Prostate gland & seminal vesicles

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Authors: Aliaksandr Aksionau, M.D., Komal Arora, M.D., Daniel Athanazio, M.D., Ph.D., Megan L. Brown, M.D., Bonnie Choy, M.D., Rebecca Czaja, M.P.H., M.D., Sara Moscovita Falzarano, M.D., Ph.D., Sarah Findeis, M.D., Alcino Pires Gama, M.D., He Huang, M.D., Ph.D., Peter A. Humphrey, M.D., Ph.D., Kenneth A. Iczkowski, M.D., Rafael E. Jimenez, M.D., M.H.A., Zhongbo Jin, M.D., Andre Kajdacsy-Balla, M.D., Ph.D., Deepika Kumar, M.D., Brian Ma, M.D., Cristina Magi-Galluzzi, M.D., Ph.D., Andres Matoso, M.D., Chinedum Okafor, M.D., Anil Parwani, M.D., Ph.D., M.B.A., Nat Pernick, M.D., Andrii Puzyrenko, M.D., Ph.D., Arpan Samaddar, M.B.B.S., Margaret Sanders, M.B.B.Ch., Ankur Sangoi, M.D., Francesca Sanguedolce, M.D., Ph.D., Ruhani Sardana, M.B.B.S., Faryal Shoaib, M.D., Emma Short, B.M.B.Ch., Steven Christopher Smith, M.D., Ph.D., Sami Talibi, M.D., Maria Tretiakova, M.D., Ph.D., Theodorus van der Kwast, M.D., Ph.D., Murali Varma, M.B.B.S., Erica Vormittag-Nocito, M.D., Jiejun Wu, M.D., Ph.D., Guang-Qian Xiao, M.D., Ph.D., Ximing J. Yang, M.D., Ph.D., Y. Albert Yeh, M.D., Ph.D., Debra L. Zynger, M.D.

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Superpage Topics

Aberrant p63 positivity Abscess Adenocarcinoma Adenocarcinoma Adenoid cystic (basal cell) carcinoma Adenosis / atypical adenomatous hyperplasia Adenosquamous carcinoma Amyloid Anatomy & histology-Cowper glands Anatomy & histology-paraganglion Anatomy & histology-prostate Anatomy & histology-seminal vesicles / ejaculatory duct Atrophic adenocarcinoma Atrophy Atypical intraductal proliferation Atypical small acinar proliferation suspicious (ASAP) Basal cell hyperplasia Benign prostatic hyperplasia Biopsy Clear cell cribriform hyperplasia Cystadenoma Ductal adenocarcinoma Foamy gland adenocarcinoma Gleason grading Granulomatous lesions Grossing & features to report HGPIN with adjacent atypical glands High grade prostatic intraepithelial neoplasia (HGPIN) IHC overview Intraductal carcinoma Large cell neuroendocrine carcinoma Low grade PIN Malakoplakia Mesonephric remnant hyperplasia Microcystic pattern Mixed epithelial and stromal tumor Mucinous (colloid) pattern Nephrogenic metaplasia / adenoma Nonneoplastic metaplasia Nonspecific granulomatous prostatitis PIN-like carcinoma Pleomorphic giant cell adenocarcinoma (pending) Postatrophic hyperplasia Prostatic stromal sarcoma Prostatic stromal tumor of uncertain malignant potential Prostatitis Pseudohyperplastic pattern Sarcomatoid adenocarcinoma Sclerosing adenosis Signet ring-like cell adenocarcinoma Small cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Squamous cell carcinoma Squamous cell carcinoma (pending) Staging Treatment effect Treatment related neuroendocrine prostatic carcinoma (pending) Urethral polyp Vanishing cancer Verumontanum mucosal hyperplasia Well differentiated neuroendocrine tumor WHO classification WHO classification (pending)

Aberrant p63 positivity

Table of Contents

Definition / general

A small subset of prostatic acinar carcinoma is characterized by strong p63 nuclear immunoexpression; distinctive morphologic and molecular phenotypes have been described in these cases

Essential features

p63 protein is normally present in basal cells of benign acini but is absent in usual type acinar or ductal cancers
However, starting in 2008, a rare subset of cancers with diffuse p63 positivity has been described
Atrophic and basaloid phenotype has been noted on H&E slides
Immunostains for cytokeratin 34 beta E12 (negative) and AMACR / P504s (positive) can help resolve problematic foci
References: Am J Surg Pathol 2008;32:461, Am J Surg Pathol 2013;37:1401

ICD coding

ICD-O: 8140/3 - acinar adenocarcinoma
ICD-10: C61 - malignant neoplasm of prostate
ICD-11: 2C82.0 & XH4PB1 - adenocarcinoma of prostate & acinar adenocarcinoma of prostate

Epidemiology

Demographically identical to prostatic adenocarcinoma in general (Am J Surg Pathol 2008;32:461)

Diagnosis

Immunostaining is performed with either the triple immunostain (high molecular weight cytokeratin, p63 and p504S) or with p63 alone

Laboratory

Serum PSA elevation is a usual feature (Am J Surg Pathol 2008;32:461, Int J Surg Pathol 2011;19:131)

Prognostic factors

The first description of this entity was comprised of all organ confined cases (Am J Surg Pathol 2008;32:461)
A subsequent report described 76% as organ confined, with relatively low Gleason scores, although 38% were 3 + 5 = 8 (Am J Surg Pathol 2013;37:1401)
However, one case with metastasis has been reported (Cureus 2022;14:e22753)
- Thus, most but not all cases seem to have favorable pathology
- Long term outcome has not been studied yet
Parenthetically, p63 staining can assume predominant cytoplasmic reactivity in prostate cancer (unlike its strong nuclear staining in basal cells) but this is a separate matter
- Aberrant expression of p63 in the cytoplasm was noted to be associated with increased tumor proliferation and apoptosis as well as with more prostate cancer specific mortality up to 20 years after diagnosis (Asian Pac J Cancer Prev 2012;13:1943, Cancer Epidemiol Biomarkers Prev 2009;18:595)
  - The same trend was observed in dogs (PLoS One 2018;13:e0199173)

Case reports

60 year old man whose diagnosis was delayed because of p63 positive prostatic adenocarcinoma (Int J Surg Pathol 2011;19:131)
65 year old man with aberrant diffuse p63 expression and serum PSA of 6.7 (Arch Pathol Lab Med 2013;137:1179)
76 year old man with the first p63 positive carcinoma reported in a metastatic site (Cureus 2022;14:e22753)

Microscopic (histologic) description

The first series in 2008 by Osunkoya et al. described 21 cases on needle biopsy, including 8 with matched prostatectomy in which > 70% of cancer cells were p63 positive (Am J Surg Pathol 2008;32:461)
- Distinctive, atrophic-like morphology was noted
21 matched biopsy / prostatectomy cases were characterized (Am J Surg Pathol 2013;37:1401)
- Besides atrophic-like change, salient features that have been described include a basaloid appearance and high N:C ratio, with multilayered and sometimes spindled nuclei
- Notably, at prostatectomy, 86% of cases had coexisting usual type p63 negative adenocarcinoma while 14% were pure

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Atrophic-like dilated cancer acini

Basaloid appearance

Atrophic, mucinous cancer

Strong diffuse nuclear p63 expression

Few p63 positive acini

Cytoplasmic p63

Positive stains

Strong nuclear positivity for p63 is required for the diagnosis
AMACR (P504S) is the most useful
Positivity for markers of luminal cells is present, including CK8 and CK18, androgen receptor, NKX3.1 and prostein (Mod Pathol 2015;28:446)

Negative stains

High molecular weight cytokeratin 34 beta E12 is the most useful (Mod Pathol 2015;28:446)
Negative for other basal markers such as CK14 and CK15 (Mod Pathol 2015;28:446)
CK5/6 negative in most cases, although weak and focal positivity was noted in 4/11 cases (Mod Pathol 2015;28:446)

Molecular / cytogenetics description

37 p63 positive cancer cases were compiled to investigate the molecular phenotype (Mod Pathol 2015;28:446)
- These tumors were almost all positive for ΔNp63 isoform by immunofluorescence and p63 mRNA by in situ hybridization
- 100% of these tumors lacked ERG rearrangement at the molecular level by FISH and the protein level by immunostaining; moreover, 100% lacked PTEN loss
  - These 2 features are found in ~50% and 33% of usual acinar carcinomas, respectively
- Tumors frequently express GSTP1 (14/19; higher than usual)
In one case report, 5 tumor foci in a prostatectomy were present, of which one was p63 positive; this focus did not show a TMPRSS::ERG translocation by FISH, while the other foci did (Int J Surg Pathol 2011;19:131)
ETS2 tumor suppressor gene is highly expressed in 95% (18/19) of p63 expressing prostatic carcinomas and benign prostate basal cells, with lower to undetectable expression in luminal cells and primary usual type adenocarcinomas (Prostate 2018;78:896)

Sample pathology report

Prostate, right mid, biopsy:
- Prostatic adenocarcinoma, Gleason 3 + 4 (grade group 2) (see comment)
- Comment: The tumor demonstrates a basaloid appearance with aberrant p63 nuclear reactivity. This is a rare subtype of prostatic adenocarcinoma and cancer is confirmed by lack of immunoreactivity for cytokeratin 34 beta E12.

Differential diagnosis

Benign acini:
- Lack of atypia and AMACR (P504S) while cytokeratin 34 beta E12 is positive (Am J Surg Pathol 2008;32:461, Arch Pathol Lab Med 2013;137:1179)
Atypical basal cell proliferations (adenoma, carcinoma):
- These stain diffusely for cytokeratin 34 beta E12 but are negative for prostate specific antigen (PSA)
- Conversely, p63 positive prostate cancer will be negative for cytokeratin 34 beta E12 while positive for PSA
Prostatic carcinoma of usual type:
- It is not uncommon for a few nuclei to have weak p63 positivity in usual cancers but this is in contrast to the special type discussed here
Urothelial carcinoma with a glandular morphology:
- This should be p63 positive
- Negative PSA or NKX3.1 staining should raise the possibility of a nonprostatic tumor

Board review style question #1

Which of the following are features of the rare type of prostatic carcinoma pictured above?

Basaloid H&E appearance and negative for all luminal and basal markers
Basaloid H&E appearance and positive for basal markers such as cytokeratin 34 beta E12, CK5/6, CK14 and CK15
Basaloid H&E appearance and positive for luminal markers such as CK8, CK18, androgen receptor, NKX3.1, prostein and P504S
Luminal H&E appearance and positive for basal markers such as cytokeratin 34 beta E12, CK5/6, CK14 and CK15
Luminal H&E appearance and positive for luminal markers such as CK8, CK18, androgen receptor, NKX3.1, prostein and P504S

Board review style answer #1

C. Basaloid H&E appearance and positive for luminal markers such as CK8, CK18, androgen receptor, NKX3.1, prostein and P504S. The H&E appearance of these rare tumors is basaloid and atrophic but paradoxically they retain luminal marker expression and are negative for basal cell markers such as cytokeratin 34 beta E12.

Comment Here

Reference: Adenocarcinoma with aberrant p63

Board review style question #2

What is the p63 stain morphology shown above expected to display?

Aberrant diffuse nuclear p63 positivity
Lack of ERG rearrangement
Lack of PTEN loss
Positive reactivity for cytokeratin 34 beta E12
Reduced cancer specific survival and high grade

Board review style answer #2

E. Reduced cancer specific survival and high grade. This cytoplasmic staining is not to be confused with diffuse nuclear p63, which is the topic of this section. The cytoplasmic staining is associated with a worse outcome. B, C and D are incorrect because usual type tumors (without nuclear p63) do not necessarily show lack of ERG rearrangement or lack of PTEN loss and should have loss of basal markers such as cytokeratin 34 beta E12.

Comment Here

Reference: Adenocarcinoma with aberrant p63

Abscess

Table of Contents

Definition / general

Complication resulting from the acute infectious process of the prostate (prostatitis) characterized by a focal accumulation of purulent material within the prostate (BMC Urol 2016;16:38)

Essential features

Infection is caused mainly by gram negative rods
Neutrophils and necrotic debris fill prostatic ducts and acini

Terminology

Acute inflammatory disease of the prostate

ICD coding

ICD-10:
- N41 - inflammatory diseases of prostate
  - N41.2 - abscess of prostate
ICD-11:
- GA91 - inflammatory and other diseases of prostate
  - GA91.1 - abscess of prostate

Epidemiology

Incidence of prostatic abscess is 0.5% of all urologic diseases and 6% of all acute bacterial prostatitis
Mortality rate is 1 - 16%
Most commonly in fifth to sixth decade but can occur at any age
Older males > younger males
Prostatic abscess due to sexually transmitted organisms: younger males > older males (Int Braz J Urol 2017;43:835)

Sites

Can affect central and peripheral zones of the prostate (AJR Am J Roentgenol 1998;170:753)

Pathophysiology

Most common way of developing is a reflux of infected urinary contents into prostatic ducts (Saudi J Kidney Dis Transpl 2011;22:298)
Risk factors: indwelling catheter, underlying voiding dysfunction, poorly controlled diabetes, end stage renal disease, cirrhosis, immunosuppression (Nat Rev Urol 2011;8:207)
Hematogenous dissemination from a distant primary (septic foci in respiratory, digestive, urinary tracts, skin and soft tissue) is rare (Arch Esp Urol 2011;64:62)

Etiology

Most common causes: Escherichia coli (accounting for > 70% of cases), Klebsiella, Pseudomonas, Proteus, Enterobacter, Enterococcus species (BMC Urol 2016;16:38, Andrologia 2003;35:258)
Staphylococcus aureus is a common cause through hematogenous dissemination (Arch Esp Urol 2011;64:62)

Clinical features

Systemic (Urol Int 1992;48:358)
- Headache, fever, chills and general malaise, low back pain
Prostate (local) (Korean J Urol 2012;53:860)
- Severely tender prostate with areas of fluctuation on digital rectal examination
- Perineal pain
- Dysuria, urinary urgency or frequency, hematuria, purulent urethral discharge
- Obstructive urinary symptoms

Diagnosis

History and physical findings
Complete blood count with differential, urinalysis
Imaging with transrectal ultrasound (the diagnostic method of choice), CT, MRI (rarely used) (Korean J Urol 2012;53:860)
Blood culture, urine culture
PCR (detection of sexually transmitted organisms)

Laboratory

> 10 white blood cells per high power field and pyuria
Bacterial culture and antibiotic susceptibility identification
DNA sequencing and nucleic acid amplification by PCR
Can raise the serum prostate specific antigen (PSA) above normal (Hinyokika Kiyo 1993;39:445)

Radiology description

Transrectal ultrasound (TRUS) (Korean J Urol 2012;53:860)
- 1 or more hypoechoic areas with well defined walls
- Thick pus primarily in the transition zone and in the central zone of the prostate
Computed tomography (CT scan) of the abdomen and pelvis (AJR Am J Roentgenol 1987;148:899)
- Can better delineate the spread of infection to adjacent organs
Magnetic resonance imaging (MRI) (Indian J Radiol Imaging 2011;21:46)
- Hypointense signal on T1 and hyperintense on T2 image

Radiology images

Images hosted on other servers:

Abdominal
ultrasound showing
prostatic abscess

TRUS showing hypoechoic lesion

Pelvic CT showing an abscess in the prostate

Prognostic factors

Depends on the timely diagnosis and treatment
Also depends on underlying medical conditions
Good prognosis if recognized and treated early
Poor prognostic factors: age > 65 years, fever > 100.4°F, benign prostatic hypertrophy, chronic catheterization (BMC Urol 2016;16:38)

Case reports

31 year old man, liver transplant recipient, with methicillin resistant Staphylococcus aureus prostatic abscess (Case Rep Transplant 2014;854824)
53 year old man with Staphylococcus aureus prostatic abscess (BMC Infect Dis 2017;17:509)
68 year old man with prostate abscess due to Nocardia farcinica (IDCases 2016;5:24)
71 year old man with acute bacterial prostate abscess and urinary tract infection caused by Klebsiella pneumoniae (BMC Res Notes 2016;9:395)
77 year old man with prostatic abscess due to Candida tropicalis (Prostate Cancer Prostatic Dis 2005;8:296)
79 year old man with multiloculated prostate abscess (Clin Imaging 2003;27:251)

Treatment

Medical treatments
- Broad spectrum parenteral antibiotics (available as a single treatment if monofocal abscess cavity < 1 cm) (Ultrasound Med Biol 2004;30:719)
Surgical treatment (Urology 2004;63:1017)
- Ultrasound guided aspiration (standard procedure for drainage of prostate abscess) (Urol J Fall 2010;7:278)
  - Easy to perform under local anesthesia
  - Low morbidity
  - Can be easily repeated
Transurethral drainage (if the abscess recurs or cannot be completely evacuated) (Nephrourol Mon 2012;4:458)
Open drainage (rarely used) (J Urol 1992;148:80)

Clinical images

Images hosted on other servers:

Transurethral unroofing of a prostatic abscess

Abscess drainage with transurethral resection

Microscopic (histologic) description

Prominent neutrophilic infiltrate with gland destruction and abscess formation
Neutrophils and necrotic debris fill prostatic ducts and acini
Macrophages in stroma
Reference: Reddy: Gattuso's Differential Diagnosis in Surgical Pathology, 4th Edition, 2021

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Prostatic microabscess

Cytology description

Reactive glandular epithelium with mild cytologic atypia and degenerative changes
Granulocytes and macrophages
Reference: Reddy: Gattuso's Differential Diagnosis in Surgical Pathology, 4th Edition, 2021

Positive stains

Bacteria are visible on Gram stain

Sample pathology report

Prostate, biopsy:
- Prostatic abscess (see comment)
- Comment: Numerous neutrophilic infiltrates in lumen spaces and around glands consistent with acute inflammation. Some glands are partly damaged by microabscesses. Gram negative rods are noticed on Gram stain.

Differential diagnosis

Acute bacterial prostatitis:
- Clinically and histologically similar (neutrophils are mostly in lumens and epithelium)
- No fluctuant mass during a rectal examination
- No hypoechoic areas on ultrasound
Chronic bacterial prostatitis:
- Similar clinical symptoms but lower intensity
- Predominant lymphocytic infiltration (lymphocytes are mostly in the stroma)
Granulomatous prostatitis:
- Fever and chills are common
- Irritative voiding symptoms of urgency, frequency
- May have history of bladder cancer Bacillus Calmette Guerin (BCG) treatment
- Necrotizing or nonnecrotizing granulomas (cohesive clusters of histiocytes, usually with admixed lymphocytes, eosinophils, neutrophils)
Prostate carcinoma:
- May mimic benign acini with reactive inflammatory atypia
- Typically lack background inflammation
- Small glands, sometimes medium to large glands, papillary or cribriform glands or solid growth, single cells or necrosis
- Nucleomegaly, prominent and multiple nucleoli, lack basal cell layer

Differential diagnosis	Histological changes	Clinical presentation
Prostatic abscess	Neutrophilic infiltrate with glands destruction; abscess formation; neutrophils fill prostatic ducts and acini	Severely tender prostate with areas of fluctuation on digital rectal examination
Acute bacterial prostatitis	Predominant neutrophilic infiltrates mostly in lumens and epithelium; no abscess formation	Severely tender prostate without areas of fluctuation on digital rectal examination
Chronic bacterial prostatitis	Predominant lymphocytic infiltrates mostly in the stroma	Mildly tender prostate without areas of fluctuation on digital rectal examination
Granulomatous prostatitis	Necrotizing or nonnecrotizing granulomas (cohesive clusters of histiocytes, usually with admixed lymphocytes, eosinophils, neutrophils with or without necrosis in the center)	Mildly tender prostate on digital rectal examination; irritative voiding symptoms of urgency, frequency
Prostate carcinoma	Typically lack background inflammation; small glands with papillary or cribriform or solid growth or single cells	Firm/nodular, nontender prostate on digital rectal examination; blood in the urine

Board review style question #1

A 64 year old man comes to the clinic with the complaint of severe dysuria for the past week. Just a week before the beginning of these symptoms, the patient was treated with a short course of antibiotics for a urinary tract infection. The patient also complains of burning micturition for a week. He has a history of benign prostatic hypertrophy, causing urinary retention, sometimes needing catheterization in the past. On admission, he has a high grade fever. Rectal examination reveals an enlarged prostate that is tender to palpation. Transrectal ultrasound suggests a 2.3 cm collection in the prostate. What histological finding is most common for this entity?

Eosinophilic infiltration
Lymphocytic infiltration
Microabscesses with neutrophils
Necrotizing granulomas
Nonnecrotizing granulomas

Board review style answer #1

C. Microabscesses with neutrophils. Acute inflammation of the prostate with abscess formation due to bacterial infection can show neutrophilic infiltrates in lumen spaces and in epithelium, consistent with gland destruction and microabscesses.

Comment Here

Reference: Abscess

Adenocarcinoma

Table of Contents

Definition / general

Most common malignancy of the prostate gland
Originates from prostatic secretory epithelium

Essential features

Clinical and radiological features neither sensitive nor specific
Often diagnosed by nontargeted needle biopsies investigating raised serum prostate specific antigen (PSA)
Absence of basal cell layer is a pathognomonic histological feature
Pathognomonic diagnostic features: circumferential perineural invasion, glomerulations and collagenous micronodules (mucinous fibroplasia)
Other histological features: infiltrative architecture, nucleolar prominence, amphophilic cytoplasm and some intraluminal contents (crystalloids, blue mucin, pink amorphous material)

Terminology

Prostate cancer
Prostate adenocarcinoma
Subtypes of prostatic adenocarcinoma: acinar adenocarcinoma, ductal adenocarcinoma, atrophic adenocarcinoma, pseudohyperplastic adenocarcinoma, microcystic adenocarcinoma, foamy gland adenocarcinoma, mucinous adenocarcinoma, signet ring variant of adenocarcinoma, pleomorphic giant cell adenocarcinoma, sarcomatoid adenocarcinoma

ICD coding

ICD-O: C61.9 - prostate, NOS
ICD-10: C61 - malignant neoplasm of the prostate

Epidemiology

Second most common cancer and second leading cause of cancer related death in American men (SEER data available at NIH: Cancer Stat Facts - Common Cancer Sites [Accessed 10 December 2021])
92% of U.S. cases diagnosed in men aged 55+ years; 19.5% in men aged 75+ years (SEER data available at NIH: Cancer Stat Facts - Prostate Cancer [Accessed 10 December 2021])
Found at autopsy in 40% of men age 60+ years (J Natl Cancer Inst 2013;105:1050)
Incidental prostate cancer reported in about 25% of cystoprostatectomies performed for treatment of bladder cancer (J Urol 2017;197:385)
Globally, highest age standardized rates in Oceania, North America, Europe (World J Oncol 2019;10:63)
Lower rates in developing countries: may be due to different screening programs and diagnostic pathways
Higher incidence in men of African heritage (World J Oncol 2019;10:63)

Sites

Most tumors are multifocal (Eur Urol 2019;75:498)
75 - 80% are posterior / posterolateral peripheral zone
Approximately 13 - 20% are in transition (periurethral) zone (Prostate 1997;30:130, Urology 1994;43:11)
Most clinically significant cancers arise in the peripheral zone that is sampled by needle biopsies
Transition zone prostate cancer is associated with favorable pathologic features and better recurrence free survival (Prostate 2015;75:183)
Less frequently involved anterior prostate most likely due to inadequate sampling using standard biopsy approach (Histopathology 2012;60:142)

Pathophysiology

Germline variants can increase risk of prostate adenocarcinoma; see Molecular / cytogenetics description
Somatic mutations in genes such as ERG, ETV1/4, FLI1, SPOP, FOXA1, IDH1, PTEN, TP53, MYC, CDH1 (Cell 2015;163:1011, Adv Anat Pathol 2020;27:11)
Most common somatic genomic rearrangement is fusion of the androgen regulated gene TMPRSS2 with a member of the ETS transcription family (Adv Anat Pathol 2020;27:11)

Etiology

Obesity increases risk (Oncotarget 2018;9:34485)
Nonmodifiable risk factors: age, race and family history (Rev Urol 2002;4:S3)
- Genetic susceptibility linked to African heritage (Rev Urol 2002;4:S3)
- Increased risk with first degree relative with prostate cancer (Rev Urol 2002;4:S3)
- BRCA2 mutations increase risk by 5 fold; BRCA2 associated cancers occur at a lower age and have worse survival outcomes (Saudi Med J 2020;41:9, Adv Anat Pathol 2020;27:11)
- Additional germline variants associated with increased cancer risk occur in HOXB13 (Adv Anat Pathol 2020;27:11)
- Increased risk in Lynch syndrome (Genet Med 2014;16:553)
Numerous single nucleotide polymorphisms (SNPs) that have a low to moderate effect on risk / progression have been identified (Am J Transl Res 2021;13:3868)
High levels of IGF1 may confer increased risk (Novartis Found Symp 2004;262:193)

Clinical features

Generally asymptomatic unless locally advanced or metastatic
Often discovered following investigation of nonspecific lower urinary tract symptoms
Digital rectal examination (DRE): prostate may feel normal or may be enlarged / asymmetrical / hard / have a palpable nodule present

Diagnosis

Generally diagnosed by systematic transrectal ultrasound guided prostate biopsies
Transperineal needle biopsies increasingly used as associated with lower risk of infection
Prebiopsy MRI followed by systematic biopsies supplemented with targeted biopsies from any radiological abnormality leads to better identification of clinically significant prostate cancer than systematic prostate biopsy alone (Lancet 2017;389:815)
Incidental prostate cancer sometimes diagnosed in transurethral resections
Immunohistochemistry with basal cell markers (HMWCK, p63) and AMACR used to establish the diagnosis in equivocal cases

Laboratory

Raised serum PSA
Different PSA cutoffs have been used to prompt prostate needle biopsy
Age specific cutoffs, PSA velocity (rate of change in PSA over time) and PSA density (PSA per unit prostate volume - ng/mL/cc) may increase sensitivity and specificity of PSA testing (NCCN Guidelines: Prostate Cancer Early Detection [Accessed 10 December 2021])
U.S. Preventative Services Task Force (USPSTF) recommends against PSA based screening for prostate cancer in men 70 years and older
- For men aged 55 - 69 years, periodic PSA based screening should be an individual choice
- Screening in this age group offers a small potential benefit of reducing the chance of death from prostate cancer in some men; however, many men will experience potential harm (USPSTF: Recommendation - Prostate Cancer - Screening [Accessed 27 January 2022])
American Urological Association (AUA) does not recommend PSA screening in men under age 40 years or in men aged 40 - 54 years at average risk
- For men age 55 - 59 years, shared decision making is desirable
- For men aged 70 years and over or men with < 10 - 15 year life expectancy, PSA screening is not recommended (J Urol 2013;190:419)
Potential urine biomarker for prostate cancer is PCA3 (Adv Anat Pathol 2020;27:11)

Radiology description

Ultrasound scan (USS) generally used to guide prostate biopsies; prostate cancer may appear hypoechoic but USS neither sensitive nor specific
Multiparametric MRI commonly used for local tumor staging; may also be used to identify abnormalities for targeting at biopsy
MRI abnormalities generally reported using either PI-RADS (Prostate Imaging - Reporting and Data System) or Likert score
CT scan used to identify metastatic disease in lymph nodes
Bone scan used to detect bony metastases
PET scan used to detect micrometastatic disease in selected patients, such as men with raised PSA levels after treatment

Prognostic factors

Biopsy: tumor extent (mm or percentage core involvement), grade (Gleason score and grade group), perineural invasion, extraprostatic extension
Radical prostatectomy: tumor size, Gleason score and grade group, stage, margin status
Cribriform morphology and intraductal carcinoma associated with invasive prostate cancer are adverse prognostic indicators (Transl Androl Urol 2018;7:145)
Small cell carcinoma component is associated with aggressive behavior and treated differently
Some expert groups recommend incorporating intraductal component into the Gleason score while others recommend reporting it separately in a comment (Am J Surg Pathol 2020;44:e87, Arch Pathol Lab Med 2021;145:461, Histopathology 2021;78:231)

Case reports

53 year old man presented with prostate adenocarcinoma with retained basal cells in lymph node metastases (Histopathology 2016;69:338)
56 year old man with gait disturbance was found to have disseminated prostate carcinoma with bone metastases and a germline mutation in BRCA2 (J Korean Med Sci 2017;32:377)
60 year old man presented with metastatic prostate adenocarcinoma to supraclavicular lymph nodes (J Clin Diagn Res 2017;11:PD06)
64 year old man with asymptomatic case of oncocytic variant of prostate adenocarcinoma (World J Clin Oncol 2017;8:289)

Treatment

Preoperative risk stratification based on serum PSA, clinical stage, biopsy parameters (tumor extent, grade, cribriform morphology, intraductal carcinoma, perineural invasion)
Primary treatment options based on preoperative risk stratification:
- Active surveillance
- Focal therapy (cryotherapy, high intensity ultrasound)
- Radical prostatectomy
- Brachytherapy
- External beam radiotherapy
- Hormone therapy (e.g., luteinizing hormone releasing hormone [LHRH] analogues, antiandrogens)
- Orchidectomy (rare in contemporary practice)
- Chemotherapy (for metastatic disease)
Postprostatectomy options:
- Generally, PSA monitoring and early salvage therapy if rising serum PSA
- Less commonly adjuvant therapy for high stage disease or margin positivity

Gross description

Often grossly inapparent
May form a cream mass

Gross images

Contributed by Debra Zynger, M.D. and Kenneth A. Iczkowski, M.D.

Prostatectomy specimen

Extraprostatic extension (pT3a)

Seminal vesicle invasion (pT3b)

Anterior horn of
peripheral zone

Microscopic (histologic) description

Gleason grading is based on the architecture of the tumor
Gleason grades represent a morphological spectrum from well formed glands (pattern 3) to increasingly complicated glandular proliferations (pattern 4) to almost no glandular differentiation (pattern 5) (Diagnostic Histopathology 2019;25:371)
Glandular crowding and infiltrative growth pattern
Nuclear enlargement, nucleolar prominence
Round generally monomorphic nuclei
Amphophilic cytoplasm
Mitoses
Apoptotic bodies
Stromal desmoplasia
Intraluminal contents: crystalloids, pink amorphous secretions, blue mucin
Glomerulations, collagenous micronodules (mucinous fibroplasia)
Absence of basal cell layer (generally requires immunohistochemical confirmation)
Reference: Cold Spring Harb Perspect Med 2017;7:a030411

Microscopic (histologic) images

Contributed by Murali Varma, M.B.B.S.

Infiltrative growth pattern

Glomerulations

Prominent nucleoli

Perineural invasion

Atrophic variant of prostate cancer

Pseudohyperplastic variant of prostate cancer

Foamy gland variant of prostate cancer

Crystals in gland lumens

Pink amorphous material within gland lumens

Amphophilic cytoplasm

Mitosis

Collagenous micronodules

Virtual slides

Images hosted on other servers:

Prostate adenocarcinoma Gleason 4+3=7

Prostate adenocarcinoma Gleason 4+4=8

Prostate ductal adenocarcinoma

Cytology description

Urine cytology for detecting prostate cancer has a very low sensitivity (Prostate Cancer Prostatic Dis 2019;22:362)
Urine cytology is not used clinically in the diagnosis of prostate cancer
FNA of metastatic prostate cancer to a lymph node may show microacinar complexes / cell clusters / single cells with fragile cytoplasm and prominent nucleoli (Diagn Cytopathol 2007;35:565)

Positive stains

PSA
NKX3.1
AMACR (P504S, racemase)
Prostein (P501S)
PSMA
Rare tumors may have aberrant expression of p63 (Mod Pathol 2015;28:446)
Reference: Am J Surg Pathol 2014;38:e6

Negative stains

CK7
CK20
High molecular weight cytokeratins (34 beta E12, CK5, CK5/6)
p63
CDX2
GATA3
TTF1
Reference: Am J Surg Pathol 2014;38:e6

Molecular / cytogenetics description

Prostate cancer is a heritable disease
Family history of a first degree relative with prostate cancer increases the risk of developing prostate cancer by 2 fold (Nat Rev Urol 2014;11:18)
30 - 40% of familial risk is due to genetic factors (Adv Anat Pathol 2020;27:11)
Genetic factors include highly penetrable rare variants and more common low to moderate risk variants (Adv Anat Pathol 2020;27:11)
Highly penetrant variants occur in BRCA2 and HOXB13
Over 280 SNPs have been identified as prostate cancer risk factors (Adv Anat Pathol 2020;27:11)
For most SNPs, the molecular mechanism of cancer association is generally unknown, as they occur in noncoding regions of the genome (Adv Anat Pathol 2020;27:11)
Somatic mutations occur in genes such as ERG, ETV1/4, FLI1, SPOP, FOXA1, IDH1, PTEN, TP53, MYC, CDH1 (Cell 2015;163:1011, Adv Anat Pathol 2020;27:11)
Most common somatic genomic rearrangement is fusion of the androgen regulated gene TMPRSS2 with a member of the ETS transcription family (Adv Anat Pathol 2020;27:11)
Somatic mutation profiles of prostate cancer are associated with clinical and pathological outcomes
- There are 7 major subtypes, which are defined by either specific gene fusions of ETS transcription family members (ERG, ETV1, ETV4 and FLI1) or mutations (SPOP, FOXA1, IDH1) (Oncotarget 2018;9:14723)
Different subtypes have different molecular profiles, for example (Oncotarget 2018;9:14723):
- ETS subset (59% of cases) are enriched in PTEN mutations
- SPOP mutant subset (11%) of cases have distinct somatic copy number alteration profiles, including deletions of CHD1, 6q and 2q

Sample pathology report

Prostate core biopsies:
- Acinar adenocarcinoma (see comment)
- Comment:
  - Number of cores involved:
    - Right 1/6 cores
    - Location(s): right apex
    - Left 0/6 cores
    - Total number of cores involved: 1/12
  - Greatest length of cancer in a core: 5 mm (40%)
  - No evidence of perineural invasion or extraprostatic extension
  - Gleason score: 3+4=7 (10% pattern 4, no cribriform morphology)
  - Grade group 2
Radical prostatectomy:
- Histological tumor type: acinar adenocarcinoma
- Gleason score:
  - Primary Gleason grade: 3
  - Secondary Gleason grade: 3
  - Tertiary Gleason grade (< 5%): not applicable
  - Gleason score: 3+3=6
  - Grade group: 1
- Location of dominant tumor: right apex
- Extraprostatic extension: not identified
- Bladder neck: not involved
- Seminal vessels: not involved
- Margin status: not involved
- Lymphovascular invasion: not identified
- Regional lymph node status:
  - Number of nodes examined: 9
  - Number of positive lymph nodes: 0
- Primary tumor: pT2 pN0

Differential diagnosis

Benign prostate tissue:
- Pale cytoplasm
- Corpora amylacea
- No other intraluminal contents
- Basal cell marker immunoreactivity
Prostatic atrophy:
- Lobular architecture
- Scant cytoplasm
- Basal cell marker immunoreactivity
Adenosis:
- Lobular architecture
- Basal cell marker immunoreactivity (often scattered)
Atypical small acinar proliferation (ASAP):
- Small size
- Lack of significant cytological atypia, including a lack of macronucleoli
High grade prostatic intraepithelial neoplasia (HGPIN):
- Less architectural atypia
- Maintained basal cells
Postatrophic hyperplasia:
- Some glands atrophic
- Basal cell marker immunoreactivity (often scattered)
Partial atrophy:
- Atrophic glands with abundant lateral pale cytoplasm
- Irregularly distributed nuclei
- Basal cell marker immunoreactivity (often scattered)
Radiation atypia:
- Glandular atrophy
- Nuclear irregularity and pleomorphism
- Atypical stromal cells
- Basal cell marker immunoreactivity
Urothelial carcinoma:
- Nuclear irregularity and pleomorphism
- Hyaline dense eosinophilic cytoplasm
- Desmoplastic stromal reaction
- Immunoreactivity for urothelial markers (GATA3, CK7, p63)
- No expression of prostatic immunomarkers (PSA, PSAP, NKX3.1)

Board review style question #1

A 74 year old man with urinary hesitancy was found to have a PSA of 8 ng/mL. He had a transrectal ultrasound (TRUS) and prostate biopsy. A representative image is above. Which of the following is the typical immunoprofile of such a tumor?

CK7- CK20- NKX3.1-
CK7- CK20- NKX3.1+
CK7- CK20+ NKX3.1-
CK7+ CK20- NKX3.1-
CK7+ CK20+ NKX3.1+

Board review style answer #1

B. CK7- CK20- NKX3.1+

Comment Here

Reference: Prostate adenocarcinoma

Board review style question #2

A prostate biopsy shows this tumor. What is its grade?

Gleason score 2+3, grade group 1
Gleason score 3+2, grade group 1
Gleason score 3+3, grade group 1
Gleason score 3+3, grade group 2
Gleason score 3+4, grade group 2

Board review style answer #2

C. Gleason 3+3, grade group 1

Comment Here

Reference: Prostate adenocarcinoma

Adenocarcinoma

Table of Contents

Definition / general

Very rare, must confirm microscopically
Primary tumors should be localized primarily to seminal vesicle; must rule out invasion from prostate (do PSA / PAP), rectum or other sites
Usually a papillary adenocarcinoma resembling architecture of normal seminal vesicle
Resembles prostatic duct adenocarcinoma Gleason patterns 3 or 4 or mucinous (colloid) carcinoma
Usually unresectable and patients die within 2 years
Adenocarcinoma: very rare, must rule out prostate primary; often mucin producing, ulcerates through skin of scrotum

Case reports

67 year old man with neuroendocrine carcinoma (Int J Urol 2012;19:370)
87 year old man (Hum Pathol 1987;18:200)
Disseminated disease with occult primary discovered at autopsy (Int J Surg Pathol 2011;19:401)

Gross images

Images hosted on other servers:

Low grade epithelial stromal tumor

Microscopic (histologic) images

Images hosted on other servers:

Metastatic hepatocellular carcinoma

Low grade epithelial stromal tumor

Positive stains

CK7, CA125 (Mod Pathol 2000;13:46)

Negative stains

PSA, PAP, CK20

Differential diagnosis

Bladder adenocarcinoma: CA125-
Bladder urothelial carcinoma: CK20+, CA125-
Prostatic adenocarcinoma: PSA+, PAP+, CA125-
Rectal adenocarcinoma: CA125-, CK7 neg, CK20+

Adenoid cystic (basal cell) carcinoma

Table of Contents

Definition / general

Also known as adenoid basal, adenoid cystic-like tumor, adenoid basal proliferation of uncertain significance
Resembles to some extent the salivary gland tumor
Usually indolent; cases with aggressive behavior often have large solid nests with central necrosis, high Ki67%, less staining with basal cell markers (Am J Surg Pathol 2007;31:697)

Case reports

67 year old man (Int J Clin Oncol 2010;15:594)

Microscopic (histologic) description

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
Considered malignant if extensive infiltration between normal prostate gland, extension out of the prostate, perineural invasion, necrosis or metastases
Gleason grading of these tumors is not recommended

Microscopic (histologic) images

Contributed by Daniel Athanazio, M.D., Ph.D. and Maiara Souza, M.D.

Solid growth - basaloid morphology

Infiltrative growth

Basaloid morphology

Combination of basaloid and luminal cells

BCL2

p63

PSA

Synaptophysin

Positive stains

Negative stains

PSA / PAP

Additional references

Arch Pathol Lab Med 1993;117:799, Am J Clin Pathol 1988;89:49

Adenosis / atypical adenomatous hyperplasia

Table of Contents

Definition / general

Well circumscribed, microscopic nodular proliferation of crowded, small to medium glands with pale to clear cytoplasm, a fragmented and discontinuous basal cell layer and minimal atypia; may be mistaken for low grade adenocarcinoma (Histopathology 2019;74:1036, Surg Pathol Clin 2008;1:1, J Urol 2012;188:2371)
Found predominantly in the transition zone (1.6% of transurethral resection of the prostate [TURP], < 1% of core biopsies) in association with nodular hyperplasia (Int J Surg Pathol 2005;13:167, Surg Pathol Clin 2008;1:1)
Frequently multifocal (Int J Surg Pathol 2005;13:167)

Essential features

Benign lobular proliferation of small crowded glands
Similar to prostatic adenocarcinoma; in adenosis, cells may show small or medium size nucleoli, crystalloids, intraluminal secretions, minimal infiltration and positive immunostaining for AMACR (racemase)
In contrast to prostatic adenocarcinoma, in adenosis, glands have more pale cytoplasm, merge with adjacent benign glands, commonly have corpora amylacea (Am J Surg Pathol 1994;18:863, Surg Pathol Clin 2008;1:1)
Basal cells can be identified on H&E slides or with immunohistochemistry for p63, cytokeratin 5/6 or HMWCK (Pathology 2013;45:251)
AMACR (racemase) can be focally or diffusely expressed in up to 18% of cases of adenosis (Am J Surg Pathol 2002;26:921)
Lack of ERG expression in adenosis supports the notion that it is not a precursor lesion of adenocarcinoma (Hum Pathol 2013;44:1895)

Terminology

Atypical adenosis, atypical small acinar hyperplasia, atypical hyperplasia (Int J Surg Pathol 2005;13:167)

ICD coding

ICD-10: N40.2 - nodular prostate without lower urinary tract symptoms

Epidemiology

2 - 20% of transurethral resections of the prostate, 1% of prostate needle biopsies

Sites

More commonly in the transition zone of the prostate (Surg Pathol Clin 2008;1:1)

Pathophysiology

Associated with benign prostatic hyperplasia

Clinical features

Morphologic variant of benign crowded glands, a mimicker of low grade prostatic adenocarcinoma
Does not have clinical implications

Diagnosis

Detected on needle biopsy or transurethral resection

Radiology description

Multiparametric magnetic resonance imaging (mpMRI) may be difficult to interpret because it shows overlapping features with low grade prostatic adenocarcinoma (Eur Radiol 2017;27:2095)

Prognostic factors

Not a precursor lesion of prostatic adenocarcinoma (Hum Pathol 2013;44:1895)
Comparative genomic hybridization and multiplex PCR did not find common alterations between adenosis and accompanying cancer foci and concluded that adenosis should not be considered as an obligate premalignant lesion (Int J Oncol 2005;26:267)
Diffuse adenosis of the peripheral zone should be considered a risk factor for prostate cancer (Am J Surg Pathol 2008;32:1360)

Case reports

62 year old man with urinary obstruction and elevated serum PSA (Diagn Pathol 2008;3:34)
73 year old man with signs of urinary obstruction and elevated PSA (Rom J Morphol Embryol 2012;53:1093)

Treatment

Treatment not needed

Microscopic (histologic) description

Relatively well circumscribed proliferation of small, crowded, closely spaced acini merging with surrounding benign glands
Lobular proliferation of small disorderly glands with an expansile or minimally infiltrative growth pattern
Budding of small glands from larger, more obvious benign glands
Occasional single cells or poorly formed glands are common; may represent tangential section of small glands
Resembles low grade (Gleason score 3 + 3 = 6) prostatic adenocarcinoma (Am J Surg Pathol 1995;19:737, Rom J Morphol Embryol 2012;53:1093, Arch Pathol Lab Med 2010;134:427, Am J Surg Pathol 2019;43:361, Am J Surg Pathol 2005;29:874)
Clear cytoplasm, usually normal sized nuclei, normochromasia and common corpora amylacea
Occasionally, prominent nucleoli (13 - 15%) and mitotic figures (3 - 11%); rarely, blue tinged luminal mucinous secretions (3%) (Am J Surg Pathol 1994;18:863, Am J Surg Pathol 1995;19:737)
Crystalloids can be present in 24 - 40% of cases (Am J Surg Pathol 1994;18:863, Am J Surg Pathol 1995;19:737)
HMWCK labels the basal cells focally in a patchy fashion
3 dimensional renderings show network of interconnecting tubules with extensive branching, lacking obvious acinar organization (Histopathology 2019;74:1036)

Microscopic (histologic) images

Contributed by Cristina Magi-Galluzzi, M.D., Ph.D.

Well circumscribed nodule

Mixed small and large acini

Basal cells

Crowded glands

Bland nuclear features

Fragmented basal cells

Positive stains

Basal cell markers (p63, CK5/6 and HMWCK) are positive in a patchy fashion (discontinuous staining; mixture of glands with and without basal cell layer) (Pathology 2013;45:251)

Negative stains

ERG (Hum Pathol 2013;44:1895)
AMACR (racemase) can be focally or diffusely expressed in up to 18% of cases of adenosis (Am J Surg Pathol 2002;26:921)

Molecular / cytogenetics description

12% allelic imbalance, with loss within chromosome 8p11-12 (Am J Pathol 1999;155:967)

Sample pathology report

It is not recommended to report adenosis
Prostate, needle biopsy or transurethral resection:
- Benign prostatic tissue

Differential diagnosis

Low grade (Gleason score 3 + 3 = 6, grade group 1) prostatic adenocarcinoma:
- Cytologic atypia, including prominent nucleoli and lack of basal cells
Partial atrophy:
- Glands are partially atrophic with undulating luminal surface with papillary infolding; cytologic features are benign

Board review style question #1

Which of the following statements is true about the lesion depicted above?

Atypical small acinar proliferation, favor benign
Atypical small acinar proliferation, suspicious for malignancy
Benign small acinar proliferation
Prostatic carcinoma, Gleason score 3 + 3 = 6

Board review style answer #1

C. Benign small acinar proliferation. This is an example of adenosis (atypical adenomatous hyperplasia) with small acini lacking cytologic atypia and retaining basal cells.

Comment Here

Reference: Adenosis / atypical adenomatous hyperplasia

Board review style question #2

Which of the following statements is true about adenosis?

A fragmented and discontinuous basal cell layer is present
AMACR is always negative
It is a precursor lesion of prostatic adenocarcinoma
More commonly in the peripheral zone

Board review style answer #2

A. A fragmented and discontinuous basal cell layer is present. Adenosis more commonly involves the transition zone; AMACR can be focally or diffusely expressed in up to 18% of cases of adenosis. Adenosis is not a precursor lesion of prostatic adenocarcinoma.

Comment Here

Reference: Adenosis / atypical adenomatous hyperplasia

Adenosquamous carcinoma

Table of Contents

Definition / general

Adenosquamous carcinoma of the prostate is characterized by presence of both glandular / acinar and squamous components

Essential features

Adenosquamous prostatic carcinoma is a very rare aggressive tumor
Critical to exclude other sources of the squamous component through clinical history, examinations, endoscopy and immunostains
67% of cases are associated with prior androgen deprivation therapy or radiotherapy
Diagnosis requires proper morphology and immunostaining with prostate specific markers (prostate specific antigen [PSA], prostate specific membrane antigen [PSMA], prostatic specific acid phosphatase [PSAP] and prostatic acid phosphatase [PAP]), which should be positive in the glandular and negative in the squamous component

ICD coding

ICD-O: C61.9 - prostate, NOS
ICD-10: C61 - malignant neoplasm of the prostate

Epidemiology

First described by Thompson, 1942; 58 cases described as of 2023 (JAMA 1942;120:1105)
Less prevalent than pure squamous prostatic carcinoma (Clin Genitourin Cancer 2014;12:e29)
Men, mean age in 70s
Many cases are associated with having received hormonal or radiotherapy, although some cases are not associated with prior therapy (Rare Tumors 2010;2:e47, Clin Genitourin Cancer 2014;12:e29, Urol Case Rep 2019;29:101084, Int J Urol 2005;12:319, Scientific World Journal 2006;6:2491, Am J Surg Pathol 2015;39:67, Urology 1983;22:73)

Sites

Prostate, often with extraprostatic extension and seminal vesicle involvement

Pathophysiology

Theories
- Metaplastic transformation of adenocarcinoma frequently after treatment; this is supported by a case of adenosquamous carcinoma in which the squamous component rose from 5% before adjuvant radiotherapy to predominantly squamous after radiotherapy (Eur J Cancer 2018;95:109)
- Collision tumor: intermingling of squamous and glandular components with no abrupt transition argues against this, as does the observation that squamous component may be PSAP reactive (Hum Pathol 1984;15:87, Int J Urol 2005;12:319, Scientific World Journal 2006;6:2491)
- Arises from pluripotent stem cells capable of multidirectional differentiation (Urol Case Rep 2019;29:101084)

Etiology

Often association with status postandrogen ablation or prostatic radiotherapy

Clinical features

Up to 20% of patients presented with metastases in a SEER survey (Rare Tumors 2010;2:e47)
Patients frequently have urinary obstruction from a large tumor or rarely a rectal bleed (Case Rep Urol 2022;2022:7613482, Clin Nucl Med 2024;49:180, Int Urol Nephrol 2023;55:613, Clin Genitourin Cancer 2014;12:e29, Oncol Lett 2014;8:2325, Eur J Cancer 2018;95:109, Case Rep Urol 2022;2022:7613482)

Diagnosis

Histologic findings are established on transurethral resection (consistent with frequent obstructive uropathy) or biopsy
Imaging cannot distinguish it from generic prostate cancer

Laboratory

Serum PSA is usually elevated but not always, particularly if the squamous component predominates (Int Urol Nephrol 2023;55:613, Prostate Cancer Prostatic Dis 2000;3:53)

Radiology description

Notably, F18 PSMA PET / CT scan demonstrated low PSMA uptake (Int Urol Nephrol 2023;55:613)
F18 FDG PET / CT scan showing rectal mass and lung metastases (Eur J Cancer 2018;95:109)
CT scan showing heterogeneous enhancement and rectal / bladder invasion (Clin Genitourin Cancer 2014;12:e29)
CT scan showing rectal invasion, hydronephrosis, metastases (Oncol Lett 2014;8:2325)
T2 weighted MRI scan showing tumor abutting rectum / anus (Case Rep Urol 2022;2022:7613482)

Radiology images

Images hosted on other servers:

Tumor abutting anorectal canal

Prognostic factors

30% 5 year survival (Rare Tumors 2010;2:e47)
For patients undergoing prostatectomy it is 63%, whereas for those not undergoing prostatectomy 1 year survival is 39%

Case reports

54 year old man with rectal invasion (Clin Nucl Med 2024;49:180)
56 year old man with no prior therapy, with metastasis to testis and a sarcomatoid component (Scientific World Journal 2006;6:2491)
62 year old man presented with metastases after hormonal treatment for prostate cancer (Oncol Lett 2014;8:2325)
65 and 73 year old men both after radiation, with rectal invasion by tumors that were predominantly squamous with a minimal gland component and with normal serum PSA (Prostate Cancer Prostatic Dis 2000;3:53)
Man in his 70s with metastasis to penis in 1 case (Am J Surg Pathol 2015;39:67)

Treatment

No standard therapy and it depends on details
- Radical prostatectomy (Rare Tumors 2010;2:e47)
- Radical cystoprostatectomy due to bladder neck involvement, androgen deprivation therapy (ADT) and radiation with survival (Urol Case Rep 2019;29:101084)
- Radiation for inoperable cases, followed by nivolumab for a PDL1 positive case (Rare Tumors 2010;2:e47, Eur J Cancer 2018;95:109, Case Rep Urol 2022;2022:7613482, Scientific World Journal 2006;6:2491, Eur J Cancer 2018;95:109)
- Radiation plus androgen deprivation with survival in 1 of 2 cases (Scand J Urol Nephrol 1994;28:425)
- Enzalutamide then carboplatin (Int Urol Nephrol 2023;55:613)

Microscopic (histologic) description

In addition to the usual glandular prostate cancer component, there is a component of cells with eosinophilic cytoplasm
Keratin pearls and intercellular bridges are required to diagnose squamous cell carcinoma
Additional sarcomatoid transformation has been rarely reported (Histopathology 2020;77:890, Scientific World Journal 2006;6:2491)

Microscopic (histologic) images

Contributed by Susan Prendeville, M.D. and Gladell Paner, M.D.

