Prostate gland & seminal vesicles
Acinar / ductal adenocarcinoma
Adenocarcinoma


Topic Completed: 1 August 2016

Minor changes: 29 April 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: Prostatic Adenocarcinoma[title]

Kenneth A. Iczkowski, M.D.
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Cite this page: Iczkowski KA. Adenocarcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/prostateadenoNOS.html. Accessed August 3rd, 2020.
Definition / general
Tumor distribution:
  • 95% of prostate cancer is acinar type (Figs. 1-4) and 5% is ductal type
  • 70% arises from peripheral zone (posterior and lateral)
  • Often spares transition (periurethral/anterior) zone (TZ); TZ involvement is usually due to tumor expansion from the peripheral zone
  • At radical prostatectomy, > 90% have posterior tumor but only 65% have tumor anteriorly
  • Anterior tumor is associated with higher tumor volume and margin positivity (BJU Int 2006 Dec;98:1167), although outcomes are similar to posterior tumors (Prostate Cancer Prostatic Dis 2014 Mar;17:75)
  • Tumor in biopsy is clinically “significant” if Gleason score ≥3+4 and tumor length ≥ 3 mm; in prostatectomy specimens, it is significant if tumor volume ≥ 0.5 cc, or the stage is ≥ pT3a (Curr Opin Urol 2014 May;24:209).

Tumor extension:
  • Extraprostatic extension (EPE) is most common, and is defined as tumor in contact with extraprostatic fat
  • The prostate has a fibromuscular pseudocapsule that is discontinuous at its apex, bladder base and anteriorly, so the “capsule” is not relevant in staging prostate cancer
  • Local invasion occurs via seminal vesicles (if tumor infiltrates muscular wall) and bladder base; rarely via prostatic urethra
  • Rectal invasion is rare due to tough Denonvillier’s fascia which abuts pseudocapsule; may present as anterior rectal mass, stricture or serosal implants
  • Seminal vesicle invasion occurs via (a) direct spread along ejaculatory duct complex, (b) spread outside prostate, then into seminal vesicle, (c) isolated deposits of cancer in seminal vesicle with no contiguous primary cancer in the prostate (Am J Surg Pathol 1993;17:1252)

Incidentally detected:
  • In cystoprostatectomy specimens for bladder cancer, most studies describe a 50% rate of incidental prostatic adenocarcinoma; 20% were clinically significant (Fig 2) (Am J Clin Pathol 2009 Feb;131:279)
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+
  • A sizable minority of prostate cancers, those with Gleason score 3+3=6 (or less), have been shown almost never to metastasize to lymph nodes (Am J Surg Pathol 2012;36:1346), and lately it has been proposed to designate these not even as cancer, but by the name Indolent Lesion of Epithelial Origin (IDLE) (Curr Opin Urol 2015;25:238)
    • However, most pathologists endorse that Gleason 3+3=6 cancer is still cancer (Oncology (Williston Park) 2014;28:22), and a variety of surgical and non-surgical management options are now available for low-grade cancer
    • Low grade or "latent" cancers comprise 20% in cancers in men in their 50's, and 70% in men in 70'­s; usually one must examine the entire gland to find them
  • Clinical disease and high grade prostatic intraepithelial neoplasia (HGPIN) are more common in African-Americans than whites; blacks have higher stage at presentation, but stage adjusted survival is similar
  • Clinical disease is rare in Asians (3 - 4 / 100,000 vs 50 - 60 / 100,000 in 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 prepubertal castration, low incidence with hyperestrogenism (liver cirrhosis)
  • Not associated with sexually transmitted disease, smoking, occupational exposure, diet, nodular hyperplasia
Sites
  • Prostatic apex is more often involved than the bladder base
  • Peripheral zone is more often involved than transition zone or central zone
  • Posterior peripheral zones are more often involved than anterior / lateral horns of the peripheral zones
  • But bladder base, transitional / central zone and anterior / lateral horns of peripheral zones are more difficult to sample
Clinical features
  • Prostate cancer is detected by digital rectal exam (DRE), transurethral ultrasound (misses 30% of carcinomas that are isoechoic), or elevated PSA (either above 4 ng/dL or increasing over time)
  • Some evidence favors using > 2.5 ng/dL as a cutoff for biopsies to miss fewer cancers, particularly in men over 60 (J Urol 2005;174:2154)
Diagnosis
  • Today, most prostate cancer is diagnosed on needle biopsy; more rarely, it is diagnosed in transurethral resection specimens
  • Reporting standards
    • In a sample from a single vial, report the fraction of cores involved by cancer (J Urol 2000;163:174), the percent of each core with cancer (J Urol 1996;156:1375), and the length (in mm) of tumor on needle biopsy cores (J Urol 2004;171:1093); all carry important prognostic value (J Urol 2011;186:790)
      • All cancer reports should list the fraction of cores or core fragments with cancer, and at least either the percent individual core involvement or the tumor length (in mm or cm)
      • Many commercial urologic pathology laboratories and individual pathologists report both percent and tumor length
    • When there are intervening areas of benign prostate in the core biopsy, the tumor is designated multifocal or discontinuously involving the core, and one of those two terms should appear in the diagnosis

