Malignant epithelial neoplasm of the prostatic acini and ducts
See Classification/Links in left sidebar for Ductal, Intraductal, Small Cell, Mucinous types
Diagnostic Criteria
Presence of any one of the following features, even if only focal, is considered diagnostic of prostatic adenocarcinoma (none are required for diagnosis and in real life, it is rather uncommon to have these without obvious carcinoma near by)
Circumferential perineural invasion
Glands adjacent to and indenting nerves is not sufficient as a solitary diagnostic criterion
Partial surrounding of nerve may be used as supportive evidence for a diagnosis of carcinoma
Glomeruloid formations
Epithelial proliferation projecting into the gland lumen
Typically a cribriform tuft with a single attachment to the side of the gland
Resembles a glomerulus in Bowman’s space
Mucinous fibroplasia / collagenous micronodules
Dense nodules of collagen surrounded and encased by epithelium
Frequently entraps epithelial cells
Frequently appears to represent organized, hyalinized mucin
The presence of the following features can also be used to make the diagnosis of carcinoma, but none are specific by themselves and none of them is required
Generally more than one must be present and the focus must not be explainable as a benign glandular collection
Nuclear enlargement (moderate) and hyperchromasia large nucleoli
Nuclei are frequently enlarged, but typically uniform
Very large or pleomorphic nuclei suggest a non-prostatic primary (or normal seminal vesicle)
May be seen in acute inflammation, partial atrophy
Prominent enlarged nucleoli
Nucleoli >3 μ are very rare outside of carcinoma
Enlarged nucleoli but <3 μ, while not diagnostic may still be helpful
Basal cells have prominent but small nucleoli
Luminal blue (acidic) mucin or dense pink amorphous secretion
May be seen in adenosis and rarely in partial atrophy
Luminal crystalloids
Bright red, sharp corners, rectangular
May be seen in adenosis
Do not confuse with fractured corpora amylacea which may have occasional sharp edges
Sharp luminal border
Normal glands frequently have an undulating border
Nuclei consistently lined up basally
Normal glands usually have nuclei at many levels
Amphophilic cytoplasm
Not seen in all carcinomas but helpful when present
Infiltrative pattern
A distinct population of glands surrounding or separating benign glands
Lack of lobularity
Crowded, haphazard glands
Immunohistochemical demonstration of complete absence of basal cells can be confirmatory of a diagnosis of carcinoma but must be interpreted with caution (see Supplemental Studies)
See Grading at left for criteria relevant to Gleason grading
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342
Last update 2/2/16
Atypical Small Acinar Proliferation
A descriptive term, it is not an entity
Term should be restricted to lesions that are probably carcinoma but either lack definitive diagnostic features or are too small to be certain that they do not represent the edge of a benign lesion
It should not be used if the lesion is benign but just unusual looking
For small foci, immunohistochemistry is primarily useful to disprove cancer, not to prove cancer
Basal cells must not be present on immunohistochemistry
Racemase/AMACR staining may be helpful as an adjunct but its interpretation should always be secondary to that of the basal cell markers
Always decide before staining which glands you consider to make up the suspicious population and which are adjacent or surrounded normal glands
Detection of even rare basal cells in any of the glands of the suspicious population excludes carcinoma for the entire population
Absence of basal cells in a small focus of atypical glands does not prove carcinoma
Small negative foci may simply be a manifestation of sampling of a population of glands with variable/decreased numbers of basal cells
Absence of basal cells throughout a large, well sampled population with other features of carcinoma can be considered diagnostic
A diagnosis of ASAP will generally lead to repeat biopsies for a definitive diagnosis, if clinically appropriate (if other cores negative)
It is not justification for prostatectomy
Some usdful scenarios (see Epstein 2014 for more discussion)
Already some Gleason 4 on other core(s)
Don't pursue a focus that might be 3+3
Do pursue a focus that might be 3+4 (unless several cores already have some 4)
Focal 3+3 already identified or no cancer on other cores
Do pursue foci of 3+3 or 4
Extrensive 3+3 already identified
Don't pursue a focus that might be 3+3
Do pursue a focus that might be 3+4