Biopsy, prominent squamous areas

With obvious keratin

Mixed components, postradiation setting

Transition, squamous to glandular

Positive stains

PSA, PSAP and PSMA in the glandular component (Int Urol Nephrol 2023;55:613)
ERG in about half of cases (Histopathology 2020;77:890, Int Urol Nephrol 2023;55:613, Eur J Cancer 2018;95:109)
Cytokeratin 34 beta E12 in squamous component (Am J Surg Pathol 2015;39:67)

Negative stains

PSA, PSAP and PSMA usually negative in the squamous component (Int Urol Nephrol 2023;55:613, Clin Genitourin Cancer 2014;12:e29, Appl Immunohistochem Mol Morphol 2017;25:e71, Eur J Cancer 2018;95:109, Scientific World Journal 2006;6:2491, Hum Pathol 1991;22:1046)
In one study, only 12% of squamous carcinomas were positive for PSA or PSAP (Am J Surg Pathol 2004;28:651)
Another case had a squamous component positive for PSAP (however it is typically negative) (Hum Pathol 1984;15:87)
Cytokeratin 34 beta E12 negative in glandular component (Am J Surg Pathol 2015;39:67)

Molecular / cytogenetics description

TMPRSS2::BRAF fusion (Histopathology 2020;77:890, Int Urol Nephrol 2023;55:613)
FAM131A::BRAF fusion (Histopathology 2020;77:890)
TMPRSS2::ERG fusion noted in half of cases (Histopathology 2020;77:890, Int Urol Nephrol 2023;55:613)

Sample pathology report

Prostate, left apex, biopsies:
- Prostatic adenosquamous carcinoma, Gleason 4 + 4 (score = 8) (see comment)
- Comment: 30% of the tumor is a squamous component with cells showing intracellular and extracellular keratin and intercellular bridges. This finding correlates with the documented antiandrogen dosing the patient underwent after diagnosis of a Gleason 3+3 carcinoma 4 years ago. Adenosquamous carcinoma is an aggressive tumor.

Differential diagnosis

Secondary involvement by squamous neoplasms arising in bladder, urethra or anorectal region:
- Clinical endoscopic findings negative in these sites
- Normal serum PSA
- Limited use for immunostains
Pure squamous carcinoma:
- Absence of a contiguous or separate focus of glandular cancer in the specimen
Admixed prostate cancer with urothelial neoplasms arising in bladder or urethra:
- Keratin pearls and intercellular bridges are required to diagnose squamous cell carcinoma
- If these findings are absent and if GATA3 or uroplakin II staining are present, the lesion is urothelial and not prostatic
Basal cell hyperplasia with squamous features (Hum Pathol 2005;36:531):
- Lack of atypia of squamous cells
- Absent invasive glandular component
- Cytologic features of basal cells including nuclear vacuoles

Board review style question #1

Which of the following findings would exclude a definite diagnosis of prostatic adenosquamous carcinoma in a biopsy?

Close intermingling of squamous and glandular tumor components
Lack of a history of hormone deprivation or radiotherapy for prostate cancer
Prior history of muscle invasive urothelial carcinoma with squamous features
PSA staining usually negative in the squamous component
Staining of the squamous tumor with cytokeratin 34 beta E12

Board review style answer #1

C. Prior history of muscle invasive urothelial carcinoma with squamous features. Prior history of a squamous cancer in the vicinity of the prostate is critical. A urothelial carcinoma, including that with squamous features, can easily invade the prostate. Answer D is incorrect because indeed the squamous component does lose reactivity for PSA in most adenosquamous tumors. Answer E is incorrect because the squamous component of adenosquamous carcinoma should stain with cytokeratin 34 beta E12. Answer B is incorrect because while many cases of adenosquamous carcinoma do have an association with hormonal or radiotherapy, quite a few reported cases do not. Answer A is incorrect because indeed there often is close intermingling of squamous and glandular components of the tumor.

Comment Here

Reference: Adenosquamous carcinoma

Amyloid

Table of Contents

Definition / general

Primary amyloidosis of the prostate is a rare disease
Involves seminal vesicles in about 10% of radical prostatectomies, usually represents a localized form
Amyloidosis develops subepithelially spreading to include the wall of seminal vesicles and ejaculatory ducts; appears to be related to advanced age (Ann Diagn Pathol 2008;12:235)
Note: corpora amylacea may stain positive with Congo red

Essential features

Pale amorphous hyaline, eosinophilic substance that accumulates and can pressure the adjacent epithelium
Often displays processing cracks
More common in seminal vesicles and vas deferens
Subepithelial and vascular deposits

Epidemiology

Occurs in 2-10% of radical prostatectomies (Turk Patoloji Derg 2012;28:44)
Incidence increases with age, reaching 21% in men age 75 years and older (Histopathology 1993;22:173, Am J Pathol 1983;110:64)
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
Amyloidosis of the seminal vesicles involves 10% of radical prostatectomy specimens

Sites

More common in seminal vesicles and vas deferens
Deposits are more commonly subepithelial and vascular

Etiology

Although immunohistochemistry often detects lactoferrin (Ann Pathol 2004;24:236), amyloid apparently derives from semenogelin I, the major secretory product of the seminal vesicles (J Lab Clin Med 2005;145:187)
Semenogelin I and II are mainly responsible for immediate gel formation of freshly ejaculated semen, and are degraded by the proteolytic action of prostate specific antigen/PSA (J Androl 1996;17:17)

Pathophysiology

Abnormal folding of proteins that deposit as fibrils in the extracellular tissue and may accumulate preventing normal function
Amyloidosis includes multiple biochemically distinct proteins but with similar morphologic appearance
Different forms of amyloidosis include:
- Primary systemic amyloidosis (no evidence of preceding or coexisting disease, paraproteinemia or plasma cell neoplasia)
- Amyloidosis associated with multiple myeloma
- Secondary to coexisting previous chronic inflammatory or infectious conditions, hemodialysis
- Localized form

Clinical features

Most commonly asymptomatic
Can simulate prostate or bladder cancer invasion of seminal vesicles on MRI

Diagnosis

Histology: amorphous pale eosinophilic material often with cracks from processing
Histochemical stain with Congo red shows green birefringence on polarized microscopy

Radiology description

Can simulate prostate or bladder cancer invasion of seminal vesicles on MRI

Case reports

55 year old man (Int Urol Nephrol 2005;37:495)
59 and 60 year old men with localized amyloidosis of seminal vesicle and vas deferens: report of two cases (J Korean Med Sci 2003;18:447)
66 year old man with prostatectomy for adenocarcinoma (Case of Week #85)
2 cases diagnosed at biopsy (Int J Urol 2004;11:925)
Amyloidosis of the seminal vesicle; a case report and review of the literature (Scand J Urol Nephrol 2003;37:519)

Treatment

Based on the underlying condition

Gross description

Usually not seen grossly
When involvement is massive, the organ can be enlarged and firm and cut section could show a waxy appearance

Microscopic (histologic) description

Pale amorphous hyaline, eosinophilic substance that accumulates and can pressure the adjacent epithelium
Often displays processing cracks
Subepithelial location
Can compress the adjacent epithelium

Microscopic (histologic) images

Contributed by Andres Matoso, M.D., @katcollmd on Twitter and Case #85

Various images

Amyloid

66 year old man with radical prostatectomy for adenocarcinoma

Trichrome stain

Positive stains

Trichrome (stains amyloid dusky gray), Congo Red, immunohistochemistry for specific amyloid forms

Electron microscopy description

Electron microscopy shows nonbranching amyloid fibrils that measure 7.5 to 10 nm (Mod Pathol 1989;2:671)

Differential diagnosis

It is important to exclude an underlying etiology including plasma cell neoplasia or an inflammatory condition

Anatomy & histology-Cowper glands

Table of Contents

Definition / general

Cowper glands are also called bulbourethral glands because they are located surrounding the bulbar portion of the urethra, outside of the prostate

Epidemiology

Most commonly, they can be found in TURP specimens, but occasionally they may be seen in needle biopsies or in biopsies from urethral stricture

Sites

Bulbar urethra

Pathophysiology

They are the homologous of Bartholin glands in women
They secrete clear fluid prior to ejaculation that helps to lubricate the urethra and a small proportion of the fluid of the ejaculate

Microscopic (histologic) description

They are composed of mucinous acini arranged in a lobular pattern with intercalated ducts
When present in needle biopsies, they may resemble foamy gland prostate adenocarcinoma
They are surrounded by skeletal muscle, further mimicking cancer
They can be positive for prostate markers PSA, PSAP and NKX3.1
The correct diagnosis lies in recognizing the dual population of acini and ducts surrounded by skeletal muscle as opposed to benign prostatic glands
Immunohistochemistry for high molecular weight cytokeratin is positive in basal cells and can help in the differential diagnosis with prostate cancer

Microscopic (histologic) images

Contributed by Andres Matoso, M.D. and @ThatGlassTho on Twitter

Low power of Cowper glands

Glands and skeletal muscle

Mucicarmin+

PAS+

NKX3.1+

Anatomy & histology-Cowper glands

Positive stains

By immunohistochemistry, Cowper glands can be positive for prostate markers PSA, PSAP and NKX3.1
Special stains mucicarmin and PAS are also positive

Differential diagnosis

Prostate adenocarcinoma: Gleason score 3+3=6, especially foamy gland variant

Additional references

Mod Pathol 2004;17:328

Anatomy & histology-paraganglion

Table of Contents

Definition / general

Group of neuroendocrine cells derived from neural crest

Epidemiology

Usually located in posterolateral soft tissue outside of prostate
Seen in radical prostatectomy specimens and rarely in prostate needle biopsies, or in smooth muscle of bladder neck in transurethral resections of prostate or bladder

Microscopic (histologic) description

Group of cells with clear, vacuolated or amphophilic cytoplasm with a delicate blood vessel meshwork
Nuclei may show prominent nucleoli or degenerative endocrine type atypia

Microscopic (histologic) images

Contributed by Andres Matoso, M.D.

Chromogranin A+

Positive stains

Chromogranin, neuron specific enolase, synaptophysin

Negative stains

PSA, PSAP, low molecular weight cytokeratin

Differential diagnosis

The main differential diagnosis is with Gleason pattern 5 prostate cancer
- The degenerative type atypia in paraganglions is helpful when present; also absence of surrounding prostate glands
- Immunohistochemistry for prostate markers and cytokeratin is helpful

Additional references

Int J Surg Pathol 2011;19:772, Arch Pathol Lab Med 1997;121:515, Am J Surg Pathol 1994;18:412, Histopathology 2005;47:114

Anatomy & histology-prostate

Table of Contents

Definition / general

Knowledge of the normal prostate morphology can help with orientation and avoid confusion of these findings with cancer

Essential features

Benign hyperplasia expands the transition zone and obstructs the bladder outlet; cancer occurs mostly in the peripheral zone where it does not obstruct the bladder outlet
Secretory cells and basal cells are the main 2 layers of benign acini (glands) and the loss of basal cells is a key diagnostic feature of prostate cancer; other cell types in the epithelium include neuroendocrine cells and lymphoid cells
Prostate specific antigen is the most useful marker of secretory cells and 34 beta E12 / high molecular weight keratin is the most useful marker of basal cells

Anatomy

Apex contains some skeletal 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
Denonvillier's fascia (also called rectovesical septum or rectoprostatic fascia): 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° 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 are distributed evenly in apex, mid gland and base of prostate (Am J Clin Pathol 2001;115:39)

Terminology

Regions (Eur Urol 1991;20:261):
- Transition zone:
  - 5% of prostatic volume
  - 2 pear shaped lobes surrounding proximal urethra
  - Expands after age 50, causing nodular prostatic hyperplasia; may expand to 95% of gland (Urology 2017;105:136)
  - Site of 10% of prostate cancer
  - 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 cancer
  - Unlike peripheral and transition zones, ducts are large and irregular
  - Glands are complex with tall columnar, pseudostratified lining, papillary infoldings and epithelial bridging (can mimic high grade prostatic intraepithelial neoplasia or cribriform cancer)
  - Striking basal cell layer with eosinophilic cytoplasm
  - Stroma is densest in central zone, least dense in peripheral zone, in between for transition zone (Hum Pathol 2002;33:518)
- Peripheral zone:
  - 70% of prostatic volume, from apex posterior to base, surrounds transition and central zones
  - Site of > 80% of prostate cancer
  - Has loose fibromuscular stroma with widely spaced smooth muscle bundles, moderate gland complexity

Physiology

Function: conduit for urine, adds nutritional secretions to sperm to form semen during ejaculation; role in orgasm (Clin Anat 2018;31:81)

Diagrams / tables

Images hosted on other servers:

Fundus

Seminal vesicles and ducts

McNeal zones

Sagittal view

Axial views

Clinical features

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): transition, central, peripheral, periurethral zones (Prostate 1981;2:35)
- Outer (cortical) zones are termed peripheral and central
- Central is towards base
- Inner (periurethral) zone is termed transition

Laboratory

Prostate specific antigen

Gross description

In young men: 20 g, funnel shaped, 4 x 3 x 2 cm
Within true pelvis, between bladder neck (base of prostate) proximally and urogenital diaphragm / levator ani muscle (apex of prostate) distally
Seminal vesicles are posterior and superior
Reference: Am J Clin Pathol 2001;115:39

Gross images

Contributed by Kenneth A. Iczkowski, M.D. and AFIP

Cross section of gland

Normal gland

Microscopic (histologic) description

Secretory cells:
- Located along glandular lumen
- Columnar (except if atrophic)
- Nucleoplasm is dark purple
Basal cells:
- Separate secretory cells from basement membrane
- Consist of low cuboidal epithelium and columnar mucus secreting cells
- Nucleoplasm is lighter blue and may have prominent nuclear grooves, vacuoles
- Are reserve cells (stem cells) and can undergo myoepithelial metaplasia but are not myoepithelial cells
- Undergo hyperplasia causing multilayering and possibly prominent nucleoli in reactive / inflamed prostates
- Their presence distinguishes benign conditions (basal cells present) from well differentiated adenocarcinoma (basal cells absent), although prostatic intraepithelial neoplasia and intraductal carcinoma retain at least focal basal cells; also, invasive cancer can retain rare basal cells (Am J Surg Pathol 1999;23:147)
Neuroendocrine cells:
- Sparse and irregularly distributed population, function is not understood; not perceptible without stains (Precis Clin Med 2021;4:25)
Immune cells:
- Modest component of lymphocytes is normal in prostates of all ages, mainly T cells, which are more numerous in the stroma than the epithelium; neutrophils are abnormal and may correlate with clinical prostatitis and raised serum PSA (Prostate 2003;55:187)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Whole mount histology

Close up, anterior aspect

Basal versus secretory cells

Basal cell hyperplasia

Differential diagnosis of a multilayered epithelium

Hyperplastic central zone

Virtual slides

Images hosted on other servers:

Benign prostatic glands, stroma

Positive stains

Secretory cells: prostatic acid phosphatase (PAP or PSAP), prostate specific antigen (PSA), prostein, NKX3.1 (nuclear), vimentin, keratin (some), Leu7 / CD57, EMA (80%) (Histopathology 2012;60:118)
Basal cells: cytokeratin 903 (34 beta E12 / high molecular weight keratin), CK5/6, p63, androgen receptor, p40 (Mod Pathol 1999;12:1, Am J Clin Pathol 2009;132:211, Patholog Res Int 2015;2015:897927)
Neuroendocrine cells: chromogranin A / B, synaptophysin, NSE, CD56 (N-CAM), FOXA2, secretogranin II, peptide hormones, PSA (Precis Clin Med 2021;4:25)

Negative stains

Secretory cells: cytokeratin 903 (34 beta E12 / high molecular weight keratin), CK5/6, P504S racemase (may be weakly positive), p63, androgen receptor, p40
Basal cells: PSA, PAP, S100 protein, actin
Neuroendocrine cells: androgen receptor, cytokeratin 903 (34 beta E12 / high molecular weight keratin) (Precis Clin Med 2021;4:25)

Board review style question #1

Which of these immunostains marks luminal cells but not basal cells in normal prostate?

Androgen receptors
CK5/6
Cytokeratin 903 (34 beta E12 / high molecular weight keratin)
p63
PSA

Board review style answer #1

E. PSA will be positive in luminal cells but is not part of the basal phenotype; proliferations and tumors derived from basal cells are also PSA negative. Customary markers used for basal cells include nuclear p63 and cytoplasmic basal cell cytokeratin (34 beta E12) and CK5/6. They also mark with androgen receptors.

Comment Here

Reference: Prostate gland & seminal vesicles - Anatomy & histology

Board review style question #2

Thinking about the above image of benign reactive basal cells, what histologic feature is characteristic of a secretory cell but not a basal cell?

Acquiring prominent nucleoli
Nuclear vacuoles
Nuclei may have prominent nuclear grooves
Nucleoplasm is darker purple
Nucleoplasm is lighter blue

Board review style answer #2

D. Nucleoplasm is darker purple. The secretory cells are less metabolically active than basal cells, giving them a more condensed nucleoplasm. Nuclear vacuoles and grooves, however, are more characteristic of basal cells. Answer A is wrong because basal cells can get somewhat prominent nucleoli if they are reactive; in this case, in response to acute inflammation. However, prominent nucleoli in secretory cells signal PIN or cancer.

Comment Here

Reference: Prostate gland & seminal vesicles - Anatomy & histology

Anatomy & histology-seminal vesicles / ejaculatory duct

Table of Contents

Definition / general

Seminal vesicles: a pair of highly coiled tubular glands positioned below the posterior wall of the urinary bladder; produces fluid and nutrient constituents of semen (Pawlina: Histology - A Text and Atlas, 8th Edition, 2018)
Nonneoplastic diseases of the seminal vesicles, including but not limited to congenital anomalies of seminal vesicles, seminal vesiculitis and seminal vesicle calculi

Essential features

Seminal vesicles are paired, highly coiled, tubular structures composed of ducts and glands lined by pseudostratified cuboidal to columnar epithelial cells and basal cells
- Golden brown lipofuscin pigments are noted in many cells; there are a few monstrous cells and atypical cells with nuclear invaginations (Mills: Histology for Pathologists, 3rd Edition, 2006)
Epithelial cells stain positive for MUC6, PAX2, PAX8, GATA3, CK7, AE1 / AE3, CAM 5.2, CK5/6, CK19, p63 and CD10
CK20, cytokeratin 34 beta E12 and NKX3.1 immunomarkers are negative (Am J Surg Pathol 2003;27:519, Hum Pathol 2010;41:1145, Ann Diagn Pathol 2020;49:151644)
Nonneoplastic diseases of the seminal vesicles include congenital anomalies (agenesis, hypoplasia, malformations), seminal vesicle cysts, seminal vesiculitis, calcification and calculi

Terminology

Vesicular glands (seminal glands)
Agenesis of seminal vesicle
Congenital anomalies of the seminal vesicles
Seminal vesicle cysts
Seminal vesiculitis
Seminal vesicle calculi

ICD coding

ICD-9
- 608.0 - vesiculitis (seminal)
- 608.89 - other specified disorders of the male genital organs
ICD-10: N50.89 - other specified disorders of the male genital organs

Epidemiology

Congenital anomalies
- Agenesis: rare; reported incidence of 0.08% in a series of robotic assisted radical prostatectomy (Can J Urol 2009;16:4601)
- Zinner syndrome (congenital seminal vesicle cyst and ipsilateral renal agenesis): reported incidence of 0.00035 - 0.0046% (Radiol Case Rep 2020;15:437)
- Congenital cysts: 18 - 41 years of age (J Urol 1978;119:555)
  - Commonly found in 60% of autosomal dominant polycystic kidney disease (Nephrol Dial Transplant 1998;13:2825)
  - Seminal megavesicle (ectasia): 23% of men with adult polycystic kidney disease (Clin Imaging 2015;39:289)
Benign seminal vesicle cyst
- Incidence: rare, 0.001% (Scand J Urol Nephrol 1979;13:113)

Sites

Seminal vesicles are a pair of convoluted tubular glands located in the space between the urinary bladder and the rectum
Glands are positioned superior to the rectum, inferior to the fundus (posteroinferior part) of the bladder and posterior to the prostate
They are separated from the rectum by Denonvilliers fascia
Reference: J Anat 1985;143:45

Pathophysiology

Congenital anomalies of the seminal vesicles
- During the tenth week of fetal development, the distal mesonephric duct proliferates and forms the epididymis, ductus deferens and a bullous outpouching, of which the seminal vesicles develop under the influence of testosterone (J Anat 1985;143:45)
- Complete or partially complete failure to develop results in agenesis, hypoplasia or cysts (Urology 1997;49:313)
Acute seminal vesiculitis: retrograde infection with or without indwelling urinary catheter, commonly associated with prostatitis and epididymitis (Br J Urol 1991;67:632)
Seminal vesicle calcification and calculi: may be caused by reflux of urine (Curr Urol 2019;12:113)

Etiology

Congenital anomalies of seminal vesicle: a developmental anomaly of the mesonephric duct (Urology 1997;49:313)
Seminal vesicle cysts: congenital or acquired
Seminal vesiculitis: inflammation of the seminal vesicles
Seminal vesicle calculi: inflammatory (after seminal vesiculitis) or noninflammatory (Curr Urol 2019;12:113)

Diagrams / tables

Images hosted on other servers:

Seminal vesicles and prostate

Clinical features

Congenital anomalies
- Agenesis and hypoplasia (Urology 2021;149:e44)
  - Infertility: agenesis often associated with decreased semen volume, hypospermia or azoospermia, abnormal sperm motility and absence of coagulative activity (Can Urol Assoc J 2014;8:E266)
- Bilateral agenesis: mostly seen in patients with cystic fibrosis (J Clin Pathol 1969;22:725)
- Unilateral duplication of seminal vesicle (Urology 1999;54:162)
- Commonly associated with maldevelopment of other mesonephric growth
Seminal vesicle cysts (Arch Esp Urol 2004;57:165)
- Vague symptoms: perineal pain during ejaculation or defecation, dysuria, urinary retention, recurrent epididymitis
- Congenital cysts
  - Zinner syndrome: congenital seminal vesicle cyst, ipsilateral obstruction of the ejaculatory duct, ipsilateral renal agenesis and commonly with ureteral ectopia (Int J Surg Case Rep 2022;97:107434, J Urol 1976;116:833)
  - Case with monorchia (J Urol 1980;124:574)
  - Cases with hemivertebra (J Urol 1993;150:1214)
- Acquired cysts: associated with inflammation and obstruction of the ejaculatory ducts (Br J Urol 1992;69:636)
Seminal vesiculitis
- Irritative voiding symptoms, fever, scrotal and testicular pain, perineal and rectal pain and purulent ejaculation may occur (Actas Urol Esp 2005;29:523)
- Acute vesiculitis: caused by retrograde infection
- Chronic vesiculitis: associated with chronic prostatitis
- Schistosomiasis: usually with S. haematobium infection of the bladder
- Viruses (cytomegalovirus), fungi, parasites (Int J Surg Pathol 2016;24:720)
- Echinococcal (hydatid) cyst (Int J Urol 2006;13:308)
Calcification and calculi
- Hematospermia and painful ejaculation (Scand J Urol 2017;51:237)
- Often associated with postinfection (particularly tuberculosis)
- Dystrophic calcifications: associated with diabetes mellitus or uremia (J Urol 1971;105:542)

Diagnosis

Symptoms and signs: hematospermia, lumbosacral and perineal pain, groin pain, painful ejaculation, dysuria, hematuria, oligospermia, azoospermia (Int J Reprod Biomed 2016;14:293)
Digital rectal examination (DRE): detection of enlarged seminal vesicle cysts
Transrectal ultrasound (TRUS): normal seminal vesicles show elongated mass superior to prostate (Int J Reprod Biomed 2016;14:293)
Computed tomography: contrast enhanced CT shows fluid filled structure with a thin septa
Magnetic resonance imaging (MRI): normal seminal vesicles show elongated, fluid filled structure with thin septa (Semin Roentgenol 1993;28:83)
Transurethral seminal vesiculoscopy

Laboratory

Seminal fluid analysis (Fertil Steril 2015;103:e18)
- Low semen volume: < 1.5 mL
- Low sperm count: < 10 million/mL
- Sperm vitality: high number of immotile and nonviable sperm
- Sperm morphology: abnormal sperm morphology suggestive of abnormal spermatogenesis
- Other cells: assessed with peroxidase activity and leukocyte markers

Radiology description

MRI shows normal seminal vesicles with clustered, grape-like appearance (J Clin Imaging Sci 2014;4:61)
Axial contrast enhanced CT scan and MRI show absence of the seminal vesicle in agenesis of the organ (AJR Am J Roentgenol 2007;189:130)
Cysts within the seminal vesicle may be seen on a CT scan or MRI
MRI shows mild asymmetric dilation of the seminal vesicle with focal areas of wall thickening in acute seminal vesiculitis (J Clin Imaging Sci 2014;4:61)

Radiology images

Images hosted on other servers:

Normal seminal vesicles

Agenesis

Cyst

Seminal vesiculitis

Case reports

31 year old man presented with hemorrhagic giant seminal vesicle cyst (Medicine (Baltimore) 2021;100:e26142)
33 year old man with symptomatic Zinner syndrome (Int J Surg Case Rep 2020;73:61)
45 year old man with functional obstruction and painful ejaculation (Asian J Androl 2017;19:256)
63 year old man with giant seminal vesicle cyst in Zinner syndrome (Medicine (Baltimore) 2022;101:e31577)
66 year old man with seminal vesicle fistula as complication of Crohn's disease (BMJ Case Rep 2022;15:e226445)

Treatment

Antibiotics therapy for bacterial seminal vesiculitis
Complete surgical excision of seminal vesiculitis complicated by abscess, fistula or stricture
Surgical excision of symptomatic seminal vesicle cysts (Int J Surg Case Rep 2020;73:61)
Transurethral seminal vesiculoscopy and lithotripsy for small calculi
Transperitoneal laparoscopic procedure for large calculi (Scand J Urol 2017;51:237)

Clinical images

Images hosted on other servers:

Cyst

Stones

Gross description

Normal seminal vesicle (Mills: Histology for Pathologists, 3rd Edition, 2006)
- 2 highly convoluted, lobulated and tubular structures posterolateral to base of the urinary bladder and parallel with the ampulla of vas deferens
- 3.5 - 7.5 cm in length; 1.2 - 2.4 cm in thickness
- Duplication of main duct, each measuring 10 - 15 cm, may present (10%)
- Main duct has 8 first order branching ducts and several secondary ducts
- Short excretory duct joins the ampulla of the vas deferens to form ejaculatory duct
- Muscular layers, including outer longitudinal and inner circular, are thinner than that of the vas deferens
Normal ejaculatory duct (Mills: Histology for Pathologists, 3rd Edition, 2006)
- Short paired ducts, each measuring 1.5 cm
- Convergence of the excretory duct and the ampulla of vas deferens
- Extends into the prostatic central zone and enters the posterior distal prostatic urethra at the verumontanum
Agenesis of seminal vesicles (J Urol 1998;160:2126)
- Absence of seminal vesicles (unilateral or bilateral)
Seminal vesicle cysts (Urology 2004;63:584)
- Usually unilateral and unilocular, lateral to midline, up to 3 times larger than normal seminal vesicle, smaller than Müllerian duct cyst
- Gigantic cyst may occur
Seminal vesicle calcification and calculi (Br J Urol 1991;68:322)
- Brown stones, measuring up to 1 cm
- Consists of phosphate and carbonate salts

Gross images

Images hosted on other servers:

Normal seminal vesicle

Acquired cystic dilatation

Cyst

Calculus

Microscopic (histologic) description

Normal seminal vesicle (Mills: Histology for Pathologists, 3rd Edition, 2006)
- Seminal vesicle wall consists of a thin, external, longitudinal muscle and a thicker, internal, circular muscle
- Complex alveolus-like papillary mucosal folds lined by stratified columnar epithelium; basal cells are present
- Columnar epithelial cells with short microvilli and cytoplasmic golden brown lipofuscin pigment that are also found in ampulla of vas deferens and ejaculatory duct
- 2 types of lipofuscin pigment
  - Type 1: uniform size (1 - 2 μm); coarse, highly refractile, golden brown granules
  - Type 2: variable size (0.25 - 4 μm); nonrefractile and yellow-brown, gray-brown or blue-pink
- Atypical monstrous epithelial cells characterized by enlarged hyperchromatic and irregular nuclei; may represent response to hormones (i.e., Arias-Stella reaction) and are increased in aged seminal vesicles (Int J Clin Exp Pathol 2011;4:727)
- Lumen contains eosinophilic crystalloid secretions and dense, plate-like secretions mimicking that of prostate adenocarcinoma; spermatozoa may be present (Arch Pathol Lab Med 2001;125:141)
- Eosinophilic hyaline bodies (small, 15 - 20 μm) represent degenerating smooth muscle cells that are present in the muscular wall of seminal vesicles, vas deferens and in fibromuscular tissue of prostate
Normal ejaculatory duct (Mills: Histology for Pathologists, 3rd Edition, 2006)
- Cells lining the epithelium resemble the seminal vesicle and ampulla of the vas deferens
- Ductal cells may contain lipofuscin pigment and are negative for prostate specific antigen (PSA)
Seminal vesicle cysts (Yonsei Med J 2009;50:560)
- Unilocular cyst is lined by cuboidal or flattened epithelium and consists of fibrous wall
Seminal vesicle calcification and calculi: calcified material and calculi in the lumens

Microscopic (histologic) images

Contributed by Faryal Shoaib, M.D., Y. Albert Yeh, M.D., Ph.D. and Andres Matoso, M.D.

Multilobulated tubular structures

Branching side ducts

Lining columnar cells

Enlarged epithelial cells

Large atypical cells

Alveolar-like mucosal folds

Eosinophilic crystalloids

Stromal hyaline body

Monstrous epithelial cells

Prostatic glands

Nuclear pleomorphism

Yellow pigment

Positive stains

Seminal vesicle tissue
- MUC6 in contrast to prostate (negative) (Am J Surg Pathol 2003;27:519)
- PAX2 in contrast to prostate (negative) (Hum Pathol 2010;41:1145)
- GATA3 (Actas Urol Esp 2017;41:577)
- CK7 (Hum Pathol 2017;69:123)
- PAX8 (Hum Pathol 2017;69:123)
- Pancytokeratin AE1 / AE3
- CAM 5.2
- CK5/6 (Int J Clin Exp Pathol 2011;4:727)
- CK19 (Int J Clin Exp Pathol 2011;4:727)
- p63
- CD10 (Int J Clin Exp Pathol 2011;4:727)
- PSA and PSAP could be positive (Histopathology 2004;44:405)

Negative stains

Seminal vesicle tissue

Sample pathology report

Prostate, right base, needle biopsy:
- Benign prostatic tissue and seminal vesicle, negative for carcinoma (see comment)
- Comment: The prostate biopsy shows prostatic glands and fibromuscular stroma. There is a group of small glands lined by epithelial cells with bland nuclei. A few atypical cells with slightly enlarged nuclei are noted. Immunohistochemical stains MUC6, PAX2, PAX8, CK7 and CK5/6 are positive in this group of small glands. NKX3.1 and PSA are negative. These features are consistent with seminal vesicle tissue. There is no evidence of carcinoma.

Differential diagnosis

Normal seminal vesicle:
- Prostatic adenocarcinoma (Am J Surg Pathol 2003;27:519):
  - Infiltrative growth pattern
  - Scattered cells with extreme nuclear atypia uncommon
  - Lacks type 1 golden brown, refractile lipofuscin pigment but can have rare type 2 nonrefractile, brown-blue lipofuscin pigment
  - Immunostains NKX3.1 and PSA positive; negative for MUC6, PAX2, PAX8 and p63
- High grade prostatic intraepithelial neoplasia (Mod Pathol 2004;17:360):
  - Diffuse enlargement of nuclei with atypia, hyperchromasia and prominent nucleoli
  - Lacks type 1 golden brown refractile lipofuscin pigment
Seminal vesicle cyst:
- Large, lateral, may contain spermatozoa (Urology 2004;63:584)
  - Diverticulum of ejaculatory duct:
    - Variable in size, usually midline, may contain spermatozoa
  - Prostatic cyst:
    - Variable in size, usually lateral, lack of spermatozoa
  - Müllerian duct cyst:
    - Large, usually midline, lacks spermatozoa
Ectopic prostatic tissue (Urology 1996;48:490):
- Ectopic prostatic or urothelial tissue usually present in the wall of a seminal vesicle cyst
- Epithelial cells negative for MUC6, PAX2 and PAX8 immunohistochemical stains

Additional references

Andrologia 2020;52:e13397, Abdom Radiol (NY) 2020;45:2049, Andrologia 2017;49:e12618, Urology 2014;84:e7, J Int Med Res 2014;42:236, Asian J Androl 2005;7:449, J Urol 2004;171:1550, BJU Int 2002;90:265, Eur Urol 1998;33:433

Board review style question #1

A 74 year old man was found to have an elevated PSA of 8.0 in a routine health examination. A prostate needle biopsy was performed and revealed a prostatic adenocarcinoma, Gleason score 4 + 3, with perineural invasion. Radical prostatectomy was performed. A photomicrograph of one of the tissue sections is shown above. What is the diagnosis?

Adenocarcinoma of the seminal vesicle
Cystadenoma of the seminal vesicle
High grade prostatic intraepithelial neoplasia
Normal seminal vesicle
Prostatic acinar adenocarcinoma, Gleason score 4 + 3

Board review style answer #1

D. Normal seminal vesicle. The image shows glands lined by pseudostratified, cuboidal secretory cells and basal cells. The ductal and glandular lumens contain many eosinophilic crystalloids with some eosinophilic, plate-like crystalloids. These features are characteristic of normal seminal vesicles. Answer B is incorrect because the alveolar-like mucosal folds are lined by normal cuboidal to columnar epithelial cells. Answers C and E are incorrect because this is not prostatic tissue, although there are some crystalloids in the ductal and glandular lumens. Answer A is incorrect because there are no malignant glands in the seminal vesicle.

Comment Here

Reference: Seminal vesicles / ejaculatory duct

Board review style question #2

A 64 year old man was found to have an elevated PSA of 10.2 in a routine health examination. A prostate needle biopsy was performed and revealed a prostatic adenocarcinoma, Gleason score 4 + 4, with perineural invasion. Radical prostatectomy was performed. A photomicrograph of one of the tissue sections is shown above. The epithelial cells are positive for MUC6 and PAX2 immunohistochemical stains. What is the diagnosis?

Adenocarcinoma of the seminal vesicle
High grade prostatic intraepithelial neoplasia
Normal seminal vesicle
Prostatic acinar adenocarcinoma, Gleason score 4 + 4, tertiary 5
Seminal vesicle with dysplasia

Board review style answer #2

C. Normal seminal vesicle. Seminal vesicles stain positive for MUC6 and PAX2 immunomarkers, while prostatic glands are negative for the 2 biomarkers. Answers B and D are incorrect because this is not prostatic tissue. Answers A and E are incorrect because there are no malignant or dysplastic cells in the seminal vesicle. The atypical monstrous cell with a nuclear invagination represents a degenerative cell usually seen in aging seminal vesicles.

Comment Here

Reference: Seminal vesicles / ejaculatory duct

Atrophic adenocarcinoma

Table of Contents

Definition / general | Microscopic (histologic) description | Differential diagnosis

Definition / general

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

Microscopic (histologic) description

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 (Am J Surg Pathol 1997;21:289, Am J Clin Pathol 1998;109:695)
Also luminal eosinophilic proteinaceous secretions, blue mucin, crystalloids, apocrine blebs, collagenous micronodules, high-grade PIN within two high-power fields (Am J Surg Pathol 1997;21:931)

Differential diagnosis

Benign atrophy: no associated carcinoma, small and indistinct nucleoli, basal layer present but may be fragmented

Atrophy

Table of Contents

Definition / general

Atrophy and its less common subtype postatrophic hyperplasia often comprise small acini and are the most frequent histologic mimics of prostatic adenocarcinoma

Essential features

Very common microscopic finding: up to 75% of biopsies (Ann Diagn Pathol 2016;24:55)
Most frequent mimic of cancer (Am J Surg Pathol 2005;29:874)
When associated with fibrosis, the atrophic glands may appear infiltrative
Atrophy includes several histologic variants: simple, cystic, partial and postatrophic hyperplasia
Radiographic abnormalities have been described and serum prostate specific antigen (PSA) may be increased
Immunostains may help in the distinction from cancer but caution is needed in their interpretation

Terminology

Benign prostate tissue with atrophy
When associated with inflammation and increased Ki67 index, it has been termed proliferative inflammatory atrophy (PIA)

ICD coding

ICD-9: 602.2 - atrophy of prostate
ICD-10: N42.89 - other specified disorders of prostate

Epidemiology

Atrophy is a common incidental finding in prostate biopsy and prostatectomy and increases with age

Pathophysiology

Can be partly reversed by prolactin (Reprod Biol Endocrinol 2021;19:94)
Whether atrophy is a precursor to high grade prostatic intraepithelial neoplasia (HGPIN) and cancer has been controversial; atrophy with inflammation has some spatial association to low grade cancer (Int Urol Nephrol 2011;43:397, Hum Pathol 2014;45:54)

Etiology

Increases with age

Diagnosis

Diagnosis is by prostate biopsy or transurethral resection

Laboratory

Atrophy correlates with serum total or free PSA elevation; for this reason, it may be desirable to report atrophy in a negative biopsy set (Abdom Imaging 2009;34:271)

Radiology description

Atrophy can simulate cancer by Doppler transrectal ultrasound and on magnetic resonance spectroscopic imaging studies (Abdom Imaging 2009;34:271, Radiographics 2016;36:162)
When cystic, can produce high signal intensity areas on T2 weighted imaging (Eur Radiol 2017;27:2095)

Radiology images

Images hosted on other servers:

mpMRI findings, cystic atrophy

Prognostic factors

Not associated with increased risk of malignancy; in fact, baseline prostatic atrophy may be associated with reduced risk of subsequent cancer (Prostate 2016;76:1501, Cancer Epidemiol Biomarkers Prev 2011;20:2280, J Urol 2015;194:1241)

Treatment

Does not require treatment

Microscopic (histologic) description

4 subtypes have been categorized (Am J Surg Pathol 2006;30:1281):
- Simple atrophy:
  - Characterized by its basophilic appearance at low magnification
  - Glands may be crowded or back to back with little intervening stroma
  - When associated with sclerosed stroma, the glands may assume a more angulated shape and infiltrative appearance
- Simple atrophy with cyst formation:
  - Ballooning large acinar spaces
- Postatrophic hyperplasia (PAH):
  - Postatrophic hyperplasia also appears basophilic at low power but often surrounds a dilated duct and is arranged in lobules of crowded acini
  - Normally has more mitotic figures than adjacent nonatrophic glands
- Partial atrophy:
  - In contrast to simple atrophy and postatrophic hyperplasia, acini have a pale appearance and nuclei are more spaced apart

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Small acinar atrophy

Dilated acinar atrophy

Red doesn’t equal cancer

Sclerosing adenosis

Cancer mimicking atrophy

Positive stains

High molecular weight cytokeratin, p63
- Caution: in prostate cancer, p63 rarely may have nuclear positivity, causing underdiagnosis as atrophy; its use combined with basal cell cytokeratin is best (Histopathology 2012;60:847)
NKX3.1 is present but is decreased compared with nonatrophic acini (Cancer Res 2006;66:10683)

Negative stains

Atrophic glands can occasionally be negative or have patchy staining for basal cell markers High molecular weight cytokeratin and p63 (Mod Pathol 2002;15:1302)
AMACR should be negative in most instances but may be positive; in that event, the dual immunostain (prostate basal cell markers and AMACR) usually show at least focal basal cells but sometimes not (Histopathology 2004;45:218, Am J Clin Pathol 2006;126:849)

Sample pathology report

Prostate, biopsies:
- Benign prostatic tissue with focal / multifocal / diffuse atrophy

Differential diagnosis

Must distinguish from the atrophic variant of prostatic adenocarcinoma, which has these features:
- Less cytoplasm, dilated lumens, macronucleoli in the majority of cells and absence of basal cells
- Infiltrative growth between benign glands without atrophy
- Usually coexists with usual type adenocarcinoma

Board review style question #1

Which of the following is true of prostatic atrophy?

It is a strong predictive finding for subsequent cancer detection
It is characterized exclusively by a small acinar pattern
It cannot be associated with increased serum prostate specific antigen (PSA)
It has no characteristic radiologic findings
It is mimicked by a variant of cancer

Board review style answer #1

E. Atrophy is mimicked by a variant of cancer, called the pseudoatrophic variant. Atrophy is not a predictor of subsequent cancer detection (answer A) and may even lessen the chances of eventual cancer. Atrophy is not exclusive to small acini (answer B) and large acinar (cystic) types exist. Atrophy sometimes can be associated with increased serum prostate specific antigen (PSA) (answer C). Atrophy may have certain characteristic radiologic findings (answer D).

Comment here

Reference: Prostatic atrophy

Board review style question #2

What does the red staining AMACR signal indicate?

Lack of cytologic atypia rules out cancer, even when red AMACR signal is present
It indicates that some of these acini are suspicious for cancer
It indicates cancer
It indicates high grade prostatic intraepithelial neoplasia

Board review style answer #2

A. This red signal is present in benign, nonatypical atrophic acini. Remember that AMACR / P504S can give false positive results and atrophy is one source of such results. The dual stain should be interpreted with caution, based on corresponding hematoxylin eosin findings. High grade PIN should be AMACR positive but would have atypia.

Comment here

Reference: Prostatic atrophy

Atypical intraductal proliferation

Table of Contents

Definition / general

Atypical intraductal proliferation (AIP) of the prostate is a gland space containing a usually cribriform arrangement of cells that have mild to moderate atypia, bounded by at least a partial basal cell layer
It is a diagnosis of uncertainty on the continuum between high grade prostatic intraepithelial neoplasia and intraductal carcinoma, which is most applicable if tissue sampling is limited, as with biopsies

Essential features

AIP is a continuum of proliferations, mostly (90%) cribriform (but 10% may be noncribriform) in which a distinction is not possible between high grade prostatic intraepithelial neoplasia (HGPIN) and intraductal carcinoma of prostate (IDC) (Histopathology 2019;75:346)
AIP architectural complexity or cytologic atypia exceed that of HGPIN but fall short of the criteria for IDC
At least a partial basal cell layer is retained by H&E or immunostain
Location of AIP / atypical cribriform lesion (ACL) within 3 mm from infiltrating cancer is considered to favor IDC, while > 3 mm from infiltrating cancer favors HGPIN
Exclusion criteria: comedonecrosis or extreme nuclear atypia; total loss of a basal cell layer
Most AIP occurrence on needle biopsy is accompanied by invasive carcinoma; whereas if there is only isolated AIP, repeat biopsy may show invasive carcinoma (Histopathology 2019;75:346)

Terminology

Atypical cribriform lesion (ACL) (Hum Pathol 2014;45:1572)
Atypical cribriform intraductal proliferation
Atypical proliferation suspicious for intraductal carcinoma (ASID) (Pathology 2018;50:60)

ICD coding

ICD-9: 602.3 - dysplasia of prostate

Epidemiology

Mean age: 65; mean serum PSA: 8 (Histopathology 2019;75:346)
Incidence in radical prostatectomy cases: incidence was 17.9% of cases for all lesions, among which 12.8% were isolated lesions; that is, not associated with infiltrating cancer (Am J Surg Pathol 2010;34:470)
Incidence in needle biopsies: incidence was estimated at 1% (8/796) (Histopathology 2019;75:346)
- AIPs unaccompanied by invasive carcinoma comprised only 10% of the above, for a 0.1% incidence

Sites

Prostate

Diagnosis

Histologic finding of prostate biopsy or prostatectomy; rarely sampled in transurethral resection
No radiologic correlates are known

Laboratory

Elevated serum PSA

Prognostic factors

Histologic findings in prostatectomy specimens
- AIP was associated with higher Gleason score and larger tumor volume, than in prostates without it (Am J Surg Pathol 2010;34:470)
- Compared to prostatectomy with high grade PIN, AIP was associated by multivariate analysis with higher Gleason score, larger tumor volume and more advanced stage than in cases with only high grade PIN (Hum Pathol 2014;45:1572)
Clinical findings in prostatectomy specimens
- AIP / ACL showed a risk for biochemical recurrence that was intermediate between cases with high grade PIN and intraductal carcinoma (Hum Pathol 2014;45:1572)
- High grade PIN only, without AIP, by multivariate analysis indicated a less frequent biochemical recurrence

Treatment

On biopsies if there is concomitant invasive carcinoma, definitive treatment or active surveillance is needed
On biopsies if the AIP finding is isolated, repeat biopsy is advisable; this may show cancer (4 of 6 cases) or benign prostate (2 of 6) (Histopathology 2019;75:346)

Microscopic (histologic) description

Concept of AIP / ACL was introduced in a pair of articles in 2010 (Am J Surg Pathol 2010;34:470, Am J Surg Pathol 2010;34:478)
One definition of AIP was a loose cribriform intraductal proliferation with greater architectural complexity when compared to HGPIN but lacking significant nuclear pleomorphism or necrosis (Hum Pathol 2014;45:1572)
In another study, cases were divided into isolated ACL and ACL associated with invasive cancer (Am J Surg Pathol 2010;34:470)
- Isolated ACL almost never (1/23 cases) had a branching contour, none had comedonecrosis and none had 6x nuclear enlargement, standing in contrast to 84%, 33% and 28%, respectively of cases associated with invasive cancer
- Cases with associated cancer were considered intraductal carcinoma

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Basal cells in AIP

Papillary AIP, with invasive acini

Cocktail immunostain of AIP

Isolated AIP on biopsy

Cribriform AIP

AIP, favor intraductal

Grade 5 foamy glands

Not an AIP

Not an AIP, immunostain

Positive stains

NKX3.1, prostate specific antigen, prostatic acid phosphatase, prostein (P501S), AMACR
Basal cell reactivity at least focally retained as shown by CK 34 beta E12, p63 or CK5/6
ERG reactivity in some cases (Am J Surg Pathol 2010;34:470)

Molecular / cytogenetics description

Break apart FISH probe was used to investigate AIP
- In prostatectomy lesions that were cribriform HGPIN, 0/16 (0%) had ERG rearrangement
- ACL lesions with associated invasive cancer were presumed to be intraductal carcinoma and 75% (36/48) had ERG rearrangement
- Among these, 65% were through deletion and 35% through insertion (Am J Surg Pathol 2010;34:478)
- Those ACL with marked atypia (comedonecrosis or 6x nuclear enlargement) had a similar incidence of ERG rearrangement to those that did not (78% versus 72%)
PTEN loss status was similar to adjacent invasive cancer in 88% of biopsy cases designated AIP and in 91% of cases designated IDC, suggesting 2 different morphologic spectra of IDC (Histopathology 2017;71:693)

Sample pathology report

Prostate, right apex, biopsy:
- Isolated atypical intraductal proliferation, cannot distinguish between prostatic intraepithelial neoplasia and intraductal carcinoma (see comment)
- Comment: This lesion may be associated with invasive cancer. Repeat biopsy may be advisable to rule out unsampled prostate cancer.

Differential diagnosis

Clear cell cribriform hyperplasia:
- Located in central zone / base of prostatic biopsies
- Typically clear cytoplasm
- No cytologic atypia; nucleoli not visible in central cells but may be visible in basal cells
- Basal cell layer is retained
- No comedonecrosis
High grade prostatic intraepithelial neoplasia (HGPIN):
- The cribriform pattern is 1 of 4 HGPIN patterns
- Cytologic atypia is not extreme
- Usually stratified vesicular nuclei
- At least a patchy basal cell layer is retained
- No comedonecrosis
Intraductal carcinoma of prostate:
- Defined as a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification 10x); there should be no intervening stroma or mucin separating individual or fused glandular structures (Am J Surg Pathol 2020;44:e87)
- More extreme cytologic atypia and nuclear enlargement (up to 6x)
- Branching of duct contours is common
- Possibly comedonecrosis
Ductal carcinoma of prostate:
- Lacks a basal cell layer
- Pseudostratified columnar epithelium with cytoplasmic tufting
- May have pagetoid spread
Invasive Gleason 4 (or 5) cribriform prostatic adenocarcinoma:
- Lacks a basal cell layer, unlike AIP or intraductal carcinoma
- May have comedonecrosis; if so, the grade is elevated to Gleason 5

Board review style question #1

This lesion is found in a prostate biopsy. Which of the following features favor an atypical intraductal proliferation diagnosis?

6x nuclear enlargement
Comedonecrosis
Loose cribriform arrangement of cells
Total absence of basal cells by immunostain

Board review style answer #1

C. Loose cribriform arrangement of cells. Most atypical intraductal proliferations (or atypical cribriform lesion [ACL]), like this one, do contain a loose cribriform pattern. We do not see 6x nuclear enlargement in this example and if present, it would favor intraductal carcinoma (IDC) (answer A). We do not see comedonecrosis here and again this would favor IDC (answer B). Atypical intraductal proliferation (AIP) should retain at least some basal cells and there probably are some by H&E on the left edge of the proliferation. Absence of basal cells would favor IDC (answer D).

