bladder carcinoma
Causes caseating or non-caseating granulomas; usually AFB negative
Located along periurethral or transition zone or diffuse
No specific therapy required, although rarely disseminates as tuberculosis
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Aka benign prostatic hypertrophy
Periurethral nodules may compress urethra and cause obstructive symptoms
Present in 20% of men at age 40, 50% at age 50, 70% at age 60
No correlation between histology and symptoms (50% with histologic disease have clinical enlargement of prostate, 50% of these have symptoms)
Recommended to not use this diagnosis on biopsies due to lack of correlation with obstructive symptoms; however presence of stromal nodules does correlate with increased prostatic weight, Hum Path 2002;33:796
Physiology: requires intact testes; testosterone and dihydrotestosterone (DHT, 10x more potent than testosterone because it dissociates from receptor more slowly) bind nuclear androgen receptors in stromal and epithelial cells, causing growth factor activation
Stromal cells produce 5 alpha reductase (converts testosterone to DHT)
Estradiol, increased in aging men, may also increase androgen receptors
Symptoms: urinary tract infection, obstruction, acute urinary retention, bladder hypertrophy, trabeculation, diverticula
NOT associated with prostatic adenocarcinoma, although it may develop in residual gland after TURP
One study showed transition from nodular hyperplasia to transition zone adenocarcinoma in some cases, Hum Path 2003;34:228
Treatment: transurethral resection of prostate (TURP, #2 most common surgery after cataracts in men > 65, 400,000 per year in US); suprapubic prostatectomy; androgen antagonists, smooth muscle relaxers (5 alpha reductase inhibitors decrease DHT and in many cases, prostatic volume and symptoms)
Note: may recur after TURP as peripheral tissue expands to surround the prostatic urethra
Gross: large, discrete, periurethral nodules; mean size of surgical prostatectomy specimens is 100g; usually in transitional and periurethral zones (5% in peripheral zone), although enlarged prostate may compress other zones; glandular hyperplasia is yellow-pink, soft, oozing prostatic fluids; stromal hyperplasia is gray, tough
Gross images: image1, image2, image3, image4, image5
Micro: Hyperplasia of glandular and stromal tissue with papillary buds, infoldings and cysts; associated with squamous metaplasia and infarction; begins around urethra where ejaculatory ducts enter (transitional or periurethral zone); basal cell layer is continuous; stromal changes are increased smooth muscle, less elastic tissue, lymphocytes around ducts (not associated with infectious process or prostatitis in most cases)
Variations include sclerosing adenosis, fibroadenoma-like and phyllodes-like hyperplasia, leiomyoma-like nodules, fibromyxoid nodules, associated with infarct
Micro images: image1, image2, image3, image4
Positive stains: CD10 (Hum Path 2003;34:450)
Benign or non-neoplastic conditions of prostate and prostatic urethra
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Vascular amyloid deposits are present in 2-10% of prostates with nodular hyperplasia or adenocarcinoma
Higher incidence of amyloid deposits in patients with myeloma, primary amyloidosis of kidney or chronic diseases
Amyloid usually subepithelial or vascular
Note: corpora amylacea may stain nonspecifically for amyloid
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Melanin confined to ovoid melanocytes in S100+ prostatic stroma (probably melanocytes), not glands
EM: melanin present in mature melanosomes
Reference: AJCP 1988;90:530
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Identified in 7% of prostates with nodular hyperplasia
Stones usually contain phosphate salts of calcium, magnesium, potassium, calcium carbonate or calcium oxalate
Corpora amylacea may act as nidus for stone formation
Radioopaque, are detected by Xray
Rarely are infected and cause abscesses
Treatment: prostatectomy may be required for large calculi
Gross: brown-gray, round-ovoid, usually smooth surface
Micro: stratified in concentric layers resembling calcified corpora amylacea
DD: carcinoma (both hard), prostatic urethra calculi from bladder, ureter or renal pelvis
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Case reports in men age 28 and 37 at AJSP 1991;15:131
May extend into retroperitoneum and be attached to prostate by a small pedicle
May be termed ectopic prostate if detached from prostate
Benign behavior
Micro: large, multilocular mass of glands/cysts lined by prostate-type epithelium in hypocellular fibrous stroma
Positive stains: PSA, PAP
DD: nodular hyperplasia
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Very rare, < 10 cases described
Case report #1: presacral mass in 78 year old man, Archives 2001;125:286
Case reports #2-6: ectopic prostatic tissue in uterine cervix, AJSP 2000;25:1224, AJSP 2001;25:1215
Cervical cases were incidental (2 patients) or present in cone biopsy for high grade dysplasia
May be similar to multilocular prostatic cystadenoma, although distinct from prostate
Prostatic differentiation in ovarian mesonephric remnants has also been described, AJSP 1999;23:232
Micro: ducts and acini, some papillary or cribriform, with prominent squamous metaplasia
Positive stains: PSA, PAP, high molecular weight keratin (for basal cells)
Micro image: image1
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Case report in 78 year old man after long course of estrogen therapy, AJSP 1985;9:374
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Rare, case report of 75 year old man with myelofibrosis and bladder outlet obstruction
TURP revealed atypical megakaryocytes, immature granulocytes and normoblasts in prostatic stroma, AJSP 1991;15:486
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Rare, case report associated with neurofibromatosis, Archives 1994;118:938
Gross images: image1
