Acinar Adenocarcinoma

Gladell P. Paner, MD

Rafael E. Jimenez, MD

Jesse K. McKenney, MD

Key Facts

Terminology

Malignant neoplasm arising from secretory cells

Etiology/Pathogenesis

˜ 50% PCa harbor TMPRSS2 and ETS gene fusion

Macroscopic Features

75-80% of PCas arise in PZ; ˜ 15-25% arise in TZ

Microscopic Pathology

Diagnosis based on constellation of architectural, nuclear, cytoplasmic, and intraluminal features
Crowded uniform glands that infiltrate between preexisting benign glands
- Small caliber, crowded clusters, rigid or “sharp” lumina, tinctorial staining of cytoplasm distinct from adjacent benign glands
Malignant glands lack basal cells by immunohistochemistry
Nuclear enlargement and hyperchromasia with prominently enlarged &/or multiple and peripherally located nucleoli
Pathognomonic features for malignant glands
- Glomerulations or collagenous micronodules
- Circumferential perineural/intraneural invasion or growth within fat
Less differentiated tumors have poorly formed, fused, or large cribriform glands
Poorly differentiated tumors may grow as infiltrative single cells or solid sheets
Treated PCa glands usually poorly formed but retain infiltrative appearance

Schematic diagram shows modified Gleason grading system for PCa. The Gleason score is a powerful prognostic variable in predicting PCa behavior. This grading system is based purely on glandular architectural patterns, divided into 5 histologic categories or grades with decreasing differentiation. First developed in 1966 by Dr. Donald F. Gleason, it underwent refinements in 1974 and 1977 and had its latest modification by ISUP in 2005. This grading scheme is now universally accepted and recognized by World Health Organization and by American Joint Committee on Cancer as the grading system of choice for PCa.

TERMINOLOGY

Abbreviations

Prostate adenocarcinoma (PCa)

Synonyms

Prostatic adenocarcinoma

Definitions

Malignant neoplasm arising from secretory cells

ETIOLOGY/PATHOGENESIS

Molecular Genetics

TMPRSS2 and ETS gene fusion
- Most common recurrent arrangement identified
- ˜ 50% PCa harbor these recurrent gene fusions; individual estimates vary between 15-78%
- TMPRSS2 encodes for serine protease secreted by prostatic cells in response to androgen exposure
- ETS family of transcription factors include ERG, ETV1, ETV4, and ETV5
- TMPRSS2:ERG gene fusion most common (˜ 90%)
  - ERG brought under control of androgen-regulated promoter causing protein overexpression
- Intra- and interchromosomal genetic rearrangements lead to creation of fusion transcript
  - In ˜ 2/3 of cases, fusion results from deletion (intervening 3 Mb between TMPRSS2 and ERG)
  - Fusion may also occur by more complex rearrangement, such as translocation
  - Over 20 TMPRSS2:ERG variants now described
- Morphological features of prostate cancer associated with TMPRSS2:ERG gene fusion
  - Blue-tinged mucin, cribriform pattern, intraductal spread, macronucleoli, and signet ring cells
- Clinical significance of this gene fusion not yet fully understood
  - Conflicting reports in literature
Hereditary prostate cancer
- Compelling evidence suggests familial predisposition to prostate cancer in some cases
- High-risk alleles identified with either autosomal dominant or X-linked mode of inheritance
- 3 candidates genes identified: HPC2/ELAC2 on 17p, RNASEL on 1q25, and MSR1 on 8p22-23
Other genes and molecular alterations
- Most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q and gains at 1q, 2p, 7, 8q, 18q, and Xq
- Genes implicated in PCa include GST-pi, NKX3.1, PTEN, AMACR, hepsin, KLF-6, EZH2, p27, E-cadherin
- Mutations in androgen receptor gene may promote cancer growth at lower circulating androgen levels
- Hedgehog pathway has been shown to play a role in growth and metastasis of prostate cancer

MACROSCOPIC FEATURES

General Features

Unlike most other visceral organ tumors, PCa often has no reliably distinguishable gross mass lesion
- Grossly evident tumors are usually pT3, ≥ Gleason score (GS) 8, or ≥ 1 cm size tumors
  - Indurated yellow to yellow-tan homogeneous areas
  - More dense or firmer than surrounding benign spongy parenchyma
- Typically lack necrosis or hemorrhage
- Tumor border blends imperceptibly with benign parenchyma
- Lesions < 5 mm generally inapparent
- Tumors often larger when examined by microscopy than when measured grossly
- False-positivity rate in gross identification up to 19%
Tumors usually in posterior or posterolateral aspect (peripheral zone [PZ]) of the gland
Anterior tumors more difficult to recognize as they are usually admixed with nodular hyperplasia

Site

75-80% of PCas arise in PZ, and 15-25% arise in transition zone (TZ)
Central zone is usually only secondarily involved
Multifocal tumors present in more than 50% of PCas