Comment Here

Reference: Atypical intraductal proliferation

Atypical small acinar proliferation suspicious (ASAP)

Table of Contents

Definition / general

Atypical small acinar proliferation suspicious (ASAP) was devised to represent our inability to render an incontrovertible diagnosis of cancer within a focus of concern that generally has fewer than 2 dozen acini, less than 1 mm (Am J Surg Pathol 1997;21:1489, Urology 1998;51:749)
A fallacy among nonpathologists is that it is an early neoplastic lesion or precancerous along with high grade prostatic intraepithelial neoplasia (HGPIN) or a precursor lesion to cancer; rather, it is already cancer or already benign - we cannot tell (Arch Ital Urol Androl 2019;91:153, Curr Urol 2017;10:199, Prostate 2019;79:195)

Essential features

2 - 5% of prostatic needle biopsy sets in numerous series that have been studied contain a final diagnosis wherein the worst finding in any specimen part is atypical small acinar proliferation suspicious for carcinoma
Diagnosis represents pathologists’ inability to reach a definitive benign or cancer diagnosis, usually after performing immunostains; immunostains may be omitted if the grade of the suspicious focus is less than the highest grade of definite cancer (which is at least 3 + 4 =7) in the biopsy set; however, the immunostain is worth performing if one site has any grade of cancer and the stain might confirm the same grade cancer in other sites (Am J Surg Pathol 2014;38:e6)
34 - 60% predictive value for detection of cancer on repeat biopsy
When cancer is detected on repeat biopsy, about 80% are of low grade (Gleason ≤ 6); most meet the criteria for insignificant cancer but repeat biopsy within 3 - 6 months is probably indicated in most instances, particularly if serum PSA is persistently elevated

Terminology

In the line diagnosis, "Atypical small acinar proliferation" should be followed by words such as "suspicious for but not diagnostic of cancer"
Atypical small acinar proliferation suspicious synonyms include focal glandular atypia (FGA) and atypical glands suspicious for cancer

ICD coding

ICD-10: N42.32 - atypical small acinar proliferation of prostate
ICD-9: 602.3 - dysplasia of prostate

Epidemiology

Age group overlaps with the prostate cancer population; no difference in predictive value for cancer between African Americans and non African Americans (Clin Genitourin Cancer 2017;15:e995)
2 - 5% of sets of needle biopsies (more rarely in transurethral resection specimens) (Pathol Case Rev 2014;19:147)

Clinical features

Generally, there was a clinical suspicion of cancer to justify the biopsy (elevated PSA or abnormal digital rectal exam)

Diagnosis

In order to diagnose definitive cancer in a suspicious focus, consider:
- Would you remain absolutely confident of this biopsy diagnosis if it were followed by a negative radical prostatectomy?
- Are you certain there would be diagnostic agreement for cancer if your work was audited by another pathologist?
- Can the findings in this one core alone support an overall confident diagnosis of cancer for the case?
- If these questions cannot be answered in the affirmative, atypical small acinar proliferation suspicious for carcinoma is the most appropriate diagnosis
Immunohistochemical work up:
- Immunostains may be omitted if the grade of cancer for which atypical small acinar proliferation is suspicious is less than the highest grade of definite cancer (which is at least 3 + 4 = 7) in the biopsy set
- Immunostains are worth performing if one site has any grade of cancer and the stain might confirm the same grade cancer in other sites (Am J Surg Pathol 2014;38:e6)
- Staining for AMACR, HMWK/cytokeratin 34βE12/CK5 and p63 separately or simultaneously using two different colored chromogens can, under ideal conditions, resolve up to 76% of atypical small acinar proliferations per consensus of 3 urologic pathologists studied (Histopathology 2004;45:218)
- However, in the remaining cases, immunostains cannot resolve a diagnostic dilemma but will support or reinforce a diagnosis of atypical small acinar proliferation suspicious

Laboratory

Serum PSA, PSA density and PSA velocity in the setting of atypical small acinar proliferation suspicious was not found to be predictive of adenocarcinoma (Curr Urol 2017;10:199, Can J Urol 2017;24:8714, World J Urol 2017;35:1009)
Low serum testosterone, present in 20% of an atypical small acinar proliferation study population, predicted benign repeat biopsy; cancer was detected in 24% of low testosterone men and 40% of eugonadal men (Asian J Androl 2018;20:15)

Prognostic factors

A recent study showed that an initial biopsy with atypical small acinar proliferation, high grade prostatic intraepithelial neoplasia or Gleason ≤ 6 insignificant cancer (criteria: ≤ 2 cores, ≤ 50% of a tissue site with cancer and unilateral cancer only) all had a similar rate (14%) of Gleason ≥ 7 cancer upon repeat biopsy (Hum Pathol 2018;79:116)
- This rate was 9% or 6% in other studies (see table below) (Clin Genitourin Cancer 2017;15:e995, Can J Urol 2017;24:8714)
- Thus, cancer following an atypical small acinar proliferation diagnosis is skewed toward mostly low grade cancer on repeat biopsy
- However, these findings do not negate the recommendation for repeat biopsy

Treatment

Atypical small acinar proliferation is never an indication for definitive therapy
The standard recommendation is repeat biopsy within 3 - 6 months, however, in recent studies, failure to get a repeat biopsy was noted in up to 63% (see table below); one recommendation (regardless of serum PSA) is to sample 3 cores from the site of the initial atypical sextant site, 2 cores from the adjacent atypical sextant sites and 1 core from other sextant sites (Mod Pathol 2004;17:307)
A review of all studies through 2014 revealed, 34 - 60% of repeat biopsies show cancer following the diagnosis of atypical small acinar proliferation but the vast majority place the predictive value for cancer in the 40 - 50% range; this exceeds the approximate 25 - 30% predictive value for high grade prostatic intraepithelial neoplasia (Pathol Case Rev 2014;19:147)

Findings in more recent studies have been largely similar:

Study	Frequency of ASAP as worst diagnosis	Repeat biopsy rate of ASAP	Cancer rate on repeat biopsy	Rate of Gleason ≥ 7 cancer	*Rate of clinically significant cancer**
Hum Pathol 2018;79:116	5.8%	11% (included HGPIN)	42%	14%	26%
Prostate 2019;79:195	n/a	n/a	38%
Curr Urol 2017;10:199	n/a	37%	43%
Int Urol Nephrol 2018;50:1	4.6%	41%	36%	9%
Res Rep Urol 2017;9:187	1.6%	71%	83%	20%
Urology 2017;110:161	4.4%	47%	34%	14%	8%
Asian J Androl 2018;20:15	n/a	25%	36%
Clin Genitourin Cancer 2017;15:e995	n/a	n/a	40%		24%
Can J Urol 2017;24:8714	5%	20%	31%	20%
World J Urol 2017;35:1009	n/a	n/a	65% (with 24 region bx)	36%
Prostate Cancer Prostatic Dis 2016;19:68			34%	8%
Prostate 2015;75:673	5.3%	50%	36%	19%	51%

*≤ 2 cores, ≤ 50% of a tissue site with cancer and unilateral cancer only

The predictive value of atypical small acinar proliferation plus high grade prostatic intraepithelial neoplasia is about the same as that of atypical small acinar proliferation alone or slightly higher (Pathol Case Rev 2014;19:147, Hum Pathol 2018;79:116)

Microscopic (histologic) description

Certain histologic features that most often preclude a definitive diagnosis of malignancy:
- Small size of the focus (70% of cases)
- Disappearance on step levels (61%)
- Lack of significant cytologic atypia such as nucleolomegaly (55%)
- Associated acute / chronic inflammation (9%)
Lack of sufficient findings for a diagnosis of cancer raises the possibility of one of many benign mimics including:
- Atrophy, atypical basal cell hyperplasia and reactive change (Am J Surg Pathol 1997;21:1489)

Microscopic (histologic) images

Contributed by Kenneth Iczkowski, M.D.

Quantitative ASAP

Three atypical acini and triple stain

Four atypical acini and triple stain

Qualitative ASAP

Upper left atypical acini and triple stain

Large atypical acini and triple stain

Eight small acini and triple stain

ASAP + HGPIN

ASAP + HGPIN and triple stain

Contributed by Debra Zynger, M.D.

Straight luminal border

Triple stain

Crowded, straight luminal border, mucin and nuceloli

Crowded, straight luminal border, mucin and nuceloli

Positive stains

AMACR (alpha-methylacyl CoA racemase, P504S) often positive but reactivity may be weaker than expected for cancer, causing hesitation in diagnosing cancer

Negative stains

Prostatic basal cell stains (HMWK/cytokeratin 34βE12/CK5 cytoplasmic and p63 nuclear) often negative or retain a stray basal cell, again causing hesitation in diagnosing cancer

Molecular / cytogenetics description

Some molecular markers have been helpful in predicting repeat biopsy outcome; TMPRSS2-ETS family fusions were higher (63%) in atypical small acinar proliferation patients with subsequent cancer diagnosis than in those without (25%), MMP2 upregulation showed a similar trend; these figures were 56% and 27% in another study by the same authors (Prostate 2019;79:195, Gene 2018;645:69)

Sample pathology report

Prostate, right mid lateral, biopsy:
- Atypical small acinar proliferation, suspicious for but not diagnostic of cancer
- Immunohistochemical results: positive: AMACR; patchy: HMWK, p63

Differential diagnosis

Atrophy
Postatrophic hyperplasia
Basal cell hyperplasia
Reactive changes
Atypical adenomatous hyperplasia
Verumontanum mucosal gland hyperplasia
Ganglion
Seminal vesicle
High grade prostatic intraepithelial neoplasia (HGPIN)

Board review style question #1

Atypical small acinar proliferation, suspicious for malignancy, shown in the image

Carries a predictive value for cancer on repeat biopsy of 15 - 25%
Is a precursor to invasive carcinoma
Usually should be diagnosed only after basal cell and AMACR immunostaining if the worst finding in a prostate needle biopsy case
When followed by repeat biopsy that shows cancer, the cancer grade distribution is the same as for all newly detected cancers

Board review style answer #1

C. Usually should be diagnosed only after basal cell and AMACR immunostaining, unless there is definitive cancer in other sites and the additional diagnosis of carcinoma would not impact patient management. Choice A is wrong because the predictive value is closer to > 40%. Choice B is wrong because ASAP is not a precursor lesion but rather an indeterminate diagnosis. Choice D is wrong because cancer following an ASAP diagnosis is skewed toward mostly low grade cancer on repeat biopsy.

Comment Here

Reference: Atypical small acinar proliferation (ASAP), suspicious for but not diagnostic of malignancy

Basal cell hyperplasia

Table of Contents

Definition / general

Basal cell hyperplasia (BCH) is a benign histologic finding characterized by the proliferation of the basal cells within the prostatic acini (Urology 2019;129:160)
Benign mimicker of adenocarcinoma and basal cell carcinoma of the prostate gland
Divided into usual BCH (most common), florid BCH, BCH with prominent nucleoli / atypical hyperplasia, atrophy associated and adenoid cyst / cystic-like hyperplasia (Review Arch Pathol Lab Med 2012;136:721, Urology 2019;129:160)
Most commonly seen in the transition zone occupying 10 - 60% volume and often associated with nodular, glandular and stromal hyperplasia (Prostate 2017;77:1344)
Peripheral zone BCH is associated with acinar atrophy and chronic inflammation

Essential features

Solid nests, small crowded acini or pseudocribriform glands; multilayering of round to polygonal uniform cells with scant eosinophilic to clear cytoplasm and conspicuous nucleoli; can show coarse calcifications or eosinophilic cytoplasmic globules (J Clin Pathol 2005;58:290)
HMWCK / 34 beta E12, p63, GATA3 and CK8 / 18 are positive markers
AMACR and prostatic markers are typically negative
No malignant features, including perineural invasion or infiltration into the periprostatic adipose tissue or seminal vesicle(s), are seen

Terminology

Fetalization or embryonal hyperplasia of the prostate gland as the foci of basal cell hyperplasia has its resemblance with fetal prostatic acini
Embryonal hyperplasia and atypical basal cell hyperplasia are terms that are no longer used
Florid basal cell hyperplasia refers to extensive proliferation of basal cells involving > 100 small crowded acini (per section) forming a nodule (Hum Pathol 2005;36:480)

Epidemiology

Incidence ranges from 8 - 10% of needle biopsies to almost 80% in whole prostate mounts (Review Arch Pathol Lab Med 2012;136:721, Mod Pathol 2003;16:598, Urology 2019;129:160)
More common in transurethral resection (TURP) specimens (due to sampling from the transition zone); can also be seen in needle biopsies and radical prostatectomies
Prevalence of BCH in biopsies varies according to the sampled area (transitional versus peripheral zone) and gland characteristics such as associated benign prostatic hyperplasia (Urology 2019;129:160)
No association with ethnicity, BMI, PSA or prostate volume
2% of needle core biopsies may show BCH with prominent nucleoli (> 10% of nuclei)

Sites

More common in the transition zone of the prostate gland; can be present in the peripheral zone
Although more commonly seen in the TURP specimens, can also be seen in needle biopsies and radical prostatectomies

Pathophysiology

Hypothesized to be either a primary response to the luminal epithelial apoptosis or a secondary response to the inflammation
Role of BCL2 antiapoptotic protein and hormones (androgen and estrogen) is attributed (Mod Pathol 2003;16:598)
Increase in proliferation index with a diminished apoptotic index
Gene expression study suggests metaplastic BPH nature with conversion of the single layer of basal epithelial to a stratified squamous epithelium (Prostate 2017;77:1344)
Diffuse BCH along with squamous and urothelial metaplasia are observed in benign prostate glands following androgen deprivation therapy

Etiology

Increases in response to androgen deprivation and 5 alpha reductase inhibitor therapy (Am J Surg Pathol 2002;26:237, Prostate 2014;74:923, J Urol 1996;156:1194)
Atrophy associated basal cell hyperplasia is related to post hormonal (androgen deprivation) therapy, radiation or cryosurgery

Clinical features

Seen in adults (Am J Clin Pathol 1983;80:850)
Usually asymptomatic, unless coexisting BPH or prostatic cancer or any other pathology present
Symptoms of urinary retention seen in florid BCH (BMJ 1999;318:921)

Diagnosis

Diagnosis is made on microscopic findings aided by immunohistochemical stains (HMWCK and p63)
Immunohistochemistry is very valuable in differentiating BCH from high grade prostatic intraepithelial neoplasia, prostatic adenocarcinoma and basal cell carcinoma

Laboratory

Serum PSA usually within normal limits
Decrease in PSA may be seen in a post androgen deprivation setting due to ongoing antiandrogen therapy / androgen ablation

Radiology description

Sometimes calcification may be visible, though very rare

Prognostic factors

Not associated with adverse prognosis or high risk of prostatic cancer

Case reports

50 year old man presented with chronic retention of urine and bilateral hydronephrosis (JCR 2016;6:153)
72 year old man with acute urinary retention (Indian J Urol 2000;17:61)

Microscopic (histologic) description

At low magnification, basal cell hyperplasia has a basophilic appearance of nodular proliferation and back to back uniform glands with stratified crowded nuclei
Solid nests of benign appearing round to elongated to polygonal acinar epithelial cells, with similar cells having clear to eosinophilic scant cytoplasm
Piling up of the nuclei within the lumen, ranging from a double cell layer in a few glands to 3 - 4 cells thick in the other glands
Basal cells show zonal variations: triangular in the peripheral zone, while flattened or low cuboidal with scant cytoplasm in the transition zone (Prostate 2007;67:1686)
Pseudocribriform gland pattern with back to back small round glands of BCH rather than a solid nest of cells with punched out lumina that characterize true cribriform glands
Surrounding stroma either unremarkable or very cellular with abundant spindly fibroblasts or smooth muscle cells; occasionally minimally myxoid stroma; typically lacks desmoplasia
Lobular configuration is not always obvious, as an entire nodule cannot physically be sampled in a single core; in some instances of florid BCH, the proliferation still retains a lobular configuration, while in other instances, the lobular configuration may either be lost or not appreciated because of the fragmented nature of the transurethral resection specimen
Intracytoplasmic eosinophilic (hyaline) inclusions (53%)
Well formed lamellar calcifications (40%)
Psammomatous calcifications differing from the fine stippled calcifications seen in areas of comedo necrosis within high grade prostatic carcinoma (Am J Surg Pathol 2002;26:237)
Rare atypical features include perineural involvement, prominent nucleoli, dense intraluminal secretions, luminal blue mucin, intracytoplasmic hyaline globules, crystalloid and individual cell necrosis
Florid BCH: extensive proliferation of basal cells involving > 100 small crowded acini (per section) forming a nodule (Hum Pathol 2005;36:480)
BCH with prominent nucleoli: nuclear enlargement, hyperchromasia and nucleolar prominence (earlier known as atypical hyperplasia)
Adenoid cyst-like hyperplasia: focal glandular anastomosis and cribriform structures with small luminal spaces
Adenoid basal form of BCH: areas of luminal differentiation similar to the lesions of the salivary gland

Microscopic (histologic) images

Contributed by Anil Parwani, M.D., Ph.D., M.B.A. and Andres Matoso, M.D.

Benign mimicker of prostatic cancer

Basal epithelium proliferation

Intraluminal amorphic secretions

Florid basal cell hyperplasia

Basal cell carcinoma

Contributed by Debra L. Zynger, M.D.

H&E

Triple stain with CK5-p63-AMACR

Positive stains

HMWCK / 34 beta E12, p63, GATA3, AR and CK8 / 18
HMWCK shows multilayered staining of the basal cells in some of the glands and a continuous layer of immunoreactivity
Basal cells show zonal variations; in the peripheral zone they express HMWCK and p63, whereas in the transition zone they express p63 and variable HMWCK (weak or absent) (Prostate 2007;67:1686, Prostate 2017;77:1344, Hum Pathol 2003;34:462)

Negative stains

AMACR / P504S (may be focally positive), CD10, AR, NKX3.1, P501s (prostein), PSA, PSMA

Electron microscopy description

Basal cells oriented parallel or perpendicular to the basement membrane
2 types of intracytoplasmic inclusions (Hum Pathol 2003;34:462)
- Type 1: fine, uniform, granular, surrounded by a halo
- Type 2: irregular shape, amorphous content of variable electron density, close to the nucleus

Molecular / cytogenetics description

BCH glands characterized by K14- / p63+ layers on dual immunostaining and loss of luminal cell AR (Prostate 2017;77:1344)
RNA sequence analysis confirmed by qPCR shows upregulation of keratinocyte differentiation genes, assuming BCH to be a metaplastic process (Prostate 2017;77:1344)

Sample pathology report

Prostate, transurethral resection:
- Benign prostatic hyperplasia with florid basal cell hyperplasia
- No evidence of malignancy is seen

Differential diagnosis

High grade prostatic intraepithelial neoplasia (HGPIN):
- Architecturally benign prostatic acini or ducts lined by cytologically atypical luminal cells that are columnar and pseudostratified perpendicular to the basement membrane
- Basal cells are not readily identifiable (no distinct 2 cell population)
Prostate adenocarcinoma:
- Unilayered small acini, single cells or true cribriform structures with more abundant amphophilic cytoplasm, enlarged prominent nucleoli, prominent nucleoli and luminal blue mucin or eosinophilic crystalloids
- Negative for HMWCK, p63, GATA3, S100
- Positive for AMACR, P501s (prostein), PSMA, NKX3.1 and PSA
Basal cell carcinoma:
- Anastomosing basaloid nests and tubules centrally lined by eosinophilic cells, adenoid cystic pattern, large basaloid nests with necrosis and variably small to medium sized nests with irregular contours
- Diffuse and strong BCL2 expression and > 20% Ki67 proliferation index

Additional references

Am J Surg Pathol 1993;17:645

Board review style question #1

Which of the following is true regarding the pictured prostatic pathology?

AMACR positivity
Calcifications and intracytoplasmic eosinophilic inclusions are not seen
Most commonly seen in the transition zone of prostate
Necrosis is usually associated

Board review style answer #1

C. Most commonly seen in the transition zone of prostate. The picture shows basal cell hyperplasia of prostate, which is commonly seen in the transition zone of prostate as nodular, glandular or stromal hyperplasia. It is frequently encountered during TURP due to its preference to transition zone. Although rare, BCH can also be seen in the peripheral zone.

Comment Here

Reference: Basal cell hyperplasia

Board review style question #2

Basal cell hyperplasia of the prostate, a benign mimicker, can be diagnosed by which set of findings?

Anastomosing basaloid nests and tubules centrally lined by eosinophilic cells with strong BCL2 reactivity
Architecturally benign prostatic acini or ducts lined by luminal cells that are columnar and pseudostratified perpendicular to the basement membrane
Solid nests of epithelial cells with piling up of the nuclei within the lumen and well formed lamellar calcifications, GATA3+ and AMACR-
Unilayered small acini, single cells with enlarged prominent nucleoli and nuclei, showing HMWCK negativity

Board review style answer #2

C. Solid nests of epithelial cells with piling up of the nuclei within the lumen and well formed lamellar calcifications, GATA3+ and AMACR-. BCH is the benign proliferation of basal cells within the prostatic acini. Histologically, solid nests of benign appearing round to polygonal acinar epithelial cells and back to back glands with similar cells having clear to eosinophilic cytoplasm (usually atrophic cytoplasm) are seen. There is piling up of the nuclei within the lumen ranging from a double cell layer in a few glands, to 3 - 4 cells thick in the other glands.

Comment Here

Reference: Basal cell hyperplasia

Benign prostatic hyperplasia

Table of Contents

Definition / general

Benign nodular enlargement of the prostate gland
Histopathologically, hyperplasia (nonneoplastic new growth) of stromal and glandular components

Essential features

Benign nodular lesion with proliferation of stromal and glandular components
Predominantly located in the transition zone of the prostate
Diagnosis of benign prostatic hyperplasia (BPH) should not be used on routine prostate biopsies (Hum Pathol 2002;33:796)

Terminology

Benign prostatic hypertrophy (misnomer)
Nodular hyperplasia

ICD coding

ICD-10: N40.1 - benign prostatic hyperplasia with lower urinary tract symptoms
ICD-10: N40.0 - benign prostatic hyperplasia without lower urinary tract symptoms

Epidemiology

50% prevalence in men between 51 - 60 years (J Urol 1984;132:474)
Increasing incidence with increasing age (J Urol 1984;132:474)

Sites

Transition (periurethral) zone of the prostate (Invest Urol 1978;15:340)

Pathophysiology

Proliferation of both stromal and epithelial cells, leading to new glandular budding and branching, with formation of nodules
Central role of sex steroids (5αdihydrotestosterone, estrogens) and growth factors (fibroblast growth factor, transforming growth factor beta) (Nat Rev Urol 2011;8:29)

Etiology

Exact etiology unknown
Multiple theories, including embryonic reawakening, stem cell proliferation and hormonal imbalances (Nat Rev Urol 2011;8:29)

Clinical features

Increased bladder outlet resistance
Lower urinary tract symptoms (LUTS), including:
- Obstructive symptoms (hesitancy, intermittent stream and straining)
- Urinary bladder irritation symptoms (frequency, urgency and urge incontinence)
- Urinary retention (whether acute or chronic)
Severity assessed through self administered questionnaire (Am Fam Physician 2014;90:769)

Diagnosis

Clinical history
Physical examination (including digital rectal exam, assessment of bladder distention, motor and sensory deficits of the lower extremities and perineum and decreased anal sphincter tone to identify neurogenic bladder)
Urinalysis
Serum prostate specific antigen (PSA) measurement not recommended routinely (Annu Rev Med 2016;67:137)
Other studies, depending on symptoms (Am Fam Physician 2014;90:769)

Laboratory

Urinalysis may reveal hematuria, proteinuria or evidence of urinary tract infection
Prostate specific antigen (PSA) may be elevated (Curr Opin Urol 2000;10:3)

Radiology description

Imaging typically not specific for benign prostatic hyperplasia
Often performed to rule out other causes of lower urinary tract symptoms
Hypoechogenic nodules or variable echogenicity on ultrasound
Nodules ranging from hypointense to hyperintense on MRI T2 weighted images, depending on stroma / gland ratio (Diagn Interv Radiol 2016;22:215)
- 7 subtypes of benign prostatic hyperplasia on MRI based on location of the hyperplasia (Diagn Interv Radiol 2016;22:215)

Radiology images

Images hosted on other servers:

BPH on MRI

Prognostic factors

Not a precursor or risk factor for prostate cancer (Practitioner 2012;256:13, Am J Epidemiol 2011;173:1419)
Side effects of medications may increase with increasing age (Ther Adv Urol 2020;12:1756287220929486)
Immediate and long term complications of surgical treatment are relatively rare (Annu Rev Med 2016;67:137)
Risk of recurrence varies with type of treatment (Annu Rev Med 2016;67:137)

Case reports

17 year old boy with acute urinary retention due to benign prostatic hyperplasia (J Pediatr Urol 2016;12:267.e1)
61 year old man with spontaneous prostatic hematoma in a case of benign prostatic hyperplasia (BMJ Case Rep 2019;12:e228787)
71 year old man with primary prostate intravascular large B cell lymphoma presenting as prostatic hyperplasia (Medicine (Baltimore) 2019;98:e18384)
78 year old man with giant benign prostatic hyperplasia (Urol Case Rep 2019;28:101051)

Treatment

Watchful waiting for patients with mild symptoms or moderate to severe symptoms with minimal impairment in quality of life (Annu Rev Med 2016;67:137)
Medical treatment based on alpha blockers (nonselective; alpha-1A selective), 5-alpha-reductase inhibitors, phosphodiesterase type 5 inhibitors and combination products (Am Fam Physician 2014;90:769, Front Pharmacol 2020;11:658, Ther Adv Urol 2020;12:1756287220929486)
Surgical treatment, including ablative (such as transurethral resection, simple prostatectomy, transurethral laser vaporization, ablation, enucleation) and other procedures (such as transurethral incision, prostatic urethral lift device) reserved for patients who either have failed medical management or have complications (Curr Urol Rep 2020;21:32, BJU Int 2020;126:317, Am Fam Physician 2014;90:769)

Gross description

Variably sized nodules with a gray to yellow color and a granular appearance bulge above the cut surface of a prostate section

Gross images

Contributed by Sara Moscovita Falzarano, M.D., Ph.D.

Prominent periurethral nodularity

Microscopic (histologic) description

Epithelial hyperplasia is characterized by nodular lesions composed of variably sized glandular structures lined by basal and secretory cells
Glandular dilatation with papillary infoldings and cysts, often containing corpora amylacea, sometimes calcifications
Epithelial lining ranging from flat to columnar, with pink pale cytoplasm, regular, centrally located nuclei and inconspicuous nucleoli
Stromal nodules are composed of bland spindle cells with round to ovoid nuclei with open chromatin
Thick walled small capillary vessels can be seen on cross sections
Ischemic changes / infarcts can be seen within the nodules
Morphologic variants include:
- Clear cell cribriform hyperplasia
- Basal cell hyperplasia
- Adenosis / atypical adenomatous hyperplasia
- Leiomyomatous nodules
- Fibroadenomatous
- Phyllodes type hyperplasia
Reference: Am J Surg Pathol 1988;12:619

Microscopic (histologic) images

Contributed by Sara Moscovita Falzarano, M.D., Ph.D.

Glandular / epithelial type

Benign prostatic glands

Stromal nodule

p63

p63 / HMWK

Positive stains

Immunostains typically not needed
Basal cells
- High molecular weight cytokeratin (e.g. 34 beta E12, CK5/6, CK14)
- p63
Secretory (luminal) cells
- PSA, PSAP, NKX3.1
Stromal cells
- CD34, smooth muscle actin (SMA)
- Desmin variable
Reference: Am J Surg Pathol 1988;12:619

Negative stains

S100, CD117

Sample pathology report

Prostate chips, transurethral resection:
- Benign prostatic hyperplasia

Prostate tissue, transurethral laser enucleation:
- Benign prostatic tissue with stromal and glandular hyperplasia (58 grams)

Differential diagnosis

Prostatic adenocarcinoma (e.g. pseudohyperplastic type):
- Infiltrative growth, cytologic atypia (may be focal)
- Absent basal cell layer (p63 / HMWK negative)
Specialized stromal tumors (Am J Surg Pathol 2006;30:694)
- Stromal tumor of uncertain malignant potential (STUMP):
  - Higher degree of cellularity
  - Lacks numerous thick walled small blood vessels
- Stromal sarcoma:
  - Significant cytologic atypia, increased mitotic activity, necrosis
Other mesenchymal tumors
- Leiomyosarcoma:
  - Significant cytologic atypia, increased mitotic activity, necrosis (Cancer 1995;76:1422)
- Solitary fibrous tumor:
  - Patternless growth of uniform spindled cells with bland nuclei in background ropy collagen, staghorn hemangiopericytomatous vessels
  - STAT6 positive (strong diffuse) (Hum Pathol 2016;54:184)
- Gastrointestinal stromal tumor (GIST):
  - CD117 positive
  - May involve prostate secondarily from rectum (Am J Surg Pathol 2006;30:1389)

Additional references

Goldblum: Rosai and Ackerman's Surgical Pathology, 11th Edition, 2017, Mills: Sternberg's Diagnostic Surgical Pathology, 6th Edition, 2015

Board review style question #1

The above image is from an open suprapubic prostatectomy specimen. Which of the following is true about the disease?

Increasing incidence with increasing age
It is considered a precursor to prostate adenocarcinoma
It is more frequent in the peripheral zone of the prostatic gland
Medical therapy has no role in the management of the disease
Surgical treatment is contraindicated

Board review style answer #1

A. Increasing incidence with increasing age. The image shows benign prostatic hyperplasia.

Comment Here

Reference: Benign prostatic hyperplasia

Board review style question #2

The lesion was seen on transurethral resection of the prostate (TURP) from a patient with a prior clinical diagnosis of benign prostatic hyperplasia. What is the most likely immunohistochemical stain shown in the picture?

CK7
NKX3.1
PSA
P504S (AMACR)
p63

Board review style answer #2

E. p63

Comment Here

Reference: Benign prostatic hyperplasia

Biopsy

Table of Contents

Definition / general

Biopsies may be taken in several formats
Systematic approach may involve sextant (6) samples from selected regions of prostate by a spring loaded 18 gauge biopsy
Currently, up to 18 samples are taken; more for mapping biopsies (J Urol 2019;202:264)
Region of interest (ROI) biopsies at a multiparametric MRI targeted lesion carry greater sensitivity for cancer detection and prognosis (Hum Pathol 2018;76:68)
- Sampling may be region of interest only, systematic only or combined

Essential features

4 strongest features for cancer diagnosis: an infiltrative (rather than clustered) pattern of acini, nuclear enlargement, prominent nucleoli and loss of basal cells
2019 International Society of Urological Pathology (ISUP) biopsy reporting requirements:
1. Report the percentage Gleason pattern 4 for all Gleason score 7
2. Intraductal carcinoma presence should be mentioned and it should be graded when in the presence of invasive cancer and not graded when an isolated finding
3. Cribriform carcinoma presence / absence in Gleason 4 cancer should be specified
4. For systematic biopsies, Gleason score (ISUP grade group) should be reported per individual site, whereas for an MRI targeted biopsy, a global (aggregate) score should be reported for each region of interest
Note: the presence of intraductal carcinoma should be noted
- Isolated (pure) intraductal carcinoma should not be graded (consensus recommendation by ISUP and GUPS)
- In the presence of invasive carcinoma, incorporation of the intraductal carcinoma component in the Gleason score remains debatable and requires further studies (see pros and cons on reporting IDCP with coexisting invasive carcinoma in a recent review (Histopathology 2021;78:231, Pathology 2020;52:192, Histopathology 2021;78:342)

ICD coding

ICD-9:
- 60.11 - closed [percutaneous] [needle] biopsy of prostate
- 60.12 - open biopsy of prostate
ICD-10:
- C61 - malignant neoplasm of prostate
- Z85.46 - personal history of malignant neoplasm of prostate
- N40.1 - benign prostatic hyperplasia with lower urinary tract symptoms
- Z12.5 - encounter for screening for malignant neoplasm of prostate
ICD-11: 2C82.Z - malignant neoplasms of prostate, unspecified
As of 2014, Medicaid has limited the number of biopsy sites to 9 for full 88305 reimbursement so some practices are capping the number of biopsies at 9

Diagrams / tables

Contributed by Kenneth A. Iczkowski, M.D.

Reporting MRI targeted biopsies

Clinical features

25% of tumor bearing specimens contain only a small focus of carcinoma
Transperineal biopsies are alternative approach to transrectal biopsies
Gleason score in biopsy correlates with that of prostatectomy (same: 58%, variable 1 unit: 92%)
Tumor seeding of needle tract is a rare complication of perineal needle biopsy; more likely with poorly differentiated carcinomas and less common with transrectal biopsy (BJU Int 2015;115:698)
Findings at 12 core transrectal ultrasound guided prostate needle biopsy plus preoperative PSA predict advanced local disease at prostatectomy (Am J Clin Pathol 2012;137:739)

Diagnosis

Common cancer features are nucleomegaly (96%), infiltrative growth pattern (88%), intraluminal secretions (78%), prominent nucleoli (64%), associated high grade prostatic intraepithelial neoplasia (PIN) (40%), amphophilic cytoplasm (36%), hyperchromatic nuclei (30%), intraluminal crystalloids (22%)
Uncommon features are perineural invasion (2%), collagenous micronodules (2%), mitotic figures (2%) (Mod Pathol 1998;11:543)
- Glomerulations are rounded tufts of cancer cells within glands reminiscent of renal glomeruli;
  - Glomerulations are present in 5% of radical prostatectomy specimens (5 - 20% of each tumor) and 3% of needle biopsies with cancer (5 - 10% of each cancer)
  - They are not observed in benign lesions (Hum Pathol 1998;29:543)
Photo essay of general principles (Ann Diagn Pathol 2014;18:301)
Minimal cancer on biopsy is defined as < 1 mm but there is usually pathologically significant tumor at prostatectomy
Collagenous micronodules are nodular masses of paucicellular, eosinophilic, fibrillar stroma that impinge on acinar lumens (Arch Pathol Lab Med 1995;119:444)
Reporting of prostate cancer for each specimen part includes the fraction of biopsy cores or fragments that are involved by cancer and either the percent of each involved core on the slide or the length in millimeters of each involved core on the slide (Am J Surg Pathol 2020:44:e87)
- For example: prostatic adenocarcinoma, Gleason 3+4 (score = 7) within 20% and 40% of 2 out of 3 core fragments, tumor lengths 3 mm and 5 mm
Perineural invasion and extraprostatic extension should be mentioned in the line diagnosis if present
- If absent throughout the tumor, a comment at the conclusion of the line diagnoses should mention the absence of these findings
- Caution should be taken with perineural invasion, as perineural impingement by benign acini can mimic invasion by cancer (see Figure 2 below)
Intraductal prostate carcinoma (IDC) should be recognized
- An uncommon finding in biopsies, intraductal prostate carcinoma consists of a cribriform to solid, large, often dilated gland space, bounded by basal cells, that contains cells with marked nuclear enlargement and atypia which exceeds the atypia in high grade prostatic intraepithelial neoplasia (see Figure 6 below)
- Intraductal prostate carcinoma has characteristic genetic alterations (Mod Pathol 2013;26:587)
- Intraductal prostate carcinoma almost always occurs with invasive carcinoma and the invasive component is almost always high grade
- Intraductal prostate carcinoma must be mentioned, whether isolated or associated with invasive carcinoma
  - ISUP and GUPS disagree on whether intraductal prostate carcinoma should be graded into the invasive cancer or not counted for grading (Am J Surg Pathol 2020:44:e87, Arch Pathol Lab Med 2021;145:461)
    - This may infrequently alter overall grade; intraductal prostate carcinoma is not graded when an isolated finding (Histopathology 2020;77:503)
    - Intraobserver agreement, even among expert urologic pathologists, is only mediocre and certain findings interfere with consensus, although immunostains may help (Ann Diagn Pathol 2014;18:333)
Targeted biopsy reporting is different
- Aggregated findings of all cores sampled per region of interest (ROI) should be reported
- If the targeted cores are negative, the nonneoplastic findings (particularly inflammation) should be reported to explain the radiologic false positive abnormality (see Diagram 1 above) (Hum Pathol 2018;76:68)
Adequacy: biopsy is unsatisfactory if no prostatic glands or stroma are found; stroma only may indicate a stromal hyperplastic nodule and is satisfactory
Use of second opinion:
- Second opinion of core biopsies from outside institutions is beneficial before radical prostatectomy is performed (Am J Surg Pathol 1996;20:851, Int J Clin Exp Pathol 2011;4:468)
  - Standard practice at NCI designated comprehensive cancer centers
- Second opinion produces Gleason scores on biopsy that are significantly more predictive of radical prostatectomy findings than the outside diagnoses
- More errors occur with Gleason score 6, which tends to underestimate the prostatectomy Gleason score (Am J Surg Pathol 1997;21:566)
  - Pure Gleason 3 cancer may be managed by watchful waiting, thus second opinions are particularly called for to help discriminate the threshold between Gleason 3+3 (grade group 1) and Gleason 3+4 (grade group 2)
- Most important finding missed by outside pathologists is extraprostatic extension (EPE), which elevates the tumor stage from T2 to T3a (see Figure 3 below)
  - In a cohort of 65 cases, 11 patients had EPE
  - In 5 of those 11 patients, the outside pathologists failed to comment on the presence of the EPE (Int J Clin Exp Pathol 2011;4:468)
- Another finding that is easily missed yet sometimes overcalled is grade 5 prostate cancer (see Figure 4 below) (Urology 2012;79:178)
  - If there are single cells or clusters of cells without even the tiniest lumen formation, a component of Gleason grade 5 cancer should be diagnosed
  - It often forms a secondary part of the Gleason score; that is, 3+5 or 4+5
  - Gleason grade 5 cancer, however, may itself mimic inflammatory cells (see Figure 5 below)

Laboratory

Serum prostate specific antigen is often elevated above 4 ng/mL
- Some urologists use 2.5 ng/mL as a more sensitive but less specific threshold for biopsy (Urol Int 2010;84:141)

Prognostic factors

In order to facilitate prognosis, certain reporting standards are endorsed by CAP Cancer Protocols and both USCAP urologic pathology societies:
- Each separately submitted vial gets its own line diagnosis
- Fraction of cores per specimen involved by cancer should be stated; recommended to report the either the percentage or the length (millimeters) of each individual core involved by cancer since these strongly predict prostatectomy findings (Am J Surg Pathol 2005;29:1228)
  - Many laboratories and pathologists report both the percentage and the length
    - For example: prostatic adenocarcinoma, Gleason 3+4 (score of 7) involving 20% and 30% of 2 out of 2 cores, tumor lengths 3 mm and 4 mm
- Reporting the percent of Gleason 4 cancer is now required in Gleason 3+4 or 4+3 cancer (grade groups 2 or 3) (Am J Surg Pathol 2020:44:e87)
  - Although it is not necessary when the highest score in any specimen part is Gleason 8 - 10 (grade groups 4 or 5) (Arch Pathol Lab Med 2021;145:461)
- Reporting the presence or absence of cribriform pattern is also required whenever Gleason 4 cancer is diagnosed, because of its adverse prognostic impact (Adv Anat Pathol 2018;25:31)
  - Reporting other patterns of Gleason 4 is optional
- Whether perineural invasion and extraprostatic extension are present or absent can be stated as a comment at the end of the list of line diagnoses
- Sextant approach has a false negative rate up to 25% due to sampling error (Mol Urol 2000;4:93)

Case reports

42 - 78 year old men with rectal adenocarcinoma (Hum Pathol 2007;38:1836)
46 - 75 year old men with solitary fibrous tumor on needle biopsy and transurethral resection of the prostate (Am J Surg Pathol 2007:31:870)
51 - 87 year old men with urothelial carcinoma diagnosed on prostate needle biopsy (Am J Surg Pathol 2001;25:794)
58 - 93 year old men with primary mucin producing urothelial type adenocarcinoma of prostate (Am J Surg Pathol 2007:31:1323)
65 year old man with prostatic sarcoidosis and PSA elevated to 7.2 ng/mL (J Urol 2013;190:711)
67 year old man with squamous cell carcinoma of the prostate (Case Reports in Clin Pathol 2016;3:60)
76 year old man with renal-like clear cell carcinoma, positive for CD10 and PSA (In Vivo 2020;34:2751)
16 prostate needle biopsies with distorted benign rectal glands that mimic prostate cancer (Am J Surg Pathol 2006;30:866)

Treatment

Nonsurgical approaches include radiotherapy with hormone ablation and cryotherapy
Alternative is surgery which nowadays is usually robotic radical prostatectomy

Gross description and processing

Method of gross submission of prostate biopsies is crucial
Most laboratories submit up to 2 cores (a core being defined as ≥ 1 cm length) per cassette, regardless of the number of cores per vial
- If a vial contains a dozen cores or core fragments, submission of all the material in 1 cassette leads to almost uninterpretable slides because of specimen crossing over and fragmentation (see Figure 1 below) (Ann Diagn Pathol 2014;18:301)
- Having no more than 2 full cores per cassette minimizes the tissue that falls out of the plane of section
However, some laboratories are able to submit 3 cores (from 3 different vials) in 1 cassette using differential inking to indicate sites of the cores
- Great care must be taken with this approach but the diagnostic yield is comparable to 1 specimen per cassette (Ann Diagn Pathol 2013;17:357)
- Advantages are reducing the number of slides for the pathologist to look at and reducing processing costs and storage space
3 levels are recommended for maximal detection of cancer (Arch Pathol Lab Med 1998;122:833, Am J Clin Pathol 1997;107:26, Am J Surg Pathol 1999;23:257)
- 5 levels may be cut with levels 2 and 4 unstained, reserved for stains such as investigation of atypical small acinar proliferation (ASAP), suspicious for but not diagnostic of malignancy; 1, 3 and 5 are used for hematoxylin eosin (Am J Clin Pathol 1998;109:416)
- Average of 23% of total length of a core is missed by a single histologic level
- Pre-embedding 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 ≤ 3 mm of Gleason 6 or less cancer (Hum Pathol 2000;31:1102)

Frozen section description

Frozen section is not recommended for prostate biopsy

Microscopic (histologic) description

Features suggestive of malignancy in a core are (malignant versus benign specimens) (Arch Pathol Lab Med 2002;126:554):
- Prominent nucleoli (94% versus 25%)
- Marginated nucleoli (88% versus 7%)
- Multiple nucleoli (64% versus 0%)
- Blue tinged mucinous secretions (52% versus 0%)
- Intraluminal crystalloids (41% versus 1%)
- Intraluminal amorphous eosinophilic material (87% versus 2%)
- Collagenous micronodules (2% versus 0%)
- Glomerulations (15% versus 0%)
- Perineural invasion (22% versus 0%)
- Retraction clefting (39% versus 7%)
- Invasion of fat (1% versus 0%)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Too many cores
or core fragments

Impingement

Extension of
prostate cancer

Grade 5 prostate cancer

Intraductal carcinoma

Atypical small
acinar proliferation

Prostate basal cell cocktail plus P504S

Atypical adenomatous hyperplasia

Virtual slides

Images hosted on other servers:

Benign prostate with a nodule of hyperplasia

Reactive benign acini

Prostatic adenocarcinoma, Gleason 4+3

Cytology description

Frozen section is not recommended for prostate biopsy

Positive stains

Immunostains should be reserved for equivocal cases where hematoxylin eosin is inconclusive (Int Urol Nephrol 2010;42:325)
- Or to distinguish intraductal from invasive cancer (Am J Surg Pathol 2020:44:e87, Arch Pathol Lab Med 2021;145:461)
Sensitive and specific for prostate carcinoma on needle biopsies but not all suspicious / atypical small acinar proliferation (ASAP) cases can be resolved by immunostain cocktail (see Figures 7 and 8 above)
Can also destain / restain needle biopsies and put original sections on coated slides (Hum Pathol 2000;31:1155)
Prostatic intraepithelial neoplasia (PIN) cocktail with P504S (red) and 34ΒE12 + p63 (brown) is widely used to diagnose limited prostatic adenocarcinoma (Am J Surg Pathol 2002;26:1169, Am J Surg Pathol 2003;27:365)
Caveat: P504S stains some hyperplastic nodules and benign glands adjacent to transition zone carcinomas (Hum Pathol 2003;34:228)
P504S / p63 can be used as a single color cocktail to distinguish prostatic cancer involvement in seminal vesicles versus cancer mimickers because of the architectural complexity of the seminal vesicles and ejaculatory ducts (Arch Pathol Lab Med 2010;134:983)

Negative stains

High molecular weight cytokeratin 34ΒE12 and p63 are lacking in adenocarcinoma since basal cells are absent
Positive staining can identify benign mimickers of cancer including benign crowded glands, adenosis and atrophy and occasionally discriminate high grade PIN versus cancer
Negative high molecular weight keratin 34ΒE12 is diagnostic of adenocarcinoma only if there is a high (90%) H&E suspicion of carcinoma, one must also see staining of obviously benign glands as internal control (Am J Surg Pathol 2002;26:1151)
Negative or very light staining with P504S in suspicious foci does not necessarily indicate a benign diagnosis (Am J Surg Pathol 2002;26:1169)

Molecular / cytogenetics description

FISH for PTEN loss is a precise test for this adverse finding but immunostaining is usually done first

Sample pathology report

Give Gleason sum, the grade group, percentages of cores, fraction of cores and tumor lengths; if primary and secondary Gleason are different and the highest Gleason sum = 7, give the % of secondary

Prostate, left apex, biopsy:
- Prostatic adenocarcinoma, Gleason 3+3 (score = 6, grade group 1) within 80% and 90% of 2 out of 3 cores; tumor lengths 4 mm and 6 mm
- Perineural invasion is present
- Benign fibromuscular stroma only (1 core)

Prostate, left mid, biopsy:
- Prostatic adenocarcinoma, Gleason 3+4 (score = 7, grade group 2) within 80%, 90%, 90% and 100% of 4 out of 5 cores; tumor lengths 4 mm, 6 mm, 6 and 10 mm
- 30% of tumor is Gleason 4, not cribriform
- Perineural invasion is present
- Benign fibromuscular stroma only (3 cores)

Prostate, left base, biopsy:
- Benign prostatic tissue. Mild atrophy. Mild chronic inflammation. Et cetera.

Comment (end of report): Tumor shows no extraprostatic extension.

Differential diagnosis

Atrophy:
- Most common mimic of cancer
- Histologic similarity (small acini) but not cytologic similarity (lack of cellular atypia)
High grade PIN (Am J Clin Pathol 2000;114:896):
- Conversely, mimics cancer by having cytologic similarity (cellular atypia) but not histologic similarity (larger gland space and retained basal cells)
Atypical adenomatous hyperplasia:
- Another small acinar cancer mimic: clustered, not infiltrative like cancer
- See Figure 9 above, also called adenosis

Board review style question #1

What is a feature that is lacking in this low grade cancer but would have favored a benign diagnosis?

Corpora amylacea
Glomerulations or dense cribriform pattern
Infiltrative growth pattern
Mitotic figures
Prominent or marginated nucleoli

Board review style answer #1

A. Corpora amylacea. Corpora amylacea are usually a mark of benign acini. Cancer findings that are more common include prominent nucleoli and infiltrative growth. Less common but very specific for cancer are glomerulations and mitotic figures.

Comment Here

Reference: Prostate gland & seminal vesicles - Biopsy

Board review style question #2

Required findings to report based on current consensus include

Global (case level) grading
Glomeruloid pattern
Percentage of grade 4 cancer if the Gleason score is 7
Percentage of grade 4 cancer if the Gleason score is 8 - 10

Board review style answer #2

C. Percentage of grade 4 cancer if the Gleason score is 7. This is a reporting requirement. Within 3+4 cancer (grade group 2), it matters greatly whether the 4 is 1% or 49%. If the cancer is 4+4=8 or if Gleason 5 is present in any specimen part, then stating percentage of Gleason 4 is optional for the remaining parts.

Global (case level) grading is optional according to current recommendations; however, if multiple cores are from a single radiologically targeted site / region of interest, a global grade should be assigned to all those cores. The glomeruloid pattern, although specific for cancer, is not necessary to report but the presence or absence of cribriform pattern is since it carries a special prognostic impact.

Comment Here

Reference: Prostate gland & seminal vesicles - Biopsy

Clear cell cribriform hyperplasia

Table of Contents

Definition / general

Epithelial cribriform proliferation that is considered to be a histological variant of benign prostatic hyperplasia (BPH)

Essential features

Nodular clusters of cribriform acini lined by clear cells with small monotonous nuclei and inconspicuous nucleoli
Basal cell layer is intact
Predominantly occurs in the transitional zone of the prostate

Terminology

Synonym: cribriform hyperplasia (Virchows Arch 2009;454:1)

ICD coding

ICD-11: GA90 - hyperplasia of prostate

Epidemiology

As a morphologic variant of benign prostatic hyperplasia, clear cell cribriform hyperplasia shares the same epidemiology

Sites

Transitional zone of the prostate

Pathophysiology

Considered a variant of benign prostatic hyperplasia whose pathophysiology is incompletely understood
Dominant role of androgens and androgen receptors is recognized and recently the role of prostatic inflammation and metabolic factors has been described (Gerontology 2019;65:458)

Diagnosis

Mostly in transurethral resection of the prostate (TURP) specimens of men with lower urinary tract obstruction secondary to benign prostatic hyperplasia (Am J Surg Pathol 1986;10:665)

Prognostic factors

Not a risk factor for prostate cancer

Case reports

58 - 88 year old men with clear cell cribriform hyperplasia of the prostate (Am J Clin Pathol 1991;95:446)
60 year old man with benign prostatic hyperplasia (Ann Int Med Den Res 2017;3:25)
62 - 87 year old men with clear cell cribriform hyperplasia of prostate (Am J Surg Pathol 1986;10:665)

Treatment

Mostly found incidentally in TURP specimens treated for benign prostatic hyperplasia; no additional therapy is required

Gross description

No specific gross features

Microscopic (histologic) description

Focal or diffuse nodular clusters of acini with cribriform morphology
Involved ducts follow the architectural distribution of adjacent benign prostatic hyperplasia
Cuboidal to columnar cells with clear to pale eosinophilic granular cytoplasm and small, monotonous nuclei with inconspicuous nucleoli
Basal cell layer is prominent and frequently discernible on light microscopic examination
Stroma surrounding glands is cellular (benign prostatic hyperplasia-like)
References: Am J Clin Pathol 1991;95:446, Surg Pathol Clin 2022;15:591

Microscopic (histologic) images

Contributed by Rafael E. Jimenez, M.D. and Arpan Samaddar, M.B.B.S.