Micro images: image1
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Mean age 71; usually associated with nodular hyperplasia in TURP specimens, not needle biopsies
Usually clinically silent, may cause acute urinary retention due to associated edema; may cause gross hematuria if adjacent to urethra; may cause marked PSA elevation that returns to normal after removal of infracted tissue
Causes: trauma, catheter, cystitis, prostatitis
Gross: variable size; speckled, gray-yellow, with streaks of blood and sharp peripheral margins
Micro: ischemic type infarcts with sharply outlined areas of coagulative necrosis of glands and stroma
May see prominent squamous metaplasia with mitotic figures at the periphery of the infarct (but no keratinization, no pleomorphism, localized to area of infarct only); cyst formation often present within glands, corpora amylacea and collagenous rings present around metaplastic glands; zonation is present, but may not be appreciated by needle biopsy
DD: necrosis from infectious granulomas, post-biopsy granulomas (fibrinoid necrosis surrounded by pallisading epithelioid histiocytes), squamous and urothelial carcinoma
Reference: AJSP 2000;24:1378
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Similar to bladder tumor
Micro: myxoid stroma, granulation tissue vascularity, inflammatory cells
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May be difficult to distinguish from nodular hyperplasia (no well organized fascicles, no hyalinization, no necrosis, no calcification)
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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)
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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
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Symptomatic cysts, 1-2 cm, usually unilocular, adjacent to urethra
Lined by flattened prostatic glandular epithelium or urothelium
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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
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
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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
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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
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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)
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
High grade PIN with adjacent small atypical glands (PINATYP)
May be difficult to determine if small glands represent budding / tangentially sectioned glands from high-grade PIN or invasive cancer next to high grade PIN; no reliable differentiating features
Risk of cancer on repeat biopsy was 46%, higher than high grade PIN alone, indicating patients should be rebiopsied, Hum Path 2001;32:389
Prostatic carcinoma-general
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Epidemiology: 300,000 cases/year in US (#1 after skin cancer), 41,000 deaths/year (#2 after lung cancer)
20% of American men are diagnosed with prostate cancer during their lifetimes; 3% die of prostate cancer
Age adjusted incidence is increasing
99% with clinical disease are age 50+
Latent cancers: 20% in men in 50’s, 70% in men in 70’s; usually must examine entire gland to find; rarely metastasize, Archives 1995;119:731
Clinical disease and high grade prostatic intraepithelial neoplasia (PIN) more common in blacks than whites with higher stage at presentation; stage adjusted survival is similar
Clinical disease rare in Asians (3-4/100,000 vs 50-60/100,000 among US whites); higher rates in Scandinavians; all groups have similar incidence of latent cancers, suggesting importance of environmental or other genetic factors
No carcinoma if pre-pubertal castration, low incidence with hyperestrogenism (liver cirrhosis)
Case report of prostatic adenocarcinoma in karyotypic female with congenital adrenal hyperplasia due to 21-OHase deficiency, AJCP 1996;106:660
Not associated with sexually transmitted disease, smoking, occupational exposure, diet, nodular hyperplasia
Clinical: detect with rectal exam, transurethral ultrasound (misses 30% of carcinomas that are isoechoic), elevated PSA (above 4 or increasing over time)
Note: prostate carcinomas secrete 10x the PSA of normal tissue (in the past, 50% had levels > 10 mg/ml)
DD of firm prostate is granulomatous prostatitis, nodular hyperplasia, tuberculosis, infarct, lithiasis
DD of elevated PSA is nodular hyperplasia (mild increase in PSA), prostatitis, infarct, trauma (biopsy, TURP), rarely other tumors (case report of salivary duct carcinoma, AJCP 1996;106:242); for benign disease, increase in PSA is usually transient
Histologic treatment effect
Estrogen therapy
Causes cytoplasmic vacuolization, nuclear pyknosis, naked nuclei; also squamous metaplasia of normal and malignant glands
LHRH agonists and flutamide
Cause striking vacuolization of tumor cells and benign cells; nuclear pyknosis, squamous metaplasia, atrophy with prominence and hyperplasia of basal cell layer; may cause pseudomyxoma ovarii type changes of minute to large pools of extravasated basophilic acid mucin dissecting through prostatic stroma with an infiltrative appearance on low power; secretions positive for mucicarmine, Alcian blue (pH 2.5), PAS after diastase; no basal cells present, AJSP 1998;22:347, AJSP 1996;20:86, AJSP 1994;18:979, AJSP 1991;15:111; high grade PIN persists after endocrine treatment, Hum Path 1999;30:1503
Difficult to evaluate margin status after androgen deprivation
Antiandrogen cyproterone acetate
Micro: normal prostate showed atrophy, basal cell hyperplasia and prominence; adenocarcinoma showed reduced cytoplasmic, cytoplasmic vacuolation, nuclear pyknosis, reduced gland diameter, mucinous breakdown; often collagenous stroma obscuring malignant glands; recommended to NOT give a Gleason grade to these specimens.