Basically, if it isn't going to make a difference clinically, just call it ASAP
Supplemental Studies
Immunohistology
Immunohistochemistry is primarily used in prostate pathology in three situations:
Identification of a differentiated, gland forming metastasis as prostatic in origin
Prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) are very sensitive and specific in this context
Virtually all untreated gland forming prostatic adenocarcinomas are positive for PSA and PAP
Either one is generally sufficient
Hormone treatment may lead to a negative result
Reactivity with other carcinomas is quite limited
PSA and PAP can stain salivary gland and breast neoplasms
PSA can stain cystitis glandularis and bladder adenocarcinoma
PAP stains rectal carcinoids
PSA is negative
Synaptophysin and chromogranin frequently stain rare to scattered cells in prostate carcinoma
Backup equivocal cases with NKX3.1
The choice of the complementary marker depends upon the context
TTF1 (lung) may stain small cell carcinoma of the prostate but is otherwise negative
CDX2 (GI tract) may react with a subset of prostate adenocarcinoma
Usually focal and weak but may be strong (including non-mucinous carcinomas)
GATA3 is sensitive (90%) and specific (also reacts with TCC)
BRST2 (GCDFP15) stains 60% of breast carcinoma and may stain nearly half of prostate adenocarcinomas
CK7 and 20 are of use only if they can exclude a carcinoma of another site
For example, a CK7 negative result is strongly against lung adenocarcinoma
Staining of prostate carcinomas is not very helpful as they may express a variety of CK phenotypes, most often CK7-20-
Racemase/AMACR is not useful in this situation
It is present in carcinomas of many types and sites
Distinction of very high grade prostatic adenocarcinoma from high grade urothelial carcinoma
NKX3.1 (nuclear) is most sensitive for prostate and quite specific
PSA and PAP may miss some (20%?) of very high grade or treated carcinomas
All three may be needed
Other backup p53 (cytoplasmic),
GATA3, p63 and/or high molecular weight cytokeratins are useful complementary markers
Nearly 90% of TCC are positive
Only extremely rare prostate adenocarcinomas are reactive
Distinction of benign from malignant prostate
p63 and high molecular weight cytokeratins (34BE12, CK5/6) are effective markers for basal cells
The presence of even one basal cell in a population may be sufficient to rule out carcinoma
Ducts filled with cribriform, papillary and/or solid growth without fibrovascular stroma required
Basal cells present at least focally around periphery required
High grade cytology, comedonecrosis
or solid/dense cribriform pattern required
High grade cytology means nuclei 6 times larger than normal
Dense cribriform means spaces make up <50% of intraluminal mass
Pleomorphic cells may preferentially localize to the periphery of nests
This is considered to represent high grade carcinoma that has invaded pre-existing ducts
Grading
The 2014 ISUP coonsensus proposal is to group Gleason patterns as defined below iinto clinically important groups
Group 1
Gleason score ≤6 (3+3 and below)
Group 2
Gleason 3+4=7
Group 3
Gleason 4+3=7
Group 4
Gleason score 8 (4+4, 3+5 or 5+3)
Group 5
Gleason scores 9 and 10
We report both Group and Gleason Score
The Gleason grading system is intended to be applied primarily at low power
Don’t go down on high power looking for one or two fused glands
Should be visible at 100x (10x objective)
The Score is the sum of the two most prevalent patterns subject to the following:
For needle biopsies
The predominant pattern is given first
The second most predominant pattern is given second, e.g. Gleason score 3+4 as long as the second score applies to >5% of the carcinoma
If the tertiary pattern is higher than both of the first two, it becomes the second pattern, regardless of its prevalence, e.g. 3+4 with tertiary 5 becomes 3+5
For prostatectomies
As for needle biopsies except that a high tertiary pattern is reported simply as a tertiary pattern e.g. Gleason score 3+4 with tertiary 5
The entire January 2012 issue of Histopathology is devoted to reviews on prostate cancers:
Epstein, J. I. (2012), Diagnosis of limited adenocarcinoma of the prostate. Histopathology, 60: 28–40.
Montironi, R., Scarpelli, M., Mazzucchelli, R., Cheng, L. and Lopez-Beltran, A. (2012), The spectrum of morphology in non-neoplastic prostate including cancer mimics. Histopathology, 60: 41–58.
Humphrey, P. A. (2012), Histological variants of prostatic carcinoma and their significance. Histopathology, 60: 59–74.