Clusters of cribriform acini

Clear cells

Intact basal cell layer

Small nuclei without atypia

Positive stains

High molecular weight cytokeratin, p63 and p40 highlight the basal cells, supporting a nonneoplastic diagnosis

Negative stains

AMACR (may have patchy positivity)
PTEN and ERG

Molecular / cytogenetics description

Flow cytometry showed diploid DNA (n = 13) (Am J Clin Pathol 1991;95:446)

Sample pathology report

Prostate, transurethral resection:
- Benign prostatic hyperplasia
Note: it is not necessary to specify clear cell cribriform hyperplasia in the diagnosis as it has no clinical impact and the term may cause confusion

Differential diagnosis

Central zone histology (Hum Pathol 2002;33:518, Cancers (Basel) 2022;14:3041):
- Central zone of the prostate near the base can have focal cribriform glands
- Also lacks cytological atypia and inconspicuous nucleoli
Basal cell hyperplasia (cribriform / pseudocribriform pattern) (Hum Pathol 2005;36:480, Cancers (Basel) 2022;14:3041):
- Commonly found in the transition zone
- Clusters of proliferating basal cells within back to back acini that are growing in a solid or cribriform pattern
- Scant cytoplasm with hyperchromatic nuclei, rendering a basophilic appearance
- May have prominent nucleoli
- Positive for basal cell markers (p63, HMWCK)
Atypical intraductal cribriform proliferation (AIDCP):
- Loose cribriform (lumen spanning) architecture
- Moderate cytological atypia (enlarged, hyperchromatic nuclei) and prominent nucleoli
- Previously classified as high grade prostatic intraepithelial neoplasia with cribriform architecture
Intraductal carcinoma:
- Basal cells retained at the periphery of the lesion
- Expanded acini and ducts with a dense cribriform architecture
- Marked cytological atypia with nonfocal comedonecrosis
- PTEN and ERG can be positive (invariably negative in clear cell cribriform hyperplasia)
Invasive acinar adenocarcinoma with cribriform Gleason pattern 4:
- Common in peripheral zone
- Confluent glands in an infiltrative growth pattern without a basal cell layer
- Nucleomegaly and prominent nucleoli
- Negative for basal cell markers (p63, HMWCK)
Ductal type adenocarcinoma:
- Lacks basal cell layer
- Large confluent glands with infiltrative papillary growth pattern, lined by columnar cells with prominent nucleoli
- Negative for basal cell markers (p63, HMWCK)

Additional references

Arch Pathol Lab Med 2010;134:427

Board review style question #1

Which of the following is true about the prostatic lesion shown above?

Carries a risk of progressing to high grade prostatic intraepithelial neoplasia
Commonly encountered in the peripheral zone
Considered to be an architectural variant of nodular prostatic hyperplasia
Cytologically atypical with prominent nucleoli

Board review style answer #1

C. Considered to be an architectural variant of nodular prostatic hyperplasia. The image shows clear cell cribriform hyperplasia, which is considered to be a histological variant of benign prostatic hyperplasia. Answer B is incorrect because clear cell cribriform hyperplasia is commonly encountered in the transitional zone of the prostate. Answer D is incorrect because clear cell cribriform hyperplasia is cytologically bland with monotonous nuclei and inconspicuous nucleoli. Answer A is incorrect because clear cell cribriform hyperplasia is not a premalignant condition.

Comment Here

Reference: Clear cell cribriform hyperplasia

Board review style question #2

Which of the following matches the immunohistochemical profile for clear cell cribriform hyperplasia of the prostate?

HMWCK-, p63-, AMACR-
HMWCK-, p63-, AMACR diffuse +
HMWCK-, p63+, AMACR-
HMWCK+, p63+, AMACR-
HMWCK+, p63+, AMACR diffuse +

Board review style answer #2

D. HMWCK+, p63+, AMACR-. Acini are lined by an intact basal cell layer positive for HMWCK and p63. AMACR is usually negative but may be focally positive in some cases of this entity, a histological variant of benign prostatic hyperplasia. This immunohistochemical profile would also be seen in central zone histology and basal cell hyperplasia with a cribriform / pseudocribriform pattern. Answer E is incorrect because atypical intraductal cribriform proliferation and intraductal carcinoma will show an intact basal cell layer positive for HMWCK and p63 (may show discontinuous staining) with AMACR positivity. Answer B is incorrect because invasive acinar adenocarcinoma with cribriform Gleason pattern 4 and ductal type adenocarcinoma do not have an intact basal cell layer and will be negative for HMWCK and p63, while being positive for AMACR. Answers A and C are incorrect because these immunohistochemical profiles do not align with any other entities in the differential.

Comment Here

Reference: Clear cell cribriform hyperplasia

Cystadenoma

Table of Contents

Definition / general

Rare, benign epithelial tumor composed of variably sized cysts lined by bland cuboidal cells

Essential features

Distinguished from mixed epithelial and stromal tumor of the seminal vesicle by the absence of stromal hypercellularity
Should be distinguished from prostatic stromal tumor of uncertain malignant potential entrapping glands
- Factors that favor seminal vesicle cystadenoma:
  - Cystic tumor centered in the seminal vesicle
  - No expression of prostatic differentiation markers

Terminology

Some authors consider it as the expression of lowest grade (benign) of mixed epithelial and stromal tumor of the seminal vesicle (Adv Anat Pathol 2015;22:113)

ICD coding

ICD-O: 8440/0 - cystadenoma, NOS
ICD-11: 2F34 & XH5RJ2 - benign neoplasm of male genital organs & cystadenoma, NOS

Epidemiology

Rare (< 30 described cases)
Wide age distribution (23 - 66 years old)

Sites

Centered within seminal vesicles

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Obstructive urinary symptoms
Some patients present with an asymptomatic mass or the masses are incidentally detected in imaging studies

Diagnosis

Cystic or solid and cystic masses detected in imaging studies

Radiology description

Cystic or solid and cystic masses centered within the seminal vesicles

Radiology images

Images hosted on other servers:

Mass of cystic component between bladder and rectum

Cystic mass with solid component connected to the seminal vesicle

Solid and cystic pelvic mass

Prognostic factors

Benign neoplasm; local resection is considered curative

Case reports

31 year old man with an 8.8 cm cystic pelvic mass (Asian J Androl 2013;15:697)
48 year old man with a 3.5 cm mass in the right seminal vesicle (J Endourol Case Rep 2015;1:62)
49 year old man with a 12.0 cm solid and cystic pelvic mass (Pan Afr Med J 2017;28:149)
59 year old man with a 9.8 cm oval cyst between bladder and rectum (Chin Med J (Engl) 2018;131:2897)
71 year old man with a 5.5 cm oval cyst between bladder and rectum (Asian J Androl 2017;19:384)

Treatment

Surgical resection

Clinical images

Images hosted on other servers:

Laparoscopic view

Gross description

Cystic mass centered in the seminal vesicle with variable solid components

Gross images

Contributed by Daniel Athanazio, M.D., Ph.D.

Cystic mass centered in the seminal vesicle

Cut surface

Images hosted on other servers:

Multilobulated cystic mass

Cut surface

Microscopic (histologic) description

Glandular spaces of varying sizes are lined by cuboidal cells without atypia (Adv Anat Pathol 2015;22:113)
Lobular pattern, forming branching lumina and cysts that contain granular intraluminal secretions
No hypercellularity or atypia in stromal cells

Microscopic (histologic) images

Contributed by Daniel Athanazio, M.D., Ph.D.

Cystic tumor

Finger-like projections

Leaf-like projections

Nonproliferative stroma

Bland epithelium

GATA3

PSA negative

Calretinin negative

Prostein negative

Positive stains

Epithelial lining stains for pancytokeratin and CK7
Basal cells express high weight molecular keratins
Stromal cells may stain for smooth muscle actin
Normal epithelial lining of a seminal vesicle usually strongly expresses GATA3; however this marker is also positive in the prostate and should be interpreted with caution (Actas Urol Esp 2017;41:577)
Normal and neoplastic seminal vesicle epithelium is strongly positive for PAX8 (Am J Surg Pathol 2011;35:1837, Hum Pathol 2017;69:123)

Negative stains

Epithelial cells usually do not express PSA, prostein / P501S or calretinin
Stromal cells are negative for S100

Sample pathology report

Prostate and seminal vesicles, radical prostatectomy:
- Cystadenoma of the seminal vesicle (see comment)
- Comment: This is a benign neoplasia. Surgical resection is considered curative.

Differential diagnosis

Mixed epithelial and stromal tumor of the seminal vesicle:
- Stromal hypercellularity
Prostatic stromal tumor of uncertain malignant potential entrapping glands:
- Centered in the prostate, entrapped prostatic glands express PSA and other markers of prostatic differentiation
Adenomatoid tumor:
- Expresses mesothelial markers such as calretinin
Mesothelial cysts:
- Express mesothelial markers such as calretinin
Cystic ductal adenocarcinoma of the prostate:
- Pseudostratified and atypical epithelial neoplastic cells
Primary seminal vesicle carcinoma:
- Atypical cells
- Tumor centered in a seminal vesicle
- Adenocarcinomas usually show papillary glandular and trabecular growth patterns
- Exclusion of other primary sites and immunophenotype excluding primary prostate adenocarcinoma

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

What major criterion favors the diagnosis of mixed epithelial and stromal tumor of the seminal vesicle over cystadenoma of the seminal vesicle?

Expression of PSA in epithelial cells
Expression of smooth muscle actin in stromal cells
Stromal proliferation and hypercellularity
Tumor grossly centered in the seminal vesicle

Board review style answer #1

C. Stromal proliferation and hypercellularity. Seminal vesicle cystadenoma shows no stromal hypercellularity (image shown above).

Comment Here

Reference: Cystadenoma

Board review style question #2

Which feature of immunohistochemistry favors the diagnosis of benign mesothelial cysts over cystadenoma of the seminal vesicle?

Expression of calretinin in epithelial cells
Expression of GATA3 in epithelial cells
Expression of pankeratins in epithelial cells
Expression of smooth muscle actin in stromal cells

Board review style answer #2

A. Expression of calretinin in epithelial cells. Seminal vesicle cystadenoma is negative for calretinin in the photo above.

Comment Here

Reference: Cystadenoma

Ductal adenocarcinoma

Table of Contents

Definition / general

Rare subtype of prostatic carcinoma composed of large glands lined by tall columnar cells with pseudostratified nuclei

Essential features

Frequently mixed with acinar adenocarcinoma
Similar mortality rate to Gleason score 8 - 10 acinar adenocarcinoma for usual ductal adenocarcinoma

Terminology

Prostatic ductal adenocarcinoma, ductal carcinoma

ICD coding

ICD-O: 8500/3 - ductal adenocarcinoma
ICD-10: C61 - malignant neoplasm of prostate
ICD-11: 2C82.0 & XH7KH3 - adenocarcinoma of prostate & infiltrating duct carcinoma, NOS

Epidemiology

Accounts for 3.2% of all prostate cancers
- Most are mixed with acinar adenocarcinoma; pure ductal carcinoma incidence: 0.4 - 0.8% of prostate cancers (Histopathology 2012;60:59, Cancer 1986;57:111)

Sites

Prostate
Most common in peripheral zone but also can be in the urethra and transition zone (Virchows Arch 2013;46:429)

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Periurethral tumor may cause hematuria and urinary tract symptoms; peripheral tumors have clinical features similar to acinar adenocarcinoma
More likely to present with distant disease than acinar adenocarcinoma (J Urol 2010;184:2303)
Can metastasize, including to unusual visceral metastases (including penis and testis) (Cancer 2020;126:3667, Urol Oncol 2008;26:368, Am J Surg Pathol 2015;39:67, Cancer 2002;94:2610)

Diagnosis

Similar to other prostate cancers, often diagnosed through transrectal needle biopsies
Periurethral tumor may be diagnosed by transurethral resection of the prostate

Laboratory

PSA can be highly variable
More likely to have a PSA < 4.0 ng/mL; has a mean lower PSA at presentation compared with acinar adenocarcinoma (J Urol 2010;184:2303, Urology 2015;86:777)

Radiology description

Not diagnostically helpful at this time; however, pure ductal adenocarcinoma may be seen as a noncystic mass with periurethral distribution or a multicystic mass (Abdom Radiol (NY) 2022;47:1929)

Radiology images

Images hosted on other servers:

Cystic ductal adenocarcinoma

Prognostic factors

Similar mortality rate to acinar carcinoma with Gleason score of 8 - 10 (Urology 2015;86:777)
Similar to acinar adenocarcinoma, cribriform features in ductal adenocarcinoma have been shown to have more aggressive behavior (Ann Diagn Pathol 2019;39:59)
Is an aggressive subtype and has a high risk of biochemical failure due to similar genetic changes to castration resistant acinar adenocarcinoma (Eur Urol 2021;79:298, Hum Pathol 2017;69:1, Nat Rev Urol 2021;18:337)
Has worse outcome compared to prostatic acinar adenocarcinoma (Eur Urol 2021;79:298)

Case reports

64 year old man with mixed acinar and macrocystic ductal prostatic adenocarcinoma (Lancet Oncol 2021;22:e37)
67 year old man with gastric metastasis (mixed ductal and acinar) (Urol Case Rep 2016;7:28)
76 year old man with ductal carcinoma which mimicked a urethral polyp (Pathology 2007;39:476)
86 year old man with ductal adenocarcinoma presenting with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (J Cancer Res Ther 2012;8:308)
29 men with metastatic prostatic ductal adenocarcinoma to the penis (Am J Surg Pathol 2015;39:67)

Treatment

Hormonal therapy, radiation or surgery
Tends to have a worse outcome compared to prostatic acinar adenocarcinoma (Eur Urol 2021;79:298)

Gross description

Similar to prostatic acinar adenocarcinoma

Microscopic (histologic) description

Large glands composed of tall columnar cells which often have pseudostratified nuclei
Patterns include cribriform, papillary, solid and prostatic intraepithelial neoplasia-like pattern
- Cribriform: similar to acinar adenocarcinoma, cribriform pattern in ductal adenocarcinoma has been shown to be more likely to have extraprostatic extension, seminal vesicle invasion, lymphovascular invasion and advanced pathologic stage (Ann Diagn Pathol 2019;39:59)
  - Cribriform pattern is composed of intraglandular epithelial bridging with slit-like lumens instead of the punched out lumens of cribriform acinar adenocarcinoma (Am J Surg Pathol 2011;35:615)
- Papillary: true fibrovascular cores (Histopathology 2014;65:216)
- Solid: often not columnar shaped (Mod Pathol 2018;31:S71)
  - Not specific; must see together with the other ductal patterns for diagnosis (Mod Pathol 2018;31:S71)
- Prostatic intraepithelial neoplasia-like: assigned as Gleason pattern 3 (Histopathology 2012;60:59, Am J Surg Pathol 2008;32:1060)
Arises in primary periurethral ducts or in peripheral prostatic ducts
Frequently is mixed with an acinar component (Virchows Arch 2013;46:429)
Most ductal adenocarcinoma is considered to be Gleason pattern 4 (5 if with comedonecrosis) (scored via the Gleason scoring system)
Cytoplasm is typically amphophilic, although it can be clear (Med Princ Pract 2010;19:82)
May have desmoplastic stromal reaction, hemorrhage, edema and inflammation (Mod Pathol 2018;31:S71)
May have intraductal spread (Mod Pathol 2018;31:S71)
Other unusual patterns that have been reported are foamy gland, Paneth cell-like neuroendocrine, micropapillary and cystic papillary (Pathology 2010;42:319)
Associated with seminal vesical invasion and less likely to be confined to the prostate than acinar adenocarcinoma with a Gleason score < 7 (Hum Pathol 2010;41:281, Virchows Arch 2013;46:429)

Microscopic (histologic) images

Contributed by He Huang, M.D., Ph.D. and Sarah Findeis, M.D.

Glandular, cribriform and papillary patterns

Pseudostratified columnar cells

Mitotic figures

Papillary architecture

Papillary and cribriform pattern

Core with papillae

Pseudostratification
and papillae

Mixed acinar and ductal adenocarcinoma

Pseudostratification
and
fibrovascular
core

Virtual slides

Images hosted on other servers:

Prostatic ductal adenocarcinoma

Cytology description

Sheets of columnar cells with some gland formation or papillary architecture with inconspicuous nucleoli (Acta Cytol 2013;57:184)
Abundant cytoplasm, oval nuclei, flat or folded sheets, peripheral nuclear palisading (Am J Clin Pathol 2006;126:302)

Positive stains

PSA, PSAP, AMACR (77%), NKX3.1, androgen receptor (Am J Surg Pathol 2007;31:889)
PSMA

Negative stains

CK7, CK20 (can be patchy positive); typically negative for CDX2

Molecular / cytogenetics description

PTEN loss by IHC was less frequent compared with pure acinar carcinoma; TMPRSS2::ERG gene fusion is infrequent (Mod Pathol 2009;22:359, Prostate 2015;75:1610)
PTEN, RB1 and TP53 alterations, in a case report of ductal adenocarcinoma having neuroendocrine phenotype (BMC Med Genomics 2021;14:245)
Low rates of ERG rearrangement by IHC and FISH (Prostate 2015;75:1610)
Considerable gene expression overlap with acinar adenocarcinoma; however, early research suggests that prolactin receptor protein is overexpressed in ductal (compared to acinar) adenocarcinoma (Mod Pathol 2009;22:1273)
High percentage of DNA damage repair pathway alterations (JCO Precis Oncol 2019;3:PO.18.00327)
Often the genomic profile is similar to castration resistant prostatic acinar adenocarcinoma (Nat Rev Urol 2021;18:337)
MAP3K1 homozygous deletion (case report) (IJU Case Rep 2021;4:176)
Most often are clonally related, in cases of mixed acinar and ductal adenocarcinoma (Prostate 2022;82:576)
Aneuploidy (Prostate 2022;82:576)

Sample pathology report

Prostate, radical prostatectomy:
- Prostatic ductal adenocarcinoma, Gleason score 4+4=8, grade group 4 (see synoptic report)

Differential diagnosis

Acinar adenocarcinoma, Gleason pattern 4:
- Cuboidal tumor cells with smooth and rounded luminal space
- Lack of true papillary structure
- Both can have patchy p63 / HMWCK basal cells (Am J Surg Pathol 2007;31:889)
Intraductal adenocarcinoma:
- Can be quite difficult to distinguish as there is some morphological overlap
- Preserved basal cells, highlighted by p63, HMWCK or CK5/6
  - Note that p63 / HMWCK basal cells may stain in a patchy pattern for ductal adenocarcinoma (Am J Surg Pathol 2007;31:889)
- Cuboidal neoplastic cells, rounded luminal spaces and lack of true papillae (Am J Surg Pathol 2011;35:615)
- May show more nuclear pleomorphism
High grade prostatic intraepithelial neoplasia:
- Micropapillary frond without fibrovascular stalks of true papillae
- No comedonecrosis, large glands or back to back glands
- Features that point to ductal adenocarcinoma: stromal reaction, crowded glands, expansile morphology, necrosis and other ductal adenocarcinoma morphologies (Mod Pathol 2018;31:S71)
- Preserved basal cells, highlighted by p63, HMWCK or CK5/6
- Low Ki67 (Hum Pathol 2005;36:531)
Metastatic carcinoma from other primary site:
- Potential other primary sites include nearby colon and bladder
- Stains to rule out other possible primaries
Prostatic urethral polyp:
- Especially on needle core biopsy since it can look relatively bland (Am J Surg Pathol 1999;23:1471, Med Princ Pract 2010;19:82)
- No nuclear atypia and basal cells are present (Mod Pathol 2018;31:S71)
- AMACR-, p63+ and CK7+ (Pathology 2007;39:476)

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

A single discrete lesion is identified within the prostate. What immunohistochemical profile would you expect to have with the above prostatic tumor?

CDX2+, AMACR+, PSAP+
CK5+, CK20+, NKX3.1+
NKX3.1+, CK20-, PSA+
PSA+, CK7+, AMACR+

Board review style answer #1

C. NKX3.1+, CK20-, PSA+. Ductal adenocarcinoma is CDX2-, CK7-, CK20-, PSA+, PSAP+, AMACR+ (77%), NKX3.1+.

Comment here

Reference: Ductal adenocarcinoma

Board review style question #2

You suspect prostatic ductal adenocarcinoma but your differential includes high grade prostatic intraepithelial neoplasia (HGPIN). Which of the following features favor ductal adenocarcinoma over HGPIN?

Comedonecrosis
Micropapillary formation
Stronger AMACR staining pattern
Very high PSA serum levels

Board review style answer #2

A. Comedonecrosis. Other answer choices: both can have AMACR positivity. Micropapillary pattern (and not true papillary fibrovascular cores) is more associated with HGPIN.

Comment here

Reference: Ductal adenocarcinoma

Foamy gland adenocarcinoma

Table of Contents

Definition / general

Rare variant with abundant foamy cytoplasm and minimal cytologic atypia (Am J Surg Pathol 2001;25:618, Am J Surg Pathol 1996;20:419, Am J Surg Pathol 1997;21:616)
Usually large volume, bilateral, extraprostatic extension
Foamy appearance due to intracytoplasmic vesicles, not lipid or neutral mucin
Aggressive behavior despite its benign histologic appearance

Microscopic (histologic) description

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
Usually Gleason score 3+3=6, occasionally Gleason 7 or higher (Am J Surg Pathol 2009;33:583)
Needle biopsies may have only a few atypical foamy glands (Ann Diagn Pathol 2008;12:349)

Microscopic (histologic) images

Contributed by @prietopath on Twitter

Contributed by @prietopath on Twitter (see original post here)">

Contributed by @prietopath on Twitter (see original post here)">

Foamy gland adenocarcinoma

Contributed by @prietopath on Twitter (see original post here)">

Foamy gland adenocarcinoma

CK34BE12

p63

AMACR

Positive stains

Colloidal iron
Alcian blue
P504S (Am J Surg Pathol 2003;27:772)

Negative stains

Mucicarmine
PAS
Lipid

Electron microscopy description

Intracytoplasmic vesicles
Polyribosomes

Differential diagnosis

Clear cell cribriform hyperplasia: basal cells readily identified
Cowper's glands: ducts often embedded in skeletal muscle
Gleason hypernephroid pattern 4: cytoplasm is optically clear but not foamy
Mucinous metaplasia: focal, cells positive for mucicarmine, PAS

Gleason grading

Table of Contents

Definition / general

In 1966, Dr. Donald Gleason devised grades of 1 - 5 based on glandular architecture and microscopic appearance using a 4x - 10x objective eyepiece that were shown to predict an outcome in prostate cancer (Cancer Chemother Rep 1966;50:125)

Terminology

Gleason score is the sum of the 2 most prevalent Gleason grades: primary and secondary, designated according to separate rules for biopsy and prostatectomy
If only 1 pattern is present, the primary and secondary patterns are given the same grade (ex: 3+3=6)
Systematic needle biopsy sets contain cores from different anatomically designated sites
- Gleason score should be assigned separately for each anatomically designated site
- Highest score may serve as a basis to determine treatment
- Additional reporting of a global (case level) Gleason score is optional and global scoring may show a marginal benefit over using highest score according to Trpkov et al. (Am J Surg Pathol 2020;44:e87, Am J Surg Pathol 2018;42:1522)
Any glands showing perineural invasion must be excluded in assigning Gleason grading because perineural invasion distorts gland morphology such that Gleason 3 glands resemble Gleason 4
Grading rules:
- Recommendations are based on 3 International Society of Urological Pathology (ISUP) grading consensus conferences:
  - 2005 (Am J Surg Pathol 2005;29:1228, J Urol 2010;183:433)
  - 2014 and 2019 (Nice, France) (Am J Surg Pathol 2020;44:e87)
  - Consensus of the GU Pathology Society that is nearly identical (Arch Pathol Lab Med 2021;145:461)
  - Minor variances are highlighted (Am J Surg Pathol 2021;45:1007)
- Some specimens may show a pattern that is the third most prevalent; this is called a minor pattern
In radical prostatectomy:
- Gleason score should be based on the primary and secondary patterns; if a minor pattern constitutes < 5%, the pattern should be mentioned as a minor (tertiary) pattern; any higher grade minor pattern ≥ 5% should be incorporated into the Gleason score and ISUP group as the secondary pattern (2019 consensus) (Eur Urol 2018;73:674)
- Ex: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+3=6 with minor (tertiary) 4
- Ex: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7
In needle biopsy:
- Most prevalent pattern is graded as primary and any amount of a worst pattern is graded as secondary
- Ex: Gleason pattern 3=96% and pattern 4=4%, Gleason score=3+4=7
- Ex: Gleason pattern 3=95% and pattern 4=5%, Gleason score=3+4=7
For multiparametric MRI targeted biopsies:
- Gleason scores should be given for the aggregate of cores from each individual biopsy site but not for each core (2019 consensus)
- This method of reporting is by research by Gordetsky et al. (Hum Pathol 2018;76:68)
- Benign histologic changes (chronic inflammation, acute inflammation, atrophy) should be reported in high suspicion lesions (PI-RADS 4 and 5) that are negative for cancer (Am J Surg Pathol 2020;44:e87)

Epidemiology

In 2014, the ISUP and World Health Organization adopted a simplified patient centric grading system composed of 5 prognostic grade groups as proposed in 2013 based on data and subsequently validated by biochemical recurrence hazard ratios on cases from 5 large academic centers (Am J Surg Pathol 2016;40:244, Prostate 2016;76:427, BJU Int 2013;111:753, Eur Urol 2016;69:428)
Grade groups are as follows:
1. Gleason score 3+3=6
2. Gleason score 3+4=7
3. Gleason score 4+3=7
4. Gleason score 8 (4+4=8, 3+5=8, 5+3=8)
5. Gleason score ≥ 9 (4+5=9, 5+4=9, 5+5=10)
Note that Gleason grades 1 and 2 are no longer recommended for use, since those patterns of cancer have an outcome no different from grade 3; moreover, pure grade 3 cancer almost never metastasizes and is reasonable to treat by active surveillance, which has sparked speculation about whether it should even be labeled cancer (Oncology (Williston Park) 2014;28:22, Curr Opin Urol 2015;25:238)
Divisions of Gleason score 3+4=7 from 4+3=7 and of 8 from 9-10, which had often been bundled together for prognostic and research purposes, are supported by studies showing significantly different outcomes (J Clin Oncol 2009;27:3459, World J Urol 2014;32:1067, J Urol 2015;194:91)
- Percentage of grade 4 or 5, when heterogeneous grades are present, should be mentioned in all specimens, although biopsy and prostatectomy have different rules for scoring (Am J Surg Pathol 2020;44:e87)
Grade group 4 is heterogeneous as it includes 4+4=8, 3+5=8 and 5+3=8, with recent data showing no or minimal long term outcome difference when present as the highest score in biopsy sampling; instead, the presence or absence of cribriform growth of cancer was a significant prognosticator (J Urol 2016;196:1076)
If tumor is minimal on biopsy (≤ 1 mm), Gleason score does not predict tumor stage and this can be noted on the report (ex: in a minimal focus with pattern 4, rather than doubling to 4+4=8, tumor can be designated on the report as too small for scoring) (Am J Surg Pathol 2000;24:1634)
Targeted biopsies detect a higher percentage of pattern 4 than systemic ones and are less likely to be upgraded on prostatectomy (Arch Pathol Lab Med 2019;143:86)

Diagrams / tables

Evolution of grading of special prostate cancer patterns
Histologic pattern	2005 consensus	2014 consensus	2019 consensus
Branched / undulating glands		Include as Gleason 3
Cribriform (under Gleason scheme: mostly 3, sometimes 4)	4 but can be 3 if much larger than benign gland, round and has loose cells	Always 4	Always 4 and presence or absence should be specified for 3+4, 4+3 or 4+4
Glomeruloid variant	No consensus, 3 versus 4	Always 4	--
Mucinous variant	No consensus, some favored 4	Depends on growth pattern regardless of mucin; could be 3, 4 or 5	--
Small cell (pure)	Do not grade	--	--
Intraductal, pure form	--	Do not grade	Do not grade
Intraductal, associated with invasive cancer	--	--	Include in estimating the percentage of grade 4, instead of keeping it separate
Ductal	4+4=8	--	--
Adenoid cystic / basal cell carcinoma	--	Do not grade	Do not grade

Microscopic (histologic) description

Discontinued Gleason grades 1 and 2
- It was agreed at the 2014 consensus conference that Gleason grades 1 and 2 should be discontinued because grade 1 or 2 cancer in needle biopsy does not predict better prostatectomy findings than grade 3 and these grades show marked interpathologist variability
- Gleason score of 1+1=2 was originally described as single, separate, closely packed, uniform round glands arranged in a circumscribed nodule with pushing borders; many of such cases would, with the benefit of today's immunostains, be referred to as atypical adenomatous hyperplasia (AAH or adenosis)
Gleason grade 3
- Single, separate glands
- May be either minute or large and cyst-like; glands have an irregularly separated, ragged, poorly defined edge, looser than a nodule and are infiltrative
- Key feature is retention of at least a wisp of stroma intervening between neighboring glands
- Tangentially cut glands may appear as if they are poorly formed but should not get graded as a 4 unless poorly formed and fused glands persist on several levels (J Urol 2011;186:465)
- Patterns of Gleason grade 3 prostatic adenocarcinoma:
  1. Most common pattern is well formed, relatively uniform glands infiltrating between benign glands; glands may be angulated or compressed, separated by > 1 gland diameter
  2. Small glands with pinpoint lumina, glands still separate
  3. Medium sized glands with undulating luminal contours or large glands or branching
  4. Large glands with a pseudoatrophic appearance
- Cribriform cancer no longer qualifies as Gleason 3, even if the glands are similar in size to normal glands (J Urol 2010;183:433)
Gleason grade 4
- Key finding is coalescent or fused glands with > 1 lumen and absence of intervening stroma between adjacent glands
- Patterns of Gleason grade 4 prostatic adenocarcinoma:
  1. Most common is small acinar structures, some with well formed lumina, fusing into cords or chains; may be undergraded as Gleason 3
  2. Cribriform (often merging with papillary, see Microscopic (histologic) images) by consensus has a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification 10x); there should be no intervening stroma or mucin separating individual or fused glandular structures (Ann Diagn Pathol 2021;52:151733, Am J Surg Pathol 2021;45:1118)
    - Nodule of a cribriform gland should be larger than normal prostate gland
    - Large nodules of cribriform Gleason 4 lack supporting stroma and tend to fragment
    - Thus, fragments of cribriform glands on needle biopsy represent Gleason 4
  3. Hypernephroid pattern, with nests of clear cells resembling renal cell carcinoma; small, hyperchromatic nuclei; fusion of acini into more solid sheets with the appearance of back to back glands without intervening stroma
  4. Intraductal carcinoma, when admixed with invasive carcinoma, should be counted as Gleason 4 and not counted separately for quantitation purposes (Am J Surg Pathol 2020;44:e87)
    - Its presence and significance should be mentioned
    - This emphasizes the adverse influence which has a unique phenotype of certain driver mutations as shown by Khani et al. (J Pathol 2019;249:79)
  5. Glomeruloid pattern (2014 consensus), a rare small cribriform variant, contains a tuft of cells that is mostly detached from its surrounding duct space except for a single point of attachment (see Microscopic (histologic) images)
- Research and 2014 consensus support grading all cribriform cancer as Gleason 4 because the presence and amount of cribriform cancer carries a distinctly adverse prognosis for recurrence and for death from cancer (Am J Surg Pathol 2013;37:1855, Am J Clin Pathol 2011;136:98, Mod Pathol 2015;28:457, Adv Anat Pathol 2018;25:31, Surg Pathol Clinics 2018;11:687)
  - Its presence or absence in Gleason 4 cancer should be commented on (J Urol 2016;196:1076)
- Note: patients with Gleason 8 at biopsy may have Gleason 7 at prostatectomy due to unsampled Gleason 3
- Note: basal cell markers are crucial in distinguishing cribriform high grade prostatic intraepithelial neoplasia, cribriform intraductal carcinoma and invasive cribriform carcinoma
- Rarely, pure intraductal carcinoma occurs in biopsy specimens
  - Rare in totally embedded prostatectomies as shown by Robinson (J Urol 2010;184:1328)
  - In its pure form it should not be graded (Am J Surg Pathol 2020;44:e87)
  - Diagnosis of intraductal carcinoma has modest reproducibility (Ann Diagn Pathol 2014;18:333, Virchows Arch 2019;474:525)
Gleason grade 5
- Grade 5 has 2 patterns:
  - Comedonecrosis: central necrosis with intraluminal necrotic cells or karyorrhexis within papillary / cribriform spaces; caution should be exercised since many such foci have demonstrable basal cells, making them intraductal carcinoma instead; thus, immunostaining is recommended if this would alter the grade group (Histopathology 2019;74:1081, Am J Surg Pathol 2018;42:1036)
  - Single cells, possibly forming cords, possibly with vacuoles (signet ring cells) but without glandular lumens; this pattern may mimic lymphocytes at low power
- Gleason 5 pattern has moderately good reproducibility, although certain patterns are more problematic (Am J Surg Pathol 2015;39:1242)
- Gleason 5 cancer is often missed or underdiagnosed on needle biopsy (Int J Clin Exp Pathol 2011;4:468, Urology 2012;79:178)
- Presence of Gleason grade 5 in prostate biopsy specimens predicts higher rates of metastasis and death compared with Gleason 4+4=8 cancer and even the smallest amounts of 5 predict outcome after prostatectomy (J Urol 2015;194:91, World J Urol 2014;32:1067, Eur Urol 2018;73:674)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Gleason grade 3

Gleason grade 4

Gleason grade 5

Virtual slides

Images hosted on other servers:

Gleason 4+3=7 versus 3+4=7

Gleason 4+3=7, cytokeratin 34 beta E12

Gleason 4+4=8, cribriform to solid

Sample pathology report

Prostate, left lateral, prostate needle core biopsy:
- Prostatic adenocarcinoma, Gleason score 4+3=7 (Grade group 3) involving 2 of 4 cores and 30% of the tissue (40%, 2 mm and 20%, 4 mm) (60% of the tumor is Gleason pattern 4, not cribriform)
Prostate, radical prostatectomy:
- Prostatic adenocarcinoma, Gleason score 3+3=6 with tertiary 4 (Grade group 1) (Gleason pattern 3=96% and pattern 4=4%) (see synoptic report)

Board review style question #1

Per the 2019 ISUP consensus conference, a prostate biopsy report for high grade cancer must include

A case level global Gleason score
A grade if the entire cancer focus consists of perineural invasion
Both a primary and secondary grade for tumor measuring less than 1 mm
For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present
Gleason grades 1 and 2, if present

Board review style answer #1

D. For Gleason grade 4, a mention of whether or not cribriform / large gland pattern is present. By consensus, the presence of cribriform carcinoma should be reported. Gleason grades 1 and 2 are discontinued. Grading is not recommended for perineural invasion because perineural invasion distorts gland morphology (grade 3 looks like 4). For tumor that is 1 mm or less, only 1 grade needs to be assigned, avoiding doubling Gleason 4 to 4+4=8, which would be misleading if cancer in other cores is mostly Gleason 3. A case level global score is optional.

Comment Here

Reference: Gleason grading

Board review style question #2

This field from a prostate biopsy shows

Entirely Gleason 3 cancer
Entirely Gleason 4 cancer
Entirely Gleason 5 cancer
Mixture of Gleason 3 and Gleason 4 cancer
Mixture of Gleason 4 and Gleason 5 cancer

Board review style answer #2

B. Entirely Gleason 4 cancer. The tumor consists entirely of ragged and fused glands. Discrete, round to angulated gland spaces, separated by stroma, diagnostic of Gleason 3 are not present. Single cells without glandular lumen formation, diagnostic of Gleason 5 are not present.

Comment Here

Reference: Gleason grading

Granulomatous lesions

Table of Contents

Definition / general

Uncommon entity of chronic inflammation with formation of granuloma(s) in the prostate (Prostate Int 2017;5:29)
First described by Tanner and McDonald in 1943 (cited in Urol Int 1988;43:97)

Essential features

Classification includes nonspecific granulomatous prostatitis, infectious granulomas, postsurgical granulomas, systemic granulomatous prostatitis, xanthogranulomatous and malakoplakia prostatitis (Hum Pathol 1984;15:818)
Most commonly granulomatous prostatitis presents as dilated ducts, acini and surrounding stroma with mixed inflammatory infiltrate, necrosis, palisading epithelioid histiocytes, foamy macrophages, neutrophils, lymphocytes and rare multinucleated giant cells (Figures 1 - 4, 7)

ICD coding

ICD-10:
- N41.4 - granulomatous prostatitis
- N41.1 - chronic prostatitis
ICD-11:
- GA91.0 - chronic prostatitis
- GA91.Y - other specified inflammatory and other diseases of prostate

Epidemiology

1 - 2% of prostate specimens (Prostate Int 2017;5:29)
Nonspecific granulomatous prostatitis: most common type (> 50% of cases)
Affect ages: from 18 to 86 years old, mean and median age of 62 years

Sites

Prostate and other organs in systemic diseases (Medicine (Baltimore) 2012;91:67)

Etiology

Nonspecific granulomatous prostatitis: a reaction to bacterial toxins, cellular debris and glandular secretions spilling into the stroma from destructive ducts or acini (J Urol 2012;187:2209)
Infectious prostatitis:
- Mycobacterial: Bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (Am J Surg Pathol 2012;36:418, Prostate 2018;78:1134)
- Bacterial: Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella, Enterobacter, Chlamydia trachomatis, Treponema, Actinomyces, Brucella species (Curr Opin Infect Dis 2016;29:86)
- Mycotic: Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Candida species (Prostate 2020;80:1006)
- Viral: cytomegalovirus (CMV), herpes zoster (HSV) (Transpl Infect Dis 2019;21:e12998)
- Parasitic: Trichomonas vaginalis, Schistosoma haematobium, Entamoeba histolytica, Ecchinococcus granulosus, Enterobius species (Emerg Infect Dis 2018;24:602, Prostate 2019;79:1316)
Postprocedural granuloma: a reaction to the alteration of epithelium and stroma caused by the trauma from previous surgical procedure (Am J Surg Pathol 1984;8:217)
Foreign body granuloma: introduction of foreign material or destruction of glands with prostatic secretions spilling into the stroma
Systemic: sarcoidosis, granulomatosis with polyangiitis (Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), allergic prostatitis, allergic (eosinophilic) prostatitis (J Clin Pathol 2007;60:325)
Xanthogranulomatous: possibly caused by destruction of ducts or acini (Am J Case Rep 2021;22:e932869)
Malakoplakia: bactericidal defect in macrophages (Case Rep Pathol 2014;2014:150972)

Clinical features

Symptoms include urinary frequency, urgency or hesitancy as well as burning micturition, dysuria, fever and chills (Prostate Int 2017;5:29)
May be asymptomatic
Hematuria
Firm and fixed nodule on digital rectal examination, urinary obstruction in severe cases
Serum PSA ranging from 0.5 ng/mL to 114 ng/mL (mean 12.7 ng/mL) (Arch Pathol Lab Med 1997;121:724)

Diagnosis

Chronic granulomatous inflammation by histopathological examination of the prostate (Hum Pathol 1984;15:818)
Xanthogranulomatous: presence of foamy macrophages by microscopic examination (Res Rep Urol 2016;8:165)
Malakoplakia: calcified and lamellated Michaelis-Gutman bodies (Case Rep Pathol 2014;2014:150972)
Infectious: identify microorganisms on special stains, positive microbiologic cultures
Postprocedural: previous history of prostatic biopsy, transurethral resection of prostate (TURP), introduction of foreign material, intravesical BCG immunotherapy (J Urol 2012;188:961)
Systemic: other organ systems involved by granulomas
Nonspecific granulomatous prostatitis: histopathological features (J Urol 2012;187:2209)

Laboratory

Microbiological studies including Gram stains and cultures for infectious prostatitis (Clin Microbiol Rev 1998;11:604)

Radiology description

Transrectal ultrasound of the prostate reveals hypoechoic lesions mimicking adenocarcinoma (Ultrason 2016;16:404)
Magnetic resonance imaging of the prostate reveals hypointense lesions mimicking adenocarcinoma (Radiology 2018;289:267)

Radiology images

Images hosted on other servers:

Prostatic hypoechoic lesion (ultrasound)

Prostatic hypointense lesion (MRI)

Case reports

21 year old man with weight loss, lethargy and dysuria (BMJ Case Rep 2018;2018:bcr2018225379)
55 year old man with prostate cancer underwent prostatectomy (J Clin Pathol 2007;60:325)
58 year old man with progressive increase in PSA level (Case Rep Oncol 2012;5:80)
59 year old man presented with progressive difficulty in urination (Indian J Pathol Microbiol 2010;53:152)
63 year old man presented with lower urinary tract symptoms (Urol Case Rep 2021;40:101887)
64 year old man presented with a nonmuscle invasive bladder tumor (Mol Clin Oncol 2015;3:249)

Treatment

Warm sitz baths, fluids and antibiotics (if there is a urinary tract infection) for nonspecific granulomatous prostatitis
Antibiotics for infectious prostatitis (Prostate 2020;80:1006)
Prednisone for granulomatosis with polyangiitis, prednisone plus either rituximab or cyclophosphamide for severe disease (N Engl J Med 2010;363:221)
Simple prostatectomy or transurethral resection (TURP) to relieve obstructive symptoms

Clinical images

Images hosted on other servers:

Xanthogranulomatous
prostatitis with
abscess

Gross description

Nonspecific appearance; may be hard and nodular

Microscopic (histologic) description

Nonspecific granulomatous prostatitis: dilated ducts and acini filled with histiocytes, foamy macrophages, neutrophils, lymphocytes and rare multinucleated giant cells (Figures 1 - 3) (Hum Pathol 1984;15:818)
- Surrounded stroma consists of heavy mixed inflammatory infiltrate composed of epithelioid histiocytes, neutrophils, lymphocytes, plasma cells, rare eosinophils and occasional multinucleated giant cells (Figure 4)
Foreign body granuloma: foci of destructive acini filled with multinucleated (foreign body type) giant cells with fusion forms, some lymphocytes and histiocytes (Figures 5 - 6)
Infectious granuloma: multiple granulomas with or without necrosis, positive staining with Gram, AFB, PAS or GMS special stains
Postsurgical granuloma: multiple granulomas with or without caseating necrosis, palisading histiocytes, lymphocytes and Langhans giant cells (Figure 7)
Systemic granulomatous disease: multiple granulomas composed of Langhans giant cells, epithelioid histiocytes and lymphocytes (Figures 8 - 11), mainly eosinophils in allergic (eosinophilic) prostatitis

Microscopic (histologic) images

Contributed by Y. Albert Yeh, M.D., Ph.D.

Dilated ducts with inflammation

Histiocytes and giant cells

Expansile inflammatory areas

Foreign body giant cells

BCG related giant cells

Sarcoid related lesions

Sarcoid related giant cells

Sarcoid related Langhans cells

Contributed by Ximing J. Yang, M.D., Ph.D.

Multiple granulomas

Langhans giant cells

BCG induced granuloma

Foreign body giant cell granuloma

Indeterminate granuloma

Positive stains

CD68 and CD163 highlight epithelioid and foamy histiocytes (Diagn Pathol 2012;7:12)
Gram stain for bacterial prostatitis
AFB stain for mycobacterial prostatitis
Warthin-Starry stain, Steiner and Steiner stain and immunohistochemical stain for spirochetes
PAS and GMS stains for mycotic prostatitis
Immunohistochemical stains for CMV and HSV prostatitis
Von Kossa stain, Prussian blue (iron) stain for malakoplakia (Histochem Cell Biol 2021;156:523)

Negative stains

Sample pathology report

Prostate, needle core biopsy:
- Granulomatous inflammation consistent with nonspecific granulomatous prostatitis (see comment)
- Comment: The prostate biopsy shows prostatic tissue with dilated destructive ducts filled with epithelioid histiocytes, foamy macrophages, neutrophils and lymphocytes. Some areas in the stroma consist of heavily mixed inflammatory infiltrate composed of histiocytes, neutrophils, lymphocytes and plasma cells. Occasional multinucleated (Langhans type) giant cells are seen. There is no caseating necrosis. AFB special stain is negative for mycobacteria. PAS and GMS stains are negative for fungal organisms. With no known clinical history of systemic granulomatous disease, this lesion is consistent with nonspecific granulomatous prostatitis

Differential diagnosis

Adenocarcinoma associated with granulomas:
- Proliferation of malignant glands, epithelial cells positive for NKX3.1, AMACR and PSA immunomarkers
- Negative for CD68 or CD163 (Ann Diagn Pathol 2004;8:242)
Lymphoma associated with granulomas:
- Monoclonal staining pattern of B lymphocytes (Int J Surg Pathol 2012;20:610)
Malakoplakia:
- Calcified and lamellated Michaelis-Gutman bodies stained with von Kossa and Prussian blue (iron) stains
- CD68 and CD163 highlights histiocytes (Ann Diagn Pathol 2016;22:33)
Xanthogranulomatous:
- Presence of foamy macrophages (Urol Case Rep 2021;40:101887)
Infectious:
- Presence of microorganisms on Gram, AFB, PAS or GMS stains, presence of parasites and eggs in schistosomiasis (Prostate 2019;79:1316)
Postprocedural and foreign body giant cell:
- Previous history of prostatic biopsy, transurethral resection of prostate (TURP), introduction of foreign material, intravesical BCG immunotherapy (J Urol 2012;188:961)
Systemic:
- Other organ systems involved by granulomas
Nonspecific granulomatous prostatitis:
- Exclude any specific cause of inflammation (Arch Pathol Lab Med 1997;121:724)

Additional references

J Urol 2014;191:215, Anal Quant Cytopathol Histpathol 2013;35:178, Indian J Pathol Microbiol 2020;63:S34, Medicine (Baltimore) 2020;99:e19391, J Clin Immunol 2020;40:1204

Board review style question #1

Which of the following is the most common type of granulomatous lesion of the prostate?

Infectious granulomas
Nonspecific granulomatous prostatitis
Postsurgical granulomas
Systemic granulomatous prostatitis

Board review style answer #1

B. Nonspecific granulomatous prostatitis

Comment Here

Reference: Granulomatous lesions

Board review style question #2

A 60 year old man presented with dysuria, fever, chills and progressive increase in PSA level. Prostatic biopsy is performed. Special stains including Gram, AFB, PAS and GMS are negative for microorganisms. Von Kossa stain and Prussian blue stain are negative. A photomicrograph is shown above. What is the diagnosis?