References: AJSP 2002;26:1400
External beam therapy
Clinician may NOT be aware of treatment history
Causes effects on vascular, stromal and epithelial compartments
Vascular: arterial luminal narrowing due to myointimal proliferation and thrombi, foam cells in vessel walls, vascular hyalinization
Stroma: stromal fibrosis
Epithelium: no or marked cytologic atypia; also glandular atrophy with scant eosinophilic cytoplasm and small pyknotic nuclei, basal cell prominence, Paneth cell-like change, squamous and mucinous metaplasia, blue-tinged mucinous secretions, AJSP 1999;23:1021; also fibrosis and atrophy of seminal vesicles, AJSP 1982;6:541; may persist for a long time after treatment, AJSP 2003;27:206
Persistent tumor usually retains pretreatment architectural pattern with fewer tumor cells; benign tissue shows cytologic atypia so diagnose residual tumor based on architecture, not cytology
Post-treatment tumor not graded if treatment effect is present
Less treatment effect in radical prostatectomy specimens than needle biopsies, AJSP 1999;23:1173
Malignant features: infiltrative growth, perineural invasion, intraluminal crystalloids, blue mucin secretions, high grade PIN, no corpora amylacea
Benign glands: nuclear enlargement (86%), prominent nucleoli (50%)
Micro images: brachytherapy change
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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
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
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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
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)
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Grade is 1 to 5, based on glandular differentiation at low power
Score is 2 to 10, based on Gleason grade for first and second most predominant patterns
If only one pattern present, primary and secondary patterns are given the same grade
Score 2-4 (well differentiated) almost never develop aggressive disease, 8-10 usually die of disease
Clinically important distinctions are Gleason scores 2-6, 7, 8, 9-10
Upgrading is seen in 1/3 of prostatectomy specimens after biopsy, down grading in 5%
1/3 of Gleason 8 at biopsy are Gleason 7 at radical prostatectomy
If minimal tumor on biopsy (1 mm or less), Gleason score does not predict tumor stage; perhaps should note this on report, AJSP 2000;24:1634
Gleason grades
Grade 1 - single, separate, closely packed, uniform round glands arranged in a circumscribed nodule with pushing borders; separation of glands at the periphery from the main collection by more than one gland diameter indicates a component of at least grade 2
Uncommon pattern except in transitional zone adenocarcinomas; almost never seen in needle biopsies
Grade 2 - like grade 1 but more variability in gland shape and more stroma separating glands; most glands are separated by less than one average gland diameter; less circumscribed at periphery, although no infiltration into stroma or between benign glands; more common in transitional zone adenocarcinoma, less frequent in peripheral zone adenocarcinomas; presence of even a few well-formed malignant glands in a needle biopsy (often interspersed among benign elements) indicates a grade 3 pattern
Tends to be periurethral and not sampled
Note: don't diagnose Gleason grades 1 or 2 on prostate needle biopsies since (a) are uncommon in peripheral zone, (b) there is marked inter-pathologist variability, (c) usually reflects undergrading compared to experts, (d) doesn't correlate with radical prostatectomy.
Grade 3 -single, separate, much more variable glands, may be closely packed but usually irregularly separated, ragged, poorly defined edge, but still in circumscribed structure, looser than nodule, slightly infiltrative, but can draw a circle around each gland; tangentially cut glands may be poorly formed
Patterns of Gleason grade 3 prostatic adenocarcinoma:
(a) most common pattern is well-formed, relatively uniform glands infiltrating between benign glands; glands may be angulated or compressed, separated by > 1 gland diameter, tend to have basophilic cytoplasm and larger nucleoli than grades 1 or 2
(b) small glands with inconspicuous or absent lumina, glands still separate
Micro images: #1
(c) papillary or cribriform patterns, with smooth, rounded, pushing type edges without stromal infiltration; uncommon; cribriform unit should be small (size of normal prostate gland), and well circumscribed without a ragged or infiltrative border
It is difficult to differentiate cribriform Gleason 3 from cribriform PIN
Reference: AJSP 2001;25:147
(d) large gland variant
Grade 4 - chopped up fused glands; either all glands without stroma or small fragments of glands
Patterns of Gleason grade 4 prostatic adenocarcinoma:
(a) most common is small acinar structures, some with well-formed lumina, fusing into cords or chains; may be undergraded as Gleason 3
Micro images: #1, #2, #3, #4, #5, #6, #7, #8
(b) papillary-cribriform tumors with irregular / invasive edges; includes many but not all endometrioid carcinomas; nodule of cribriform gland should be larger than normal prostate gland; large nodules of cribriform Gleason 4 lack supporting stroma and tend to fragment; thus large fragments of cribriform glands on needle biopsy represents Gleason 4.
Note: patients with Gleason 8 at biopsy may have Gleason 7 at prostatectomy due to unsampled Gleason 3
(c) hypernephroid pattern, with nests of clear cells, small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma
Micro images: #1
Grade 5 - two patterns:
5a: comedocarcinoma -papillary / cribriform carcinomas with central necrosis
5b: carcinomas with minimal glandular differentiation, ranging from infiltrating single cells (including signet ring cells) to solid sheets of tumor cells
The presence of Gleason grade 5 and high percent carcinoma at prostatectomy predicts early death, AJCP 2001;116:864
CK903 / 34 beta E12 / high molecular weight cytokeratin
Basal cell specific anti-keratin monoclonal antibody raised against human stratum corneum is not present next to carcinomatous glands but is present in normal glands (usually is an internal positive control even on biopsies)