Delahunt, B., Miller, R. J., Srigley, J. R., Evans, A. J. and Samaratunga, H. (2012), Gleason grading: past, present and future. Histopathology, 60: 75–86.
Cheng, L., Montironi, R., Bostwick, D. G., Lopez-Beltran, A. and Berney, D. M. (2012), Staging of prostate cancer. Histopathology, 60: 87–117.
Egevad, L. (2012), Handling of radical prostatectomy specimens. Histopathology, 60: 118–124.
Kristiansen, G. (2012), Diagnostic and prognostic molecular biomarkers for prostate cancer. Histopathology, 60: 125–141.
Two recent reviews in Archives of Pathology:
Brian Robinson, Cristina Magi-Galluzzi, Ming Zhou , (2012) Intraductal Carcinoma of the Prostate. Archives of Pathology & Laboratory Medicine: April 2012, Vol. 136, No. 4, pp. 418-425.
Lars Egevad, Roberta Mazzucchelli, Rodolfo Montironi , (2012) Implications of the International Society of Urological Pathology Modified Gleason Grading System. Archives of Pathology & Laboratory Medicine: April 2012, Vol. 136, No. 4, pp. 426-434.
Eble JN, Sauter G, Epstein JI, Sesterhenn IA (Eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press. Lyon 2004.
Kaleem Z, Swanson PE, Vollmer RT, Humphrey PA. Prostatic adenocarcinoma with atrophic features: a study of 202 consecutive completely embedded radical prostatectomy specimens. Am J Clin Pathol. 1998 Jun;109(6):695-703.
Egan AJ, Lopez-Beltran A, Bostwick DG. Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol. 1997 Aug;21(8):931-5.
Cina SJ, Epstein JI. Adenocarcinoma of the prostate with atrophic features. Am J Surg Pathol. 1997 Mar;21(3):289-95.
Levi AW, Epstein JI. Pseudohyperplastic prostatic adenocarcinoma on needle biopsy and simple prostatectomy. Am J Surg Pathol. 2000 Aug;24(8):1039-46.
Arista-Nasr J, Martinez-Benitez B, Valdes S, Hernández M, Bornstein-Quevedo L.
Pseudohyperplastic prostatic adenocarcinoma in transurethral resections of the prostate. Pathol Oncol Res. 2003;9(4):232-5.
Yaskiv O, Cao D, Humphrey PA. Microcystic adenocarcinoma of the prostate: a variant of pseudohyperplastic and atrophic patterns. Am J Surg Pathol. 2010 Apr;34(4):556-61.
Hudson J, Cao D, Vollmer R, Kibel AS, Grewal S, Humphrey PA. Foamy gland adenocarcinoma of the prostate: incidence, Gleason grade, and early clinical outcome. Hum Pathol. 2012 Jan 3. [Epub ahead of print]
Zhao J, Epstein JI. High-grade foamy gland prostatic adenocarcinoma on biopsy or transurethral resection: a morphologic study of 55 cases. Am J Surg Pathol. 2009 Apr;33(4):583-90.
Tran TT, Sengupta E, Yang XJ. Prostatic foamy gland carcinoma with aggressive behavior: clinicopathologic, immunohistochemical, and ultrastructural analysis. Am J Surg Pathol. 2001 May;25(5):618-23.
Nelson RS, Epstein JI. Prostatic carcinoma with abundant xanthomatous cytoplasm. Foamy gland carcinoma. Am J Surg Pathol. 1996 Apr;20(4):419-26.
Hameed O, Humphrey PA. Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia. Mod Pathol. 2006 Jul;19(7):899-906.
Tavora F, Epstein JI. High-grade prostatic intraepithelial neoplasialike ductal adenocarcinoma of the prostate: a clinicopathologic study of 28 cases. Am J Surg Pathol. 2008 Jul;32(7):1060-7.
Shah RB, Magi-Galluzzi C, Han B, Zhou M. Atypical cribriform lesions of the prostate: relationship to prostatic carcinoma and implication for diagnosis in prostate biopsies. Am J Surg Pathol. 2010 Apr;34(4):470-7.
Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005 Sep;29(9):1228-42.
Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: Histologic features and clinical significance. Mod Pathol. 2006 Dec;19(12):1528-35.