Adenocarcinoma associated with granuloma
Malakoplakia with granuloma
Nonspecific granulomatous prostatitis
Prostatic adenocarcinoma, giant cell type

Board review style answer #2

C. Nonspecific granulomatous prostatitis

Comment Here

Reference: Granulomatous lesions

Grossing & features to report

Table of Contents

Grossing | Gross images | Features to report | Additional references

Grossing

Needle core biopsies

Inking of all prostate core biopsies with colored inks, in sequential order, helps maintain specimen identity (Arch Pathol Lab Med 2009;133:295)

Radical prostatectomy

Totally embed or systemic sampling (Mod Pathol 2011;24:6, International Journal of Breast Cancer 2012:2012, Article ID 932784)

Systemic sampling (12 - 13 blocks)

Ink surface with 2 colors to designate left versus right
Amputate apex and serial section parallel to urethra
For base, thin shave or amputate and serial section parallel to urethra
Submit base of seminal vesicles, margins of right and left vas deferens
Serial section prostate perpendicular to urethra, submit all gross tumor (look in peripheral zone, posterior or posterior-lateral area for asymmetry in size, color, density between left and right sides)
Special device may assist in generating sections of uniform thickness (J Magn Reson Imaging 2010;32:992)

Transurethral resection biopsies (prostate chips)

If specimen 12 g or less, submit all
If specimen more than 12g, submit at least 12 g
If unsuspected carcinoma found that involves 5% or less of tissue examined, submit remaining tissue (may increase stage from T1a to T1b)
Reference: Arch Pathol Lab Med 2006;130:936

Gross images

Images hosted on other servers:

Device to generate uniform thickness of sections in radical prostatectomy

Whole mount sectioning

Features to report

Prostatectomies

Structures included in specimen (prostate [complete or not], seminal vesicles, vas deferens, bladder neck)
Weight, size in 3 dimensions
Histologic type and location of tumor (if any)
Gleason pattern / grade and score
% of prostate involved by tumor (need not give volume but an indication of minute vs. voluminous)
Presence of perineural invasion (diameter may be prognostic factor (Hum Pathol 2001;32:828)
Presence of angiolymphatic invasion (Am J Surg Pathol 1996;20:1351, J Urol 2005;174:2181)
Presence of extraprostatic tissue invasion
Presence of high grade PIN
Margins
Lymph nodes (# involved, # sampled) and diameter of largest metastasis (Am J Surg Pathol 1998;22:1491)
Acute or chronic inflammation (often doesn’t correlate with clinical prostatitis)
Granulomatous prostatitis (may elevate PSA, produce suspicious feeling gland)
Note: extranodal tumor extension not related to survival (Mod Pathol 2000;13:113)

Biopsies (core or transurethral prostate resection)

Histologic type
Gleason primary and secondary grades and total score
# cores involved, # cores total
% of prostatic tissue involved by tumor or total linear mm of carcinoma / total linear mm of tissue
Presence of perineural, angiolymphatic, periprostatic fat invasion, seminal vesicle invasion, extraprostatic tissue invasion
Presence of high grade PIN (if no carcinoma, report # of cores involved and pattern of high grade PIN)
Therapy related changes

Features to report by organization

Additional references

Arch Pathol Lab Med 2009;133:1568, Hum Pathol 2007;38:1305

HGPIN with adjacent atypical glands

Table of Contents

Definition / general

High grade prostatic intraepithelial neoplasia (HGPIN) with small atypical glands present in adjacent stroma (Epstein: Biopsy Interpretation of the Prostate, 6th Edition, 2021)

Essential features

Single or a few small atypical glands located within 0.01 - 0.4 mm of adjacent HGPIN (Hum Pathol 2001;32:389)
Adjacent atypical glands stained positive (focal or patchy) on p63 or CK903 immunohistochemical stains

Terminology

HGPIN with adjacent small atypical glands (Hum Pathol 2001;32:389)
HGPIN with adjacent small atypical glands suspicious for infiltrating carcinoma (PINATYP) (Am J Surg Pathol 2006;30:1184)
HGPIN with adjacent atypia (Urology 2001;57:296)
HGPIN and ASAP (atypical small acinar proliferation) (BJU Int 2007;99:780)

ICD coding

ICD-O: 8148/2 - glandular intraepithelial neoplasia, grade III
ICD-10:
- N42.31 - prostatic intraepithelial neoplasia
- D07.5 - grade III, severe dysplasia
ICD-11: XH5C49 - prostatic intraepithelial neoplasia, grade III

Epidemiology

More commonly arises in the peripheral zone
Incidence of HGPIN with adjacent atypical glands (2.5%) is lower than that of HGPIN alone (4.3%) (Urology 2001;57:296)

Sites

More commonly arises in the peripheral zone of the prostate (Urology 2001;57:296)

Pathophysiology

Hypothesis of proliferative inflammatory atrophy as a precursor to HGPIN and prostate cancer (N Engl J Med 2003;349:366)
Focal epithelial atrophy occurs in prostatic glands
Chronic inflammatory cells infiltrate immediately adjacent to the areas of glandular atrophy
HGPIN and localized prostate carcinoma develops as a result of DNA methylation and inactivation of DNA repair genes including GSTP1 and MGMT
Reduced expression of PTEN, NKX3.1 and p27 is involved in prostate cancer progression (Nat Rev Urol 2018;15:222)

Etiology

Gene mutation
- Germline mutations in familial prostate cancer: ELA2 (HPC2), MSR, RNASEL
- Somatic mutations: TP53, PTEN, AR, ZFHX3, RB1, APC, MLL2, OR5L1, CDK12, ATM, FOXA1, EZH2 (Nature 2012;487;239, Genes Dev 2018;32:1105)
Gene fusion
- TMPRSS2::ERG gene fusion results in ETS overexpression (Cold Spring Harb Perspect Med 2019;9:a034942)
- 19% in HGPIN with cancer foci, 48.5% in localized prostate adenocarcinoma
WNT signaling and beta catenin
- Increased level of CTNNB1 detected by immunohistochemical staining in prostate cancer
DNA hypermethylation (Biochim Biophys Acta 2004;1704:87)
- Invasion: GSTP1, MGMT, RASSF1A, RARβ2, CDH1 (E-cadherin), CAV1 (caveolin-1), LAMA3, LAMB3, LAMC2
- Metastasis: APC, CDH1 (E-cadherin), CD44
Histone modification: MLL2 mutation
MicroRNA upregulation: overexpression of DICER, a key gene involved in biosynthesis of miRNA

Diagrams / tables

Images hosted on other servers:

Prostate cancer pathogenesis

Clinical features

May be asymptomatic, present with dysuria or hematuria (JAMA 2017;317:2532)

Diagnosis

May present with dysuria or hematuria if there is a coexisting prostatic nodule or urinary tract infection
Solid, firm nodule on digital rectal examination (DRE) may be detected
A few atypical glands immediately adjacent to HGPIN is present on microscopic examination of the prostatic samples obtained from biopsy, TURP or prostatectomy (Urology 2001;57:296, JAMA 2017;317:2532)

Laboratory

Elevated PSA (ng/mL): HGPIN (mean 6.71), ASAP (mean 7.2), HGPIN and ASAP (mean 8.0) (Am J Surg Pathol 2005;29:1201)

Prognostic factors

Higher cancer detection rates: HGPIN alone (23%), ASAP (37%), HGPIN and ASAP (33%) (Am J Surg Pathol 2005;29:1201)
HGPIN or ASAP: 47% risk for cancer on repeat biopsy (J Urol 2001;166:866)
Higher incidence of cancer on repeat biopsy: HGPIN alone (14%), HGPIN and ASAP (75%) (Urology 2001;57:296)

Treatment

No definitive treatment for ASAP and HGPIN
For ASAP and multifocal (> 2 sites) HGPIN, rebiopsy within 6 months; includes sampling more from the previous affected and adjacent areas
For focal HGPIN, close follow up with PSA and DRE within 6 - 24 months; consider other testing, including free PSA, 4Kscore, PHI, PCA3 or ConfirmMDx (J Natl Compr Canc Netw 2016;14:509)

Microscopic (histologic) description

Single or a few small atypical glands located within 0.01 - 0.4 mm of adjacent HGPIN (Hum Pathol 2001;32:389)
The lining epithelial cells of HGPIN show high grade nuclei with nuclear enlargement, hyperchromasia and prominent nucleoli
A layer of horizontally lined basal cells presents in the HGPIN
Epithelial cells of the atypical glands show nuclear enlargement, prominent nucleoli and amphophilic cytoplasm, mimicking the cytologic features of HGPIN

Microscopic (histologic) images

Contributed by Y. Albert Yeh, M.D., Ph.D. and Nicholas P. Reder, M.D., M.P.H.

HGPIN with atypical glands

Atypical gland with basal cells

Single atypical gland

2 atypical glands

Atypical gland in 2 HGPINs

Atypical cytologic features

Small atypical glands adjacent to larger HGPIN glands

PIN4

Positive stains

HGPIN (Epstein: Biopsy Interpretation of the Prostate, 6th Edition, 2021)
- p63 (continuous or patchy)
- High molecular weight cytokeratin CK903 (continuous or patchy)
- AMACR
Adjacent atypical glands (Epstein: Biopsy Interpretation of the Prostate, 6th Edition, 2021)
- p63 (focal or patchy)
- High molecular weight cytokeratin CK903 (focal or patchy)
- AMACR

Negative stains

Adjacent atypical glands
- Very few in total, could be negative for p63 or high molecular weight cytokeratin CK903 (Epstein: Biopsy Interpretation of the Prostate, 6th Edition, 2021)

Sample pathology report

Prostate, needle biopsy:
- Atypical small acinar proliferation (ASAP)
- High grade prostatic intraepithelial neoplasia (see comment)
- Comment: The prostatic needle biopsy shows prostatic tissue with high grade intraepithelial neoplasia (HGPIN). Immediately adjacent to the HGPIN are 3 well formed small glands composed of cells with enlarged nuclei and prominent nucleoli, mimicking the cellular features of HGPIN. Immunohistochemical stains p63 and CK903 show focal positive staining in the small atypical glands and continuous positive staining in HGPIN. AMACR immunomarker staining is positive in both lesions. These features are consistent with HGPIN with adjacent atypical glands (HGPIN and ASAP). It has been shown that the cancer detection rate of HGPIN and ASAP is higher than that of HGPIN alone. Repeat biopsy within 6 months is advised (Am J Surg Pathol 2005;29:1201).

Differential diagnosis

Acinar adenocarcinoma (Hum Pathol 2001;32:389):
- More than a few (many) or numerous small malignant glands infiltrating the stroma
- Located at either > or < 0.4 mm from HGPIN
- Negative staining of immunomarkers for basal cells (p63, CK5/6 or CK903)
HGPIN with tangential sectioning or outpouching of glands (BJU Int 2007;99:780):
- Immediately adjacent to HGPIN
- Cellular features and immunostaining pattern mimicking HGPIN (continuous or patchy staining pattern with basal cell immunomarkers)
- May have connection with HGPIN on deeper levels of tissue sectioning

Additional references

Urology 2000;55:553, Asian J Urol 2022;9:12, Korean J Urol 2011;52:736, Prostate Cancer 2015;2015:810159, Res Rep Urol 2017;9:187, Urology 2017;110:161, Curr Urol 2017;10:199

Board review style question #1

A 68 year old man presented with dysuria. A firm nodule was detected on digital rectal examination. PSA level was 6.4 ng/mL. Prostatic needle biopsy followed by microscopic examination was performed. The photomicrograph is shown in the image above. Immunohistochemical stains are performed. The large and small glands show patchy positive staining with p63 and CK903. AMACR immunomarker is positive in the large and small glands. What is the best interpretation?

High grade prostatic intraepithelial neoplasia
High grade prostatic intraepithelial neoplasia with atypical glands
Prostatic adenocarcinoma, Gleason 3+3=6
Prostatic intraductal adenocarcinoma

Board review style answer #1

B. High grade prostatic intraepithelial neoplasia with atypical glands

Comment Here

Reference: HGPIN with adjacent atypical glands

Board review style question #2

What is the best clinical management of high grade prostatic intraepithelial neoplasia with adjacent atypical glands?

Close follow up with PSA and digital rectal examination within 6 months
Close follow up with PSA only within 6 months
Rebiopsy including increased sampling from previous affected and adjacent areas within 6 months
Rebiopsy within 6 to 12 months

Board review style answer #2

C. Rebiopsy including increased sampling from previous affected and adjacent areas within 6 months

Comment Here

Reference: HGPIN with adjacent atypical glands

High grade prostatic intraepithelial neoplasia (HGPIN)

Table of Contents

Definition / general

Putative precursor of prostatic adenocarcinoma

Essential features

Nucleoli visible at 200x magnification (Am J Surg Pathol 1995;19:873)
Surrogate marker for missed cancer in negative prostate biopsies; less useful in contemporary practice as lower incidence of unsampled prostate cancer with extended biopsy protocols
No clinical utility in radical prostatectomies and biopsies containing foci suspicious or diagnostic of prostate cancer
Would not account for raised serum PSA or radiological abnormality

Terminology

Formerly known as severe dysplasia, PIN 2 / PIN 3 and carcinoma in situ
PIN = high grade prostatic intraepithelial neoplasia (HGPIN); low grade PIN is not reported due to wide interobserver variability (Am J Surg Pathol 1995;19:873)

ICD coding

ICD-O: 8148/2 - glandular intraepithelial neoplasia, high grade
ICD-10: D07.5 - carcinoma in situ of prostate
ICD-11: 2E67.5 - carcinoma in situ of prostate

Epidemiology

Needle biopsy prevalence: 0 - 25%, mean 7.7% (Korean J Urol 2012;53:297)
Cystoprostatectomy prevalence: 11 - 34% (BJU Int 2007;99:780, Urology 2007;70:1100, Hum Pathol 2016;55:117)
Earlier age and more diffuse in African Americans, lower incidence in Asians (Pathol Res Pract 1995;191:838)

Sites

Prostate gland

Clinical features

Would not account for elevated serum PSA or abnormal digital examination findings or radiological abnormality

Diagnosis

Diagnosis is made on histologic examination of biopsied prostate tissue, typically from a needle core biopsy

Radiology description

No radiological abnormality

Prognostic factors

Contemporary value of HGPIN as predictor of missed cancer is contentious
- Risk of finding cancer on rebiopsy following unifocal HGPIN diagnosis is similar to benign diagnosis (Pathology 2010;42:325, J Urol 2009;182:485)
- Risk of finding cancer on rebiopsy following multifocal HGPIN (2 or more cores) diagnosis is substantially higher at 30 - 40% (Pathology 2010;42:325, J Urol 2009;182:485, Urol Oncol 2020;S1078-1439:30488)
- Cancers associated with HGPIN diagnosis on initial biopsy are more likely to be low grade and organ confined as compared to cancers diagnosed in the first biopsy without preexisting HGPIN (Can J Urol 2015;22:8056, Am J Surg Pathol 2011;35:1165)
Prostate cancer detected at rebiopsy following diagnosis of HGPIN generally low grade and organ confined (Can J Urol 2015;22:8056, J Urol 2009;181:1069, Am J Surg Pathol 2011;35:1165)
- Rebiopsy Gleason ≥ 7 rate following diagnosis of HGPIN in contemporary practice similar to that following an initial benign biopsy (17% versus 14%) (Hum Pathol 2018;79:116)

Case reports

60 year old man with foamy gland HGPIN (Am J Surg Pathol 2000;24:140)
69 year old man with foamy gland HGPIN (Human Pathology Case Reports 2017;10:32)

Treatment

Follow up PSA
Repeat biopsy if PSA remains elevated
NNCCN guidelines (2021) recommendations for isolated HGPIN:
- Focal (HGPIN in 1 site): follow-up as following benign biopsy
- Multifocal (HGPIN in > 2 sites): If extended biopsies performed initially then rebiopsy only those at high risk of more aggressive prostate cancer (NNCCN.org: National Comprehensive Cancer Network Clinical Guidelines in Oncology - Prostate Cancer Early Detection, 2021 [Accessed 19 February 2021])
No therapy is needed for HGPIN as an isolated finding in needle biopsy (Mod Pathol 2018;31:S71)

Microscopic (histologic) description

Diagnostic feature: prominent nucleoli visible at 200x or lower magnification
Medium to large ducts and acini with enlarged hyperchromatic nuclei and amphophilic cytoplasm
Common architectural patterns:
- Flat: 1 - 2 layers of simple epithelium
- Tufted: stratified epithelium with small luminal protrusions
- Micropapillary: filliform structures lacking true fibrovascular core
- Cribriform: epithelial proliferation with punched out spaces
  - In contemporary practice, most experts report such proliferations as atypical intraductal proliferation suspicious for intraductal carcinoma of the prostate (IDC-P), particularly on needle biopsy (Arch Pathol Lab Med 2020 Jun 26 [Epub ahead of print])
Less common patterns: signet ring cell, foamy gland, mucinous, inverted and small cell neuroendocrine (Am J Surg Pathol 1997;21:1215, Rev Urol 2004;6:171, Oncol Lett 2015;10:2395)

Microscopic (histologic) images

Contributed by Murali Varma, M.D.

Flat HGPIN

Tufted HGPIN

Micropapillary and flat HGPIN

Micropapillary HGPIN

Inverted HGPIN

p63

CK5/6

AMACR

Positive stains

Basal cells: high molecular weight cytokeratin (34 beta E12 / CK903), p63; may be discontinuous
Acinar cells: P504S / AMACR
PTEN: normal retained pattern (Am J Surg Pathol 2015;39:169)

Negative stains

ERG could be positive in rare cases of isolated HGPIN (see ERG, Am J Surg Pathol 2011;35:608)

Molecular / cytogenetics description

Deletions of 8p most common allelic loss; telomere shortening activity similar to prostatic adenocarcinoma
Other chromosomal abnormalities in both HGPIN and carcinoma include gains of chromosomes 7, 8, 10 and 12 (Am J Surg Pathol 1995;19:506, Rev Urol 2004;6:171)
TMPRSS - ERG fusion (Science 2005;310:644, Clin Cancer Res 2008;14:3380)
- Found in approximately 50% of prostate carcinoma
- Present in approximately 20% of HGPIN admixed with adenocarcinoma
- Less common in HGPIN not associated with invasive adenocarcinoma
Hypermethylation GSPT1, the most common epigenetic change in prostate carcinoma, is also seen in HGPIN
Other genetic features of HGPIN
- Aneuploidy (present in approximately 50%)
- Increased expression of CDKN2A, TP53, tumor suppressor genes involved in cell cycle regulation and MYC oncogene amplification (Clin Cancer Res 2001;7:544, Mod Pathol 1997;10:1113)

Sample pathology report

Prostate, left lateral mid, needle core biopsy:
- High grade prostatic intraepithelial neoplasia

Differential diagnosis

Prostatic central zone glands:
- Increased architectural complexity (cribriform / micropapillary)
- Cytologically bland with inconspicuous nucleoli
- Central / basal location
Ejaculatory duct epithelium / seminal vesicle epithelium:
- May show cribriform architecture
- Increased nuclear pleomorphism and cytoplasmic golden lipofuscin pigment (degenerative phenomena)
- Usually immunonegative for prostatic markers
Urothelial metaplasia:
- No architectural complexity
- No prominent nucleoli
Inflammatory reactive atypia:
- No architectural complexity
- Inflammatory cells including polymorphs
- Reactive nuclear features
Radiation atypia:
- No architectural complexity
- Nuclear pleomorphism but no macronucleoli
- Basal cells prominent
Clear cell cribriform hyperplasia:
- Clear cytoplasm
- Inconspicuous nucleoli and lacks nucleomegaly
Basal cell hyperplasia:
- Proliferation of peripheral basal cells showing prominent nucleoli
- Central secretory cells lack nucleoli
- Basal cell markers demonstrate basal cell predominance
PIN-like carcinoma:
- Architecture resembling HGPIN
- Greater crowding / dilated glands lined by columnar pseudostratified cells
- May show cystically dilated glands lined by ductal type epithelium
- Immunonegative for basal cell markers (Am J Surg Pathol 2018;42:1693)
Pattern 4 cribriform acinar adenocarcinoma:
- Confluent, increased architectural complexity
- Immunonegative for basal cell markers
Ductal carcinoma:
- Peri-urethral or peripheral prostatic ductal location
- Expansive, complex cribriform / papillary / solid architecture
- Tall columnar cells, oval pleomorphic nuclei
- Immunonegative for basal cell markers (Med Princ Pract 2010;19:82)
Intraductal carcinoma:
- Solid or dense cribriform architecture
- Loose cribriform or micropapillary architecture with either marked nuclear atypia or comedonecrosis (Virchows Arch 2019;474:525, Am J Surg Pathol 2016;40:e67)
- Markedly distended glands (Mod Pathol 2018;31:S71, Mod Pathol 2006;19:1528)
HGPIN with adjacent atypical small glands (PINATYP):
- Unresolved differential of tangential sectioning / budding of HGPIN and invasive adenocarcinoma (Hum Pathol 2001;32:389)
- AMACR immunohistochemistry unhelpful: generally positive in both scenarios (Histopathology 2005;47:1)

Board review style question #1

High grade prostatic intraepithelial neoplasia (HGPIN)

Which of the following is true about this prostatic lesion?

Clinically identifiable as a palpable mass lesion on digital rectal examination
More common in Asians
Not associated with raised serum PSA
Nucleolar prominence at magnification 400x is a diagnostic feature
PIRADS 5 on MRI

Board review style answer #1

C. It is not associated with raised serum PSA. This is high grade prostatic intraepithelial neoplasia.

Comment Here

Reference: High grade prostatic intraepithelial neoplasia (HGPIN)

Board review style question #2

Which of the following is the common immunoprofile of high grade PIN?

HMWCK-, p63-, AMACR-
HMWCK-, p63-, AMACR+
HMWCK-, p63+, AMACR-
HMWCK+, p63+, AMACR-
HMWCK+, p63+, AMACR+

Board review style answer #2

E. HMWCK+, p63+, AMACR+

Comment Here

Reference: High grade prostatic intraepithelial neoplasia (HGPIN)

IHC overview

Table of Contents

Definition / general

Diagnostic biomarker study of prostate tissue is one of the most common applications of immunohistochemistry in surgical pathology, especially for prostate needle biopsies (Mod Pathol 2018;31:S12)
In an appropriate histomorphologic setting, immunohistochemistry is very helpful in distinguishing between prostatic adenocarcinoma and its benign mimickers (Adv Anat Pathol 2018;25:387)

Essential features

Most used immunohistochemical stains include basal cell markers and prostate specific markers (Mod Pathol 2018;31:S12)
Hallmark of prostatic adenocarcinoma is the loss of basal cells; however, not all prostate glands without basal cells are carcinoma (Mod Pathol 2018;31:S12)

Terminology

Triple antibody cocktail (also called PIN4 or PIN cocktail): mixture of p63, 34 beta E12 and AMACR / P504s

Pathophysiology

Survival and growth of normal and prostate cancer cells relying on the constitutive expression of AR and its signaling (Front Oncol 2019;9:858)
Prostate cancer often with increased fatty acid metabolites by overexpression of AMACR (J Cancer Res Ther 2017;13:21)
Overexpression of ERG from TMP-RSS2:ERG gene rearrangement playing an important role in the initiation of almost half of prostate cancer (Oncogene 2016;35:403)

Uses by pathologists

Diagnosis of primary invasive prostatic adenocarcinoma, mainly in the following settings:
- Small focus of atypical glands / atypical small acinar proliferation
- Atypical hyperplastic appearing glands
- Postradiation prostatic adenocarcinoma with treatment effect
- Differentiation of invasive cribriform carcinoma from intraductal carcinoma / atypical intraductal proliferation / atypical cribriform lesion
Confirming prostatic origin of disseminated / metastatic carcinoma (Arch Pathol Lab Med 2020;144:290, Mod Pathol 2018;31:S12)
Markers for primary prostatic neoplasia (Arch Pathol Lab Med 2020;144:290, Mod Pathol 2018;31:S12, Adv Anat Pathol 2018;25:387, Am J Clin Pathol 2020;153:407):
- Triple antibody cocktail (PIN cocktail): most widely used
- ERG: highly specific (in the setting of absence of basal cells) but not sensitive for prostatic adenocarcinoma
- Acinar prostatic adenocarcinoma:
  - Positive staining:
    - AMACR / p504s (often, ~80%)
  - Negative staining:
    - p63, 34 beta E12 (no basal cells)
- Ductal adenocarcinoma
  - Positive staining:
    - AMACR / p504s (often, ~80%)
  - Negative staining:
    - p63, 34 beta E12 (no basal cells)
  - Can occasionally be p63 and 34 beta E12 positive (focal / sparse basal cells)
- Intraductal carcinoma / atypical intraductal proliferation / atypical cribriform lesion / carcinoma in situ
  - Positive staining:
    - AMACR / p504s (often, ~80%)
    - p63, 34 beta E12 (continuous or discontinuous layer of basal cells)
Markers for prostatic origin of disseminated / metastatic carcinoma
- Positive staining:
  - NKX3.1, AR: highly sensitive and specific
  - ERG, PSA, prostein: highly specific, moderately sensitive
  - PSMA: moderately specific and sensitive
  - Others:
    - CK7, CK20:
      - Negative in low grade prostatic carcinoma
      - Negative or focally positive in high grade prostatic carcinoma
    - CDX2 can be positive
- Negative staining:
  - PAX8, PAX2, TTF1, GATA3, 34 beta E12, p63, p40

Microscopic (histologic) description

Nuclear markers: AR (androgen receptor), NKX3.1, p63, ERG
Cytoplasmic markers: AMACR / p504s (alpha methylacyl CoA racemase), PSA, prostein / p501s
Cytoplasmic and membrane markers: 34 beta E12 (also called cytokeratin 903), PSMA (prostate specific membrane antigen)

Microscopic (histologic) images

Contributed by Guang-Qian Xiao, M.D., Ph.D.

Adenosis

Prostatic adenocarcinoma

Atypical cribriform lesion

Prostatic adenocarcinoma

Partial atrophy

Carcinoma with radiation effect

Positive staining - normal

Prostate:
- Basal cells: p63, 34 beta E12
- Luminal cells: PSA, prostein, PSMA, NKX3.1, AR
- Neuroendocrine cells: chromogranin, synaptophysin, CD56
Seminal vesicles:
- AR, PAX8, p63 and 34 beta E12
References: Mod Pathol 2018;31:S12, Adv Anat Pathol 2018;25:387

Sample pathology report

For primary atypical prostatic glands: IHCs reveal atypical prostatic glands negative for p63 and 34 beta E12 (absence of basal cells) and positive for AMACR / p504s, supporting the diagnosis of prostatic adenocarcinoma
For disseminated tumor: IHCs reveal tumor cells positive for NKX3.1, PSA and AR, supporting prostatic origin

Differential diagnosis

Benign immunohistochemical mimickers of prostatic carcinoma - small acini without or patchy for basal cells (p63 and 34 beta E12 negative) (Arch Pathol Lab Med 2020;144:290, Mod Pathol 2018;31:S12, Adv Anat Pathol 2018;25:387):
- Adenosis
- Partial atrophy
- AMACR can be weakly positive
- ERG if positive supports prostatic adenocarcinoma
Prostate cancer, when involving bladder, not infrequently misdiagnosed as urothelial carcinoma if immunohistochemistry not performed (Arch Pathol Lab Med 2020;144:290, Adv Anat Pathol 2018;25:387):
- Positive for prostatic carcinoma: NKX3.1, AR, ERG, PSA, PSMA, prostein
- Positive for urothelial carcinoma: GATA3, p63, CK5/6, 34 beta E12

Board review style question #1

Which is the most sensitive marker for prostate origin?

ERG
NKX3.1
P504s / AMACR
PSA

Board review style answer #1

B. NKX3.1

Comment Here

Reference: Prostate gland & seminal vesicles - Immunohistochemistry

Board review style question #2

Which of the following lesions in the prostate can present with no basal cell layer?

High grade PIN
Intraductal carcinoma
Partial atrophy
Atypical cribriform lesion

Board review style answer #2

C. Partial atrophy

Comment Here

Reference: Prostate gland & seminal vesicles - Immunohistochemistry

Intraductal carcinoma

Table of Contents

Definition / general

New addition to the most recent WHO classification of urinary tumors and male genital organs (Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016)
Intraacinar or intraductal neoplastic epithelial proliferation that has some features of high grade prostatic intraepithelial neoplasia but exhibits much greater architectural or cytological atypia, typically associated with high grade, high pT prostate carcinoma (Eur Urol 2016;70:106)

Essential features

High degree of cytological atypia, commonly with necrosis that fills prostatic ducts and acini
Usually associated with high grade and high pT invasive carcinoma
Should not be included in Gleason pattern scoring
Appropriate to use immunohistochemistry to demonstrate presence of basal cells if grade of invasive component will be impacted

Terminology

Intraductal carcinoma of the prostate: currently recognized term
Ductal carcinoma in situ: less favorable term
Acinar carcinoma in situ: less favorable term

ICD coding

ICD-11: 2E67.5 - carcinoma in situ of prostate

Epidemiology

Seen in ~3% of prostate biopsies (Histopathology 2013;63:574)

Sites

Prostate ducts and acini

Pathophysiology

Possible theories include:
- End stage spread of invasive carcinoma into ducts and acini (J Pathol 2016;238:31)
- In situ component of high grade tumor leading to invasive carcinoma (eLife 2014;3:e02224, J Urol 2010;184:1328)

Etiology

Familial prostatic adenocarcinoma with BRCA2 mutations have higher proportion of intraductal carcinoma (Eur Urol 2015;67:496)

Diagnosis

Prostate core needle biopsy, prostatectomy or transurethral resection specimens

Laboratory

Elevated prostate specific antigen

Radiology description

In situ disease not identified by imaging; microscopic diagnosis only

Prognostic factors

Associated with higher Gleason grade (patterns 4 or 5) invasive prostatic acinar adenocarcinoma (Urol Oncol 2017;35:673.e9)
Associated with higher pT including extraprostatic extension and seminal vesicle invasion (Urol Oncol 2017;35:673.e9)
Higher rate of biochemical recurrence (Prostate 2019;79:1065)

Case reports

56 year old man with firm right lobe of prostate (Arch Pathol Lab Med 2007;131:1122)
58 year old man with urinary frequency, urgency and nocturia (Case #286)
59 year old man with free floating intraductal tumoral aggregates (Int J Surg Pathol 2016;24:535)
Man with molecular evidence of intraductal carcinoma clone metastasizing to lymph node (Eur Urol 2015;67:819)

Treatment

Immediate rebiopsy (within 3 months) or definitive treatment by radiation or radical prostatectomy if only intraductal tumor is present (Yonsei Med J 2016;57:1054)
If concurrent invasive carcinoma is present, typically definitive treatment is recommended

Gross description

Not seen on gross examination; microscopic disease entity

Microscopic (histologic) description

Basal cells present at periphery of lesion
Dense cribriform, loose cribriform, solid and micropapillary patterns possible (Mod Pathol 2006;19:1528)
Various shapes also possible including round, irregular and branching; if diffuse, it is more likely invasive (Pathol Res Pract 2018;214:1681)
Major criteria (Arch Pathol Lab Med 2015;139:1234):
- Markedly enlarged nuclei (6x normal)
- Nonfocal comedonecrosis
- Solid or dense cribriform architecture
Minor criteria (Arch Pathol Lab Med 2015;139:1234):
- > 6 glands involved
- Irregular shaped glands with right angle branching
- Frequent / easily identifiable mitoses
- 2 cell populations (mitotically active at periphery and quiescent cells in the center)
Important to distinguish from invasive carcinoma as this should not be graded

Microscopic (histologic) images

Contributed by Erica Vormittag-Nocito, M.D. and Case #286

Cribriform architecture

p63

Comedonecrosis

p63

Gleason pattern 5

Gleason pattern 5, p63

Diffuse intraductal carcinoma

Cribriform growth

CK903

Cytology description

Cytology not performed for the diagnosis of this disease entity

Positive stains

p63, CK5/6 and 34betaE12 / HMWCK / high molecular weight highlights basal cells in 100% of cases
Prostate specific markers such as PSA and PSAP stain acinar cells (Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016)
Ki67 increased in acinar cells

Negative stains

PTEN: cytoplasmic loss in 79 - 89% (Mod Pathol 2013;26:587, Prostate 2016;76:394)

Electron microscopy description

Electron microscopy not used to diagnose this disease entity

Molecular / cytogenetics description

PTEN deletions detected by molecular analysis in ~50% (Mod Pathol 2013;26:587, Virchows Arch 2019;474:525, J Pathol 2019 Apr 16 [Epub ahead of print])
ERG fusions detected in ~7% (J Pathol 2019 Apr 16 [Epub ahead of print])

Sample pathology report

Prostate, core needle biopsy:
- Intraductal carcinoma, involving 1 of 2 cores, 10 mm of 20 mm and 50% of the tissue (see comment)
- Comment: No invasive carcinoma is present. Intraductal carcinoma without evidence of invasive carcinoma is associated with high grade invasive prostatic carcinoma at prostatectomy or repeat biopsy. Clinical and serologic follow up is recommended and a repeat biopsy may be clinically indicated.
Prostate, core needle biopsy:
- Prostatic adenocarcinoma, Gleason score 3+4=7, involving 1 of 2 cores, measuring 8 mm of 16 mm and 50% of the tissue
- Intraductal carcinoma is present

Differential diagnosis

High grade prostatic intraepithelial neoplasm:
- Also has retained basal cell layer
- No high grade cytologic atypia
- Clear / vesicular nuclei
- Smaller nuclear size
Ductal carcinoma of prostate:
- Lacks basal cell layer
- Pseudostratified columnar epithelium with more cytoplasm and tufting
- Infiltrative growth and pagetoid spread common
High grade invasive acinar prostatic adenocarcinoma:
- Lacks basal cell layer
- Also can have necrosis and cribriform architecture and may grow admixed with intraductal carcinoma
Urothelial carcinoma in situ within prostatic ducts:
- Also has retained basal cell layer
- Solid growth pattern, lacks cribriform architecture
- Diffusely positive for CK7, p63, GATA3, uroplakin III and negative for PSA (Hum Pathol 2002;33:1136)
Urothelial carcinoma:
- Lacks basal cell layer
- Solid growth pattern, lacks cribriform architecture
- Greater cytologic atypia and pleomorphism
- More nuclear pleomorphism; nucleoli less uniform; more frequent mitoses
- Diffusely positive for CK7, p63, GATA3, uroplakin III and negative for PSA (Hum Pathol 2002;33:1136)

Board review style question #1

Which of the following is true regarding intraductal carcinoma of the prostate?

A basal cell layer is not present in intraductal carcinoma
Intraductal carcinoma is a common finding in prostate biopsies
Intraductal carcinoma should be graded based on the Gleason pattern scoring system
PTEN alterations are common in intraductal carcinoma

Board review style answer #1

D. Intraductal carcinoma commonly has loss of PTEN expression seen by immunohistochemistry.

Comment Here

Reference: Intraductal carcinoma

Board review style question #2

A 65 year old man had a radical prostatectomy for invasive carcinoma found on prostate biopsy. What does the following finding on histology predict about this patient's clinical course?

The patient has a higher probability of biochemical recurrence
The patient is cured with prostatectomy alone
The patient was overtreated as he did not need a prostatectomy
The patient will do the same as other patients within his same grade group without this finding

Board review style answer #2

A. This is prostatic intraductal carcinoma. The patient has a higher probability of biochemical recurrence. Patients with intraductal carcinoma have higher pT category, higher grade tumors with higher likelihood of biochemical recurrence when matched for grade group.

Comment Here

Reference: Intraductal carcinoma

Large cell neuroendocrine carcinoma

Table of Contents

Definition / general

High grade prostatic carcinoma composed of large cells with diffuse neuroendocrine features
Neuroendocrine differentiation of prostate carcinoma is classified as follows (Am J Surg Pathol 2014;38:756, Endocr Pathol 2016;27:123):
- Usual prostatic adenocarcinoma with neuroendocrine differentiation
- Prostatic adenocarcinoma with Paneth cell neuroendocrine differentiation
- Carcinoid tumor
- Small cell carcinoma
- Large cell neuroendocrine carcinoma
- Mixed (small or large cell) neuroendocrine carcinoma with usual prostatic adenocarcinoma

Essential features

Composed of tumor cells larger than those in small cell (neuroendocrine) carcinoma, also with slightly more cytoplasm (Am J Clin Exp Urol 2014;2:273, Am J Clin Exp Urol 2014;2:337); however the size cut-off point is not well established
This tumor is similar to small cell carcinoma (Am J Surg Pathol 2008;32:65) in the following features:
- high grade, with no prominent glandular differentiation
- diffuse, not focal neuroendocrine features
- high rates of mitosis and apoptosis
- poor prognosis
Can be pure or mixed with conventional high grade prostatic adenocarcinoma, either acinar or ductal type
Paraneoplastic syndromes such as Cushing syndrome (ACTH producing tumor induced) may be present but are rare

Epidemiology

Same as prostatic adenocarcinoma

Etiology

Unknown
May occur after androgen deprivation therapy for prostate cancer (Can J Urol 2015;22:7752)
However, many cases develop de novo or with untreated high grade prostatic adenocarcinoma (Am J Surg Pathol 2008;32:65)

Clinical features

Similar to prostatic adenocarcinoma
Although the serum PSA may be elevated, many cases do not show significant elevations, particularly considering the high tumor volume
Other symptoms and signs of advanced prostate cancer may occur
Serum neuroendocrine markers such as chromogranin may be elevated

Diagnosis

Tissue diagnosis with histology is essential, either from needle core biopsy, transurethral resection or prostatectomy
Cytology diagnosis of a primary tumor is not generally accepted as an initial diagnosis, but may be used for metastatic sites

Prognostic factors

Often advanced disease at the time of diagnosis
High volume disease is associated with poorer prognosis

Case reports

69 year old man with prostate needle core biopsy (Individual Case Report [pdf])

Treatment

There is very limited treatment experience, because it is rare and probably underreported
Generally requires systemic therapy similar to small cell carcinoma, but may not respond well to this treatment or to that for conventional prostatic adenocarcinoma

Gross description

Usually large tumor nodule(s) with a high volume of disease in the prostate

Microscopic (histologic) description

Large islands or sheets of tumor cells
Large tumor cells with prominent neuroendocrine features such as salt and pepper chromatin and small nucleoli (see fig 1A)
High grade features such as lack of glandular formation (see fig 2A), frequent mitoses and apoptotic bodies and tumor necrosis are frequent findings

Microscopic (histologic) images

Contributed by Ximing J. Yang, M.D., Ph.D.

Large tumor cells
have slightly more
cytoplasm and
fine "salt-pepper"
chromatin

Strong/diffuse
chromogranin
staining

Sheets of large
tumor cells with
"salt and pepper"
chromatin

Minor
component of
prostatic
adenocarcinoma

Diffuse chromogranin+

AMACR (triple stain)

Negative HMWCK,
p63, PSA

Ki67 proliferative index up to 50%

Positive stains

At least one of these neuroendocrine markers should be positive: chromogranin A, synaptophysin, neuron specific enolase, CD56
May be positive:
- TTF1 positive in less than 50% cases
- AMACR positive, but may be focal or weaker than prostatic adenocarcinoma
- Prostate markers such as PSA, PSMA, NKX3.1 prostein (P501S) are negative in most cases, but they can be focally positive in a small subset of tumors

Negative stains

Urothelial markers such as GATA3, p63 and high molecular weight cytokeratins such as CK5 / 6
CD99

Differential diagnosis

Carcinoid tumor
PNET / Ewing sarcoma
Prostatic adenocarcinoma with focal neuroendocrine differentiation
Urothelial carcinoma with neuroendocrine differentiation

Low grade PIN

Table of Contents

Definition / general

Intraepithelial proliferation along pre-existing ducts and acini with mild atypia, at the lower end of the prostatic intraepithelial neoplasia (PIN) spectrum
Do NOT include in pathology reports - variability in diagnosis exists even among experts (Am J Surg Pathol 1995;19:873, Virchows Arch 2009;454:1)

Essential features

Not recommended to report
Often associated with high grade PIN
PSA may be elevated

Terminology

Formerly known as grade 1 intraductal dysplasia or PIN 1 (mild dysplasia) (Hum Pathol 1986;17:64)

ICD coding

ICD-10: N42.31 - prostatic intraepithelial neoplasia I
ICD-10: N42.31 - prostatic intraepithelial neoplasia II
Synonyms: low grade prostatic intraepithelial neoplasia, prostatic intraepithelial neoplasia low grade

Epidemiology

Tends to be present in younger men, first appearing in men in their 30s - 40s (J Urol 1993;150:379)
No increase in prostate adenocarcinoma in patients with low grade PIN (risk of carcinoma on subsequent biopsy is 18%, as compared with 19% in a man with PSA levels of 4 - 10 ng/mL and an initial benign biopsy) (BJU Int 2011;108:1394)

Sites

No specific regions of the prostate

Pathophysiology

Loss of function of tumor suppressors (SPRY1, SPRY2) without losses of PTEN (Proc Natl Acad Sci U S A 2012;109:20023)

Etiology

None specific to low grade PIN

Clinical features

No specific clinical features
Associated with high grade PIN

Diagnosis

Seen incidentally on prostate biopsy

Laboratory

Elevations in PSA

Radiology description

Normal radiologic findings

Prognostic factors

~ 20% of patients with low grade PIN with cancer on rebiopsy (Eur Urol 1997;32:155)

Case reports

Ectopic prostatic adenoma in retrovesical space (J Urol 1987;137:998)
Ectopic prostatic tissue in the uterine cervix, four cases (Am J Surg Pathol 2000;24:1224)

Treatment

No specific treatment recommended, treatment based on higher grade lesions

Gross description

No specific gross findings

Microscopic (histologic) description

Architecture:
- At scanning magnification, darker and more complex than normal glands
- Cellular crowding, pseudostratification with irregular spacing
- Intact basal layer
Cytology:
- Enlarged nuclei with increased variability in nuclear size and nuclear hyperchromasia
- Indistinct and rare nucleoli
- Amphophilic or eosinophilic cytoplasm
Reference: Virchows Arch 2009;454:1

Microscopic (histologic) images

Contributed by Nicholas P. Reder, M.D., M.P.H.

Acinar cells with crowded nuclei

Atypical acinar cells

Low grade PIN next to high grade PIN

Positive stains

No need for IHC, although high molecular weight keratin (34βE12) and p63 will highlight a circumferential basal cell layer (BJU Int 2011;108:1394)
Can be AMACR positive (Mod Pathol 2004;17:1180)

Molecular / cytogenetics description

Usually diploid, in contrast with high grade PIN, which can be aneuploid

Sample pathology report

It is not recommended to report low grade PIN

Differential diagnosis

Benign central zone glands:
- Can have complex architecture with papillary infoldings and pseudostratified epithelium but lacking nuclear atypia
Clear cell cribriform hyperplasia:
- Clear cells forming crowded cribriform glands without atypia and with a very prominent basal cell layer
High grade PIN:
- Prominent nucleoli (1 - 3 microns in diameter), robust cellular crowding and multilayering
Low grade PIN-like low grade prostatic adenocarcinoma:
- Lack of basal cells (Pathology 2014;46:88)

Additional references

Prostate Cancer Prostatic Dis 2003;6:305

Board review style question #1

The above finding may be regarded as low grade prostatic intraepithelial neoplasia. How should this be described in the pathology report?

Benign central zone glands
Clear cell cribriform hyperplasia
Do not report, consider as no significant pathologic change
High grade prostatic intraepithelial neoplasia
Low grade prostatic intraepithelial neoplasia

Board review style answer #1

C. Do not report, consider as no significant pathologic change

Comment Here

Reference: Low grade PIN

Malakoplakia

Table of Contents

Definition / general

Rare chronic inflammatory reaction that affects multiple sites, most commonly the bladder and rarely the prostate

Essential features

Rare inflammatory condition strongly associated with infection (especially gram negative bacilli) and immunosuppression
Michaelis-Gutmann bodies (intracytoplasmic calcific inclusions) are pathognomonic
Clinically mimics prostatic adenocarcinoma and histology is definitive

ICD coding

ICD-10: N41 - inflammatory diseases of prostate
ICD-11: GA91.Y - other specified inflammatory and other diseases of prostate

Epidemiology

Affected men reported between 43 to 85 years old (Ann Diagn Pathol 2016;22:33)
More common in immunocompromised patients (Ann Diagn Pathol 2016;22:33)

Sites

May occur in multiple sites, including mucosa, skin and most commonly the bladder; however, has been reported in the prostate

Pathophysiology

Gram negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, infect the urinary tract
Undigested bacteria accumulate, which is thought to be secondary to a defect in host macrophage and monocyte lysosomal degradation (Histol Histopathol 2020;35:177)
Michaelis-Gutmann bodies are formed when iron and calcium accumulate around the undigested bacteria
Eventually, a mass-like lesion may form in the prostate (Urol Case Rep 2020;32:101222)

Etiology

Frequently associated with culture positive, predominantly enteric gram negative bacilli, urinary tract infections

Clinical features

Majority of cases associated with positive urinary cultures, E. coli and K. pneumoniae being the most frequently isolated bacteria (Folia Med Cracov 2019;59:67)
Affected men may present with an enlarged prostate or bladder outlet obstruction
There have been several cases reported with concomitant prostatic adenocarcinoma (Ann Diagn Pathol 2016;22:33)

Diagnosis

Clinical findings may prompt follow up imaging or procedures
Imaging with MRI is suspicious for carcinoma
Histologic examination for definitive diagnosis

Laboratory

Elevated prostate specific antigen (PSA) (Folia Med Cracov 2019;59:67)
Often positive urine culture for gram negative bacilli

Radiology description

Multiparametric magnetic resonance imaging (mpMRI) with hypointense lesion(s), which may correspond to higher prostate imaging reporting and data system (PI-RADS) scores (Urol Case Rep 2020;32:101222)

Radiology images

Images hosted on other servers:

mpMRI of hypointense lesion

mpMRI showing hypointense mass

Case reports

43 year old man with fever and elevated PSA (Int J Clin Exp Pathol 2018;11:4153)
57 year old man with rising PSA over 3 years (Urol Case Rep 2020;32:101222)
61 year old man with recurrent E. coli urinary tract infection and months of urinary obstruction symptoms (J Endourol Case Rep 2020;6:231)
63 year old man with persistently elevated PSA (Urol Case Rep 2017;18:94)
75 year old man with elevated PSA (J Endourol Case Rep 2017;3:74)

Treatment

Combined medical, such as antibiotics for the background urinary tract infection and surgical approach, depending on extent of disease and anatomic site of involvement (Int J Clin Exp Pathol 2018;11:4153)

Microscopic (histologic) description

Prostatic tissue with infiltration by round histiocytes with eosinophilic, granular cytoplasm (von Hansemann cells) (Urol Case Rep 2017;18:94)
Histiocytes contain round and basophilic intracytoplasmic inclusions with bullseye appearance known as Michaelis-Gutmann bodies
Admixed acute and chronic inflammation may be present

Microscopic (histologic) images

Contributed by Theodorus van der Kwast, M.D., Ph.D.

Histiocytes and inclusions

Histiocytic inflammation

PAS stain

Positive stains

von Kossa stain (calcium) highlights Michaelis-Gutmann bodies
Prussian blue (iron) stains Michaelis-Gutmann bodies blue
Periodic acid-Schiff (PAS) stain highlights histiocytic eosinophilic cytoplasm
CD163 and CD68 show extent of histiocytic involvement
Reference: Urol Case Rep 2014;3:6

Negative stains

AE1 / AE3

Sample pathology report

Prostate, needle core biopsy:
- Malakoplakia (see comment)
- Comment: The specimen shows diffuse involvement by histiocytes with eosinophilic granular cytoplasm and frequent intracytoplasmic inclusions consistent with Michaelis-Gutmann bodies. The inclusions are emphasized by von Kossa and Prussian blue stains, while PAS highlights the granular cytoplasm of the histiocytes.

Differential diagnosis

Prostatic adenocarcinoma:
- Small glands with nuclear enlargement, hyperchromasia and prominent nucleoli
- May be associated with acute or chronic inflammation but histiocytic inflammation is not typically identified (Ann Diagn Pathol 2016;24:55)
- Lacks Michaelis-Gutmann bodies
- Positive for AE1 / AE3
- Negative for CD68 and CD163
Xanthogranulomatous inflammation:
- Collections of histiocytes with abundant foamy cytoplasm
- Lacks Michaelis-Gutmann bodies
- Negative for von Kossa and Prussian blue
Infectious granulomatous prostatitis, tuberculous prostatitis:
- Central caseous necrosis surrounded by epithelioid histiocytes, plasma cells and multinucleated giant cells
- Negative for von Kossa and Prussian blue
Nonspecific granulomatous prostatitis:
- Lacks Michaelis-Gutmann bodies
- Negative for von Kossa and Prussian blue

Board review style question #1

A 57 year old man presents with a transurethral resection of the prostate showing the above images (H&E on left, PAS stain on right). Which organism is most likely associated with this reaction?

Chlamydia trachomatis
Escherichia coli
Prevotella bivia
Staphylococcus saprophyticus

Board review style answer #1

B. Escherichia coli. E. coli is one of the most commonly associated organisms which have been associated with prostatic malakoplakia and is an enteric gram negative bacillus. Prevotella bivia is another gram negative bacillus; however, is typically recovered from oral and vaginal sites. P. bivia may cause urinary tract infections; however, there has not, as of the drafting of this article, been a case associated with malakoplakia. Chlamydia trachomatis is a gram negative bacteria that is transmitted through infected secretions, infects mucosal membranes and is most commonly associated with sexually transmitted infections. Staphylococcus saprophyticus is a gram positive coccus and is associated with urinary tract infections in young women.

Comment Here

Reference: Malakoplakia

Board review style question #2

A 49 year old man presents with urinary obstructive symptoms and imaging is concerning for malignancy. On histopathology, several intracytoplasmic inclusions are noted in the histiocytes. Which of the following groups of special stains would help the most with the diagnosis?

Prussian blue, PAS, reticulin
Prussian blue, PAS, von Kossa
Prussian blue, trichrome, von Kossa
Prussian blue, trichrome, reticulin

Board review style answer #2

B. Prussian blue, PAS, von Kossa. Prussian blue (iron) and von Kossa (calcium) highlight Michaelis-Gutmann bodies, as they are formed from the accumulation of iron and calcium. Trichrome stains connective tissue, including collagen, while reticulin highlights reticular fibers and basement membrane materials; neither is utilized in supporting the diagnosis of malakoplakia.

Comment Here

Reference: Malakoplakia

Mesonephric remnant hyperplasia

Table of Contents

Definition / general

Mesonephric remnant hyperplasia is a proliferation of small glands that mimic prostatic carcinoma
This is more common in the female genital tract and can rarely be seen within the prostate

Essential features

Cluster of small acini with eosinophilic secretion, cells with bland nuclei and inconspicuous nucleoli usually in a lobular distribution
An infiltrating pattern can be seen occasionally, mimicking cancer
Papillary infolding or small ill formed glands may mimic high grade prostate cancer
No clinical significance

Epidemiology

Mean age 60 years (range, 40 to 80 years)

Sites

Prostate and periprostatic tissue

Pathophysiology

Believed to represent an embryologic remnant

Clinical features

Asymptomatic

Prognostic factors

Not associated with increased risk of cancer

Treatment

Not required

Microscopic (histologic) description

Cluster of small acini with eosinophilic secretion, with cells with bland nuclei and inconspicuous nucleoli usually in a lobular distribution
An infiltrating pattern can be seen occasionally, mimicking cancer
Papillary infolding or small ill-formed glands may mimic high grade prostate cancer

Microscopic (histologic) images

Contributed by Andres Matoso, M.D.

Mesonephric remnant / hyperplasia with acini

Positive stains

High molecular weight cytokeratin and p63 are typically positive but can be negative
Racemase can be focally positive; when positive, along with negative p63 and high molecular weight cytokeratin, can erroneously lead to a diagnosis of adenocarcinoma of the prostate
PAX8 is positive

Negative stains

PSA and PSAP

Differential diagnosis

Prostate adenocarcinoma

Additional references

Am J Surg Pathol 1993;17:454, Am J Surg Pathol 2011;35:1054, Mod Pathol 2003;16:630

Microcystic pattern

Table of Contents

Definition / general

One of the unusual histological patterns of acinar adenocarcinoma
While often easier to recognize at radical prostatectomy given the juxtaposition to usual pattern acinar adenocarcinoma (incidence of 11%), deceptive morphology can be challenging to recognize on prostate biopsy (incidence of 1%) (Am J Surg Pathol 2010;34:556, Int J Surg Pathol 2020;28:584)
As these are graded in the usual fashion, formal designation as microcystic pattern is not indicated in the pathology report and is more important to recognize for accurate diagnosis

Essential features

Cystic glands with marked dilatation (reminiscent of cystic atrophy) at low power magnification but often showing luminal crystalloid, blue intraluminal mucin and prominent nucleoli at higher power magnification

Terminology

Sometimes synonymous with pseudohyperplastic pattern prostatic adenocarcinoma

ICD coding

ICD-O: 8140/3 - acinar adenocarcinoma
ICD-10: C61 - malignant neoplasm of the prostate
ICD-11: 2C82.0 & XH4PB1 - adenocarcinoma of prostate & acinar adenocarcinoma of prostate

Sites

Prostate

Diagnosis

Core needle biopsies or transurethral resection of the prostate
Immunohistochemistry may be used to confirm the absence of basal cells

Case reports

Limited series of atrophic / microcystic prostatic adenocarcinoma (Int J Surg Pathol 2020;28:584)

Microscopic (histologic) description

Cystic glands with marked dilatation (reminiscent of cystic atrophy; glands can become quite attenuated), approximately 10x the size of typical malignant acini (Am J Surg Pathol 2010;34:556)
Sometimes crowded growth at low power magnification but often showing luminal crystalloid, blue intraluminal mucin and prominent nucleoli at higher power magnification
Typically coexists with usual acinar pattern prostatic adenocarcinoma
One of the important deceptively bland histological patterns of prostate cancer, alongside atrophic, pseudohyperplastic and foamy gland prostatic adenocarcinoma

Microscopic (histologic) images

Contributed by Ankur Sangoi, M.D.