False negative staining in 5% of benign acini after pepsin predigestion in performing stain; includes inflamed acini, atypical adenomatous hyperplasia, postatrophic hyperplasia, atrophy, high grade PIN, basal cell carcinoma/adenoid cystic carcinoma (fragmented or continuous staining)
Optimize CK903 using pretreatment of citrate buffer on a hot plate (may give weak staining focally in cancer cells) or steam heat and EDTA buffer; others use pepsin predigestion or microwave, Mod Path 1999;12:472
Positive staining rules out cancer; negative staining cannot be the sole criteria for diagnosing cancer; not useful in differentiating high grade PIN and invasive carcinoma
Note: most peripheral acini in a lobule (furthest from large duct) is often CK903 negative, AJCP 1999;112:69
In TURP specimens, CK903 only stains basal cells in normal glands in 25% of specimens; can restore keratin antigenicity using low pH citrate buffer and microwave heat technique, Archives 2000;124:1764
Note: rare strong positivity in <1% of tumor cells (that don’t resemble basal cells) in lymph node metastases; rare weak diffuse positivity, AJSP 1999;23:147
Note: use of intervening unstained slides for immunohistochemistry recommended, AJSP 1999;23:567
Prostate specific antigen (PSA) / prostatic acid phosphatase (PAP)
Positive in tumor and benign cells; identifies prostatic origin of most metastatic tumors, differentiates between prostatic and urothelial carcinomas
PSA more sensitive (intense, diffuse staining) and specific than PAP; PSA present in endoplasmic reticulum, vesicles, vacuoles, lumina, while PAP is localized to lysosomal granules
PSA/PAP less sensitive in poorly differentiated adenocarcinoma, AJSP 1986;10:765, AJSP 1982;6:553
PSA/PAP may become negative after hormonal treatment, Hum Path 1996;27:1377
Non-prostate tumors usually are negative or weak with PSA/PAP; bladder adenocarcinomas and rectal carcinomas may be strongly PAP+ but PSA-
Rectal carcinoids also positive for PAP, perhaps due to shared cloacal derivation of rectum and prostate, AJSP 1991;15:785
P504S/AMACR
Gene encodes protein involved in beta-oxidation of branched chain fatty acids
Relatively sensitive and specific for prostatic adenocarcinoma vs. benign lesions / mimics, AJSP 2001;25:1397
Recommended to use with high molecular weight cytokeratin, AJSP 2002;26:1588
Other positive stains: low molecular weight cytokeratin, CD57/Leu7, B72.3, EMA (80%), CEA (25%), cathepsin D (50%)
Other negative stains: thrombomodulin (AJCP 1998;110:385), CK7, CK20 (Mod Path 2000;13:962), MUC6 (AJSP 2003;27:519), CD10 with Gleason 2 & 3 patterns (Hum Path 2003;34:450)
Gleason 8-10 adenocarcinomas usually have negative or focal (<25%) staining for CK7 and CK20, may be PSA and PAP negative, and are negative for CK 5/6, CK17, WT1, CA125, TTF-1 and villin, AJCP 2002;117:471; may be CD10+ (Hum Path 2003;34:450)
Atypical glands, suspicious for malignancy
Diagnosed in ~5% of biopsies; due to enlarged nucleoli (100%), enlarged nuclei (83%); intraluminal eosinophilic secretions (74%); infiltrative growth (68%); small acinar proliferation (68%); intraluminal basophilic mucin (42%); amphophilic cytoplasm (33%); high-grade PIN (31%); crystalloids (22%)
Diagnosis of malignancy not made due to small size of the focus, small number of cells with enlarged nucleoli, clustered growth pattern, presence of high-grade PIN within many foci.
60% with additional sampling had adenocarcinoma, suggesting need for additional biopsies, AJCP 1997;108:633, AJSP 1997;21:1489
Back off diagnosis if small atypical glands plus a few neutrophils
Most tumors outside central zone are multifocal (75%+) in radical prostatectomies
Note: fibroblastic nuclei surrounding obvious cancer may mimic basal cells
Micro images: image1, image2, image3
Aka minimal residual cancer at radical prostatectomy
3-4% of cases
Review of initial biopsies in cases with no residual cancer showed either confirmation of cancer, high grade PIN only or mislabeled specimen, AJSP 1997;21:174, AJSP 1995;19:1002
Other prostate carcinomas
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Aka adenoid cystic like tumor
Resembles to some extent the salivary gland tumor
Usually does not develop progressive disease
Micro: expansive (not circumscribed) growth pattern, multinodular, basaloid cells in clusters, some with punched out lumens; surrounding fibromyxoid stroma, squamous differentiation, merges with basal cell hyperplasia; may be associated with minor component of usual type prostatic adenocarcinoma
Micro images: image1, image2, 34betaE12
Positive stains: 34betaE12, p63
Negative stains: PSA/PAP
Case reports: Archives 1993;117:799, AJCP 1988; 89:49, AJCP 1984;81:257
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De novo or post-radiation or hormonal therapy for ordinary adenocarcinoma
References: AJSP 1987;11:403, Hum Path 1995;26:123, Hum Path 1984;15:87
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Definition: proliferation of malignant acini that architecturally resembles atrophy or postatrophic hyperplasia but retains the diagnostic cytologic features of cancer
Usually NOT associated with hormone therapy
Micro: acini are round, often dilated and distorted and lined by flattened attenuated epithelium with scant cytoplasm and infiltrative growth pattern; nuclear enlargement and prominent nucleoli present; atrophic features represent mean 25% of total tumor (range 10-90%) in needle biopsies and prostatectomy specimens; usually Gleason score 6-7; AJSP 1997;21:289
also luminal eosinophilic proteinaceous secretions, blue mucin, crystalloids, apocrine blebs, collagenous micronodules, high-grade PIN within two high-power fields, AJSP 1997;21:931
DD: benign atrophy
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Rare; main differential diagnosis is high grade PIN vs. cribriform carcinoma (Gleason patterns 3 or 4) [other cribriform lesions without atypia are listed below]
55% had cancer on follow-up; predictors were positive digital rectal examination or transrectal ultrasound, bilateral atypical cribriform glands, detached cribriform glands, AJSP 2001;25:147
High grade cribriform PIN may be a late event in tumor progression, more compatible with the intraductal spread of tumor than dysplasia, AJSP 1998;22:840