Urinary cytology:
  • Not used since 1980s; largely replaced by automated spring loaded 18 gauge biopsy
  • Not useful for screening because difficult to identify well differentiated tumors with cytology, easier for poor/moderately differentiated tumors

Core biopsy (see also separate topic):
Transurethral resection:
  • Presence of tumor indicates either extensive spread by conventional carcinoma or central carcinoma
  • Humphrey et al. recommend complete sampling for patients younger than age 60 years (Humphrey: Prostate Pathology, 2003, page 40)
  • For patients over age 60, random sampling of 8 blocks (Hum Pathol 2007 Sep;38:1305) or 10 blocks (Humphrey book) can be performed; if cancer is detected, then complete submission is warranted.
  • If only high grade PIN is found, embed all tissue and obtain deeper levels

Frozen section diagnosis:
  • Look for architectural disarray or perineural invasion
  • Lymph node frozen section/imprints: 10% false negatives
Laboratory
  • Clinical screening:
    • Prostate carcinomas secrete 10x the PSA of normal tissue (in the past, 50% had levels > 10 mg/ml), BUT
      • The U.S. Preventive Services Task Force (USPSTF) issued a blanket "D" recommendation against all prostate-specific antigen (PSA) based early detection efforts for prostate cancer (Ann Intern Med 2012;157:120)
      • The American Urological Association (AUA) counteracted the USPSTF statement (J Urol 2013;190:419), noting that this recommendation is based on crucial misinterpretations of the risks and benefits of screening and issued its own recommendation that men aged 55-69 be offered biennial (every 2 year) screening and that men under age 40 or over 69 not normally be screened
      • Overall impact of this controversy on the volume of prostate biopsies prompted by an elevated PSA seems to be minimal
    • Use of the PCA3 molecular urine assay (Urology 2007;69:532) in addition to the PSA improves sensitivity and specificity for cancer detection
Radiology description
Radiology images

Images hosted on other servers:
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Bone metastates

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Bone scan

Prognostic factors

    Recurrence after radical prostatectomy:
    • Median interval 40 months
    • Mean tumor size 3.2 mm
    • Often lacks overt histologic features of malignancy, but need lower threshold for diagnosis because atypical prostate glands should not be present at all (Am J Surg Pathol 2002;26:431)
Case reports
  • 67 year old man with shortness of breath and huge mediastinal mass (COW #430)
  • Prostatic adenocarcinoma in karyotypic woman with congenital adrenal hyperplasia due to 21-OHase deficiency (Am J Clin Pathol 1996;106:660)
Treatment
  • Radical prostatectomy (not warranted if positive pelvic nodes), brachytherapy (radioactive seeds), targeted focal cryotherapy, external beam radiation therapy, watchful waiting (for low grade tumors, localized tumor or limited life expectancy), chemotherapy or hormonal therapy (LHRH analogs, antiandrogens, orchiectomy).
  • Most tumors are androgen sensitive
  • Use PSA to monitor tumor response
Gross description
  • Gritty and firm, gray-yellow, poorly delimited, more easily felt than seen
  • Accurate identification of prostate cancer by gross inspection is possible in only 63% of cases, with a 19% false positive rate (Am J Clin Pathol 1998;110:38)
Gross images

Contributed by Debra Zynger, M.D.
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Prostatectomy specimen

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Extraprostatic extension (pT3a)

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Seminal vesicle invasion (pT3b)



Contributed by Kenneth A. Iczkowski, M.D.

Readily recognizable cancer
in anterior horn of peripheral
zone; grossly, cancer is not
always so obvious