Compact dilated cysts

Basal nuclei with amphophilic cytoplasm

Prominent nucleoli and luminal crystalloid

Cytoplasmic P504S

Positive stains

AMACR (P504S) luminal expression in 96% of cases (Am J Surg Pathol 2010;34:556)

Negative stains

Complete loss of basal cell reactivity (34 beta E12, p63) in 96% of cases (Am J Surg Pathol 2010;34:556)

Sample pathology report

Same as typical acinar adenocarcinoma; it is not needed to report the presence of this histological pattern
Prostate, radical prostatectomy:
- Prostatic adenocarcinoma, Gleason score 3 + 3 = 6, grade group 1 (see synoptic report)

Differential diagnosis

Cystic atrophy:
- Lacks amphophilic cytoplasm, prominent nucleoli, luminal mucin / crystalloid
- While it may show patchy, cytoplasmic P504S staining, it shows retained basal cell reactivity (p63 / high molecular weight keratin)
High grade prostatic intraepithelial neoplasia:
- While it may show luminal crystalloid, it typically lacks luminal mucin
- Basal cells are somewhat appreciable on H&E staining but immunohistochemistry shows retained basal cell reactivity (p63 / high molecular weight keratin)
Atrophic pattern prostatic adenocarcinoma (including aberrant p63 positivity)
- Often shows reduced cytoplasm compared to microcystic pattern prostatic adenocarcinoma
- Can show aberrant nuclear staining for p63 in the tumor cells (absent p63 / high molecular weight keratin staining in basal cells)

Additional references

Mod Pathol 2018;31:S64, Histopathology 2012;60:59, Curr Opin Urol 2022;32:643

Board review style question #1

Which of the following statements is true regarding microcystic pattern prostatic adenocarcinoma?

It is one of the patterns of prostatic adenocarcinoma that is excluded from grading
It most closely mimics cystic atrophy but shows an immunoprofile of usual acinar adenocarcinoma (cytoplasmic P504S, loss of basal cell reactivity)
It rarely shows luminal crystalloid or prominent nucleoli
It shows atrophic glands with aberrant nuclear positivity for p63

Board review style answer #1

B. It most closely mimics cystic atrophy but shows an immunoprofile of usual acinar adenocarcinoma (cytoplasmic P504S, loss of basal cell reactivity). Answer A is incorrect because Gleason grading is applicable to microcystic pattern prostatic adenocarcinoma (graded on architecture, usually Gleason grade 3 + 3). Answer C is incorrect because it often shows luminal crystalloid with prominent nucleoli. Answer D is incorrect because it does not show features of p63 positive prostatic adenocarcinoma (atrophic glands with aberrant nuclear positivity for p63).

Comment Here

Reference: Microcystic adenocarcinoma

Mixed epithelial and stromal tumor

Table of Contents

Definition / general

Biphasic seminal vesicle tumors with both benign epithelial component (often cystic) and benign to malignant stromal component

Essential features

Rare biphasic tumor as defined above
3 tiered system has been proposed, including benign lesion to a low grade or high grade malignancy based on the stromal cellularity, atypia, mitosis and necrosis (Adv Anat Pathol 2015;22:113)
- WHO Urinary and Male Genital Tumors does not mention this 3 tiered system but still emphasizes evaluating the stroma for possible malignant features
Main differential diagnoses include seminal vesicle cystadenoma, mesenchymal tumors of seminal vesicle, prostatic stromal tumor of uncertain malignant potential (STUMP), spread of prostate cancer and prostatic stromal sarcoma; biopsy may not be able to differentiate a cystadenoma from a mixed epithelial and stromal tumor (MEST)

Terminology

Alternative terms discouraged by WHO 2022: (cystic) epithelial-stromal tumor, fibroadenoma, adenomyoma, cystomyoma, mesenchymoma, mesonephric hamartoma, Müllerian adenosarcoma-like tumor, phyllodes tumor, cystosarcoma phyllodes
Cystadenoma once was included in this category but now is recognized as a separate entity with limited stromal proliferation and stromal hypocellularity (WHO)

ICD coding

ICD-O: 8959/0 - benign cystic nephroma
ICD-11: 2F34 & XH0533 - benign neoplasm of male genital organs & mixed epithelial and stromal tumor

Epidemiology

MEST of the urogenital tract is comparatively much more common in women than men
Very rare (38 reported male cases up to February 2022) (Urology 2022:167:13)
Median age: 49 years (Urology 2022:167:13)

Sites

Seminal vesicle

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Obstructive lower urinary tract symptoms, dysuria, hematuria, lower abdominal pain or asymptomatic

Diagnosis

Mass above the prostate may be detected by digital rectal examination
Computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound; imaging may be the key to determining the origin of the tumor and is especially helpful in biopsy
Transrectal biopsy, fine needle aspiration or rarely transurethral seminal vesiculoscopy (Urology 2022:167:13)
- Biopsy may not be able to differentiate a cystadenoma from a MEST

Radiology description

MRI can show tissue planes between the lesion and adjacent structures, allowing a conservative surgical approach and not laparotomy (World J Surg Oncol 2008:6:101)
Benign mass is distinct from the prostate, in the middle of the seminal vesicle, surrounded by thin capsule with contrast enhanced irregularities of low and high signal intensity by T1 and T2 weighted imaging, respectively (IJU Case Rep 2020;3:103, Int J Urol 2006;13:640)
- Findings were similar with MEST of low grade malignancy (BMJ Case Rep 2021;14:e238526)
For rare high grade malignant cases, mass was still distinct from other structures but with some hyperintensity on T1 (Case Rep Urol 2014:2014:302708)

Radiology images

Images hosted on other servers:

Pelvic MRI, seminal vesicle mass

Prognostic factors

Majority are low grade (94%) (Urology 2022:167:13)
Rarely recur (2/15 or 13%) (Urology 2022:167:13)
Rare metastatic cases reported (2 cases of cystosarcoma phyllodes with lung metastasis reported) (IJU Case Rep 2020;3:103)

Case reports

Benign (or low grade) cases
- 46 and 60 year old men with low grade tumors detected on rectal exam or at radical prostatectomy for prostate cancer (Adv Anat Pathol 2015;22:113)
- 48 year old man with a 65 cm benign MEST of seminal vesicle (J Surg Case Rep 2023;2023:rjad490)
- 50 year old man with low grade MEST (World J Surg Oncol 2008:6:101)
- 52 year old man with MEST treated with robot assisted laparoscopic prostatectomy and vesiculectomy (IJU Case Rep 2020;3:103)
- 70 year old man with a MEST but without symptoms of bladder outlet obstruction (Int J Urol 2006;13:640)
Malignant cases
- 37 year old man with a large MEST of seminal vesicle (low grade malignancy) (BMJ Case Rep 2021;14:e238526)
- 49 year old man with cystosarcoma phyllodes of the right seminal vesicle (Case Rep Urol 2014:2014:302708)

Treatment

Majority are benign and surgical excision (robot assisted or laparoscopic) is curative
Asymptomatic patients may be considered for observation
High grade malignant MEST may need chemotherapy (Amin: Diagnostic Pathology - Genitourinary, 3rd Edition, 2022)

Gross description

Well circumscribed, lobulated, solid and cystic mass in the seminal vesicle; contiguous with seminal vesicle remnants and separable from prostate or bladder
Most reported MESTs are unilateral
Size range: 2.5 - 65 cm (J Surg Case Rep 2023;2023:rjad490)

Gross images

Contributed by Gladell Paner, M.D.

Mass of seminal vesicle

Microscopic (histologic) description

Benign epithelial component
- Usually cystic or slit-like architecture
- Cuboidal to columnar epithelium; occasionally hobnailing, papillary infoldings or tufting are seen; 2 cell layers with basal layer may be seen
- Homogeneous eosinophilic or other material may be seen in cystic lumens (Adv Anat Pathol 2015;22:113, Int J Urol 2002;9:599, Cancer 1993;71:2055, Am J Surg Pathol 1987;11:210)
- Lipofuscin pigment and other seminal vesicle features can be focally appreciated
Stromal component
- Determines biologic behavior of the tumor
- Ranges from benign spindle cells separated by collagenous stroma, overlapping with adenofibroma and adenomyoma, to malignant morphology, including reported malignant adenosarcoma or cystosarcoma phyllodes patterns
- Tendency of spindle cells to be more cellular or condensed around cysts / glands
- Benign versus malignant distinction is based on cellularity, atypia, mitosis and necrosis
- Degenerative atypia or mature adipose tissue may be present (Adv Anat Pathol 2015;22:113, Int J Urol 2002;9:599, Cancer 1993;71:2055, Am J Surg Pathol 1987;11:210)
- May need immunohistochemical staining for differential diagnosis (Adv Anat Pathol 2015;22:113)

Microscopic (histologic) images

Contributed by Fiona Maclean, M.D. and Gladell Paner, M.D.

Cellular stroma surrounds epithelium

Urothelial component

Positive stains

Epithelial cells: CK7 and PAX8 (Amin: Diagnostic Pathology - Genitourinary, 3rd Edition, 2022)
Stromal component: ER, PR, CD34, vimentin, desmin, SMA, h-caldesmon (Adv Anat Pathol 2015;22:113)

Negative stains

Epithelial cells: CK20, PSA and PAP (Adv Anat Pathol 2015;22:113)
Stromal component: inhibin, S100 protein and KIT (CD117) (Adv Anat Pathol 2015;22:113)

Sample pathology report

Seminal vesicle, biopsy:
- Proliferation of bland spindle cells around benign columnar epithelium consistent with mixed epithelial and stromal tumor (see comment)
- Comment: This is a rare tumor. There are some cases reported in which the stromal component is malignant; however, in the current case, the stroma exhibits benign histologic features.

Differential diagnosis

Seminal vesicle cystadenoma:
- Lacks stromal component proliferation and usually with hypocellular stroma
Angiomyofibroblastoma or mesenchymal tumor of seminal vesicle, such as leiomyoma, leiomyosarcoma and solitary fibrous tumor (J Surg Case Rep 2023;2023:rjad490):
- These lack a lesional epithelial component, which may not be evident on biopsy of MEST
Prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma:
- Lesion centered in the prostate, not seminal vesicle
- Epithelial component should express prostatic markers, such as PSA, PAP, NKX3.1 and be negative for CK7 and PAX8
Prostatic adenocarcinoma spread to seminal vesicles:
- Glands with nuclear atypia
- Positive for PSA, PSAP and P504S
- Mixed epithelial and stromal tumor should have no atypia in the epithelium; also, the reactive stroma is usually much less cellular

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumors, 5th Edition, 2022, Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016

Board review style question #1

What is the most likely diagnosis of this seminal vesicle tumor?

Benign mixed epithelial and stromal tumor of seminal vesicle
Leiomyoma
Leiomyosarcoma
Malignant mixed epithelial and stromal tumor of seminal vesicle
Seminal vesicle cystadenoma

Board review style answer #1

A. Benign mixed epithelial and stromal tumor of seminal vesicle. The lesion arises from the seminal vesicle with both bland epithelial and spindle-like proliferation of stromal component, which meets the definition of MEST. The stromal component also has a cellular appearance but without atypia, mitosis and necrosis that raise the concern of malignancy. Therefore, this is most likely a benign MEST.

Answers B and C are incorrect because these 2 entities are pure stromal tumors without epithelial components. In this case, there is an epithelial component that does not strongly resemble smooth muscle and nuclear orientation is too random for leiomyoma. The diagnosis is not leiomyosarcoma because of the epithelial component, plus the stroma lacks any atypia. Answer D is incorrect because the stromal component lacks malignant features such as atypia, mitosis and necrosis. Answer E is incorrect because per the 5th edition of WHO, seminal vesicle cystadenoma lacks stromal component proliferation usually with hypocellular stroma and is currently separated from MEST.

Comment Here

Reference: Mixed epithelial and stromal tumor

Board review style question #2

Which of the following is true for mixed epithelial stromal tumor of seminal vesicle?

Biphasic tumor with benign or malignant epithelial and stromal components
Epithelial component is usually positive for CK7, PAX8 and NKX3.1
It includes seminal vesicle cystadenoma
Majority are benign
Stomal component is usually negative for ER, PR and CD34

Board review style answer #2

D. Majority are benign. Answer A is incorrect because per the 5th edition of WHO, the epithelial component cannot be malignant. Answer B is incorrect because the epithelial component is benign and usually positive for CK7 and PAX8 but negative for prostatic markers such as NKX3.1. Answer E is incorrect because the stromal component is usually positive for ER, PR and CD34. Answer C is incorrect because seminal vesicle cystadenoma lacks a stromal component proliferation and is currently separated from MEST.

Comment Here

Reference: Mixed epithelial and stromal tumor

Mucinous (colloid) pattern

Table of Contents

Definition / general | Microscopic (histologic) description | Positive stains | Differential diagnosis

Definition / general

Uncommon (< 1%)
Intra and extracellular mucin must comprise 25%+ of tumor
May be more hormone independent, less responsive to radiation therapy
Aggressive biologic behavior (Am J Surg Pathol 1985;9:299, Am J Surg Pathol 2008;32:468, Mod Pathol 2004;17:316)

Microscopic (histologic) description

Tumor cells float in pools of mucin
Resembles mucinous (colloid) carcinoma of breast
Has microglandular, cribriform, comedo, solid and hypernephroid patterns
Signet ring cells are rare

Positive stains

PSA, PAP, MUC2 (Mod Pathol 2008;21:789)

Differential diagnosis

Extension of large bowel carcinoma, Cowpers gland carcinoma
Mucinous adenocarcinoma of bladder (PSA-, PAP+)
Post-hormone treatment changes which leave behind acellular pools of mucin (Am J Surg Pathol 1998;22:347)

Nephrogenic metaplasia / adenoma

Table of Contents

Definition / general

Benign polypoid, papillary, fungating or velvety lesion found in the bladder or prostatic urethra after urothelial injury
Has multiple histologic patterns

Essential features

Evidence that it is derived from shed renal tubular cells (N Engl J Med 2002;347:653)
Alternatively, it is postulated that a subset of cases might be a metaplastic reaction (Int Sch Res Notices 2015;2015:704982)
Tubules lined by flattened, cuboidal or hobnail cells
Many morphologic variants: papillary, tubular, flat, cysts and microcysts, signet ring cell-like, fibromyxoid
Hyaline rim surrounds the tubules
No mitotic activity
Only occasional solid areas or rare clear cells present
May focally involve the prostatic parenchyma and mimic prostate adenocarcinoma

ICD coding

ICD-10: N32.9 - bladder disorder, unspecified

Epidemiology

Any age (mostly old adults) (Int Sch Res Notices 2015;2015:704982)
Usually following a urothelial injury (instrumentation, urethral catheterization, recurrent infection, stones, bacillus Calmette-Guérin [BCG] therapy or renal transplant) (Urology 2016;95:29)

Sites

Prostatic urethra
Described throughout the entire urothelium (see nephrogenic metaplasia in the bladder chapter)

Pathophysiology

Evidence that it is derived from shed renal tubular cells (N Engl J Med 2002;347:653)
Alternatively, it is postulated that a subset of cases might be a metaplastic reaction (Int Sch Res Notices 2015;2015:704982)

Etiology

Prior injury to the urothelium

Clinical features

May present as a mass or with irritative lower urinary tract symptoms, hematuria, dysuria, obstruction
Usually small (< 1 cm) but may be up to 7 cm

Diagnosis

Biopsy, transurethral resection

Prognostic factors

May recur; risk factors not known

Case reports

39 year old woman with nephrogenic adenoma arising in urethral diverticulum (Cureus 2023;15:e36578)
62 year old man with giant prostatic hypertrophy and recurrent nephrogenic adenoma of the prostate (BMC Urol 2013;13:18)
67 year old man with asymptomatic macroscopic hematuria and a history of laser photovaporization of the prostate for benign prostate hyperplasia (Urol Case Rep 2020;33:101382)
72 year old man with nephrogenic adenoma presenting with irritative voiding symptoms as benign prostatic hyperplasia and mimicking prostatic and bladder carcinomas (Cureus 2023;15:e35998)

Treatment

Transurethral resection with regular follow ups

Gross description

Friable soft tissue fragments

Microscopic (histologic) description

Tubules lined by simple cuboidal, flattened or hobnail cells, forming an exophytic papillary or endophytic lesion (Urology 2016;95:29)
Associated acute and chronic inflammation and edema in the stroma; lack of desmoplastic reaction
Many morphologic variants (multiple patterns may occur in the same cases): papillary, tubular, tubulocystic, polypoid, flat, fibromyxoid, signet ring cell-like (Mod Pathol 2013;26:792)
Hyaline rim surrounds the tubules (PAS positive thickened basement membrane) (Adv Anat Pathol 2019;26:171)
No mitotic activity
Scant cytoplasm, finely granular uniform chromatin; usually inconspicuous nucleoli (Ann Diagn Pathol 2019;38:11)
Only occasionally solid areas, rare clear cells, blue mucin within the tubules present
Sometimes atrophic tubules filled with eosinophilic colloid-like material mimicking thyroid follicles and mesonephric hyperplasia
May be associated with radiotherapy
Rare fibromyxoid variant features, including compressed spindle shaped cells in a prominent fibromyxoid background; it can present as pure fibromyxoid or combined with classic (tubular) morphology (Am J Surg Pathol 2023;47:37)

Microscopic (histologic) images

Contributed by Francesca Sanguedolce, M.D., Ph.D.

Multiple morphologies

Inflammation, thickened basement membrane

Cytological features

Ki67

AMACR

PAX8

CK7

Cytology description

Numerous vacuolated, polygonal and columnar shaped cells singly or in small groups
Papillary fragments resembling low grade papillary urothelial carcinoma (Am J Clin Pathol 2016;145:373)

Positive stains

PAX2, PAX8, AMACR, CD10, CK7 (Am J Surg Pathol 2014;38:1664)
CK903, EMA, S100A1 (Ann Diagn Pathol 2013;17:41)
Napsin A (Hum Pathol 2020;102:23)
Weakly positive or negative for PSA and PSAP

Negative stains

p63, CEA (Virchows Arch 2013;463:819)
GATA3 (positive in 40% of cases) (Am J Surg Pathol 2014;38:1664)
Very low Ki67 proliferation rate (< 5%) (Ann Diagn Pathol 2019;38:11)

Sample pathology report

Prostate, biopsy / transurethral resection:
- Nephrogenic adenoma

Differential diagnosis

Prostatic adenocarcinoma:
- Tubular structures extending into the prostatic parenchyma may mimic prostatic adenocarcinoma
- Positive for NKX3.1 and PSA but negative for PAX8 and CK7
Especially atrophic variant of prostate adenocarcinoma:
- Not associated with genitourinary trauma
- Infiltrative, more atypia
- No adjacent urothelium present, no thyroidization, usually no inflammation (Am J Surg Pathol 2001;25:802)
Clear cell adenocarcinoma of the bladder:
- Occasional clear cells, more prominent pleomorphism, especially hyperchromatic enlarged nuclei and extensive muscular invasion
- Increased mitotic index and proliferation rate
- More common in women (Hum Pathol 2010;41:594)
Invasive urothelial carcinoma:
- Especially some subtypes of urothelial carcinoma with bland morphology, such as tubular and microcystic urothelial carcinoma (Int J Surg Pathol 2012;20:123)
- Size and shape variation of the epithelial structures and haphazard infiltrative growth
- Lack of inflamed stroma and presence of desmoplasia
- PAX8 negative and p63 positive

Additional references

Pathology 2021;53:44, Pathol Res Pract 2019;215:152561

Board review style question #1

Which of the following statements is true about nephrogenic adenoma?

Can have multiple morphological patterns
Carcinoembryonic antigen (CEA) is often positive
Has a high proliferative index
Is a metaplastic lesion

Board review style answer #1

A. Can have multiple morphological patterns. Nephrogenic adenoma often features multiple different morphologies within the same lesion, the most common being tubular, cystic and papillary. Answer D is incorrect because it has been established that nephrogenic adenoma, which has been thought to be a metaplastic lesion, actually results from shed renal tubular cells. Answer C is incorrect because this entity has a very low proliferative index. Answer B is incorrect because this entity lacks CEA staining.

Comment Here

Reference: Nephrogenic metaplasia / adenoma

Board review style question #2

Which of the following is a variant of nephrogenic adenoma?

Fibromyxoid
Glycogen rich
Nested
Plasmacytoid

Board review style answer #2

A. Fibromyxoid. The rare fibromyxoid variant features compressed, spindle shaped cells in a prominent fibromyxoid background; it can present as pure fibromyxoid or combined with classic (tubular) morphology. Answers B, C and D are incorrect because they all refer to subtypes of urothelial cancer.

Comment Here

Reference: Nephrogenic metaplasia / adenoma

Nonneoplastic metaplasia

Table of Contents

Mucinous metaplasia

Definition / general

Mucinous metaplasia is a form of glandular differentiation

Essential features

Acini with tall, mucin filled cells with flat, basal pyknotic nuclei
May occur as a group of glands or single cells within glands
More common in the periurethral area
May mimic cancer but not associated with malignancy
Resembles Cowper glands

Epidemiology

One autopsy study described a frequency of mucinous metaplasia of ~1% (Am J Surg Pathol 1993;17:618)
However, in another study with entirely sampled prostates, up to ~50% of cases showed a focus of it (Br J Urol 1996;77:113)
In 2 cases, mucinous metaplasia was associated with postatrophic hyperplasia (Am J Surg Pathol 1995;19:1068)

Sites

Prostate

Pathophysiology

Pathophysiology and etiology are unknown

Etiology

Mucinous metaplasia in 21% of prostatic biopsies after radiation therapy (Am J Surg Pathol 1999;23:1021)

Clinical features

The only clinical significance is that it may mimic cancer in a needle biopsy

Diagnosis

Mucin filled vacuoles distend the cytoplasm of benign cells

Treatment

Not required
Mucinous metaplasia is a morphologic variant of prostatic acini

Microscopic (histologic) description

Acini with tall mucin filled cells with flat, basal pyknotic nuclei

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Focal mucinous metaplasia

Reactive change and mucinous metaplasia

Positive stains

PAS diastase resistant, mucicarmine, Alcian blue (Br J Urol 1996;77:113)

Negative stains

Cytokeratins and prostatic markers PSA, PSAP in the mucinous cells (Br J Urol 1996;77:113)

Differential diagnosis

Tall columnar cells bear a resemblance to prostatic ductal adenocarcinoma:
- In contrast to adenocarcinoma, mucinous metaplasia does not show an infiltrative growth pattern, usually does not display prominent nucleoli and is positive for basal cell markers p63 and high molecular weight cytokeratin by immunohistochemistry

Additional references

Am J Surg Pathol 1993;17:287

Paneth cell-like change

Definition / general

Associated with both benign and malignant lesions (Arch Pathol Lab Med 1992;116:274)
Collections of prostatic cells with eosinophilic granules resembling intestinal Paneth cells (Am J Surg Pathol 1992;16:1013, Int J Clin Exp Pathol 2014;7:3454)
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 epithelium (Am J Surg Pathol 1992;16:62, Hum Pathol 1994;25:135, Am J Surg Pathol 2006;30:980)

Essential features

Small focus of cells with bright pink granules in cytoplasm
No cytologic atypia

Terminology

Eosinophilic metaplasia (Prostate 2019;79:622, Indian J Pathol Microbiol 2017;60:409)

Epidemiology

Noted in 32% of prostatic biopsies after irradiation (Am J Surg Pathol 1999;23:1021)
- Another study found it in ~20% of both biopsy and prostatectomy cases (Anal Quant Cytol Histol 2008;30:226)
- In transurethral resections, it may be as high as 56% (Indian J Pathol Microbiol 2020;63:423)

Pathophysiology

It is a reactive change of the prostatic epithelium, often seen with inflammation

Etiology

Radiation therapy
Granulomatous prostatitis
Possibly a phenotypic adaptive mechanism directed against intraluminal antigens or lipids (APMIS 2005;113:564, Indian J Pathol Microbiol 2017;60:409)

Clinical features

Hormone therapy, radiotherapy, inflammation

Diagnosis

Morphology

Laboratory

Serum prostate specific antigen (PSA) is elevated if associated with inflammation or benign prostatic hyperplasia (BPH)

Case reports

49 and 52 year old men with serum PSAs of 4 - 5 ng/mL and incidental findings in benign biopsies (Int J Clin Exp Pathol 2014;7:3454)
68 year old man with nonspecific granulomatous prostatitis in association with eosinophilic epithelial metaplasia and prostatic adenocarcinoma (Indian J Pathol Microbiol 2017;60:409)
71 year old man with serum PSA of 10 ng/mL in association with nonspecific granulomatous prostatitis and BPH (APMIS 2005;113:564)

Treatment

Not required

Microscopic (histologic) description

Nests of squamous epithelial cells with eosinophilic cytoplasm and focal keratin
Mitoses may be seen but should not be frequent

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Paneth cell metaplasia, bottom

P504S reactivity

PAS positive, diastase resistant

Positive stains

P504S (also called AMACR) marker has been reported as strongly positive, a finding that overlaps with cancer, high grade prostatic intraepithelial neoplasia (HGPIN) and nephrogenic adenoma (Int J Clin Exp Pathol 2014;7:3454)
PAS+, diastase resistant (benign epithelium)
Neuroendocrine markers (in malignant epithelium), PSA (Am J Surg Pathol 1992;16:62)
MUC1 (Prostate 2019;79:622)

Negative stains

Lysozyme
Neuroendocrine markers (in benign epithelium) (Am J Surg Pathol 1992;16:62)

Electron microscopy description

Large exocrine type or lysosomal-like electron dense granules in the apical cytoplasm of benign epithelium that measure 240 - 480 nm (Anal Quant Cytol Histol 2008;30:226, APMIS 2005;113:564)

Differential diagnosis

Possible differential diagnosis is prostatic adenocarcinoma with Paneth cell differentiation:
- Those lesions have infiltrating, angulated glands, often with collapsed gland lumina, although they tend to be of low grade and low stage (Hum Pathol 2020;102:7)
- In contrast, benign Paneth cell metaplasia has well rounded, uniform and circumscribed groups of glands without atypia
Cancer of no specific type:
- Also has strong P504S reactivity but would have atypia and lack a granular pink cytoplasm

Squamous metaplasia

Definition / general

Squamous metaplasia is usually an incidental finding in the setting of infarction in the nodules of benign prostatic hyperplasia (BPH) or secondary to treatment (hormonal therapy and radiation)

Essential features

Usually an incidental finding in the setting of inflammation, acute infarction of benign prostatic hyperplasia or secondary to hormone / radiation therapy or following prostatic artery embolization therapy for benign prostatic hyperplasia
Can present with cytologic atypia that is reactive to the underlying process
Key to avoiding misinterpretation as cancer is to identify the underlying cause (i.e., adjacent hemorrhage or obvious necrosis indicating infarction, clinical history of hormone therapy or radiation)

Epidemiology

~0.3% incidence in unselected series (Urol J 2009;6:109)
Seen in transurethral resection of the prostate (TURP) specimens, some with benign prostatic hyperplasia, particularly with infarct of nodules of BPH; also associated with radiation
Feminizing hormone therapy for gender transition (Arch Pathol Lab Med 2022;146:252)

Pathophysiology

It is a reactive change of the prostatic epithelium

Etiology

Squamous metaplasia was found in 6% of prostatic biopsies after radiation therapy (Am J Surg Pathol 1999;23:1021)
Also with ischemia / infarction, hormone therapy, inflammation, schistosomiasis (Neoplasma 1985;32:613)

Diagnosis

Cells are nonneoplastic without atypia
- They should have a pavemented configuration with crisp cell borders, intracellular keratin, extracellular keratin pearls or intercellular bridges (tonofilaments) visible on high power

Treatment

Not required

Microscopic (histologic) description

Nests of squamous epithelial cells with eosinophilic cytoplasm and focal keratinization
Mitoses can be seen but should not be frequent

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Keratinizing squamous metaplasia

Posttherapeutic squamous metaplasia

Benign squamous metaplasia and cancer

Focal squamous metaplasia

Positive stains

Squamous metaplasia is positive for the classic squamous markers, including p63, CK5/6, HMWCK

Negative stains

Differential diagnosis

Main differential diagnoses are squamous cell carcinoma and urothelial carcinoma
Differential diagnosis is based on the degree of cytologic atypia and the presence of stromal invasion
- Squamous cell carcinoma has intercellular bridges and intracellular or extracellular keratin while urothelial carcinoma does not

Additional references

Int Braz J Urol 2013;39:222

Urothelial metaplasia

Definition / general

Urothelium normally lines the glands and ducts of the prostate

Essential features

Epithelium contains oval or spindle cells with occasional nuclear grooves
Urothelial cells may be located underneath the prostatic luminal epithelium
Prostatic ducts may also show the spread of urothelial carcinoma but in contrast to urothelial metaplasia, carcinoma has high grade nuclear atypia, similar to carcinoma in situ in the bladder

Epidemiology

Urothelial metaplasia is an exceedingly common finding, at any age

Sites

Peripheral prostate acini and ducts

Clinical features

Urothelial metaplasia is a histologic finding and has no clinical manifestations

Diagnosis

Diagnosis of urothelial metaplasia is morphologic

Treatment

Not required

Gross description

Urothelial metaplasia is not seen grossly

Microscopic (histologic) description

Epithelium is multilayered, with oval or spindle cells with occasional nuclear grooves (Ann Diagn Pathol 2019;38:11)
Focally, the cells may be oriented parallel to the basement membrane
Urothelial cells may be located underneath a prostatic luminal epithelium

Microscopic (histologic) images

Contributed by Andres Matoso, M.D., Ziad El-Zaatari, M.D. and Kenneth A. Iczkowski, M.D.

Group of prostatic ducts

Urothelial metaplasia, prostatic ducts

Urothelial metaplasia

Positive stains

Stains positive for urothelial markers include p63, GATA3

Negative stains

Prostate makers: PSA, PSAP, NKX3.1

Differential diagnosis

Urothelial carcinoma spreading in prostatic ducts:
- In contrast to urothelial metaplasia, urothelial carcinoma is characterized by high grade nuclear atypia
Intraductal prostatic adenocarcinoma:
- This is another multilayered epithelium but it would be solid to cribriform growth, with marked nuclear enlargement and prominent nucleoli, surrounded by basal cells
High grade prostatic intraepithelial neoplasia:
- Multilayering of epithelium but usually with a tufted or micropapillary pattern
- Atypia is present but to a lesser degree than in intraductal prostatic carcinoma
Urothelial metaplasia has been reported in the seminal vesicle (Ann Diagn Pathol 2012;16:145)
- In that location, golden-brown pigmented granules and a widely branched pattern of epithelium would be distinctive

Board review style question #1

Which type of benign metaplasia in the prostate can be positive for both P504S (AMACR) and PAS, as well as diastase resistant, thus necessitating caution in interpretation because of its similarity to cancer?

Mucinous metaplasia
Paneth cell-like metaplasia
Squamous metaplasia
Urothelial metaplasia

Board review style answer #1

B. Paneth cell-like metaplasia. Paneth cell-like metaplasia is positive for P504S, similar to cancer. Answer A is incorrect because although mucinous metaplasia is PAS positive and diastase resistant, it is not positive for P504S (AMACR). Answer C is incorrect because squamous metaplasia is negative for both of these markers. Answer D is incorrect because urothelial metaplasia is also negative for these markers.

Comment Here

Reference: Nonneoplastic metaplasia

Board review style question #2

The type of benign prostatic metaplasia shown in the image above is uniquely associated with which condition in the prostate?

Acute inflammation
Granulomatous inflammation
Ischemia or infarction
Radiation therapy

Board review style answer #2

C. Ischemia or infarction. The figure shows squamous metaplasia, which is the only metaplasia associated with ischemia or infarct. Answer A is incorrect because inflammation can be associated with Paneth cell-like metaplasia as well as with squamous metaplasia. Answer B is incorrect because granulomatous inflammation has been associated with Paneth cell-like metaplasia. Answer D is incorrect because radiotherapy can be associated with mucinous, Paneth cell-like or squamous metaplasias. Meanwhile, urothelial metaplasia has no specific associations and is very common.

Comment Here

Reference: Nonneoplastic metaplasia

Nonspecific granulomatous prostatitis

Table of Contents

Definition / general

Granulomatous inflammation of the prostate not associated with specific causes, such as biopsy, transurethral resection, tuberculosis (TB), fungi infection or Bacillus Calmette-Guérin (BCG) treatment
Though uncommon, nonspecific granulomatous prostatitis (NSGP) is the most frequent granulomatous inflammatory condition of the prostate, accounting for more than half of cases of prostatic granulomatous inflammation (Zhou: Genitourinary Pathology, 2nd Edition, 2015)

Essential features

Mixed, mostly chronic granulomatous inflammation (epithelioid histiocytes, giant cells, lymphocytes, plasma cells and other inflammatory cells)
No specific etiology can be established on the basis of clinical and serological findings

ICD coding

ICD-10: N41.4 - granulomatous prostatitis
ICD-11: GA91.Y - other specified inflammatory and other diseases of the prostate (includes granulomatous prostatitis)

Epidemiology

NSGP accounts for ~70% of all cases of granulomatous prostatitis (Int J Urol 2005;12:474, Ultraschall Med 2005;26:203)
NSGP is present in < 1% of needle biopsies (Zhou: Genitourinary Pathology, 2nd Edition, 2015)

Sites

Prostate

Pathophysiology

Prominent inflammatory reaction to extravasated prostatic fluid containing bacterial toxins and cell debris within the prostate

Etiology

NSGP is most likely caused by the blockage of prostatic ducts (possibly due to benign prostatic hyperplasia) and associated inflammation, which can cause epithelial disruption and damage
Cellular debris and prostatic secretion leaking into the stroma induce a granulomatous inflammatory reaction, which is typically centered around the ruptured ducts or acini (Zhou: Genitourinary Pathology, 2nd Edition, 2015)

Clinical features

May be highly suspicious for prostate cancer (Arch Pathol Lab Med 1997;121:724)
- Serum prostate specific antigen (PSA) is frequently elevated, up to 10 - 15 ng/mL
- Hypoechoic region can be seen on transrectal ultrasound
- ~50% are symptomatic with irritation, fever or chills
- Some patients have symptoms of urinary obstruction or hematuria (Epstein: Biopsy Interpretation of the Prostate, 5th Edition, 2014)

Diagnosis

Digital rectal examination: the prostate is firm, symmetrically or asymmetrically indurated
Multiparametric MRI (mpMRI): findings are often suspicious for carcinoma, hence pathology is the gold standard in disease diagnosis (Diagnostics (Basel) 2022;12:2302)

Case reports

54 year old man with lower urinary tract symptoms, PSA of 8.0 ng/mL and asymmetric prostate enlargement with a prominent, firm, right prostate lobe on digital rectal examination (Radiol Case Rep 2016;11:78)
55 year old man with left flank pain and mild lower urinary tract symptoms, PSA of 12.48 ng/mL and extensive low signal in the peripheral zone bilaterally on mpMRI (J Clin Urol 2020;15:141)
71 year old man with PSA of 6.70 ng/mL, a focal area of fixed induration involving the right lobe on digital rectal examination and a 4 cm nodular lesion characterized by low signal intensity on T2 weighted sequences, involving both the peripheral and transition zone of the right lobe with extension to the peripheral zone of the mid basal left lobe on mpMRI (Future Sci OA 2020;6:FSO591)

Treatment

Can be self limiting
Generally treated with antibiotics and steroids
Transurethral prostatic resection (TURP) or other surgical procedures may be needed in case of persistent clinical symptoms of urinary obstruction (Zhou: Genitourinary Pathology, 2nd Edition, 2015)

Gross description

Prostate is often small, firm, gray-yellow and nodular

Microscopic (histologic) description

NSGP is generally a diffuse process
Inflammation often presents as poorly defined, expansile nodular infiltrates, usually involving entire lobules
In the early phase, acute inflammation or microabscesses are present within the ducts or acini, which in turn are often filled with sloughed epithelial cells
Subsequently, rupture and destruction of the epithelial lining occur, hence the inflammatory reaction is centered on ruptured glandular structures
In the later stage, parenchymal loss, stromal fibrosis and sclerosis and chronic inflammation become prominent and giant cells are occasionally seen
Granulomas are composed predominantly of epithelioid histiocytes, lymphocytes and plasma cells, with sometimes intermixed scattered neutrophils and eosinophils, foamy macrophages and multinucleated foreign body giant cells
These granulomas are typically poorly formed and noncaseating
Cytologic atypia can be seen in the reactive glandular cells, which may resemble adenocarcinoma (Am J Clin Pathol 1991;95:330)
In rare cases, adenocarcinoma may coexist with NSGP and tumor cells and glands may be obscured by the overt inflammation (Ann Diagn Pathol 2004;8:242)

Microscopic (histologic) images

Contributed by Francesca Sanguedolce, M.D., Ph.D. and Ximing J. Yang, M.D., Ph.D.

Inflammatory cells

Duct inflammation and granuloma

Microabscesses

Foreign body giant cell

Early fibrosis

Benign glandular cells

Positive stains

CD68 (KP1), CD163 stain the histiocytes

Negative stains

Cytokeratin AE1 / AE3, CAM5.2, pancytokeratin, PSA, PSAP, AMACR (in order to rule out carcinoma) (Zhou: Genitourinary Pathology, 2nd Edition, 2015)
PAS, Grocott methenamine silver (GMS) and acid fast bacilli (AFB) histochemical stains (in order to rule out infections)
Calcium and iron histochemical stains (in order to rule out malakoplakia)

Sample pathology report

Prostate, biopsy / transurethral resection:
- Idiopathic (nonspecific) granulomatous inflammation

Differential diagnosis

Prostate adenocarcinoma:
- Prostatic epithelial cells may feature reactive and regenerative changes
- Tumor cells with foamy cytoplasm may mimic lipid laden epithelioid histiocytes (Mod Pathol 2018;31:S64)
- Tumor cells show nuclear atypia, lack basal cells and are positive for AMACR
BCG induced granulomas (Clin Imaging 2012;36:413):
- History of high grade nonmuscle invasive bladder cancer treated with BCG instillations
- Caseating granulomas
Postbiopsy / posttransurethral resections granulomas:
- Fibroid central geographic necrosis, foreign body giant cells
Infectious prostatitis:
- Positive Grocott methenamine silver (GMS) / AFB stains
Malakoplakia:
- Presence of Michaelis-Gutmann bodies
- Positive for calcium and iron histochemical stains

Additional references

Abdom Radiol (NY) 2017;42:1956, J Clin Diagn Res 2016;10:EC20

Board review style question #1

Which cell type can be seen in nonspecific granulomatous prostatitis (NSGP), shown above at the center of the image?

Multinucleated giant cell
Neoplastic cell
Osteoclast
Syncytiotrophoblast

Board review style answer #1

A. Multinucleated giant cell. Such cells result from the fusion of several histiocytes within a granulomatous inflammation. Answers B - D are incorrect because osteoclasts, syncytiotrophoblasts and sometimes neoplastic cells may be multinucleated, yet they would be found in different places (bone tissue, placenta and tumors, respectively).

Comment Here

Reference: Nonspecific granulomatous prostatitis

Board review style question #2

In cases of nonspecific granulomatous prostatitis (NSGP), which stain(s) can be used to rule out malakoplakia?

AMACR
Calcium and iron histochemical stains
Grocott methenamine silver (GMS) and acid fast bacilli (AFB) stains
Pancytokeratins

Board review style answer #2

B. Calcium and iron histochemical stains. Malakoplakia is positive for calcium and iron histochemical stains, while NSGP is not. Answers D and A are incorrect because immunohistochemical markers (pancytokeratins and AMACR) may be useful to distinguish NSGP from carcinoma. Answer C is incorrect because negativity for GMS and AFB stains rule out infective prostatitis.

Comment Here

Reference: Nonspecific granulomatous prostatitis

PIN-like carcinoma

Table of Contents

Definition / general

PIN-like adenocarcinoma is a subtype of prostatic adenocarcinoma that exhibits prostatic intraepithelial neoplasia (PIN) type architecture with single and separate glands that display tufted, flat or micropapillary growth and often cystic glandular dilatation (Mod Pathol 2006;19:899, Am J Surg Pathol 2008;32:1060, Am J Surg Pathol 2018;42:1693)
Neoplastic glands resemble PIN with pseudostratified epithelium but without basal cells and frequently with glandular crowding

Essential features

PIN-like adenocarcinoma can mimic high grade PIN but unlike high grade PIN, the glands can be crowded or cystically dilated and of critical importance, PIN-like glands completely lack basal cells
Basal cell immunohistochemistry is needed to distinguish from high grade PIN
PIN-like adenocarcinoma is Gleason pattern 3; in pure form: Gleason score 3+3 = 6/10 (grade group 1)
PIN-like adenocarcinoma is a subtype of acinar adenocarcinoma, according to WHO 2022, although there appears be a relationship with ductal adenocarcinomas as well

Terminology

PIN-like carcinoma
PIN-like ductal adenocarcinoma
PIN-like (ductal) adenocarcinoma

ICD coding

ICD-O: 8140/3 - acinar adenocarcinoma
ICD-11: 2C82.0 & XH4PB1 - adenocarcinoma of prostate & acinar adenocarcinoma of prostate

Epidemiology

1.2% of prostatic adenocarcinomas in needle biopsy tissue (Mod Pathol 2006;19:899)
Mean age: 70 years (range: 45 - 91) (Am J Surg Pathol 2018;42:1693)

Sites

Prostate
Rare cases of PIN-like adenocarcinoma involving periprostatic fat, via direct extension, in radical prostatectomy tissues (Am J Surg Pathol 2018;42:1693)
No reports of involvement of other anatomic sites by metastasis

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Abnormal digital rectal examination: nodule palpated in 3 of 8 cases (38%) (Mod Pathol 2006;19:899)

Diagnosis

Needle biopsy: tissue diagnosis established in prostate needle biopsy tissue procured via ultrasound guidance, with or without multiparametric MRI image fusion (targeted biopsies) (Mod Pathol 2006;19:899)
Transurethral resection of prostate (TURP): tissue diagnosis can be made as an incidental finding in prostatic chip tissue from TURP, typically performed for benign prostatic hyperplasia (BPH) symptoms (Am J Surg Pathol 2008;32:1060)
Radical prostatectomy: tissue diagnosis can be rendered in radical prostatectomy cases, particularly after PIN-like carcinoma is diagnosed in needle core tissue (Am J Surg Pathol 2018;42:1693)

Laboratory

Serum prostate specific antigen (PSA) elevation: frequent, with mean of 5.9 ng/mL, median of 5.5 ng/mL and range of 1.2 - 66.2 ng/mL (Mod Pathol 2006;19:899, Am J Surg Pathol 2008;32:1060)

Radiology description

Unknown

Prognostic factors

Classic PIN-like adenocarcinoma is considered Gleason pattern 3 (unlike ductal adenocarcinomas which are usually high grade pattern 4)
Limited radical prostatectomy data show no evidence of seminal vesicle invasion or lymph node metastasis (Am J Surg Pathol 2018;42:1693)
Limited clinical follow up data show no evidence of progression, recurrence or metastasis (Am J Surg Pathol 2008;32:1060)

Case reports

68 year old man with PIN-like ductal adenocarcinoma in 3 prostate needle cores (Ann Pathol 2012;32:132)

Treatment

Active surveillance
Cryotherapy (rarely used thus far)
Radiation therapy (external beam including proton beam and cyberknife, brachytherapy)
Radical prostatectomy
Hormonal therapy
Reference: Am J Surg Pathol 2008;32:1060

Microscopic (histologic) description

Single and separate glands with tufted, flat or less commonly, micropapillary, pseudostratified neoplastic epithelial cell lining, resembling high grade PIN (Mod Pathol 2006;19:899, Am J Surg Pathol 2008;32:1060, Am J Surg Pathol 2018;42:1693)
Glands are often large and cystically dilated but can also be small to medium sized; admixture of different gland sizes common (Am J Surg Pathol 2008;32:1060)
Glands are often crowded but can be widely separated
In some cases, the pseudostratified neoplastic epithelial cells are elongated, as seen in ductal adenocarcinomas, whereas in other cases the cells are cuboidal and nuclei are rounded, as observed in usual acinar adenocarcinoma (Mod Pathol 2006;19:899)
Histologic features overlap with pseudohyperplastic subtype
True papillae with fibrovascular cores, as identified in ductal adenocarcinoma, are lacking
Cribriform or solid growth, marked nuclear pleomorphism and comedonecrosis are not present
Prominent nucleoli are variably present
Basal cells must be completely absent and immunohistochemistry is typically needed (see stains below)
In needle biopsy, tissue can present in pure form or be admixed with ductal or acinar adenocarcinoma
In needle biopsy, multiple PIN-like glands with negative basal cell markers are needed to diagnose pure PIN-like adenocarcinoma (Am J Surg Pathol 2018;42:1693)
In needle biopsy, strips of neoplastic epithelium may be seen along needle core edge, possibly reflecting sampling of a cystic component (Am J Surg Pathol 2018;42:1693)
Gleason pattern assignment is 3
Pure PIN-like adenocarcinoma: Gleason score 3+3 = 6/10 (grade group 1)
According to WHO 2022, PIN-like carcinoma is classified as a subtype of acinar adenocarcinoma (although it can be related morphologically to ductal adenocarcinoma as well) (Eur Urol 2022;82:469)

Microscopic (histologic) images

Contributed by Deepika Kumar, M.D. and Peter A. Humphrey, M.D., Ph.D.

Variably sized glands

Cystic dilatation

Flat pseudostratified lining

Crowded glands

Nuclear atypia

Prominent nucleoli

Perineural invasion

Crowded glands

Micropapillary growth

Less cytologic atypia

Mimics PIN and BPH

Positive stains

PIN4 immunostain: AMACR typically overexpressed (basal cells [p63, HMWK / CK5] are completely absent) (Am J Surg Pathol 2008;32:1060)
AMACR: 93% (Mod Pathol 2006;19:899, Am J Surg Pathol 2008;32:1060)
PTEN: 91% (Am J Surg Pathol 2018;42:1693)
Pankeratins, PSA, PSAP, prostein, NKX3.1: should be positive (but no published data)

Negative stains

Basal cell markers: p63, high molecular weight cytokeratins (34 beta E12, CK903, CK5/6, CK5) (Mod Pathol 2006;19:899, Am J Surg Pathol 2008;32:1060)
ERG: 91% negative (Am J Surg Pathol 2018;42:1693)

Molecular / cytogenetics description

Activating mutations in RAS / RAF pathway in 60% of cases; these mutations are not typical in usual acinar and ductal adenocarcinoma of the prostate (Histopathology 2021;78:327)

Sample pathology report

Prostate, right base, needle biopsy:
- Prostatic adenocarcinoma, Gleason grade 3+3 = 6/10 (grade group 1), PIN-like subtype; 4/10 mm (10%) (see comment)
- Comment: PIN4 immunostain supports the diagnosis, with AMACR overexpression and complete loss of basal cell marker expression in the PIN-like glands.

Differential diagnosis

High grade prostatic intraepithelial neoplasia (PIN):
- Small, single and separate, noncrowded glands with tufted, flat or micropapillary architecture, usually without cystic dilatation
- Basal cells identified by p63 or high molecular weight keratin (34 beta E12, CK903, CK5/6, CK5)
Ductal adenocarcinoma:
- Papillae or complex and cribriform glands with columnar pseudostratified neoplastic cells
Acinar adenocarcinoma, Gleason pattern 3:
- Single and separate well formed glands, with infiltration and typically with a single cell lining layer of neoplastic secretory prostatic epithelium

Additional references

Histopathology 2012;60:59, Mod Pathol 2018;31:S71, WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

The neoplasm shown above was detected in prostate tissue. What is the diagnosis?

Basal cell hyperplasia
Ductal adenocarcinoma
High grade prostatic intraepithelial neoplasia
PIN-like prostatic adenocarcinoma

Board review style answer #1

D. PIN-like prostatic adenocarcinoma. This section shows variably sized prostatic glands, ranging from small to larger and cystically dilated glands. The gland crowding and cystic dilatation argue against high grade PIN and this impression should be confirmed by a PIN4 immunostain. In this case the PIN4 immunostain demonstrated complete and diffuse absence of basal cells in these glands, along with AMACR overexpression. Ductal adenocarcinoma is also in the differential diagnosis but papillae and cribriform structures lined by high columnar neoplastic epithelium are not visualized. Finally, basal cell hyperplasia can exhibit multilayered structures but tufted and cystic appearances are not present in that entity. Also, multilayered cells in basal cell hyperplasia would be positive for basal cell markers and negative for AMACR. The constellation of histomorphological and immunohistochemical findings is diagnostic of PIN-like adenocarcinoma.

Comment Here

Reference: PIN-like adenocarcinoma

Board review style question #2

What is the Gleason grade of the prostatic adenocarcinoma shown in the image above?

Gleason score 3+3, grade group 1
Gleason score 3+4, grade group 2
Gleason score 4+3, grade group 3
Gleason score 4+4, grade group 4

Board review style answer #2

A. Gleason score 3+3 = 6/10 (grade group 1). The microscopic image shows pure PIN-like prostatic adenocarcinoma. PIN-like prostatic adenocarcinoma is assigned Gleason pattern 3 unlike ductal adenocarcinoma, which is usually pattern 4.