DD: clear cell cribriform hyperplasia (usually in transition zone, not on needle biopsy; no cytologic atypia; has clear cells and obvious basal cell layer); central zone glands (no cytologic atypia, tall pseudostratified nuclei with eosinophilic cytoplasm); cribriform basal cell hyperplasia (may have prominent nuclei, but usually in transition zone and not on needle biopsy; this pattern is rare, and usually represents fused glands and not true cribriform glands)
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Very rare
Reported to be variably highly aggressive or to have low malignant potential
Micro: resembles basaloid (cloacogenic) carcinoma of anal canal or upper aerodigestive tract; has desmoplastic stromal response, perineural invasion, necrosis, widespread infiltration into surrounding tissue
Positive stains: bcl-2, Ki-67 (Hum Path 1998;29:1447)
DD: basal cell hyperplasia with or without prominent nucleoli (bcl-2 and Ki-67 negative)
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Rare (<30 patients)
May represent sarcomatoid transformation of prior adenocarcinoma or be related to radiotherapy or hormonal therapy
Micro: biphasic tumor with adenocarcinoma and recognizable sarcoma components (chondrosarcoma, rhabdomyosarcoma, angiosarcoma, osteosarcoma, leiomyosarcoma)
Negative stains: sarcoma component negative for PSA, EMA, keratin
Reference: AJCP 1989;92:131, AJSP 1993;17:342
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Extremely rare in men in prostate
More common in urethra or bladder
Case reports: Case of the Week #76, 47 year old man with elevated serum CA125, normal serum PSA, metastasis to testis (AJSP 2000;24:1433), 73 year old man with organ confined disease resembling renal cell carcinoma (AJSP 2003;27:407), 16 year old boy from Uruguay with tumor of prostatic utricle (Ann Diagn Pathol 2005;9:153)
Micro: tubulocystic and papillary glands lined by glycogen-rich, cuboidal or hobnail cells with clear to eosinophilic cytoplasm; enlarged nuclei with mild pleomorphism and prominent nucleoli; may have prominent vasculature, inflammatory infiltrate, hyaline globules, psammoma bodies; resembles ovarian neoplasm
Micro images: low power - #1; #2; medium power - #3; #4; high power - #5; #6; #7; #8; #9; #10; hyaline globules #1; hyaline globules #2; psammoma bodies
Positive stains: pan-keratin, low molecular weight keratin, EMA, focal high molecular weight keratin
Negative stains: PSA, PAP
DD: urothelial carcinoma (clear cell variant), renal cell carcinoma (metastatic), nephrogenic adenoma
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Rare variant with abundant foamy cytoplasm and minimal cytologic atypia, AJSP 2001;25:618, AJSP 1996;20:419
Usually large volume, bilateral, extraprostatic extension
Foamy appearance due to intracytoplasmic vesicles, not lipid or neutral mucin
Aggressive behavior despite its benign histologic appearance
Micro: abundant xanthomatous cytoplasm, small hyperchromatic nuclei, minimal/no atypia, pink luminal secretions; hyperchromatic nuclei may make nucleoli difficult to see; cytoplasm differs between malignant and benign glands; no obvious basal layer compared to normal glands; foamy morphology comprises most of cancer
Micro images: image1
Positive stains: colloidal iron, Alcian blue, P504S (AJSP 2003;27:772)
Negative stains: mucicarmine, PAS, lipid
EM: intracytoplasmic vesicles, polyribosomes
DD: mucinous metaplasia (focal, cells positive for mucicarmine, PAS), Cowper’s glands (ducts often embedded in skeletal muscle), clear cell cribriform hyperplasia (basal cells readily identified), Gleason hypernephroid pattern 4 (optically clear, but not foamy cytoplasm due to lipid and glycogen)
Lymphoepithelial like carcinoma
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Resembles nasopharyngeal lymphoepithelial like carcinoma
Mucinous (colloid) adenocarcinoma
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Uncommon (< 1%)
Intra- and extracellular mucin must comprise 25%+ of tumor
May be more hormone independent, less responsive to radiation therapy
Aggressive biologic behavior, AJSP 1985;9:299
Micro: tumor cells float in pools of mucin; resembles mucinous (colloid) carcinoma of breast; has microglandular, cribriform, comedo, solid, and hypernephroid patterns; signet ring cells rare
Micro images: image1, image2 (focal mucin production)
Positive stains: PSA, PAP
DD: extension of large bowel carcinoma, Cowper’s gland carcinoma; mucinous adenocarcinoma of bladder (PSA-, PAP+)
Mucinous adenocarcinoma from prostatic urethra-urinary bladder type
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Case report of tumors in 2 patients confined to prostate and originating from prostatic urethra, AJSP 1996;20:1346
Identical to adenocarcinomas arising within urinary bladder but different from mucinous adenocarcinoma of the prostate
In situ adenocarcinoma component present in overlying prostatic urethra in both cases; in one case, in situ adenocarcinoma arose in villous adenoma of urethra
Both cases had mucin lakes lined by tall columnar epithelium with varying degrees of cytologic atypia; one case had mucin-positive signet cells
Note: prostatic mucinous adenocarcinomas have tubules and cribriform glands floating within mucin; mucin+ signet cells are rare
Positive stains: CEA
Negative stains: PSA, PAP
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Neuroendocrine cells found in 80% of normal prostates, 10-33% of adenocarcinomas
May have poorer prognosis and be resistant to hormonal therapy, but controversial
Extent of neuroendocrine differentiation may provide prognostic information in Gleason score 2-6 treated by radical prostatectomy, Hum Path 1996;27:683
Pure neuroendocrine carcinomas not associated with elevated PSA
Micro: may resemble Paneth cells with large, basal, eosinophilic granules; also resemble typical or atypical carcinoid
Micro images: image1, recurrent neuroendocrine carcinoma, PSA/chromogranin, chromogranin,
Positive stains: chromogranin, PSA, PAP, bcl-2, ACTH, beta-endorphin, calcitonin,
Case report: Archives 2000;124:1074
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Direct extension: bladder, urethra, colorectum, anus, soft tissue tumors
Metastases to prostate: uncommon; lung, melanomas predominate