Herawi M, Epstein JI. Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate. Am J Surg Pathol. 2007 Jun;31(6):889-94.
Herawi M, De Marzo AM, Kristiansen G, Epstein JI. Expression of CDX2 in benign tissue and adenocarcinoma of the prostate. Hum Pathol. 2007 Jan;38(1):72-8.
Brinker DA, Potter SR, Epstein JI. Ductal adenocarcinoma of the prostate diagnosed on needle biopsy: correlation with clinical and radical prostatectomy findings and progression. Am J Surg Pathol. 1999 Dec;23(12):1471-9.
Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI. Do adenocarcinomas of the prostate with Gleason score (GS) ≤6 have the potential to metastasize to lymph nodes? Am J Surg Pathol. 2012 Sep;36(9):1346-52.
Pacelli A; Lopez-Beltran A; Egan AJ; Bostwick DG. Prostatic adenocarcinoma with glomeruloid features Human Pathology, 1998 May, 29(5):543-6
Oppenheimer JR; Wills ML; Epstein JI. Partial atrophy in prostate needle cores: another diagnostic pitfall for the surgical pathologist. American Journal of Surgical Pathology, 1998 Apr, 22(4):440-5.
Bostwick DG; Wollan P; Adlakha K. Collagenous micronodules in prostate cancer. A specific but infrequent diagnostic finding. Archives of Pathology and Laboratory Medicine, 1995 May, 119(5):444-7
Giannico GA, Ross HM, Lotan T, Epstein JI. Aberrant expression of p63 in adenocarcinoma of the prostate: a radical prostatectomy study. Am J Surg Pathol. 2013 Sep;37(9):1401-6.
Warrick JI, Humphrey PA. Foamy gland carcinoma of the prostate in needle biopsy: incidence, Gleason grade, and comparative α-methylacyl-CoA racemase vs. ERG expression. Am J Surg Pathol. 2013 Nov;37(11):1709-14.
Schultz L, Maluf CE, da Silva RC, Falashi Rde H, da Costa MV, Schultz MI. Discontinuous foci of cancer in a single core of prostatic biopsy: when it occurs and performance of quantification methods in a private-practice setting. Am J Surg Pathol. 2013 Dec;37(12):1831-6. PubMed PMID: 24225844.
Epstein JI, Egevad L, Humphrey PA, Montironi R; Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the international society of urologic pathology consensus conference. Am J Surg Pathol. 2014 Aug;38(8):e6-e19. PubMed PMID: 25029122.
Mohanty SK, Smith SC, Chang E, Luthringer DJ, Gown AM, Aron M, Amin MB. sEvaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas. Am J Clin Pathol. 2014 Aug;142(2):173-83. PubMed PMID: 25015857.
Andreoiu M, Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol. 2010 Jun;41(6):781-93. PubMed PMID: 20466122.
Arias-Stella JA 3rd, Varma KR, Montoya-Cerrillo D, Gupta NS, Williamson SR. Does discontinuous involvement of a prostatic needle biopsy core by adenocarcinoma correlate with a large tumor focus at radical prostatectomy? Am J Surg Pathol. 2015 Feb;39(2):281-6. doi: 10.1097. PubMed PMID: 25353288
Amin MB, Lin DW, Gore JL, Srigley JR, Samaratunga H, Egevad L, Rubin M, Nacey J, Carter HB, Klotz L, Sandler H, Zietman AL, Holden S, Montironi R, Humphrey PA, Evans AJ, Epstein JI, Delahunt B, McKenney JK, Berney D, Wheeler TM, Chinnaiyan AM, True L, Knudsen B, Hammond ME. The critical role of the pathologist in determining eligibility for active surveillance as a management option in patients with prostate cancer: consensus statement with recommendations supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists, and the Prostate Cancer Foundation. Arch Pathol Lab Med. 2014 Oct;138(10):1387-405. doi: 10.5858/arpa.2014-0219-SA. Epub 2014 Aug 5. Review. PubMed PMID: 25092589.
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Epstein JI(1), Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA; Grading
Committe. The 2014 International Society of Urological Pathology (ISUP) Consensus
Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading
Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016 Feb;40(2):244-52. doi: 10.1097/PAS.0000000000000530..