Comment Here

Reference: PIN-like adenocarcinoma

Pleomorphic giant cell adenocarcinoma (pending)

Table of Contents

Definition / general

[Pending]

Postatrophic hyperplasia

Table of Contents

Definition / general

Postatrophic hyperplasia (PAH) is a clustered, small acinar proliferation in fibrotic stroma, with a pseudoinfiltrative appearance
Among types of atrophy, this type is the most likely to mimic carcinoma

Essential features

Postatrophic hyperplasia is a small acinar proliferation with a special tendency to mimic cancer because it can show somewhat more prominent nucleoli than benign acini and because the stroma is fibrotic (Mod Pathol 2004;17:328)
Notable differences from cancer include a lobular or clustered arrangement of the acini around a central dilated duct space, lack of macronucleoli in most cells and retention of basal cells by immunostaining
There is no clinical significance and no need to specify in a pathology report

ICD coding

ICD-10: N40.1 - benign prostatic hyperplasia

Epidemiology

As with atrophy in general, postatrophic hyperplasia increases with age

Pathophysiology

Oxidative stress is implicated, similar to atrophy
Chronic inflammation is also present in all postatrophic hyperplasia cases, suggesting a connection (J Urol 2006;176:1012)

Etiology

Same as Atrophy

Diagnosis

Histopathologic examination of tissue

Laboratory

As with atrophy in general, serum prostate specific antigen (PSA) might be elevated (Abdom Imaging 2009;34:271)

Treatment

No treatment is needed

Gross description

No distinct findings

Microscopic (histologic) description

Usually has a central, dilated atrophic gland surrounded by clustered smaller glands within a fibrotic / sclerotic stroma; each lobular unit of acini is circumscribed
May have more prominent nucleoli than simple atrophy does and this heightens its ability to mimic cancer (Am J Surg Pathol 1998;22:1073)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Lobule of small acini

Multiple clusters of acini

Lobular arrangement of small acini

Positive stains

Basal cell stains (high molecular weight cytokeratin, p63) should be at least focally positive

Negative stains

AMACR / P504S should be mainly negative, as with atrophy in general

Molecular / cytogenetics description

Can have an elevated proliferation index that is greater than that of benign, nonatrophic acini and greater than that of simple atrophy (Am J Surg Pathol 1998;22:1073)

Sample pathology report

Prostate, biopsies:
- Benign prostatic tissue (see comment)
- Comment: Prostatic basal cell cocktail / P504S immunostain rules out cancer in the small acini.

Differential diagnosis

Carcinoma with an atrophic appearance or atrophic variant of prostatic adenocarcinoma:
- Has a frankly infiltrative appearance, in which individual small cancer acini are interspersed between larger benign acini
- Nuclear enlargement and prominent nucleoli are seen in a higher percent of cells than in atrophy
- There is often concomitant presence of nonatrophic carcinoma
- Can also have a sclerotic stroma
- p63-, HMWK-
Simple atrophy:
- Far more common
- Has fewer prominent nucleoli (Am J Surg Pathol 1998;22:1073)
- Has a lower proliferation (Ki67) index

Board review style question #1

Prostate tissue is shown. Which histologic finding, if it were present in this image, would make this proliferation of small acini suspicious for cancer?

Central dilated duct space
Clustered or lobular arrangement of the small acini
Irregular and uncircumscribed infiltration of the small acini among larger definitely benign ones
Prominent nucleoli in only a few cells and no nuclear enlargement
Sclerotic stroma

Board review style answer #1

C. Postatrophic hyperplasia is shown. Irregular and uncircumscribed infiltration of the small acini would raise the suspicion of cancer. The clustered, lobular and circumscribed arrangement of the small acini (B) favors a benign diagnosis. The presence of the central dilated duct space (A) is also very characteristic of postatrophic hyperplasia. Sclerotic stroma (E) is a feature of postatrophic hyperplasia that can also occur in cancer and causes it to mimic cancer. Finally, as long as prominent nucleoli are visible in only a few cells (D) but not most cells, without nuclear enlargement (compared with other benign acini), that also is not suspicious for cancer.

Comment Here

Reference: Postatrophic hyperplasia

Prostatic stromal sarcoma

Table of Contents

Definition / general

Prostatic stromal sarcoma (PSS) is a rare entity (Pathology 2013;45:104)
Usually presents with urinary retention; also abnormal digital rectal examination, hematuria or hematospermia, palpable rectal mass
Includes phyllodes tumors (like those in the breast) (Pathology 2021;53:12)

Essential features

Cellular pleomorphism exceeds that of stromal proliferation of undetermined malignant potential (STUMP)
Necrosis
Mitotic activity
Extension outside the prostate

Terminology

Phyllodes tumor, cystic epithelial - stromal tumor, cystadenoleiomyofibroma, cystosarcoma phyllodes

ICD coding

ICD-10: C61 - malignant neoplasm of prostate

Epidemiology

Approximately 30 reported cases
Mean age of 54 years but ranges from 14 - 86 (Am J Surg Pathol 1998;22:148)
However, mean age in 1 study was 37, versus 61 for STUMP (Urol Int 2021;105:206)

Sites

Prostate and periprostatic tissue

Etiology

Unknown

Clinical features

Most common presentation is bladder outlet obstruction, followed by abnormal digital rectal exam, hematuria and rectal fullness (Am J Surg Pathol 2006;30:694)
Inclusion of phyllodes tumor is justified by its frequent early recurrence, infiltrative growth, extraprostatic extension and metastatic spread if incompletely excised (Clin Nucl Med 2021;46:348, J Urol 2004;172:894, Urol Case Rep 2019;28:101015, Mod Pathol 2007;20:175)

Diagnosis

Cellular pleomorphism, necrosis, mitotic activity, extension outside the prostate and metastasis rule out benign mimics

Laboratory

Serum PSA is usually normal

Radiology description

Lesion that became metastatic was distinguished by intense uptake on ¹⁸F-FDG PET imaging (Clin Nucl Med 2021;46:348)
- This high intensity is in contrast to the benign entity of stromal hyperplasia with atypia, also called STUMP
MRI shows a multinodular mass with homogeneous or heterogeneous low signal intensity on T1 weighted imaging and heterogenous high signal intensity on T2 weighted imaging (Oncol Lett 2016;11:2542)

Radiology images

Images hosted on other servers:

T1 weighted axial MRI image

T2 weighted axial MRI image

Prognostic factors

Low grade stromal sarcoma can invade locally, whereas high grade stromal sarcoma has the potential to metastasize
Metastatic sites include:
- Lymph nodes (J Surg Case Rep 2016;2016:rjw065, Oncol Lett 2016;11:2542)
- Liver (Mod Pathol 2013;26:1536)
- Subcutaneous (Int J Surg Case Rep 2015;17:82)
- Bones (Clin Nucl Med 2021;46:348)

Case reports

14 year old boy with fatal case (Rare Tumors 2014;6:5607)
31 year old man with stromal sarcoma with rhabdoid features (Ann Diagn Pathol 2010;14:453)
32 year old man with an 8 cm prostatic mass protruding into the bladder (Oncol Lett 2016;11:2542)
40 year old man with tumor involving the rectum; no recurrence after exenteration (J Surg Case Rep 2020;2020:rjaa165)
42 year old man with subcutaneous metastasis of tumor 5 years after prostatectomy (Int J Surg Case Rep 2015;17:82)
52 year old man with recurrent tumor (J Clin Pathol 2007;60:330)
66 year old man with 8 cm mass extending to bladder (J Surg Case Rep 2016;2016:rjw065)
71 year old man with urinary obstruction (Case Rep Pathol 2011;2011:252805)

Treatment

Can be managed by robotic procedure but surgery alone is inadequate (Korean J Urol 2014;55:620, J Surg Case Rep 2016;2016:rjw065)
Tumor does respond to chemotherapy and radiotherapy (Rare Tumors 2014;6:5607)

Microscopic (histologic) description

Greater cellularity, mitotic activity, necrosis and stromal overgrowth than STUMP
Storiform and infiltrative growth pattern
Sarcomas are subdivided into low grade and high grade based on mitotic rate, necrosis and degree of atypia (Am J Surg Pathol 2006;30:694)
There may be either stromal elements with benign glands resembling malignant breast phyllodes tumors or pure stromal elements

Microscopic (histologic) images

Contributed by Kenneth Iczkowski, M.D.

Phyllodes tumor: malignant epithelium

Positive stains

Vimentin (100%), CD34 (100%), progesterone receptor (85%), desmin (50%)
High Ki67 proliferation index stands in contrast to STUMP (Virchows Arch 2021;478:619)

Negative stains

Smooth muscle actin (33%) and HHF35 (25%) may be positive
S100 (100%), ER (usually), STAT6 (Virchows Arch 2021;478:619)

Molecular / cytogenetics description

Both prostatic stromal sarcoma (all 4 cases) and stromal hyperplasia with atypia (also termed STUMP) (7 of 8 cases) shared chromosomal aberrations by array comparative genomic hybridization (aCGH)
- Most common was loss of chromosome 13 followed by losses of chromosomes 14 or 10 (Mod Pathol 2013;26:1536)
- Additional mutations, such as CHEK2 and KTM2D, favored benign entities, whereas TP53 and RB1 mutations favored malignant (Mod Pathol 2013;26:1536)
  - This suggests 2 separate entities; however, either mutations or rearrangements were found via DNA sequencing in 10 of 10 cases of both STUMP and PSS, while only PSS included phyllodes pattern (Mod Pathol 2021;34:1763)
Also, the specificity of chromosome 13 and 14 has been questioned and whole exome sequencing found a variety of changes in STUMP and PSS, implying these 2 entities are part of the same spectrum (Mod Pathol 2021;34:2082)

Sample pathology report

Prostate, transurethral resection:
- Prostatic stromal sarcoma (see comment)
- Comment: Cells have marked nuclear atypia, mitotic activity and pleomorphism. Necrosis is present. Tumor is positive for CD34 and has high Ki67 index, confirming the diagnosis.

Differential diagnosis

Stromal hyperplasia with atypia (also termed STUMP):
- More common than stromal sarcoma
- No marked atypia or necrosis
- Degenerative nuclei
Leiomyoma:
- Much more common
- Consistently positive for smooth muscle markers
- CD34 is negative
Synovial sarcoma:
- Ruled out if CD34 is positive
Gastrointestinal stromal tumor:
- Ruled out if CD117 is negative

Board review style question #1

If only 2 positive markers were chosen to rule in prostatic stromal sarcoma, what would they be?

Desmin and S100 protein
Estrogen receptor and CD34
High Ki67 proliferation index and CD34
S100 protein and STAT6
Smooth muscle actin and estrogen receptor

Board review style answer #1

C. High Ki67 proliferation index and CD34. CD34 positivity rules out a smooth muscle tumor (leiomyoma, leiomyosarcoma) or synovial sarcoma, while a high Ki67 proliferation index rules out STUMP, which has a low index. Desmin (A) does not discriminate the sarcoma from STUMP. Estrogen receptor and CD34 (B) are mostly positive in both sarcoma and STUMP but do not distinguish them. S100 protein and STAT6 (D) are both negative in sarcoma and STUMP. STAT6 is specific for solitary fibrous tumor. Smooth muscle actin and estrogen receptor (E) do not discriminate sarcoma from STUMP.

Comment Here

Reference: Prostatic stromal sarcoma

Prostatic stromal tumor of uncertain malignant potential

Table of Contents

Definition / general

Stromal tumor of uncertain malignant potential (STUMP) is a term that should be reserved for a category of benign lesions that almost never metastasize (Arch Pathol Lab Med 2008;132:1729)
Stromal neoplasms that involve only the prostate are a heterogeneous group including:
- 2 benign entities: STUMP, leiomyoma with atypia
- 2 malignant entities: stromal sarcoma, phyllodes tumor

Essential features

Rare prostatic tumors with stromal degenerative atypia featuring vacuolated nuclei
Some cases have cyst spaces (need to rule out phyllodes tumor) (Clin Nucl Med 2021;46:348)
May recur rapidly after incomplete resection; rarely progress to stromal sarcoma

Terminology

Stromal hyperplasia with atypia (a synonym that some scholars consider preferable to STUMP) more distinctly separates it from malignant neoplasms (Pathology 2021;53:12)

ICD coding

ICD-10: N40.1 - benign prostatic hyperplasia with lower urinary tract symptoms

Epidemiology

STUMP occurs in a broad age range with median age of 58 - 61 years (Am J Surg Pathol 1998;22:148, J Urol 2004;172:894, Urol Int 2021;105:206)

Clinical features

Usually presents with urinary obstruction, followed by hematuria, hematospermia and rectal fullness
Many STUMPs are incidental findings and behave indolently
Recurrence can occur after transurethral resection if definitive surgery is not pursued (Urol Int 2021 Jul 6 [Epub ahead of print])
- Local recurrence rate has been reported as 6 of 13 cases, 2 of 12 and 3 of 18; however, metastasis should not occur (Am J Surg Pathol 1998;22:148, Urol Int 2021;105:206, Arch Pathol Lab Med 2008;132:1729)

Diagnosis

CD34, Ki67 and cytokeratin are the most helpful immunostains (see Positive stains below)

Radiology description

STUMP as a solid / cystic lesion, has high signal intensity on diffusion weighted images; STUMP is favored by restricted diffusion of FDG or low FDG accumulation by ¹⁸F-FDG-PET, correlating with no recurrence or metastasis (Eur J Radiol Open 2020;7:100233)
Conversely, a malignant lesion with proven metastases, classifiable as phyllodes tumor (cystic epithelial tumor), will show high diffusion and FDG accumulation (Clin Nucl Med 2021;46:348)

Radiology images

Images hosted on other servers:

Lesion: low FDG uptake

Prognostic factors

Proliferative index as measured by mitotic count or Ki67 may presage worse outcome, although if high enough, sarcoma should be considered

Case reports

34 year old man with prostatic stromal tumor with fatal outcome (Rare Tumors 2010;2:e57)
56 year old man with recurrent prostatic stromal tumour of uncertain malignant potential (Ann Acad Med Singapore 2005;34:441)
59 year old man with a PSA of 7.9 (Case #269)
67 year old man with incidental prostatic stromal tumor of uncertain malignant potential (Urologia 2012;79:65)
67 year old man with PSA of 8.4 and cellular myxoid neoplasm focally positive for ER (Oncology (Williston Park) 2019;33:685007)
72 year old man with PSA of 2.53, illustrating that a STUMP may recur after transurethral resection, in this instance 4 months later and with concurrent prostatic adenocarcinoma (Urol Int 2021 Jul 6 [Epub ahead of print])

Treatment

Simple excision is the usual approach (see Case reports)

Gross images

Case #269

STUMP, prostate cross section

Images hosted on other servers:

STUMP that eventually metastasized

Microscopic (histologic) description

STUMP is morphologically heterogeneous but STUMP should have rare to no mitotic activity and no necrosis
Atypical stromal cells insinuate between benign acini
4 patterns of STUMP have been described, all featuring cells with degenerative / smudged chromatin (J Urol 2004;172:894, Am J Surg Pathol 2006;30:694):
- Hypercellular stroma with scattered degenerative atypia featuring vacuolated nuclei and smudged chromatin (50% of cases) (see Micro image 1)
- Hypercellular stroma with bland spindle stromal cells
- Benign (phyllodes-like, similar to breast) leaf-like growth of hypocellular fibrous stroma surfaced by benign prostate epithelium
- Myxoid stroma with bland cells, lacking the nodularity seen in benign hyperplasia (Am J Surg Pathol 1998;22:148, Am J Surg Pathol 2006;30:694)
STUMP may also have epithelial proliferations that mask its diagnosis: most commonly glandular crowding and prominent basal cell layer, followed in frequency by prominent papillary infolding (Am J Surg Pathol 2011;35:898)

Microscopic (histologic) images

Contributed by Kenneth Iczkowski, M.D., Theo van der Kwast, M.D. and Case #269

STUMP in prostate biopsy that had cancer in other fields

Mitosis

Hypercellular stroma

Circumscription of nodule

Multinucleation

Degenerative atypia

STUMP positive for CD34

STUMP positive for desmin

STUMP positive for HHF35

STUMP with low index for Ki67

STUMP positive for progesterone receptor

Positive stains

Only a few immunostains are discriminatory for STUMP; others are not helpful:
- CD34, desmin and vimentin are almost always positive in both STUMP and sarcoma (CD34 positivity helps rule out smooth muscle proliferations or synovial sarcoma) (Prostate 1990;16:245, Mod Pathol 2021;34:1763)
STUMP arises from specialized, hormonally responsive prostatic stromal cells, thus hormonal receptor immunostains may be positive
- Panel may include progesterone receptor (85 - 90%) and androgen receptor (100%) (Arch Pathol Lab Med 2008;132:1729, Mod Pathol 2021;34:1763, Arch Pathol Lab Med 2008;132:1729)
Variable staining was noted for smooth muscle actin (J Urol 2004;172:894, Am J Surg Pathol 2006;30:694, Arch Pathol Lab Med 2008;132:1729)

Negative stains

STUMP is almost always cytokeratin negative (or may have rare cells positive), ruling out sarcomatoid carcinoma (Mod Pathol 2021;34:1763)
Low Ki67 proliferation index and negative STAT6 help rule out sarcoma and solitary fibrous tumor, respectively (Virchows Arch 2021;478:619)

Molecular / cytogenetics description

Variety of different somatic variants were detected by next generation DNA and RNA sequencing in 7 of 14 STUMP or prostatic stromal sarcoma (PSS) cases; this included genetic aberrations seen in specific mesenchymal tumors arising at other anatomic sites, including soft tissue and the uterus (Mod Pathol 2021;34:1763)
Both prostatic stromal sarcoma (all 4 cases) and STUMP (consistent with stromal hyperplasia with atypia - 7 of 8 cases) shared chromosomal aberrations by array comparative genomic hybridization (aCGH)
- Most common was the loss of chromosome 13 followed by loss of chromosomes 14 or 10 (Mod Pathol 2013;26:1536)
- Certain additional mutations such as CHEK2 and KTM2D favor benign entities, whereas TP53 and RB1 mutations favor malignant; this suggests that sarcoma and STUMP exist on the same spectrum of entities (Mod Pathol 2013;26:1536)
  - However, either mutations or rearrangements were detected via DNA sequencing in 10 of 10 cases for both STUMP and PSS (in which PSS included phyllodes pattern) (Mod Pathol 2021;34:1763)
However, the specificity of chromosome 13 and 14 has been questioned and whole exome sequencing found a variety of changes in STUMP and PSS, implying these are not specific for the entities (Mod Pathol 2021;34:2082)

Sample pathology report

Prostate, transurethral resection:
- Stromal hyperplasia with atypia (or stromal tumor of uncertain malignant potential) (see comment)
- Comment: Nuclear atypia is not present, other than degenerative features. The diagnosis is supported by CD34 positivity, a low Ki67 proliferation index and cytokeratin negativity. Sarcoma and carcinoma are ruled out. In the literature, this lesion may recur after complete excision but does not metastasize.

Differential diagnosis

Solitary fibrous tumor:
- Also can have positive staining for CD34 and progesterone receptor but reactivity for STAT6 discriminates it from STUMP (Malays J Pathol 2020;42:449, Virchows Arch 2021;478:619)
Stromal sarcoma:
- Has mitotic figures, marked atypia and necrosis; lower expression of PR (Virchows Arch 2021;478:619)
Phyllodes tumor (malignant):
- Has epithelial component
Carcinosarcoma:
- Has malignant epithelial (CK+) and stromal components
Sarcomatoid carcinoma:
- Malignant cells; epithelial cells are CK+, ERG+ (Am J Surg Pathol 2011;35:898)
Stromal nodule of nodular hyperplasia / benign prostatic hyperplasia:
- Hyperplastic, not atypical stromal cells

Additional references

Mod Pathol 2007;20:148

Board review style question #1

Expected features of STUMP include

CD34 is negative
Cytokeratin positivity
Degenerative nuclear atypia with nuclear vacuolation
Does not tend to recur after resection necrosis
Necrosis

Board review style answer #1

C. Degenerative nuclear atypia is common to all 4 patterns of STUMP, with nuclear vacuolation in most

A. CD34 should be positive, ruling out smooth muscle tumor (but not sarcoma)
B. Cytokeratin positivity should prompt consideration of sarcomatoid carcinoma or carcinosarcoma
D. Does have a tendency to recur after resection, so a prior diagnosis of STUMP is important
E. Necrosis is a malignant feature and probably rules out STUMP

Comment Here

Reference: STUMP

Prostatitis

Table of Contents

Definition / general

Prostatitis is a clinical term only, so it should not be diagnosed on pathology reports
Anatomic pathologists should simply diagnose chronic, acute or granulomatous inflammation
Should be based on symptoms of pelvic pain and sexual dysfunction, with or without bacteria, 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

Essential features

Either lymphocytes, neutrophils, eosinophils or histiocytes
When infectious, caused mainly by gram negative rods

Terminology

Inflammatory disease of the prostate

ICD coding

ICD-10: N41 - inflammatory diseases of prostate
ICD-11: GA91 - inflammatory and other diseases of prostate

Epidemiology

Chronic prostatitis / chronic pelvic pain syndrome (CPPS), also known as NIH category III prostatitis, abacterial prostatitis or prostatodynia, is the most common urological diagnosis in men older than 50 years
Current evidence suggests an inverse relationship between volume of atrophy (with or without inflammatory cells) and cancer (Hum Pathol 2014;45:54)
Clinically diagnosed prostatitis may increase prostate cancer risk and may be race dependent; whereas histological prostatic inflammation can increase serum PSA and produce a false positive result that decreases the likelihood of cancer detection (PloS One 2021;16:e0252951, Mod Pathol 2012;25:1023)

Sites

Can affect central and peripheral zones of the prostate (AJR Am J Roentgenol 1998;170:753)

Pathophysiology

Histologic prostatitis, when present along with hyperplasia (BPH), correlates with greater lower urinary tract symptoms, prostate volume and risk of acute urinary retention; this suggests that prostatitis plays a role in progression of BPH (Aging Male 2022;25:88)
Reflux of infected urinary contents into prostatic ducts is a postulated cause (Saudi J Kidney Dis Transpl 2011;22:298)
Risk factors: indwelling catheter, underlying voiding dysfunction, poorly controlled diabetes, end stage renal disease (ESRD), cirrhosis, immunosuppression (Nat Rev Urol 2011;8:207)

Etiology

Abacterial: this is a heterogeneous condition with many possible causes; however, aberrant cytokine function seems to be a final common pathway (J Urol 2010;184:1253)
- Newly recognized cause is IgG4 related prostatitis, which presents with obstruction and resolves with steroids and rituximab (BMC Urol 2022;22:35)
Bacterial: Escherichia coli (accounts for > 70% of cases), Klebsiella, Pseudomonas, Proteus, Enterobacter, Enterococcus species, Staphylococcus aureus (see Abscess)

Clinical features

Systemic:
- Headache, fever, chills and general malaise, low back pain
Prostate (local) (Korean J Urol 2012;53:860):
- Severely tender prostate with areas of fluctuation on digital rectal examination
- Perineal pain
- Dysuria, urinary urgency or frequency, hematuria, purulent urethral discharge
- Obstructive urinary symptoms

Diagnosis

Overall, history and physical findings, complete blood count with differential, urine analysis, blood culture, urine culture and even PCR (detection of sexually transmitted organisms) may be used
For specific types:
- Chronic abacterial prostatitis / chronic pelvic pain syndrome (CPPS):
  - Includes prostatodynia, category III or abacterial prostatitis
  - Defined by the International Prostatitis Collaborative Network under the National Institute of Health, and diagnosis follows clinical, microbiological and laboratory criteria (JAMA 1999;282:236, Prostate Cancer Prostatic Dis 2016;19:132)
  - Histopathologic diagnosis is less crucial or may not be required for diagnosis
  - Clinically similar to bacterial prostatitis, with persistent pain, especially after ejaculation; but no bacteria are cultured from expressed prostatic secretions (EPS)
  - Excessive white blood cells (WBC) may be present or absent
  - WBC number fluctuates within the same patient and does not correlate with symptom severity
  - Essentially incurable
- 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
- Granulomatous prostatitis:
  - Necrotizing or nonnecrotizing granulomas may be seen in men who have undergone bacillus Calmette-Guérin (BCG) treatment for bladder cancer
  - Also occurs posttransurethral resection
  - Otherwise, most cases are idiopathic and do not require acid fast stain
- Eosinophilic prostatitis:
  - According to case reports, this is capable of increasing serum PSA levels (Br J Urol 1992;69:61)
- IgG4 related prostatitis:
  - IgG4 related disease is a rare but under recognized type of chronic abacterial prostatitis that can cause urinary obstruction in young men (Case Rep Urol 2013;2013:295472)
  - Elevated serum IgG4 levels are diagnostic; serum PSA should be normal
  - There may be chronic sclerosing sialadenitis
  - Biopsy shows prominent plasma cells; if the symptoms resolve following treatment with steroids, there is no need for prostate biopsy

Laboratory

Bacterial: prostatic secretion cultures should have bacterial counts 10x higher than urethral / bladder cultures
Nonbacterial: > 10 WBC/HPF in prostatic secretions without pyuria
Can raise the serum PSA above normal (Hinyokika Kiyo 1993;39:445)

Radiology description

Computed tomography (CT scan) of the abdomen and pelvis (AJR Am J Roentgenol 1987;148:899)
- Can better delineate the spread of infection to adjacent organs
Magnetic resonance imaging (MRI) (Indian J Radiol Imaging 2011;21:46)
- Hypointense signal on T1 and hyperintense on T2 image

Prognostic factors

Depends on the timely diagnosis and treatment and type of prostatitis

Case reports

See case reports for specific types of prostatitis such as granulomatous, nonspecific granulomatous, malakoplakia and abscess

Treatment

Difficult because antibiotics penetrate poorly into prostate

Microscopic (histologic) description

WBCs in biopsied prostatic tissue do not correlate with the degree of pain in chronic prostatitis / CPPS
Density of lymphocytes in the prostate is remarkably constant across age groups and races (Prostate 2003;55:187)
Lymphoid aggregates are not specific for prostatitis but may be part of hyperplasia
Neutrophils tend to be in lumen spaces and macrophages in stroma; however, this is not specific for prostatitis
Xanthoma cells
- Localized collection of cholesterol laden histiocytes, usually idiopathic
- Abundant vacuolated foamy cytoplasm; small, uniform, benign appearing nuclei, small inconspicuous nucleoli
- May have infiltration of prostatic stroma by cords and individual cells (Am J Surg Pathol 2007;31:1225)
- No mitoses, rare / no necrosis
- May be interpreted as high grade prostate cancer or prostate cancer with treatment effect or foamy gland carcinoma, particularly in needle biopsies (Hum Pathol 1994;25:386, Am J Surg Pathol 2007;31:1225)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Reactive chronic inflammation

Acute inflammation in lumens

Idiopathic granuloma in a TURP

Xanthomatous histiocyte proliferation

CD68 positive stain - confirmatory

Positive stains

For bacterial type, bacteria may be visible on Gram stain

Sample pathology report

Prostate, biopsy:
- Benign prostatic tissue with mild / moderate / severe chronic inflammation (with mild / moderate / severe acute inflammation, with mild / moderate / severe granulomatous inflammation)

Differential diagnosis

Acute bacterial prostatitis:
- Clinically and histologically is similar (neutrophils are mostly in lumens and epithelium)
- No fluctuant mass during a rectal examination
- No hypoechoic areas on ultrasound
Chronic bacterial prostatitis:
- Similar clinical symptoms but lower intensity
- Predominant lymphocytic infiltration (lymphocytes are mostly in the stroma)
Granulomatous prostatitis:
- Fever and chills are common
- Irritative voiding symptoms of urgency, frequency
- May have history of bladder cancer BCG treatment
- Necrotizing or nonnecrotizing granulomas (cohesive clusters of histiocytes, usually with admixed lymphocytes, eosinophils, neutrophils)
Prostate carcinoma:
- May mimic benign acini with reactive inflammatory atypia
- Typically lack background inflammation
- Small glands, sometimes medium to large glands, papillary or cribriform glands or solid growth or single cells
- Nucleomegaly, prominent and multiple nucleoli, lack basal cell layer

Board review style question #1

A 67 year old asymptomatic man underwent a prostate biopsy because of elevated serum prostate specific antigen (PSA) of 4.0. Findings of a representative biopsy core are shown above. In this setting, what are the findings most consistent with?

Chronic abacterial prostatitis due to chronic pelvic pain syndrome (CPPS)
Eosinophilic prostatitis
IgG4 disease
Nonnecrotizing granulomas
Nonspecific acute and chronic inflammation

Board review style answer #1

E. Nonspecific acute and chronic inflammation. Stromal lymphocytes and a few luminal neutrophils are present. Answers D and B are incorrect because granulomas or eosinophils are not evident. Answer C is incorrect because plasma cells are not evident, which goes against IgG4 disease. Answer A is incorrect because the patient is asymptomatic, so CPPS is not consistent with the findings.

Comment Here

Reference: Prostatitis

Pseudohyperplastic pattern

Table of Contents

Definition / general

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 (Pseudo Oncol Res 2003;9:232)
60% of tumor has benign architectural but malignant nuclear features (Am J Surg Pathol 2000;24:1039)

Case reports

70 year old man ( Case #117)

Microscopic (histologic) description

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 (Am J Surg Pathol 1998;22:1239)
With core needle biopsy, only diagnostic clue may be a subtle disruption of the normal glandular - stromal relationship (Mod Pathol 2004;17:307, Am J Surg Pathol 2010;34:35)
Despite its benign appearance, may be associated with intermediate grade cancer and can exhibit aggressive behavior

Microscopic (histologic) images

Case #117

Various images

Triple stain (AMACR, p63, HMWK)

Positive stains

P504S in 70% of cases (Am J Surg Pathol 2003;27:772, Histopathology 2006;48:668)

Negative stains

High molecular weight keratin and p63 show absence of basal cells in hyperplastic glands (normal glands serve as positive control)

Differential diagnosis

Adenosis, high grade PIN (not as crowded or infiltrative), benign hyperplasia

Sarcomatoid adenocarcinoma

Table of Contents

Definition / general

WHO recognized variant subtype of prostatic adenocarcinoma
Malignant monophasic or biphasic neoplasm including a spindle cell or pleomorphic sarcomatoid component
Represents dedifferentiation from (usually high grade acinar) prostatic adenocarcinoma
Clinical, histologic, immunophenotypic or molecular evidence of origin from prostatic adenocarcinoma

Essential features

Malignant sarcomatoid neoplasm, usually admixed with recognizable prostatic adenocarcinoma but rarely monophasic
Monophasic cases have history, immunophenotypic or molecular evidence relating the sarcomatoid malignancy to prostatic adenocarcinoma
Most cases are associated with prior radiotherapy or hormone therapy
Usually clinically aggressive, high stage, poor prognosis

Terminology

Formerly carcinosarcoma

ICD coding

ICD-O: 8572/3 - adenocarcinoma with spindle cell metaplasia
ICD-10: C61 - malignant neoplasm of prostate
ICD-11: 2C82 & XH2QL8 - malignant neoplasms of prostate and adenocarcinoma with spindle cell metaplasia

Epidemiology

Rare, < 200 cases reported
Age range: 49 - 88 years (Urology 2015;86:539)
> 60% have history of prior acinar prostatic adenocarcinoma (Am J Surg Pathol 2006;30:1316)
- 9 - 22 years after initial diagnosis (Urology 2015;86:539)
90% have history of prior treatment by androgen deprivation or radiotherapy

Sites

Prostate gland
Frequent invasion of the bladder
Systemic metastases to lungs and bone

Pathophysiology

Arises via dedifferentiation from precursor conventional prostatic adenocarcinoma
Preexisting carcinoma diagnosed may be low grade (grade group 1, ~50%) or higher (grade group 2, ~50%)
Molecular features shared between sarcomatoid and carcinomatous component (Histopathology 2015;66:898)
- ERG rearrangements shared between components

Etiology

Risk factors related to precursor conventional prostatic adenocarcinoma
Strong association with prior hormone or radiation therapy

Clinical features

Organ confined disease has best prognosis
- Definitive treatment recommended
Increased aggression in locally advanced and metastatic disease (Urology 2015;86:539)
Documented metastases most often show adenocarcinomatous component

Diagnosis

Biopsy, transurethral resection or prostatectomy specimens

Laboratory

PSA elevated in some cases

Radiology description

Staging by MRI, CT and bone scan

Radiology images

Contributed by Steven Christopher Smith, M.D., Ph.D.

Liver metastases

Prognostic factors

Median overall survival < 1 year
Prognosis (overall survival) has been related to a modified staging system (Urology 2015;86:539)
- Organ confined: ≥ 5 years
- Locally advanced / bladder invasion: 9 months
- Metastatic disease: 7 months

Case reports

54 year old man with recurrence as sarcomatoid carcinoma (Case Rep Urol 2013;2013:631809)
76 year old man with urinary obstruction (Int J Clin Exp Pathol 2010;3:319)
80 year old man with large pelvic mass (Urol Case Rep 2020;34:101432)
80 and 72 year old men, each diagnosed less than 1 year from the original diagnosis of prostatic adenocarcinoma (World J Clin Cases 2021;9:1668)

Treatment

Standard treatments not established
Localized sarcomatoid carcinoma treated by radical prostatectomy or external beam radiotherapy

Gross description

Usually large transurethral resection samples
- Gray / yellow / white fibrous tissue
Hemorrhage and necrosis prominent
Reference: Journal of Case Reports 2014;4:33

Microscopic (histologic) description

Overall criteria, a tumor showing either:
- Biphasic admixture of malignant sarcomatoid component with recognizable conventional prostatic adenocarcinoma
- Monophasic sarcomatoid tumor with historical, immunohistochemical or molecular evidence relating it to prostatic adenocarcinoma
Sarcomatoid component
- Most commonly a nondescript spindle cell appearance
- Hypercellular fusiform cells
- Storiform, fascicular or patternless architecture
- High grade with large hyperchromatic nuclei
- Frequent mitotic activity and necrosis
- May resemble high grade pleomorphic sarcoma with giant cells and bizarre nuclei
- Subset with heterologous sarcoma patterns with differentiation toward other mesenchymal lineages
  - Osteosarcoma (most common)
  - Rhabdomyosarcoma
  - Chondrosarcoma
Carcinomatous component
- Most commonly high grade acinar adenocarcinoma
- Uncommonly: foamy gland, ductal, adenosquamous, signet cell presentations
- Individual polygonal or epithelioid cells may be present within the sarcomatoid component
- Adenosquamous small cell components may be present
Monophasic spindle cell morphology
- History documents a prior acinar adenocarcinoma
- Immunohistochemical evidence of epithelial differentiation
  - Expression of keratins, prostate lineage markers
- Molecular evidence of prostatic origin
  - Rearrangements of ERG of other ETS family proto-oncogenic transcription factors
Reference: Am J Surg Pathol 2006;30:1316

Microscopic (histologic) images

Contributed by Steven Christopher Smith, M.D., Ph.D.

Transurethral resection

Biphasic histology

Monophasic sarcomatoid carcinoma

Adenosquamous component

Subtle epithelial component

Focal epithelial differentiation

Heterologous chondrosarcoma pattern

Heterologous osteosarcoma pattern

Heterologous rhabdomyosarcoma pattern

Pleomorphic sarcomatoid pattern

Keratin positivity

ERG positivity

Immunohistochemistry & special stains

Carcinomatous component
- Pancytokeratins: AE1 / AE3, CAM5.2, OSCAR
- EMA
- PSA and PAP
  - If positive, only focally
  - May be lost even in carcinomatous component posttreatment
- Prostein / NKX3.1, PSMA
  - Expression may be retained even if PSA / PSAP lost
- ERG (may be positive in ERG rearranged carcinomas)
Sarcomatoid component
- Pancytokeratins: AE1 / AE3, CAM5.2, OSCAR
  - Usually focally positive in sarcomatoid spindle cell component
- High molecular weight cytokeratins: CK903 / 34 beta E12 and CK5/6
  - May show greater positivity in spindle cell component than pancytokeratins in some cases
- p63 (focally) in sarcomatoid component
- Other mesenchymal makers:
  - SMA, MSA and caldesmon positive in some cases
  - Desmin, myogenin, MyoD1 in heterologous rhabdomyosaromatous elements
  - S100 in heterologous chondrosarcoma
References: Am J Surg Pathol 2006;30:1316, Mod Pathol 2018;31:S133

Molecular / cytogenetics description

ERG rearrangements detectable by FISH or sequencing in both carcinomatous and sarcomatoid components in cases with rearrangements (Histopathology 2015;66:898, Histopathology 2020;77:890)

Sample pathology report

Prostate gland, transurethral resection:
- Sarcomatoid carcinoma of the prostate, involving 10 of 15 tissue fragments resected and ~75% of the tissue sampled (see comment)
- Focal heterologous osteosarcomatous differentiation is present
- Associated prostatic adenocarcinoma, grade group 5 (Gleason score 4+5=9)
- Comment: Sarcomatoid carcinoma of the prostate is an aggressive malignancy where carcinoma undergoes dedifferentiation to a sarcomatous component demonstrating variable but usually spindle cell or pleomorphic morphology. Many cases are associated with previous hormone or radiotherapy for prostatic adenocarcinoma.

Differential diagnosis

Prostatic stromal sarcoma:
- Arises primarily from prostatic stroma
- No admixed (or prior) adenocarcinomatous component
- Lacks keratin, p63, prostate marker expression
- Usually expresses CD34, progesterone receptor (PR)
- Variable SMA, desmin positivity
Prostatic leiomyosarcoma:
- No admixed (or prior) adenocarcinomatous component
- Usually more fascicular spindle cell growth
- Elongated cells, eosinophilic cytoplasm, cigar shaped nuclei
- Diffuse SMA, desmin positivity
- Lacks keratin, p63, prostate marker expression
Prostatic solitary fibrous tumor:
- No admixed (or prior) adenocarcinomas component
- More cytologically uniform tumor with small spindled to polygonal cells
- Uniform, angulated or carrot shaped nuclei
- Patternless architecture, staghorn thin walled vasculature
- Diffuse expression of CD34 and STAT6
- Lacks keratin, p63, prostate marker expression

Additional references

Med Oncol 2019;36:27, Cancer 1992;69:2676, Am J Clin Pathol 1989;92:131

Board review style question #1

An 81 year old man presents with an obstructing urethral mass and on CT scan imaging is shown to have recent development of a 6 cm obstructing mass arising from the prostate, compressing and displacing the urethra. Transurethral resection demonstrates a spindle cell tumor with brisk mitotic activity and nuclear pleomorphism but no prostatic or urothelial carcinoma is visible. What additional findings would argue most strongly for diagnosis of sarcomatoid carcinoma of the prostate?

Dense, fascicular growth, diffuse expression of desmin and SMA
Focal desmin positivity, diffuse vimentin positivity
Patchy high molecular weight keratin expression in subsets of the spindle cells, history of high grade prostatic adenocarcinoma treated by androgen deprivation therapy and pelvic radiotherapy 5 years previously
Staghorn vasculature, CD34 and STAT6 expression

Board review style answer #1

C. Patchy high molecular weight keratin expression in subsets of the spindle cells, history of high grade prostatic adenocarcinoma treated by androgen deprivation therapy and pelvic radiotherapy 5 years previously

Comment Here

Reference: Sarcomatoid carcinoma

Board review style question #2

A 48 year old man presents with an obstructing mass arising in the prostate and bladder neck. It demonstrates dense, organized fascicular growth of fusiform cells with dense eosinophilic cytoplasm and elongated nuclei. What features would support consideration of a prostatic leiomyosarcoma?

Positive rearrangement of the ERG locus by FISH
Scattered admixed glands with cytoplasmic atypia; focal p63 and CK903 / 34 beta E12 expression in scattered spindle cells
Strong, diffuse expression of SMA and desmin
Thin walled ramifying vasculature, nuclear STAT6 positivity

Board review style answer #2

C. Strong, diffuse expression of SMA and desmin

Comment Here

Reference: Sarcomatoid carcinoma

Sclerosing adenosis

Table of Contents

Definition / general

A mixture of well formed glands, usually very small, in a background of very cellular stroma composed of spindle cells

Essential features

Sclerosing adenosis is a benign proliferation of small well formed glands, similar to adenosis but with prominent cellular spindle cell stroma
The stroma displays a characteristic myxoid appearance
Rare finding in ~2% of radical prostatectomy specimens, more frequent in TURP specimens

Terminology

Historically designated as adenomatoid prostatic tumor, but the term sclerosing adenosis is preferred as it is unrelated to adenomatoid tumor of other sites

Epidemiology

More frequently seen in TURP specimens, but occasionally seen in needle biopsies
One series reported it in 2% of radical prostatectomies

Sites

Central zone of the prostate

Clinical features

The only clinical relevance is that it may be confused with prostatic adenocarcinoma

Diagnosis

The glands of sclerosing adenosis display cells with clear or amphophilic cytoplasm and nuclei without prominent nucleoli
Basal cell layer can be seen in H&E stained slide or highlighted with basal cell markers

Case reports

83 year old man with coexisting basal cell hyperplasia (Med Mol Morphol 2010;43:226)

Positive stains

Basal cells are positive for high molecular weight cytokeratin, S100 and muscle specific actin

Electron microscopy description

Myoepithelial type cells may arise from basal cells by metaplasia (Am J Surg Pathol 1992;16:383)

Differential diagnosis

Adenocarcinoma of the prostate is the main differential diagnosis; in contrast to carcinoma, sclerosis adenosis shows a basal cell layer

Additional references

Am J Surg Pathol 1991;15:660, Histopathology 2010;56:627

Signet ring-like cell adenocarcinoma

Table of Contents

Definition / general

< 50 cases identified in English language literature (Mayo Clin Proc 2010;85:1130)
Highly malignant

Treatment

Similar to traditional adenocarcinoma - hormonal therapy, radiation, surgery

Microscopic (histologic) description

Solid, acinar, single-line patterns
Primarily composed of tumor cells with signet ring cell pattern (at least 25%) due to intracellular accumulation of mucin compressing the nucleus into a crescent shape

Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains

PSA (variable in some studies), AE1/AE3, CAM 5.2, Ki-67 (mean 8%), PAS-diastase, mucicarmine (50%), Alcian blue (60%), α-methylacyl coenzyme A racemase (P504S) and cytokeratin 5/6

Negative stains

Bcl2 (rare cells positive), CEA (80%)

Electron microscopy description

Intracytoplasmic lumina lined by microvilli

Differential diagnosis

Artifactual changes in lymphocytes post-TURP: no classic adenocarcinoma, CD45+, negative for mucin, PSA, PAP (Am J Surg Pathol 1986;10:795)
Benign signet ring cell change: no classic adenocarcinoma, negative for mucin, PSA, PAP (Am J Surg Pathol 2002;26:1066)
GI primary: much more common; no typical prostatic adenocarcinoma, positive GI workup (abdominal CT, colonoscopy, esophagogastroduodenoscopy); PSA-, PAP-
Mucinous carcinoma with signet ring cells: > 25% of tumor is extracellular mucin and < 25% of tumor cells feature signet ring cells

Additional references

Arch Pathol Lab Med 1992;116:99, Am J Surg Pathol 1988;12:453, Mod Pathol 1998;11:552

Small cell neuroendocrine carcinoma

Table of Contents

Definition / general

Pure or combined with ordinary ductal adenocarcinoma
Diagnosis restricted to cases having either pure or mixed with an adenocarcinoma component, where the cells resemble small-cell carcinoma of the lung (and elsewhere) histologically
Serum PSA levels are often not elevated
May cause Cushings syndrome, syndrome of inappropriate antidiuretic hormone secretion
Some have endocrine features
Very aggressive, cannot monitor with PSA (unreliable)
Survival usually less than 1 year (Arch Pathol Lab Med 1986;110:1041)
Rarely associated with limbic encephalitis (Mod Pathol 1999;12:814)

Microscopic (histologic) description

Usually large number of apoptotic cells; otherwise resembles lung small cell carcinoma
Typical features of small cell carcinoma, including high mitotic rate, frequent apoptotic bodies, crush artifact and DNA encrustation of blood vessel walls (Azzopardi phenomenon) are present

Microscopic (histologic) images

Contributed by Debra Zynger, M.D.

Prostatic small cell neuroendocrine carcinoma

Prostatic
adenocarcinoma
with 100% NE
differentiation

Metastatic prostatic
small cell
neuroendocrine
carcinoma

Images hosted on other servers:

HE staining

Immunostaining for CD56

Positive stains

Chromogranin, NSE, TTF1 (Mod Pathol 2000;13:238), CD56 (Am J Surg Pathol 2008;32:65)

Negative stains

PSA, PAP (Am J Surg Pathol 2008;32:65)

Differential diagnosis

Large cell neuroendocrine carcinoma: extremely rare, described in case reports and in one small study; large and polygonal tumor cells with moderate to abundant cytoplasm, coarsely granular nuclear chromatin and prominent nucleoli (Mod Pathol 2006;19:1358)

Small cell neuroendocrine carcinoma

Table of Contents

Definition / general

Small cell neuroendocrine carcinoma of the prostate is a rare entity that may be pure or more commonly admixed with conventional acinar adenocarcinoma
Its microscopic features are indistinguishable from small cell neuroendocrine carcinomas of other body sites

Essential features

De novo small cell neuroendocrine carcinoma of the prostate is very rare and may be associated with conventional acinar adenocarcinoma (mixed carcinoma)
Dismal prognosis in spite of initial response to platinum based therapy
Diagnosis can be made on microscopic features alone, immunostaining for neuroendocrine markers is auxiliary
Must be distinguished from International Society of Urological Pathology (ISUP) grade group 5 prostate adenocarcinoma because of clinical implications and different metastatic pattern

Terminology

Small cell neuroendocrine carcinoma of the prostate (recommended)
Poorly differentiated small cell neuroendocrine carcinoma of the prostate
Small cell undifferentiated carcinoma of the prostate (not recommended)

ICD coding

ICD-O: 8041/3 - small cell neuroendocrine carcinoma
ICD-11: 2C82.Y - other specified malignant neoplasm of prostate

Epidemiology

Rare occurrence of de novo small cell neuroendocrine carcinoma of the prostate
Association with conventional acinar adenocarcinoma in over 50% of cases (Clin Genitourin Cancer 2021;19:e193)
Small cell neuroendocrine carcinoma of the prostate more common in patients with metastatic disease subsequent to androgen receptor axis targeted therapy for conventional acinar adenocarcinoma (treatment emergent or treatment related small cell neuroendocrine carcinoma)

Sites

Prostate
Metastatic sites (bone, lymph nodes, liver, brain, other)

Pathophysiology

Transdifferentiation of acinar adenocarcinoma acquiring stem cell properties and neuroendocrine features most likely underlies the development of a prostatic small cell carcinoma
Shared TP53 gene mutation and TMPRS2::ERG fusion in mixed small cell and conventional acinar adenocarcinomas point at a clonal derivation of a common precursor cell (Prostate 2009;69:603, Mod Pathol 2011;24:1120)

Etiology

No known etiology of de novo small cell neuroendocrine carcinoma

Diagrams / tables

Not applicable

Clinical features

Urinary outflow obstruction is a first local symptom of small cell carcinoma of the prostate (Semin Oncol 2007;34:22)
Bone metastatic disease or metastases to lymph nodes or to visceral sites (liver, brain, etc.) are often the first clinical manifestation
Paraneoplastic syndrome (e.g., Cushing syndrome due to ectopic ACTH production, inappropriate secretion of antidiuretic hormone or hypercalcemia due to excessive parathyroid hormone production), similar to small cell neuroendocrine carcinoma of other organ sites
Elevated serum chromogranin A or neuron specific enolase (NSE) in case of metastatic disease, while serum prostate specific antigen (PSA) remains low

Diagnosis

Prostate biopsy, transurethral resections of the prostate or prostatectomy specimens as well as biopsies of metastatic foci
Essential features: specific high grade cytonuclear features, including high N:C ratio, hyperchromatic nuclei, nuclear molding and high mitotic rate / MIB1 score of > 50%
Desirable: positive immunostaining for neuroendocrine markers (synaptophysin, INSM1, chromogranin A) (Am J Surg Pathol 2014;38:756)

Laboratory

Elevated serum chromogranin, low PSA

Radiology description

Not provided

Radiology images

Images hosted on other servers:

CT and MRI of prostate

Whole body scan

Pelvic CT with contrast

MRI of prostate

Prognostic factors

Dismal prognosis, median survival of 10 - 18 months; mixed adenocarcinoma / small cell neuroendocrine carcinoma has slightly longer survival (Nat Rev Urol 2014;11:213)
Increased risk of lytic bone lesions, presence of visceral metastases, including brain metastasis
Unresponsive to hormonal therapy
Rapid progression after initial response to chemotherapy

Case reports

48 year old man with small cell neuroendocrine carcinoma of the prostate completely negative for neuroendocrine markers (World J Clin Cases 2022;10:1630)
55 year old White man with mixed acinar adenocarcinoma (Gleason score 4 + 3 = 7) and small cell carcinoma (Prostate 2009;69:603)
61 year old man who presented with neck swelling (J Surg Case Rep 2020;2020:rjaa117)
63 year old Black man who initially presented to the hospital with an elevated PSA level of 9.41 ng/mL (Cureus 2020;12:e7074)
79 year old Caucasian man presented with acute urinary retention (Indian J Urol 2012;28:89)

Treatment

Platinum based chemotherapy

Clinical images

Not available

Gross description

Not applicable

Gross images

Not applicable

Frozen section description

Not applicable

Frozen section images

Not applicable

Microscopic (histologic) description

Small sized tumor cells (diameter of ~3 lymphocytes) with hyperchromatic nuclei, inconspicuous nucleoli and scarce cytoplasm, showing nuclear molding and crush artefact (Am J Surg Pathol 2014;38:756)
Presence of pleomorphic giant cells in a minority of cases
Tumor cells with more open chromatin and visible (not prominent) nucleoli in ~33% of cases
Tumor cell arrangement in sheets with irregular outlines with occasional rosette forming
Apoptosis and (geographic) necrosis frequently present
In the majority of mixed cases, there is a gradual morphological translation between the adenocarcinoma and small cell neuroendocrine carcinoma component (Am J Surg Pathol 2008;32:65)
ISUP grading is not applicable for small cell neuroendocrine prostate carcinoma
In mixed carcinomas, the ISUP grade group of the acinar adenocarcinoma component should be reported

Microscopic (histologic) images

Contributed by Theodorus van der Kwast, M.D., Ph.D. and Debra Zynger, M.D.