Carcinoid tumor: case report of 78 year old man with incidental 2 cm carcinoid tumor with lymph node metastases at autopsy, confirmed by EM and argyrophilic stains; also positive for PAS and PAP, AJSP 1984;8:545
Oncocytic adenocarcinoma: case report at AJSP 1992;16:1007
Wilm’s tumor
Case report, 32 year old man with tubular and glomeruloid structures and blastema-like sheets in edematous stroma; may arise from persistent nephrogenic rests related to Wolffian duct system, AJSP 1991;15:885
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Less than 1% of prostatic carcinomas
Usually periurethral, but can be seen in peripheral zone
On cystoscopy, appears villous or infiltrative into urethra, often near verumontanum
Associated with obstructive symptoms and hematuria; usually diagnosed on TURP
May have normal digital rectal examination and normal PSA
Formerly called endometrioid carcinoma of prostate but of prostatic origin, Archives 1982;106:624
Usually aggressive, less likely to respond to hormone therapy than classic adenocarcinoma, presents at higher stage, AJSP 1999;23:1471, AJSP 1985;9:595
As 80% also have a small acinar component, may represent peripheral zone adenocarcinomas infiltrating into large periurethral ducts and stroma and not represent a distinct histologic type, AJSP 1999;23:781
Micro: core biopsies usually show papillary or cribriform pattern with slit-like lumina (86%) or discrete glands lined by tall, pseudostratified epithelium with abundant, amphophilic cytoplasm (14%); may have pale / clear cytoplasm; stromal fibrosis (67%), coexisting “usual” component (48%)
May have pagetoid spread throughout prostatic urethra or intraluminally within ducts before invading into surrounding stroma; thus, the presence of basal cells does not exclude these tumors, AJSP 1997;21:435
Micro images: image1, image2, image3, image4, image5, absence of high molecular weight cytokeratin, PSA, PAP
Positive stains: high molecular weight cytokeratin may show basal cells in cribriforming ductal adenocarcinoma and also other patterns; PSA, PAP
DD: high grade PIN vs. cribriform pattern of duct carcinoma (back to back irregular glands, extensive comedonecrosis, more prominent nuclear atypia, papillary component with fibrovascular cores)
Pseudohyperplastic adenocarcinoma
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Rare carcinoma that resembles benign hyperplastic glands
Difficult to grade; Epstein recommends deferring to the grade of the associated “usual type” adenocarcinoma in the radical prostatectomy specimen, which is often Gleason score 5-7
False negative diagnostic rate was 1.3% for TURP specimens (Pathol Oncol Res 2003;9:232)
Definition: 60% of tumor has benign architectural but malignant nuclear features (AJSP 2000;24:1039)
Case reports: Case of Week #117
Micro: papillary infoldings (100%), crowded glands, large atypical glands (95%), nuclear enlargement (95%), pink amorphous secretions (70%), occasional to frequent nucleoli (45%), branching (45%), crystalloids (45%), corpora amylacea (20%); at low power, transition to typical, small acinar adenocarcinoma may be helpful (AJSP 1998;22:1239); with core needle biopsy, only diagnostic clue may be a subtle disruption of the normal glandular - stromal relationship
Micro images: low power; high power #1; #2; #3; triple stain #1 (AMACR, p63, HMWK); #2
Positive stains: P504S in 70% of cases (AJSP 2003;27:772)
Negative stains: high-molecular weight keratin and p63 show absence of basal cells in hyperplastic glands (normal glands serve as positive control)
DD: adenosis, high grade PIN (not as crowded or infiltrative), benign hyperplasia
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Rare, highly malignant
Micro: solid, acinar, single-line patterns; primarily composed of tumor cells with signet ring pattern (at least 25%) due to intracellular accumulation of mucin
Positive stains: PSA (variable in some studies), AE1/AE3, CAM 5.2, Ki-67 (mean 8%), PAS-diastase, mucicarmine (50%), Alcian blue (60%)
Negative stains: bcl2 (rare cells positive)
EM: intracytoplasmic lumina lined by microvilli
DD: artifactual changes in lymphocytes post TURP (negative for mucin, PSA, and PAP; positive for CD45, AJSP 1986;10:795), benign signet ring change (also negative for mucin, PSA, PAP, AJSP 2002;26:1066)
References: Archives 1992;116:99, AJSP 1988;12:453, Mod Path 1998;11:552
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Pure or combined with ordinary ductal adenocarcinoma
May cause Cushing’s syndrome, syndrome of inappropriate antidiuretic hormone secretion
Some have endocrine features
Very aggressive, cannot monitor with PSA (unreliable); survival usually less than 1 year, Archives 1986;110:1041
Rarely associated with limbic encephalitis, Mod Path 1999;12:814
Micro: usually large number of apoptotic cells; otherwise resemble lung small cell carcinoma
Micro images: image1, image2, chromogranin
Positive stains: chromogranin, NSE, TTF-1 (Mod Path 2000;13:238)
Negative stains: PSA, PAP
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Extremely rare
Occurs de novo or after estrogen therapy, flutamine therapy, radiation seed implantation
Poor survival
Tumors develop osteolytic metastases, don’t respond to hormone therapy
Don’t develop increased PSA with metastases
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
Microscopic mimics of prostatic adenocarcinoma
Benign tumorlike conditions (see above)
Adenosis/atypical adenomatous hyperplasia
Microscopic proliferation of small glands with minimal atypia that may be mistaken for adenocarcinoma
Found almost exclusively in transition zone (2% of TURPs, <1% of core biopsies); frequently multifocal
86% associated with nodular hyperplasia; less commonly associated with verumontanum mucosal hyperplasia, Archives 2001;125:358, AJSP 1995;19:506
Weak association with adenocarcinoma
Micro: lobular appearance; small, round, crowded, closely spaced acini mixed with larger acini with similar features within a circumscribed nodule; complex and disorderly glands with an expansile or minimally infiltrative margin, crystalloids in up to 24%; usually no prominent nucleoli, no blue-tinged mucin, has normal sized nuclei, normochromasia, corpora amylacea common, may contain acidic mucin; resembles Gleason 1 and 2 adenocarcinomas, AJSP 1995;19:737