Microscopic (histologic) description
  • Pattern depends on Gleason grade
  • Small glands, sometimes medium to large glands, papillary or cribriform glands or solid growth, single cells or necrosis
  • Cytoplasm usually finely granular, may be clear/foamy due to intracellular lipid
  • Nuclear enlargement, hyperchromasia, prominent nucleoli (>3 microns is specific for malignancy, >1 micron is suggestive)
  • 75% of high grade PIN may abuts carcinoma (Hum Pathol 2014 Jan;45:54)
  • Mitotic figures extremely rare except in high grade tumors
  • Malignant transformation is accompanied by loss of basal cells, first reported by Totten in 1953 (AMA Arch Pathol 1953;55:131)
  • Glands are “too many, too small, too crowded” (need not be clustered)
  • Most common pattern is infiltrative, small to medium sized glands (Gleason 3) - detect on low power as closely packed glands with irregular outline, smooth luminal surface, splitting stromal fibers (Figs. 5-8)
  • Large gland pattern also occurs and resembles atrophy (Fig. 1)
  • Less common, usually in transition zone or central zone, is a Gleason 2 pattern of small sized glands forming expansive nodules on low power, regular round glands, small size, usually not multifocal.
  • Assignment of Gleason 1 is discouraged in all instances and assignment of Gleason 2 is discouraged in biopsies (see Grading).
  • Cribriform pattern may appear intraductal with preserved basal cell layer, but is usually invasive and if so should be graded as Gleason 4 (Am J Clin Pathol 2011 Jul;136:98)
  • Single cell infiltration (Gleason 5 pattern) may resemble lobular carcinoma of breast
  • Ancillary findings in adenocarcinoma: perineural invasion, glomerulation, mucinous fibroplasia (collagenous micronodules, Fig. 9); rarely,perineural invasion is the only diagnostic feature of malignancy (Arch Pathol Lab Med 2000;124:98)
  • Features favoring but not diagnostic of adenocarcinoma: small glands between larger glands, crowded glands that stand out from adjacent benign glands, prominent nucleoli in at least 10% of cells, nuclear enlargement, hyperchromatic nuclei, luminal blue mucin, amphophilic cytoplasm, mitotic figures, crystalloids, adjacent high grade PIN (Arch Pathol Lab Med 2000;124:98)
  • Features associated with false positive diagnoses: atrophic cytoplasm, atypical glands associated with inflammation, small crowded glands merging with larger benign glands (adenosis), distinctive features in Central Zone (Hum Pathol 2002;33:518), high grade PIN, small atypical crowded glands adjacent to high grade PIN (may be tangential sectioning of PIN)
  • Note: As discussed in later sections, the diagnosis of ASAP (atypical small acinar proliferation suspicious for cancer) may apply if strict cancer criteria are not met

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), within lumina of Gleason pattern 3 cribriform and small acinar types, and within collagenous micronodules (Arch Pathol Lab Med 1998;122:152)

Cellularity of vessels
  • In radical prostatectomy specimens, increased vessel cellularity may be associated with higher grade tumors (Mod Pathol 2000;13:717)

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 Pathol 2000;31:94)

Crystalloids
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 postradiation therapy

Perineural invasion (PNI)
  • Common (85% of all tumors)
  • When present in needle core biopsy, suggests extraprostatic extension (Am J Clin Pathol 1999;111:223), but see (Am J Surg Pathol 2003;27:432)
  • Diameter of perineural invasion may be prognostic factor (Hum Pathol 2001;32:828)
  • May mediate local tumor spread via tumor expression of nerve cell adhesion molecule (Hum Pathol 2003;34:457)
  • Outdated theories are: (a) tumor spreads via perineurial lymphatics (they don’t exist); (b) perineurial space represents tissue plane of least resistance (Am J Surg Pathol 1980;4:143), but this doesn’t explain why morphologically similar tumors have varying neurotropism); (c) there is different nerve distribution in malignant vs. benign specimens (actually is similar, S100 not useful for identifying PNI, Am J Clin Pathol 2001;115:39)

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 Pathol 2000;31:1515)
  • Formaldehyde causes granules to appear empty (Hum Pathol 1998;29:1488)
Microscopic (histologic) images

Scroll to see all images:


Contributed by
Kenneth A. Iczkowski, M.D.

Pseudoatrophic pattern of prostate cancer


Contributed by
Semir Vranić, M.D., Ph.D.

Various images



Contributed by Grzegorz Gurda MD, PhD, Gundersen Health Systems, Wisconsin

Prostatic adenocarcinoma, Gleason 3+3, 90% NKX3.1 staining, 4x, 10x, 20x




Case of the Week #430

Metastases to mediastinum

PSA



Images hosted on other servers:

Adenocarcinoma
   

Metastases of prostatic adenocarcinoma:
H&E, PSA, PAP, NKX3.1

 

Small crowded glands with simplified architecture; round or oval lumens


Abnormal architecture

 

Prominent nucleoli

All essential histologic features present

 

Collagenous micronodules surround cancer glands



Contributed by Dr. Semir Vranić
Clinical Center University of Sarajevo
(Bosnia and Herzegovina)

Various images



Crystalloids

In benign glands


Mucin
   

Acidic mucin



Minimal prostate cancer - Images hosted on other servers:
         

Six atypical glands

 

Left: Gleason pattern 3; right: alpha methylacyl-CoA racemase (AMACR) stain

8-10 atypical glands

Basal cell specific markers (HMWCK, p63)

 

Various images



Perineural invasion (PNI)

Perineural invasion

Cluster of malignant
glands surrounds
two nerve twigs

Differential diagnosis
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