Sheets of carcinoma cells

Nuclear molding

Ribbons with pseudorosettes

Solid nests with glands

Solid sheets of adenocarcinoma

Pale and hyperchromatic tumor cells

Sheet of pale tumor cells

Dark cells within duct

Visible nucleoli

Chromogranin A staining

Virtual slides

Not available

Cytology description

Not applicable

Cytology images

Not applicable

Immunofluorescence description

Not applicable

Immunofluorescence images

Not applicable

Positive stains

MIB1 (> 80%)
Neuroendocrine markers (at least 1 marker positive in 80% of cases)
Reference: Hum Pathol 2018:79:151

Negative stains

Prostate markers (positive in 10 - 20% of cases)
Reference: Hum Pathol 2018:79:151

Electron microscopy description

Presence of neurosecretory granules

Electron microscopy images

Not available

Molecular / cytogenetics description

TMPRSS2::ERG fusion in 50% of cases detectable by FISH (Hum Pathol 2013;44:2227)
Presence of TMPRSS2::ERG fusion is evidence of prostate origin of the small cell neuroendocrine carcinoma since those of other sites (lung, bladder) do not have this specific gene fusion

Molecular / cytogenetics description

Not available

Videos

Not available

Sample pathology report

Prostate, radical prostatectomy:
- Mixed small cell neuroendocrine carcinoma (70%) and adenocarcinoma, ISUP grade group 3 (30%) (see synoptic report)
- Positive for established extraprostatic extension (right posterior), bladder neck invasion (right) and bilateral seminal vesicle invasion (pT3b)
- Positive for intraductal carcinoma
- Positive for lymphangioinvasion
- Surgical margin positive for small cell neuroendocrine carcinoma component (right posterior)
- ~40% of the prostate volume involved by carcinoma

Differential diagnosis

Adenocarcinoma, ISUP grade group 5:
- Prominent nucleoli
- Ample cytoplasm
- Low proliferative activity
Small cell-like change in intraductal carcinoma:
- Largely within prostatic ducts, may expand in invasive carcinoma
- No / scarce proliferation
- Scattered neuroendocrine cells (immunohistochemistry)
Large cell neuroendocrine carcinoma of prostate:
- Ample pale to amphophilic cytoplasm
- Large nuclei with coarse chromatin and conspicuous nucleoli

Additional references

Not applicable

Board review style question #1

Which of the following is true about de novo small cell neuroendocrine carcinoma of the prostate?

Can be diagnosed by morphological features alone even in the complete absence of neuroendocrine marker expression
Has the same metastatic site distribution as ISUP grade group 5 prostate adenocarcinoma
Is more common than treatment related small cell carcinoma
Occurs more often in a pure form as compared to mixed small cell / conventional adenocarcinoma

Board review style answer #1

A. Can be diagnosed by morphological features alone even in the complete absence of neuroendocrine marker expression. Morphological features are sufficient to make a diagnosis of small cell neuroendocrine carcinoma of the prostate. Although most would express at least 1 neuroendocrine marker, some are entirely negative for all tested neuroendocrine markers. Answer D is incorrect because small cell neuroendocrine is more commonly seen in association with conventional adenocarcinoma. Answer C is incorrect because androgen receptor axis targeted therapy may induce small cell neuroendocrine carcinoma (transdifferentiation) and this process is more common with current intensive therapies of metastatic hormone therapy resistant prostate cancer. Answer B is incorrect because small cell neuroendocrine carcinoma of the prostate metastases have a predilection for visceral sites (e.g., liver, brain) as compared to conventional acinar adenocarcinoma metastases.

Comment Here

Reference: Small cell neuroendocrine carcinoma

Squamous cell carcinoma

Table of Contents

Definition / general

Extremely rare; incidence is < 0.6% of all prostate cancers with ~70 cases reported (Rare Tumors 2010;2:e47, Am J Surg Pathol 2004;28:651)
Most are accompanied by concomitant adenocarcinoma (adenosquamous), generally high grade; some are purely squamous (Am J Surg Pathol 2004;28:651, Case Reports in Clinical Pathology 2016;3:60)

Essential features

Criteria for diagnosis of pure primary squamous cell carcinoma of the prostate:
- Unequivocal features of malignancy
- Definitive squamous differentiation
- Lack of admixed conventional carcinoma component (would be adenosquamous) (Rare Tumors 2010;2:e47)
- No squamous cell carcinoma elsewhere (Mod Pathol 2004;17:316)

Epidemiology

Most over age 70 (Cent European J Urol 2014;67:26, Rare Tumors 2010;2:e47, Am J Surg Pathol 2004;28:651)
In 35/66 cases (over 50%) it arises in the settings of previous radiation or hormonal treatment for prostatic adenocarcinoma (Diagn Pathol 2011;6:46)

Pathophysiology

Possible origin (J Clin Pathol 1988;41:1288):
- Purely prostatic with transformation of adenocarcinoma
- Collision tumor
- Derived from pluripotent stem cells
- Clonal evolution of adenocarcinoma under pressure from therapy
  - After estrogen therapy, glutamine therapy, radiation seed implantation (Prostate Cancer and Prostatic Diseases 2000;3:53)
- Squamous differentiation of a prostatic urethral primary tumor

Clinical features

Early metastasis to liver, bone and lungs (Rare Tumors 2010;2:e47)
Does not respond to hormone therapy (Radiat Oncol 2007;2:15)
Median survival 14 months (Cent European J Urol 2014;67:26)

Adenosquamous carcinoma

Incidence is < 0.6% of all prostate cancers
Have normal serum PSA and PSAP levels
Originates from the periurethral glands or prostatic acinar basal cells
Either de novo or postradiation or hormonal therapy for ordinary adenocarcinoma
Micro description: both glandular (acinar) and squamous components
Negative stains: PSA / PAP
References: Am J Surg Pathol 1987;11:403, Hum Pathol 1995;26:123, Hum Pathol 1984;15:87BJU Int 2008;102:1369

Laboratory

Can have normal serum PSA and PSAP (Clin Genitourin Cancer 2014;12:e29)

Radiology images

Contributed by Kenneth A. Iczkowski, M.D.

T2 weighted MRI

Case reports

55 year old man adenosquamous carcinoma of the prostate (Urology 1999;53:832)
57 years old primary squamous cell carcinoma of the prostate (Future Sci OA 2015;1:FSO18)
62 year old man with mixed adenocarcinoma, sarcomatoid carcinoma and adenosquamous carcinoma of the prostate (Oncol Lett. 2014 Nov;8(5):2325)
65 year old man with squamous cell carcinoma of the prostate following treatment with an LHRH agonist (Cent European J Urol 2014;67:26)
67 year old man concomitant adenocarcinoma in the absence of prior androgen deprivation therapy (Case Reports in Clinical Pathology 2016;3:60)
73 year old man in which docetaxel therapy was effective (Hinyokika Kiyo 2016;62:259)
77 year old man with pure squamous cell carcinoma involving the prostate and urinary bladder (Diagn Pathol 2011;6:46)
Primary adenosquamous carcinoma of the prostate (Clin Genitourin Cancer 2014;12:e29)
Long term survival after combined chemoradiation (Radiat Oncol 2007;2:15)

Treatment

Long term survival has been reported after combined chemoradiation (Cent European J Urol 2014;67:26)

Gross description

Tends to occur more in transition zone / periurethral (Rare Tumors 2010;2:e47)

Microscopic (histologic) description

Pure tumors exhibit infiltrating nests, strands and sheets of polygonal cells with nuclear atypia
Squamous differentiation is manifested as individual cell keratinization, intercellular bridges or keratin pearl formation

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Needle biopsy

Keratinization with necrosis

Multinucleation

Images hosted on other servers:

Squamous cell carcinoma

Positive stains

Cytokeratin 34βE12, AE3 (Am J Surg Pathol 2004;28:651, Prostate Cancer and Prostatic Diseases 2000;3:53, Clin Genitourin Cancer 2014;12:e29)
p53 strong positive consistent with mutation (Oncol Lett 2014;8:2325)
AMACR may be expressed in adenosquamous areas (maintains an immunohistochemical profile similar to adenocarcinoma) (Diagn Pathol 2011;6:46, Urology 1999;53:832)

Negative stains

Prostate specific antigen and prostatic acid phosphatase, P501S
Cytokeratin CAM5.2 (low molecular weight)
Uroplakin II, S100 protein, CDX2

Differential diagnosis

Urothelial carcinoma
- Lacks keratin or intercellular tonofilament bridges
- Negative for PSA; positive for uroplakin II and GATA3
- Will not have adenosquamous areas
Urothelial carcinoma with squamous differentiation
- May be difficult to impossible to differentiate
- Will not have adenosquamous areas
Squamous carcinoma of other origins such as penis, bladder or anorectal
- Requires clinical and radiologic correlation
- Will not have adenosquamous areas
Squamous metaplasia
- Can be seen around infarcts within the prostate
- Lacks overt pleomorphism and atypical mitotic figures; does not form a mass

Board review style question #1

What is a finding that may rule out primary pure squamous cell carcinoma of the prostate?

Negative for low molecular weight cytokeratin
Negative for prostate specific antigen
Presence of keratin
Presence of squamous cell carcinoma elsewhere

Board review style answer #1

D. Presence of squamous cell carcinoma elsewhere

Comment Here

Reference: Squamous cell carcinoma

Board review style question #2

Which of the following is true about squamous cell carcinoma of the prostate?

Does not originate adjacent to coexisting squamous metaplasia
More likely to occur as a focus separate from adenocarcinoma, rather than intermixed and merging with adenocarcinoma
More often occurs following radiotherapy or antiandrogen therapy than in the absence of those prior therapies
Serum PSA elevation is useful for diagnosis of the pure form of squamous cell carcinoma

Board review style answer #2

C. More often occurs following radiotherapy or antiandrogen therapy than in the absence of those prior therapies

Comment Here

Reference: Squamous cell carcinoma

Squamous cell carcinoma (pending)

[Pending]

Staging

Table of Contents

Definition / general

All prostate carcinomas are covered by this staging system
These topics are not covered: sarcoma, urothelial carcinoma (refer to male urethra staging for carcinoma of the prostatic urethra)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory

ICD coding

ICD-O-3: C61.9 - prostate gland

Primary tumor (pT)

pT2: organ confined
pT3a: extraprostatic extension or microscopic invasion of bladder neck
pT3b: seminal vesicle muscle invasion
pT4: fixed tumor or invasion of structures such as external sphincter, rectum, bladder, levator muscles or pelvic wall

Notes:

There is no pT1 classification
Note that cT1 is a part of clinical classification for clinically inapparent, nonpalpable tumor detected in specimens other than a prostatectomy such as a TURP or prostate biopsy with clinically inapparent, nonpalpable, incidental tumor in 5% or less of tissue defined as cT1a, clinically inapparent, nonpalpable, incidental tumor in > 5% defined as cT1b and clinically inapparent, nonpalpable tumor in a prostate needle biopsy defined as cT1c
Extraprostatic extension: usually this is dichotomized as focal (< 1 high power field in 1 - 2 slides) versus nonfocal / established (> 1 high power field in 1 - 2 slides)
Microscopic invasion of bladder neck: presence of tumor in thick muscle usually with no adjacent nonneoplastic glands
Seminal vesicle invasion: invasion of the extraprostatic seminal vesicle muscular wall

Regional lymph nodes (pN)

pNX: cannot be assessed
pN0: no regional lymph node metastasis
pN1: regional lymph node metastasis

Notes:

Regional lymph nodes include periprostatic, pelvic, hypogastric, obturator, internal iliac, external iliac, sacral

Distant metastasis (pM)

pM1a: metastasis in nonregional lymph node
pM1b: metastasis in bone
pM1c: metastasis in other distant site

Notes:

Nonregional lymph nodes include aortic, common iliac, deep / superficial inguinal, retroperitoneal

Prefixes

y: preoperative radiotherapy or chemotherapy
r: recurrent tumor stage

Histologic grade group (G)

Grade group	Gleason score	Gleason pattern
1	≤ 6	≤ 3+3
2	7	3+4
3	7	4+3
4	8	4+4, 3+5, 5+3
5	9 - 10	4+5, 5+4, 5+5

AJCC prognostic stage groups (utilizing pT categorization)

Stage group I:	pT2	N0	M0	PSA < 10	Grade group 1	Gleason score ≤ 3+3=6
Stage group IIA:	pT2	N0	M0	PSA ≥ 10 - < 20	Grade group 1	Gleason score ≤ 3+3=6
Stage group IIB:	pT2	N0	M0	PSA < 20	Grade group 2	Gleason score 3+4=7
Stage group IIC:	pT2	N0	M0	PSA < 20	Grade group 3 - 4	Gleason score 4+3=7, 4+4=7, 3+5=8, 5+3=8
Stage group IIIA:	pT2	N0	M0	PSA ≥ 20	Grade group 1 - 4	Gleason score ≤ 6 - 8
Stage group IIIB:	pT3 - 4	N0	M0	Any PSA	Grade group 1 - 4	Gleason score ≤ 6 - 8
Stage group IIIC:	pT2 - 4	N0	M0	Any PSA	Grade group 5	Gleason score 9 - 10
Stage group IVA:	pT2 - 4	N1	M0	Any PSA	Any grade group	Any Gleason score
Stage group IVB:	pT2 - 4	N0 - 1	M1	Any PSA	Any grade group	Any Gleason score

Registry data collection variables

Pretreatment serum PSA
Grade group
Gleason score
Gleason patterns
Tertiary Gleason pattern on prostatectomy
Number of cores examined
Number of cores positive
Needle core biopsies positive one on side, both sides or beyond prostate
Metastatic sites

Gross images

Contributed by Debra L. Zynger, M.D.

Extraprostatic extension, multifocal (pT3a)

Extraprostatic extension, multifocal (pT3a)

Seminal vesicle invasion (pT3b)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Extraprostatic extension (pT3a)

Bladder neck invasion (pT3a)

Seminal vesicle invasion (pT3b)

Rectal invasion (pT4)

Periprostatic lymph node metastasis (pN1)

Pelvic lymph node metastasis (pN1)

Neck lymph node metastasis (pM1a)

Bone metastasis (pM1b)

Lung metastasis (pM1c)

Brain metastasis (pM1c)

Board review style question #1

A radical prostatectomy was performed and a cross section of the seminal vesicle wall is shown above. There is involvement by high grade prostatic adenocarcinoma. Which of the following is the correct pT?

pT2
pT3a
pT3b
pT4

Board review style answer #1

C. pT3b

Comment Here

Reference: Prostate - Staging

Treatment effect

Table of Contents

Definition / general

There is some overlap of histologic alterations and some divergence, caused by androgen deprivation therapy and by radiation, to both prostate cancer and benign epithelium

Essential features

Nucleolus poor adenocarcinoma with clear cytoplasm is the hallmark of androgen deprivation effect; also, there may be loss of cytologic atypia and shrinkage of gland size and cytoplasm as well as atrophy of benign acini
Radiation effect causes atypical features of residual cancer as well as benign acini, such as marked nuclear enlargement and nucleoli in basal cells
Dual immunostain with basal cell markers and P504S / racemase is recommended to discriminate cancer from benign glands after both types of treatment
Grading is not recommended after androgen deprivation due to gland distortion; although there is some controversy about grading cancer after radiotherapy, the bulk of the evidence is in favor of grading if significant radiation change is absent
References: Clin Prostate Cancer 2004;2:228, Urology 2005;65:76

Terminology

Radiation effect, androgen deprivation effect, marked atrophy

ICD coding

ICD-10: N42.89 - other specified disorders of prostate (atrophy of prostate, infarct of prostate)

Epidemiology

History should be searched for radiotherapy to the pelvis for prostate or other cancers or for prior androgen deprivation (dutasteride or newer agents like enzalutamide and abiraterone)

Pathophysiology

Radiation damage to endothelial cells is implicated in causing ischemia, which leads to atrophy (Histol Histopathol 2007;22:107)

Diagnosis

After androgen deprivation: do not grade
- Certain immunostains are helpful to distinguish residual cancer (see Positive stains)
- Current recommendations are to not assign a Gleason grade to cancer after androgen deprivation treatment (Clin Prostate Cancer 2004;2:228)
After radiation treatment: only assign a grade if marked radiation changes are absent
- Certain immunostains are helpful to distinguish residual cancer (see Positive stains)
- Gleason grade can and should still be assigned unless treatment effect is significant, in contrast to post androgen deprivation prostate (Mol Urol 1999;3:193, Urology 2005;65:76, Cancer 1997;79:81)
- Therapy effect should be noted as a biopsy with marked radiation change to tumor may have a similar prognosis as a negative biopsy

Laboratory

Elevated serum PSA usually favors residual carcinoma; rarely, salivary ductal adenocarcinoma can produce PSA and demonstrate androgen receptor sensitivity; history of head and neck cancer should be assessed (Mayo Clin Proc Innov Qual Outcomes 2020;4:601)

Prognostic factors

Adjuvant androgen deprivation with radiotherapy has benefits for progression free survival (J Clin Oncol 2021 Jan;39:136)
- Neoadjuvant use prior to prostatectomy was given in about 2% of cases in 2004 - 2014 and correlated with lower odds of positive margins and in a minority of cases, pathologic downstaging; it caused elimination of the adverse risk factor of presence of intraductal carcinoma in some cases (Ann Surg Oncol 2019;26:297, Prostate Cancer Prostatic Dis 2018;21:364, Prostate 2020;80:284)
- However, some studies do not show a survival benefit (J Clin Oncol 2020;38:3042)
Grading of radiation effect on a 0 - 6 scale is highly predictive of local failure (Cancer 1997;79:81)
- A system proposed in 1997 takes the sum of cytoplasmic changes (0 - 3) and nuclear changes (0 - 3):
  - Cytoplasmic change grades are (1) swelling and microvesicles, (2) extensive vacuolation and voluminous cytoplasm and (3) dilated glands plus single cells without lumens
  - Nuclear change grades are (1) some swelling or smudging but nucleoli identified, (2) large bizarre nuclei and (3) pyknotic condensed nuclei
- In the above study, local failure was 55% for 0 - 2 grade effect, 30% for grade 3 - 4 and 0% for grade 5 - 6
There is no evidence for tumor dedifferentiation after radiotherapy (Cancer 1997;79:81)

Case reports

Radiotherapy - case reports mainly deal with later complications:
- 65 year old man with perineal recurrence after brachytherapy (J Contemp Brachytherapy 2020;12:612)
- 72 year old man developed malignant fibrous histiocytoma 8 years after radiation for prostate cancer (J Chemother 1997;9:162)
- 76 year old man with thigh urinary fistula (Urol Case Rep 2021;36:101558)
- 77 year old man with necrotizing fasciitis after high dose rate brachytherapy (BMC Urol 2017;17:107)
- 78 year old man presenting with vesical angiosarcoma 8 years after radiation for prostate cancer (Medicina (Kaunas) 2021;57:329)
Androgen deprivation
- 66 year old man diagnosed with prostate cancer metastasis received, over the next 17 years, various forms of androgen deprivation, including use of newer agents such as abiraterone and MDV 3100 (Clin Endocrinol Metab 2012;97:360)
- 72 and 80 year old men who developed sarcomatoid carcinoma after androgen deprivation, which is androgen independent (World J Clin Cases 2021;9:1668)
- 83 year old man whose urethral prostatic adenocarcinoma metastasis resolved after androgen deprivation therapy (Urology 2019;129:e4)

Treatment

Androgen deprivation:
- Used for patients with advanced cancer or who are not surgical candidates but also can be used as neoadjuvant treatment prior to surgery
- Newer agents, such as enzalutamide and abiraterone, have been used in addition to traditional LHRH agonists (J Clin Oncol 2019;37:923)
- Antagonists are used, including leuprolide, goserelin, triptorelin, histrelin, buserelin and degarelix; they achieve the same effect as surgical castration
Radiotherapy:
- This alternative to surgery has comparable long term outcome
- External beam radiation therapy (EBRT) uses beams of radiation from outside the body, while brachytherapy uses radioactive seed implants to the prostate, allowing delivery of higher doses of radiation to a smaller area; the two may be combined for higher risk patients (Int J Radiat Oncol Biol Phys 2004;58:25)
- Radiotherapy may be undertaken prior to prostatectomy, in which case the latter is termed salvage prostatectomy; histologic effects on the prostate are identical
Cryotherapy: this alternative to surgery uses a probe to freeze part of the prostate into an ice ball, thereby devitalizing cancer and adjacent stroma

Microscopic (histologic) description

After androgen deprivation: do not grade
- Nucleolus poor adenocarcinoma is the hallmark; also shows cytoplasmic clearing / vacuolization, reduced cytoplasmic quantity, nuclear pyknosis, reduced gland diameter, mucinous breakdown
- Difficult to evaluate margin status after androgen deprivation
- Current recommendations are to not assign a Gleason grade to androgen deprivation treatment specimens (Clin Prostate Cancer 2004;2:228)
- There is a tendency toward greater neuroendocrine differentiation at prostatectomy after neoadjuvant androgen deprivation and a molecular basis for promotion of this has been described (Eur Urol 2004;45:586, Cancer Lett 2019;440-441:35)
- High grade prostatic intraepithelial neoplasia (PIN) persists after endocrine treatment; tufted PIN may be replaced by flat high grade PIN (Hum Pathol 1999;30:1503)
- Normal prostate shows atrophy, basal cell hyperplasia and prominence
After radiation treatment: assign a grade only if significant radiation change is absent
- In cancer, the main finding is swollen cytoplasm with vacuoles and eventually glandular breakdown with possible single cells (Mol Urol 1999;3:193, Urology 2005;65:76, Cancer 1997;79:81)
- Less treatment effect in radical prostatectomy specimens than needle biopsies (Am J Surg Pathol 1999;23:1173)
- The optimal timing of biopsies is 24 months after initiation of external radiation therapy (plus androgen deprivation) to predict 7 year cancer free survival and to rule out upgrading; tumor may take more than 30 months to resolve (Cancer 2009;115:673, Urology 2012;80:649, Urology 1995;45:624)
- Any association with later angiosarcoma is weak (BJU Int 2012;110:E819)
- Normal prostate shows nuclear enlargement (86%) and prominent nucleoli (50%) with increased cytoplasm (Am J Surg Pathol 1999;23:1173)
After cryotherapy:
- The main finding is gland disappearance and washed out blue gray stroma

Microscopic (histologic) images

Contributed by Kenneth Iczkowski, M.D. and Debra L. Zynger, M.D.

Androgen deprivation, benign

Androgen deprivation, cancer

Radiotherapy, benign

Cryotherapy, benign

Cryotherapy, cancer

Suspicious for cancer

Shrunken benign acinus

Radiation change, carcinoma

Positive stains

After androgen deprivation
- PSA, pancytokeratin helps confirm cancer cells
- Post therapy, PSA and PSAP may decrease (Prostate 1985;7:195, J Urol 1983;130:95)
After radiation treatment
- High molecular weight keratin identifies basal cells in benign radiated glands (Semin Diagn Pathol 2005;22:88)
- AMACR helps to differentiate prostatic adenocarcinoma from radiation induced atypia in benign prostatic epithelium (Hum Pathol 2006;19:287)
- PSA and PSAP is usually retained by radiated prostate glands (Cancer 1997;79:81, Semin Diagn Pathol 2005;22:88)
- Caveat about GATA3: expression is positive in 100% of both secretory cells and benign cells in benign prostate with radiation atypia, whereas reactivity is limited to basal cells in the absence of radiation atypia; this finding, along with the cytologic atypia of radiation, can mimic urothelial carcinoma (Histopathology 2017;71:150)

Negative stains

Tumor cells after treatment lack high molecular weight cytokeratin expression, similar to untreated cancer cells

Sample pathology report

Prostate, left apex, needle biopsies:
- Prostatic adenocarcinoma with cytologic changes of androgen deprivation effect, not gradable
Prostate, left apex, needle biopsies:
- Prostatic adenocarcinoma, Gleason 3 + 4 (score = 7, grade group 2) or
- Prostatic adenocarcinoma with severe radiotherapy effect, not gradable

Differential diagnosis

Atrophy (without therapeutic cause):
- Exceedingly common finding in prostatic biopsies but there usually are some admixed nonatrophic glands
- In the presence of 100% of glands being atrophic, history of treatment effect should be sought, particularly androgen deprivation
- If atrophy is accompanied by basal cell hyperplasia, seek a history of radiotherapy
Xanthoma:
- Contains cells with foamy cytoplasm but atypia would be absent and immunostain would reveal positivity for CD68 and negativity for cytokeratins
Foamy gland adenocarcinoma:
- Has abundant foamy cytoplasm and less cytologic atypia than other cancers; this may mimic radiation effect but radiation effect creates vacuoles with both nuclear and cytoplasmic enlargement, which are different findings

Board review style question #1

Which immunostain may be falsely positive in benign glands after radiotherapy?

Basal cell cytokeratin
GATA3
P504S
p63
PSA

Board review style answer #1

B. GATA3 may be falsely positive and mimic urothelial carcinoma in benign glands after radiotherapy. P504S should be positive in cancer and negative in benign glands. Basal cell cytokeratin and p63 should be negative in cancer after therapy. PSA reactivity is usually retained so expected to be positive.

Comment Here

Reference: Treatment effect - prostate

Board review style question #2

A 65 year old man with a history of prostate cancer diagnosed 8 years ago has a prostatectomy. Carcinoma from his prostatectomy specimen is shown. Which of the following is the best diagnosis?

Prostatic adenocarcinoma 3+3=6
Prostatic adenocarcinoma 3+4=7
Prostatic adenocarcinoma 4+4=8
Prostatic adenocarcinoma 4+5=9
Prostatic adenocarcinoma with treatment effect

Board review style answer #2

E. Prostatic adenocarcinoma with treatment effect. In this case the patient was treated with brachytherapy. Radiation change is seen consisting of atrophic glands with nuclei that touch the cell membrane and gland retraction. A Gleason score is not rendered for tumors with marked therapy effect such as this case.

Comment Here

Reference: Treatment effect - prostate

Treatment related neuroendocrine prostatic carcinoma (pending)

[Pending]

Urethral polyp

Table of Contents

Definition / general

Uncommon, benign, polypoid or papillary growths protruding into the urethral lumen (J Urol 2015;193:2095)
2 types: prostatic type urethral polyp, fibroepithelial urethral polyp (J Urol 2015;193:2095, Am J Surg Pathol 2005;29:460)

Essential features

Prostatic type urethral polyp is characterized by delicate papillae with true fibrovascular cores lined with prostatic epithelium with focal benign urothelial cells; prostatic acini are often present in the polyp (Am J Surg Pathol 1983;7:351)
Fibroepithelial urethral polyp is composed of cloverleaf-like and club-like dense fibrovascular cores covered by benign urothelium (Am J Surg Pathol 2005;29:460)

Terminology

Prostatic type urethral polyp, also known as prostatic urethral polyp and prostatic type epithelial polyp of the urethra (J Urol 2015;193:2095)
Fibroepithelial urethral polyp, also known as fibroepithelial congenital urethral polyp (J Pediatr Surg 2014;49:835)

ICD coding

ICD-10:
- N36.9 - urethral disorder, unspecified
- D30.4 - benign neoplasm of urethra

Epidemiology

Prostatic type urethral polyp:
- Occurs in adult men, age range 27 - 41 years, uncommon in younger men (Am J Clin Pathol 1975;63:343)
Fibroepithelial urethral polyp:
- Age range 17 - 70 years, mean of 47 years (Am J Surg Pathol 2005;29:460)
- Commonly occurs in pediatric males, usually 3 - 9 years of age (Can J Urol 2013;20:6974)
- Rare patients present during infancy or adulthood
- Rarely occurs in pediatric female patients

Sites

Commonly occurs in posterior prostatic urethra adjacent to verumontanum or the bladder neck (J Urol 2015;193:2095)
Anterior urethra in rare case reports

Pathophysiology

Ectopic prostatic acinar epithelium presents focally in urothelial tract, commonly in posterior urethra, rarely in bladder neck and penile urethra
Prostatic type urethral polyp likely caused by hyperplastic proliferations of the prostatic acinar epithelium results in overgrowth of the overlying urothelium (Am J Surg Pathol 1984;8:833)

Etiology

Fibroepithelial urethral polyp may result from a congenital defect in the urethral wall or associated with a congenital anomaly (Br J Urol 1970;42:76, Urology 1977;9:423)

Clinical features

Common symptoms and signs: hematuria, dysuria, hemospermia
Urethrocystoscopic examination: a polypoid mass protruding from the posterior urethral wall (most common) or from anterior urethral wall (Urology 2020;143:238)

Diagnosis

Ultrasonography reveals a protruding hyperechogenic polypoid mass protruding from the posterior (most common) urethral wall (Urology 2020;143:238)
Filling defect on voiding cystourethrogram (Clin Imaging 2018;51:164)
Appearance of a benign polyp on urethrocystoscopy followed by histopathological examination of the excised polyp

Radiology description

Abdominal sonogram of the urinary bladder shows a hyperechogenic polypoid mass protruding to the bladder neck (Urol J 2020;18:86)
Filling defect is present at the bladder neck of a distended bladder (Clin Imaging 2018;51:164)

Radiology images

Images hosted on other servers:

Polypoid mass

Filling defect

Prognostic factors

Excellent prognosis for prostatic type urethral polyp and fibroepithelial urethral polyp
Recurrence is unusual (J Urol 2015;193:2095)

Case reports

Prostatic type urethral polyp:
- 35 year old man with urinary outflow obstruction (Diagn Cytopathol 2003;29:356)
- 47, 52 and 84 year old men with hematuria (Urology 2014;83:535)
- 62 year old man with hematuria (Arch Pathol Lab Med 2003;127:e351)
Fibroepithelial polyp:
- 3 year old boy with intermittent acute urinary retention (Urology 2020;143:238)
- 3 year old boy with abdominal pain (Clin Imaging 2018;51:164)
- 20 year old man with urinary retention (Urol J 2009;6:301)

Treatment

Cystoscopic excision and fulguration (J Urol 2015;193:2095)

Clinical images

Images hosted on other servers:

Urethrocystoscopic view of polyp

Gross description

Prostatic type urethral polyp (J Urol 2015;193:2095)
- Pink-tan, exophytic papillary, filiform to rarely sessile structure
- Single or multiple polyps
- Usually < 1 cm
Fibroepithelial urethral polyp (Clin Imaging 2018;51:164)
- Pink-tan, polypoid mass with narrow stalk
- Usually < 4 cm

Gross images

Images hosted on other servers:

Brown-tan knob-like polyp

Microscopic (histologic) description

Prostatic type urethral polyp:
- Delicate papillae with true fibrovascular cores lined by an outer layer of columnar cells and an underlying flattened to cuboidal basal cells (Am J Surg Pathol 1983;7:351)
- Focal benign urothelium is present in the benign prostatic epithelium (J Urol 2015;193:2095)
- Benign prostatic acini are present in the papillae and in adjacent fibromuscular stroma (J Urol 2015;193:2095)
Fibroepithelial urethral polyp (Am J Surg Pathol 2005;29:460):
- Pattern 1: most common pattern includes the following features
  - Broad cloverleaf-like and club-like projections covered by normal urothelium and composed of dense fibrovascular stroma with florid cytitis cystica et glandularis (most common morphologic variant)
  - Back to back glands present in the stalk
  - Anastomosing nests of benign urothelial cells resembling inverted papilloma
  - Dilated cysts with intracystic papillary contents
  - Degenerative reactive atypia of stromal cells
- Pattern 2: numerous small papillae with dense fibrous cores and areas of glandular differentiation
- Pattern 3: urothelial lined broad edematous papillae mimicking polypoid urethritis; urothelial lined broad fibrous papillae with subepithelial edema

Microscopic (histologic) images

Contributed by Y. Albert Yeh, M.D., Ph.D.

Fibroepithelial polyp

Polypoid mass

Cloverleaf-like and club-like projections

Broad based papillae

Cloverleaf-like projections

Club-like projections

Broad based finger-like papillae

Urethritis cystica and glandularis

Polypoid and club-like projections

Focal calcifications

Cytology description

Prostatic type urethral polyp:
- Clusters of benign columnar cells with uniform and oval nuclei (see Cytology images) (Arch Pathol Lab Med 2000;124:1047)
- Columnar cells have pale cytoplasm, fine nuclear chromatin and inconspicuous nucleoli (see Cytology images)

Cytology images

Images hosted on other servers:

Benign papillary cluster

Positive stains

Prostatic type urethral polyp (Am J Surg Pathol 1983;7:351):
- PSA
- PAP
- NKX3.1, PSMA

Negative stains

Fibroepithelial urethral polyp (Am J Surg Pathol 1983;7:351):
- PSA
- PAP
- NKX3.1, PSMA

Sample pathology report

Urethral lesion, prostatic, excision:
- Urethral polyp with prostatic type epithelium and changes, consistent with prostatic type urethral polyp (see comment)
- Comment: The urethral lesion shows a polypoid and papillary growth lined by prostatic type epithelium and composed of benign prostatic acini. PSA and PSAP immunohistochemical stains reveal positive cytoplasmic staining in the prostatic glandular cells. These features are consistent with prostatic urethral polyp.
Urethral lesion, prostatic, excision:
- Cloverleaf-like and club-like projections lined by normal urothelium, consistent with fibroepithelial urethral polyp (see comment)
- Comment: The urethral lesion shows papillary projections arranged in cloverleaf-like and club-like pattern. The papillary structures are composed of broad fibrovascular cores covered by unremarkable urothelial cells. Neither urothelial proliferation nor epithelial atypia is noted. These features are consistent with fibroepithelial urethral polyp.

Differential diagnosis

Fibroepithelial urethral polyp
- Prostatic type urethral polyp:
  - Delicate papillae with true fibrovascular cores lined by benign prostatic epithelium (Am J Surg Pathol 1983;7:351)
- Urothelial papilloma:
  - More slender, delicate loose fibrovascular cores lined by normal appearing urothelial cells and prominent umbrella cells with vacuolated cytoplasm (Am J Surg Pathol 2005;29:460)
- Polypoid urethritis:
  - Polypoid and broad based papillary structures with marked stromal edema, acute and chronic inflammation
  - No true fibrovascular cores (Am J Surg Pathol 2008;32:758)
Prostatic type urethral polyp
- Fibroepithelial polyp:
  - Broad cloverleaf-like and club-like projections covered by normal urothelium
  - No prostatic type epithelium (Am J Surg Pathol 2005;29:460)
- Urothelial papilloma:
  - Slender fibrovascular cores lined by normal appearing urothelial cells
  - No prostatic type epithelium (Am J Surg Pathol 2005;29:460)
- Polypoid urethritis:
  - Polypoid structures with marked stromal edema, acute and chronic inflammation
  - No true fibrovascular cores
  - No prostatic type epithelium (Am J Surg Pathol 2008;32:758)
- Prostatic ductal adenocarcinoma:
  - Complex prostatic glands lined with pseudostratified columnar cells with mild to severe nuclear atypia (J Urol 2015;193:2095)

Additional references

Prostatic type urethral polyp: Urol Int 1993;50:114, Urology 1984;24:499, Eur Urol 1989;16:92, J Urol 1984;131:120, Histopathology 1987;11:789, Br J Urol 1993;72:981, J Urol 1989;142:1218, J Urol 1981;126:129
Fibroepithelial polyp: Transl Pediatr 2020;9:272, J Endourol Case Rep 2016;2:90, J Surg Case Rep 2019;2019:rjz320

Board review style question #1

A 50 year old man presented with dysuria and hematuria for 3 months. Cystoscopic examination showed a polypoid mass protruded from the posterior wall of the prostatic urethra. Cystoscopic excision of the polyp and histopathological examination were performed. The microphotograph of the urethral polyp is shown above. What is the diagnosis?

Fibroepthelial urethral polyp
Polypoid urethritis
Prostatic type urethral polyp
Urethral caruncle

Board review style answer #1

A. Fibroepithelial urethral polyp

Comment here

Reference: Urethral polyp

Board review style question #2

A 40 year old man presented with dysuria for 2 months. During cystoscopy, a polypoid mass protruding from the posterior urethra was detected. Surgical excision of the polyp was performed and microscopic examination showed a papillary growth lined by tall benign columnar cells with pale eosinophilic cytoplasm. In the stroma are some glands lined by benign columnar cells with underlying flattened epithelial cells. What is the diagnosis?

Fibroepithelial polyp
Polypoid urethritis
Prostatic type urethral polyp
Urethral caruncle

Board review style answer #2

C. Prostatic type urethral polyp

Comment here

Reference: Urethral polyp

Vanishing cancer

Table of Contents

Definition / general

First described in 1995, vanishing cancer indicates no residual tumor found in radical prostatectomy specimen despite confirmed tumor in needle biopsy (Am J Surg Pathol 1995;19:1002)
Sometimes, only high grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation suspicious for but not diagnostic of cancer (ASAP) is found

Essential features

Contemporary incidence of vanishing cancer is 0.2% of radical prostatectomy specimens; it was higher a decade or two ago when prostatectomy was being performed for smaller / lower grade cancers
Incidence is higher in large prostates or in preoperatively treated ones
Resolution of dilemma involves complete tissue submission, cancer specific immunostains, use of second opinion, consider flipping blocks to other surface; some residual cancers simply cannot be detected after the above efforts

ICD coding

ICD-10: C61 - malignant neoplasm of prostate

Epidemiology

Most recent incidence at prostatectomy is 0.2% of 160,532 with clinically localized cancer based on Surveillance, Epidemiology and End Results (SEER) database (2004 - 2015) (Urol Oncol 2019;37:696)
This is lower than the incidence of vanishing cancer of 0.6% up to 4.9% of prostatectomy specimens a decade ago (Arch Pathol Lab Med 2011;135:1466, Virchows Arch 2007;450:371, Am J Surg Pathol 2009;33:120, Indian J Cancer 2013;50:170, Pathol Res Pract 2012;208:578)
Variation in rate is probably due to the institution and time of the study; however, the recent decrease may reflect upward stage and grade migration at prostatectomy, due to increased acceptance of active surveillance for low grade cancer (Eur Urol Oncol 2018;1:160)
Predictors of vanishing cancer included a prostate weight ≥ 60 g or patients with prostate specific antigen (PSA) < 20 ng/ml, with biopsy GS < 7, patients with < clinical T2 disease and < 2 positive biopsy cores (Am J Surg Pathol 2009;33:120, Urol Oncol 2019;37:696)

Etiology

Most often, the phenomenon is attributed to the fact that routine histologic sections cannot evaluate every cubic millimeter of prostate volume, so small cancer foci remain in the paraffin block
Rarely, prostate cancer may have been ablated by the biopsy or transurethral resection procedure (BJU Int 2004;94:939)
Currently, more patients are receiving preoperative androgen deprivation, such as enzalutamide, that shrinks the cancer (Urology 2005;65:76, Clin Cancer Res 2017;23:2169)
It is also proposed that a minute cancer focus at the edge of the prostate may be inadvertently left behind in the overzealous attempt to perform a nerve sparing procedure (Indian J Cancer 2013;50:170)

Diagnosis

Diagnostic resolution should include these steps in the following order (Urol Oncol 2019;37:696):
- If the prostatectomy tissue has been partially submitted, complete submission should be pursued
- Get a second pathologist, particularly a urologic pathologist, to reread the resection slides
- Review the biopsy that was diagnostic of cancer, if slides are available
- Immunostains (see below)
- Flip tissue in some or all of the paraffin blocks and have the opposite surfaces of the tissues cut
- DNA identity analysis can be performed if specimen switching is suspected (see below)

Laboratory

Vanishing cancer patients typically have lower serum PSA (Urol Oncol 2019;37:696)

Gross description

Larger prostates with an average size of 74 g are more likely to exhibit no residual tumor (Am J Surg Pathol 2009;33:120)

Gross images

Images hosted on other servers:

Paraffin blocks
before and
after block
flipping

Positive stains

P504S racemase is positive in cancer; get immunostains on deeper levels, on areas initially suspicious for cancer (ASAP)

Negative stains

p63 or CK903 negative in cancer

Molecular / cytogenetics description

Microsatellite analysis can be performed on the prostatectomy and biopsy specimens to confirm specimen identity; this very rarely shows a specimen switch (1 in 10 cases of vanishing cancer was attributed to specimen mixup) (Am J Surg Pathol 2005;29:467)
This is particularly indicated if there is high grade or high volume cancer on the biopsy (Am J Surg Pathol 2005;29:467)

Sample pathology report

Prostate, radical prostatectomy:
- No residual cancer (see comment)
- Comment: This diagnosis is reached after complete submission and microscopy of all prostatic tissue. The tissue in the blocks was also reembedded and the reverse sides were cut into microscopic slides. The prostatic basal cell / P504S immunostain was performed to interrogate block X and it was confirmatory. The original diagnosis of cancer was confirmed by rereviewing the biopsy specimen. Dr. X agrees with this interpretation.

Differential diagnosis

Biopsy specimen switch:
- Specimen mixup with another patient must be excluded if the biopsy showed high grade or high volume cancer and no cancer is seen in the resection
- Molecular analysis can be performed (Am J Surg Pathol 2005;29:467)
Biopsy false positive:
- Correct diagnosis of cancer on the prior biopsy should be confirmed
- Immunostains (AMACR+ / p63, HMWK-) can be used if not previously performed

Board review style question #1

A 70 year old man undergoes radical prostatectomy with an organ weight of 90 g. What is the least likely contributor to finding no residual cancer?

Partial sampling of every other tissue slice (as is commonly done for > 50 g prostates)
Preoperative course of enzalutamide ablated any residual cancer
Prior prostate biopsy specimen switch
Residual cancer remains in the paraffin, even after flipping the blocks

Board review style answer #1

C. A specimen switch of the prior prostate biopsy is the least likely explanation and could be detected molecularly. If initial partial sampling was done, complete sampling of the tissue should be pursued; if cancer is not found, flipping the blocks is recommended; use of immunostains may help if any foci are suspicious. Finally, it is possible that a preoperative course of enzalutamide has ablated any residual cancer.

Comment Here

Reference: Vanishing cancer

Verumontanum mucosal hyperplasia

Table of Contents

Definition / general

Well circumscribed small acinar proliferation in or adjacent to verumontanum and posterior prostatic urethra

Sites

The verumontanum is located in the posterior aspect of the prostatic urethra
It is the area where the utricle and the ejaculatory ducts merge with the urethra

Clinical features

The presence of verumontanum mucosa gland hyperplasia is an asymptomatic morphologic variant of the glands underlying the posterior wall of the prostatic urethra

Diagnosis

Can be identified in TURP specimens or in needle biopsies of the prostate

Case reports

5 cases of verumontanum mucosal gland hyperplasia in prostatic needle biopsy specimens (Am J Clin Pathol 1995;104:620)

Treatment

Not required

Microscopic (histologic) description

Crowded small acinar proliferation, usually arranged in a well circumscribed nodule
The glands can have intraluminal concretions that vary in color from orange to gray or green
May be seen underlying the urethral urothelium

Positive stains

The immunophenotype is identical to normal prostate glands, including basal cell markers

Differential diagnosis

Verumontanum mucosal gland hyperplasia (VMGH), when present in a prostate needle biopsy, could be mistaken for low grade prostatic adenocarcinoma (Gleason pattern 3)
The lobular architecture and the presence of basal cells are features to differentiate it from Gleason pattern 3 cancer
Another helpful feature is the presence of corpora amylacea or the orange-grey-green concretions that are features of VMGH and not of prostatic carcinoma
Occasionally, it can present with a papillary architecture simulating prostatic duct adenocarcinoma
In contrast to prostatic duct carcinoma, the cells in VMGH are more cuboidal and without nuclear atypia

Additional references

Am J Clin Pathol 1995;104:620, Am J Surg Pathol 1995;19:30, Mod Pathol 2004;17:328

Well differentiated neuroendocrine tumor

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images

Definition / general

Very rare tumor of prostate
Also called low grade neuroendocrine carcinoma
May metastasize

Case reports

7 year old boy (J Urol 1995;153:1080)
34 year old man (Int Urol Nephrol 2010;42:683)
61 year old man with primary carcinoid tumor of the verumontanum and a coexisting prostatic adenocarcinoma (J Med Case Reports 2010;4:16)
78 year old man with incidental 2 cm tumor with lymph node metastases at autopsy (Am J Surg Pathol 1984;8:545)

Microscopic (histologic) images

Images hosted on other servers:

Primary carcinoid tumor of the verumontanum

WHO classification

Table of Contents

Definition / general

The World Health Organization (WHO) 2022 Classification of Urinary and Male Genital Tumors (5th edition) replaces the previous WHO 2016 Classification

Major updates

Low grade prostatic intraepithelial neoplasia is no longer recognized as a reportable entity as it is not possible to distinguish from benign glandular hyperplasia
Cribriform subtype of high grade prostatic intraepithelial neoplasia (HGPIN) is no longer regarded as a distinct entity
- The term atypical intraductal proliferation is preferred to denote intraductal proliferations that are more complex than HGPIN but less complex than intraductal carcinoma; however, consensus on the terminology has not been reached (Pathology 2018;50:60, Arch Pathol Lab Med 2021;145:461)
Intraductal carcinoma of the prostate (IDC-P) may represent 2 distinct entities
- Small subset of IDC-P lesions is thought to have progressed from HGPIN precursor and are truly in situ
- Majority of IDC-P lesions represent late events associated with high grade invasive carcinoma colonizing nonneoplastic prostatic ducts and acini
Whether to include (or exclude) IDC-P into Gleason grading remains controversial with diverging recommendations by leading societies (Am J Surg Pathol 2020;44:e87, Arch Pathol Lab Med 2021;145:461)
Prostatic intraepithelial neoplasia-like adenocarcinoma has been moved and is discussed as a subtype of acinar adenocarcinoma (Am J Surg Pathol 2018;42:1693, Histopathology 2021;78:327)
Ductal adenocarcinoma remains separate from acinar adenocarcinoma, although there is consideration to reclassify it as a subtype of acinar adenocarcinoma (Mod Pathol 2009;22:359, Prostate 2015;75:1610, Prostate 2017;77:1242, Eur Urol Focus 2019;5:433, JCO Precis Oncol 2019;3:PO.18.00327)
Adenoid cystic (basal cell) carcinoma of the prostate is the preferred diagnostic terminology, rather than basal cell carcinoma, to avoid confusion with the more common skin tumor
The designation of subtypes has replaced variants for distinct clinical or morphologic categories within a tumor type; the term variant is used for genomic alterations
- Examples of subtypes of prostatic acinar adenocarcinoma include
  - Prostatic intraepithelial neoplasia-like adenocarcinoma
  - Signet ring-like cell acinar adenocarcinoma
  - Sarcomatoid acinar adenocarcinoma
  - Pleomorphic giant cell acinar adenocarcinoma
Neuroendocrine, mesenchymal, hematolymphoid, melanocytic, metastatic and genetic syndrome related tumors are now discussed in separate chapters
- Exceptions include
  - Mesenchymal tumors thought to arise from the prostatic stroma: prostatic stromal tumor of uncertain malignant potential and prostatic stromal sarcoma
  - Treatment related neuroendocrine prostatic carcinomas that remain under glandular neoplasms of the prostate
Urothelial carcinoma of the prostate and prostatic urethra has been moved to the urinary tract chapter

WHO (2022)

Tumors of the prostate	ICD-O	ICD-11
Epithelial tumors of the prostate
Glandular neoplasms of the prostate
Prostatic cystadenoma	8440/0	2F34 & XH5RJ2
High grade prostatic intraepithelial neoplasia	8148/2	2E67.5
Intraductal carcinoma of the prostate	8148/2	2E67.5
Prostatic acinar adenocarcinoma	8140/3	C61
Prostatic ductal adenocarcinoma	8500/3	2C822.0 & XH7KH3
Treatment related neuroendocrine prostatic carcinoma	8574/3	2C82.Y & XH0U20
Squamous neoplasms of the prostate
Adenosquamous carcinoma of the prostate	8560/3	2C82.Y & XH7873
Squamous cell carcinoma of the prostate	8070/3	2C82.Y & XH0945
Adenoid cystic (basal cell) carcinoma of the prostate	8147/3	2C82.Y & XH4ZC3
Mesenchymal tumors unique to the prostate
Stromal tumors of the prostate
Prostatic stromal tumor of uncertain malignant potential	8935/1	2F77 & XH8747
Prostatic stromal sarcoma	8935/3	2C82.Y & XH49Y5

Diagrams / tables

None

Microscopic (histologic) images

Contributed by Alcino Pires Gama, M.D. and Bonnie Choy, M.D.

Prostatic ductal adenocarcinoma

Adenoid cystic (basal cell) carcinoma of the prostate

Treatment related neuroendocrine carcinoma

Intraductal carcinoma of the prostate

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

Which of the following is most accurate according to the WHO 2022 Classification of Urinary and Male Genital Tumors (5th edition)?

Cribriform subtype of high grade prostatic intraepithelial neoplasia (HGPIN) is no longer a distinct entity
Ductal adenocarcinoma has been incorporated as a subtype of acinar adenocarcinoma
Intraductal carcinoma should be graded and incorporated in the final Gleason score
PIN-like adenocarcinoma remains a subtype of ductal adenocarcinoma

Board review style answer #1

A. Cribriform subtype of high grade prostatic intraepithelial neoplasia (HGPIN) is no longer recognized as a distinct entity as it belongs to a group of intraductal proliferations that are more complex than HGPIN but less complex than intraductal carcinoma. Answer B is incorrect because ductal adenocarcinoma remains separate from acinar adenocarcinoma, although there have been discussions to reclassify it as a subtype of acinar adenocarcinoma. Answer C is incorrect because the inclusion / exclusion of intraductal carcinoma into Gleason grading remains controversial; additional studies are required to compare the 2 approaches from a prognostic perspective. Answer D is incorrect because PIN-like adenocarcinoma has been moved to the chapter on acinar adenocarcinoma.

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Reference: Prostate gland & seminal vesicles - WHO classification

Board review style question #2

Which of the following is an update from the WHO 2022 Classification of Urinary and Male Genital Tumors (5th edition)?

Basal cell markers are useful in distinguishing adenoid cystic carcinoma of the prostate from basal cell carcinoma
Low grade intraepithelial neoplasia remains a distinct entity
The descriptors subtypes and variants can be used interchangeably
Treatment related neuroendocrine carcinomas of the prostate remain under glandular neoplasms of the prostate

Board review style answer #2

D. Treatment related neuroendocrine carcinomas of the prostate remain under glandular neoplasms of the prostate. Given the distinct risk factors, prognosis and management, treatment related neuroendocrine carcinomas of the prostate remain under glandular neoplasms of the prostate. All other mesenchymal tumors were moved to a separate chapter. Answer A is incorrect because basal cell carcinoma of the prostate has been renamed as adenoid cystic (basal cell) carcinoma of the prostate. Answer B is incorrect because low grade prostatic intraepithelial neoplasia is no longer a distinct entity. Answer C is incorrect because the designation of subtypes has replaced variant for distinct clinical or morphologic categories within a tumor type.

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Reference: Prostate gland & seminal vesicles - WHO classification

WHO classification (pending)

[Pending]

Recent Prostate gland & seminal vesicles Pathology books

Amin: 2022

Cheng: 2019

Epstein: 2021

Epstein: 2020

IARC: 2022

Lopez-Beltran: 2018

Matoso: 2020

Robinson: 2018

Shah: 2019

VandenBussche: 2022

Wobker: 2021

Yang: 2020

Zhou: 2022

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