Micro images: image1, image2, image3, image4, image5, 34betaE12
Stains: mixture of CK 903 positive and negative glands (i.e. glands with and without basal cell layer, but discontinuous staining)
Negative stains: usually P504S/AMACR (AJSP 2002;26:921)
DD: Low grade adenocarcinoma (haphazard glands, often at right angles to each other)
Atrophy
Micro: glands arranged in multiple lobules separated by fibrotic stroma; have well-formed open lumens, scant cytoplasm, hyperchromatic nuclei, small/inconspicuous nucleoli; basal layer present but may be fragmented
Micro images: image1, image2, image3, 34betaE12
Aka fetalization of prostate
Patients usually age 60+
Common in transitional zone
In peripheral zone, 10% incidence in needle core biopsies, 23% incidence in whole prostate glands, Mod Path 2003;16:598
Micro: small, solid nests of benign appearing epithelial cells with somewhat clear cytoplasm; accompanied by nodular hyperplasia; may be florid with complex architecture; may have prominent nucleoli and resemble high grade PIN or adenocarcinoma; may have adenoid cystic pattern
In peripheral zone, often associated with lymphocytic inflammation
Also intracytoplasmic hyaline globules (relatively specific, in 53% of florid cases), psammomatous calcifications (in 40% with florid cases), squamous features, cribriform pattern with multiple layers; usually no crystalloids, AJSP 2002;26:237, Hum Path 2003;34:462
In core biopsies, typically focal and associated with lymphocytic inflammation
BCH with atrophy (post anti-androgen therapy): diffuse atrophy of prostate glands, also immature squamous metaplasia
BCH with squamous features: usually mixed with atrophy, normal appearing stroma
Micro images: image1, image2, image3, image4, image5, image6, peripheral zone #1, #2, #3
Positive stains: 34betaE12, p63, CK8/18
Negative stains: P504S (may be focally positive), CD10
EM: luminal calcification and intracytoplasmic electron dense globules focally in florid cases
DD:
BCH with adenoid cystic pattern: resembles adenoid basal cell tumor, but BCH lesions are well circumscribed, no necrosis, no desmoplastic stroma
BCH with cribriform features: multilayered basal cells and mixed with noncribriform BCH, unlike cribriform PIN; lobular growth pattern without desmoplastic stroma, necrosis or perineural invasion, unlike adenoid basal cell tumor
BCH with prominent nucleoli: adenocarcinoma, high grade PIN
References: AJCP 1983;80:850
Basal cell hyperplasia with prominent nucleoli
2% incidence in needle core biopsies
Preferred term (per Epstein) instead of atypical basal cell hyperplasia
No definite risk for malignancy
Part of continuum of basal cell hyperplasia, adenoid basal cell tumor, AJSP 1993;17:645
Micro: nuclear enlargement, hyperchromasia, prominent nucleoli, mitotic figures
Positive stains: high molecular weight keratin
Negative stains: actin
Florid basal cell hyperplasia
Definition: extensive proliferation of basal cells involving more than 100 small crowded acini (per section) forming a nodule.
Micro: almost always mild to moderate nuclear atypia (including prominent nucleoli and nuclear enlargement), intraluminal amorphic secretions; also intracytoplasmic hyaline globules (53%), microcalcifications (40%), no crystalloids
Reference: Hum Path 2003;34:462
Clear cell cribriform hyperplasia
A form of nodular hyperplasia without atypia
Diploid
Micro: cribriform arrangement (glandular clusters with punched out lumens) of clear/pale eosinophilic cells with complex papillary growth simulating carcinoma; also has conspicuous basal cells, small, uniform nuclei; no prominent nucleoli
Positive stains: basal cells are CK903 positive
References: AJCP 1991;95:446, AJSP 1986;10:665
Cowpers glands
Aka bulbourethral glands
Well demarcated lobules of small, compact tubuloalveolar glands resembling minor salivary glands, radiating from a central excretory duct lined by pseudostratified epithelium, and entrapped within fascicles of muscle; have a thin connective tissue capsule; composed of simple columnar epithelium
These mucin producing glands are 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
Mesonephric remnants / hyperplasia
Rare, <1% of TURP specimens
Mesonephric ducts: embryonic structures eventually replaced by metanephric ducts to form the permanent kidney; play a critical role in development of functional urinary system and male reproductive system, including the ureter, renal pelvis, collecting tubules, ejaculatory ducts, seminal vesicles, vas (ductus) deferens; embryonic vestiges (mesonephric remnants) may persist
Located in prostate base and periprostatic soft tissue
Resembles mesonephric hyperplasia in female genital tract
Micro: proliferation of round to oval tubules/acini lined by benign cuboidal to low columnar epithelium, ranging from lobular aggregates of microacini to dilated structures containing characteristic colloid-like material; prominent nucleoli; cells have scant to moderate cytoplasm and inconspicuous small nucleoli; infiltrative growth between smooth muscle bundles without stromal desmoplasia
Positive stains: CK 903
Negative stains: PSA, PAP
References: AJSP 1993;17:454, Mod Path 2003;16:630
Mucous gland metaplasia
Rare (< 0.1% of prostates), AJSP 1993;17:618, AJSP 1993; 17:287
Micro: mucinous glands lined by tall columnar cells, small basal nuclei with inconspicuous nucleoli; resembles Cowper's gland epithelium; located randomly within glands and very small (< 1 mm2)
Micro images: image1, image2, image3
Positive stains: PAS, mucicarmine, Alcian Blue
Negative stains: PSA, PAP
Nephrogenic metaplasia/adenoma
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Aka adenomatoid metaplasia
Metaplastic response of urothelium to injury; also associated with renal transplantation and intravesical bCG for bladder urothelial carcinoma; rarely affects prostatic urethra
Extension of small tubules into fibromuscular stroma may simulate adenocarcinoma
Usually does not recur
Micro: tubules (96%), inflammation (95%), extension into muscle (77%), structures resembling vessels (73%), peritubular sheaths (65%), prominent nucleoli (54%), cords and individual cells (46%), thyroidization (38%), blue-tinged mucinous secretions (32%), papillary configurations (19%), signet ring cell-like tubules (12%), no mitotic figures; adjacent urothelium (69%) with cuboidal metaplasia (61%) or squamous metaplasia (28%); tubules composed of single layer of cuboidal or flattened cells with clear to eosinophilic cytoplasm, round nuclei with fine chromatin
Positive stains: CK7 (100%); focal PSA (36%), focal PSAP (50%), 34betaE12 (diffusely positive-11%, focally positive-44%, negative-44%)
References: AJSP 2001;25:802, AJCP 1981;75:185, Hum Path 1994;25:390, Mod Path 1992;5:617, AJSP 2003;27:407
Paraganglion tissue
Present in periprostatic soft tissue, in or adjacent to lateral neurovascular bundles; rarely in lateral prostatic stroma
Size 0.1 to 1.7 mm
Micro: clusters of cells, lateral to diffuse, usually with prominent stromal vascular component; bland round to oval nuclei, basophilic granular or vacuolated cytoplasm
Positive stains: chromogranin A, neuron-specific enolase, synaptophysin
Negative stains: PAP, PSA
References: Archives 1997;121:515, AJSP 1994;18:412
Benign prostate glands with relatively scant cytoplasm, but the glands are not fully atrophic and do not appear basophilic at low magnification
Basal cells absent/hard to identify (63%); irregular (crinkled) nuclei frequent/occasional (57%), regular atrophy (35%), frequent nucleoli (25%), no intraluminal crystalloids or blue-tinged mucinous secretions noted, AJSP 1998;22:440
Associated with adenocarcinoma or glands suspicious for cancer in other cores (16%)
DD: low grade adenocarcinoma (more cytoplasm, no crinkled nuclei, cytoplasm differs from adjacent glands, no adjacent atrophy)
Post-atrophic hyperplasia
Aka lobular atrophy
Simple atrophy: large atrophic glands without crowding
Postatrophic hyperplasia: crowded focus of small atrophic areas
Relatively common, most often seen in peripheral zone of apex/mid prostate; not associated with adenocarcinoma although may mimic it, AJSP 1999;23:932, Archives 2003;127:840
Associated with older age, Mod Path 1998;11:47
Micro: atrophic and hyperplastic glands; maintenance of lobular architecture but scanty cytoplasm; glands stand out at low power due to basophilic appearance; basal layer usually present; associated with elastosis (basophilic tinge of stroma), dilated gland with fibrosis often present in center of atrophic glands; chronic inflammation (32%), acute inflammation (21%); prominent nucleoli (14%), atrophy in adjacent areas; mitoses rare (1%), MIB staining in 3%
Micro images: image1, image2, image3, image4, image5, image6, elastic stain #1, #2, 34betaE12
DD: adenocarcinoma (usually has pale/amphophilic cytoplasm, basal nuclei, low nuclear to cytoplasmic ratio, CD10- if low grade)
References: Archives 2000;124:1306, AJSP 1999;23:925, AJSP 1998;22:1073, AJSP 1995;19:1068
Cytologic atypia but retention of lobular architecture, squamous metaplasia, stromal fibrosis, atypical fibroblasts, thickened vascular walls
Sclerosing adenosis
Present in 2% of radical prostatectomies; resembles lesion in breast; more common in transition zone
Micro: well-circumscribed nodule, with variable size/shaped glands (smaller centrally) in myxoid or cellular stroma without smooth muscle cells; double cell population of clear secretory and amphophilic basal cells; may have prominent nucleoli, luminal acid mucin
Micro images: image1, image2, image3, image4, smooth muscle actin, S100
Positive stains: glandular cells - cytokeratin, PSA, PAP; basal cells - high molecular weight keratin, smooth muscle actin, S100
EM: myoepithelial type cells (may arise from basal cells by metaplasia)
References: Archives 1987;111:363, AJSP 1992;16:383, AJSP 1991;15:1171, AJSP 1991;15:660
Seminal vesicles / ejaculatory duct
Epithelial lining of ejaculatory ducts is similar to seminal vesicles
Small glandular diverticula from central seminal vesicle lumen resemble carcinoma
Micro: large coarse golden yellow/brown lipofuscin/lipochrome granules in cytoplasm (finer granules present in normal prostate gland), also “monster” cells with prominent nuclear atypia and degenerative appearance, crystalloids, basal cells; no mitotic activity, no nucleoli
Note: significant lipochrome also found in central zone prostatic epithelium; lesser amounts in peripheral and transition zones, occasionally in nodular hyperplasia, high grade PIN, adenocarcinoma,
Negative stains: PSA (may be focal or weak positive)
Micro images: image1, image2, image3, image4
References: Archives 1999; 123:1093, Hum Path 1995;26:1302
Squamous metaplasia
Due to infarcts, inflammation, radiation therapy, estrogen or anti-androgen therapy, idiopathic
Micro: urothelial lining in peripheral ducts and glands (normally is in central ducts); no atypia
DD: high grade PIN (atypia present)
Verumontanum mucosal hyperplasia
Well-circumscribed small glandular proliferation in or adjacent to verumontanum and posterior prostatic urethra; basal cell layer identifiable with routine H & E staining; luminal contents had lamellated eosinophilic concretions typical of corpora amylacea and fragmented orange-red concretions; may involve prostatic ducts, ejaculatory ducts, utricle, or adjacent urethral mucosa; associated with adenosis; no crystalloids or intraluminal mucin
Micro image: image1
References: Archives 2001;125:358, AJCP 1995;104:620, AJSP 1995;19:30
Xanthoma cells
Seen in xanthoma or xanthogranulomatous prostatitis
Localized collection of cholesterol-laden histiocytes, usually idiopathic, may be seen in patients with hyperlipidemia
May be interpreted as Gleason 4-hypernephroid pattern or clear cell adenocarcinoma, particularly in needle biopsies,
Micro images: image1
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
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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)
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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
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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
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+)
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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
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+)
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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 2