MICROSCOPIC PATHOLOGY

Histologic Features

Diagnosis based on constellation of architectural, nuclear, cytoplasmic, and intraluminal features
- Some individual features may also be seen in benign glands
Architectural features
- Better differentiated tumors consist of compact or loose collections of well-formed glands
  - Small crowded uniform glands infiltrate between preexisting benign glands
- Malignant glands usually differ in appearance from surrounding benign glands
  - Smaller-caliber glands
  - Crowded or compact gland clusters
  - Rigid or “sharp” glandular lumina
  - May have periglandular clefts
- Malignant glands should lack basal cells
- Less differentiated tumors consist of poorly formed, fused, or large cribriform glands
- Poorly differentiated tumors may grow as infiltrative single cells or solid sheets
Nuclear features
- Nuclear enlargement and hyperchromasia
- Prominently enlarged nucleoli
- Multiple and peripherally located nucleoli
- Parachromatin clearing
- Mitoses are rare; highly suggestive of malignancy if present
- Apoptotic bodies (rare)
- Nuclei commonly uniform, nonpleomorphic
Cytoplasmic features
- Typically cuboidal to columnar cells with modest cytoplasm
- Amphophilic, clear or pale granular cytoplasm
- Taller cells with clear to pale pink cytoplasm and basally located nuclei more common in TZ
Intraluminal features
- Blue mucin
  - Usually prominent collection of wispy, bluetinged intracellular mucin
- Eosinophilic amorphous secretions
  - Granular eosinophilic luminal material
- Crystalloids
  - Geometric bright eosinophilic rhomboid to prismatic structures with sharp edges, usually associated with eosinophilic amorphous secretions
  - Present in up to 41% of PCas
  - Seen in atypical adenomatous hyperplasia and uncommonly in benign glands
- Corpora amylacea are extremely rare in PCa, should strongly suggest benign glands
- Intraluminal necrosis may be present in high-grade tumors, highly indicative of malignancy
Pathognomonic features for malignant glands
- Glomerulations
  - Cribriform cellular luminal proliferations in otherwise well-formed glands attached to 1 pole
- Collagenous micronodules (mucinous fibroplasia)
  - Hyalinized eosinophilic material usually associated with abundant intraluminal blue mucin
  - Often imparts an anastomosing epithelial pattern
- Circumferential perineural or intraneural invasion
  - Gland should completely surround the nerve or be seen within the nerve
  - Benign glands may focally touch or indent a nerve; very rarely may be intraneural
- Growth within adipose tissue
  - Intraprostatic fat is exceedingly rare
  - Indicates extraprostatic extension (EPE)

Gleason Grading System

Universally accepted grading system for PCa
Assessment of glandular architecture at low/intermediate magnification: Classified into 5 basic patterns
- Each pattern may arise de novo without progression from lower grade
In resection specimens, GS is sum of primary and secondary Gleason patterns
- Primary pattern is most prevalent pattern and secondary is 2nd most common pattern
International Society of Urological Pathology (ISUP) 2005 consensus conference proposed several modifications and guidelines
- In needle biopsies, include tertiary pattern in Gleason score if it is higher than secondary pattern
  - Similar rule applies for transurethral resection and enucleation (simple prostatectomy) specimens
  - In high-grade cancers, ignore lower grade pattern if < 5% (e.g., 4 + 4, if pattern 3 is < 5%)
  - For cancers with more than 1 pattern, include the higher grade even if it is < 5% (e.g., 3 + 4, even if pattern 4 is < 5%)
- Assign individual GS to all cores as an aggregate if submitted in 1 container; assign GS to each core separately designated (e.g., ink or separately submitted) by urologist
- In radical prostatectomy, provide GS (primary and secondary pattern); separately mention tertiary pattern
- Assign separate GS to dominant tumor(s) for multifocal tumors in radical prostatectomy
- Individualized Gleason grading approach for some PCa morphologic variants and subtypes
Gleason pattern 1
- Circumscribed nodule of tightly packed, uniform, round to oval, well-formed glands, with no or minimal infiltration of adjacent parenchyma
- Using these strict criteria, exceedingly rare and controversial in current practice
  - Most described pre-immunohistochemistry were likely atypical adenomatous hyperplasia
Gleason pattern 2
- Nodular with minimal peripheral infiltration, less uniform and more loosely arranged glands
- Also very rare and typically found in TZ
- Usually incidental with associated higher grades, but occasionally secondary pattern in resection specimens
- ISUP recommends that GS 3 or 4 should rarely, if ever, be diagnosed in needle biopsy specimens
  - Architecture cannot be assessed in its entirety
  - Poor reproducibility among experts
  - Poor correlation with grade in subsequent prostatectomy (i.e., undergrading)
  - May misguide clinicians and patients with assumption of indolent tumor
Gleason pattern 3
- Most common pattern
- Predominantly well-formed, individual glands that infiltrate between benign ducts and acini
- Includes smaller but well-formed glands (microacini)
- Glands typically smaller than in patterns 1 or 2
- Inclusion of small cribriform structures is controversial, as most experts include all cribriform patterns in Gleason pattern 4
  - Should have perfectly round contours
  - Size similar to surrounding benign glands
  - Uniform round “punched-out” lumina with bridges not thicker than lumina
  - By this strict definition, cribriform Gleason pattern 3 is extraordinarily rare; we rarely designate cribriform patterns as Gleason 3
Gleason pattern 4
- Most commonly fused, poorly formed glands
  - Tangentially sectioned pattern 3 glands may mimic fused pattern 4 glands
  - Common cause of overgrading
- 2nd most common pattern is cribriform structures with either regular or irregular outlines
- Uncommon “hypernephromatoid” pattern, consists of solid sheets of cells with optically clear cytoplasm
Gleason pattern 5
- Lacks glandular differentiation: Manifests as solid sheets, cords, or single infiltrative tumor cells
- Also includes solid, cribriform, or papillary structures with central comedo-type necrosis

Morphologic Variations and Variants

Atrophic variant
- PCa with glands lined by cells with scant cytoplasm, resembling atrophy
- Infiltrative growth, cytology of malignancy
- Usually admixed with nonatrophic PCa
- In contrast, benign atrophic glands typically have dense hyperchromatic nuclei and lobular growth
Pseudohyperplastic variant
- Large-sized or dilated glands, with branching and papillary infolding
- Tall columnar cells with abundant pale to slight granular luminal cytoplasm
- Basally located nuclei along basement membrane
- Commonly with luminal eosinophilic amorphous secretions and may have crystalloids
- Diagnostic malignant nuclear features retained, in contrast to benign hyperplastic glands
- ISUP recommends grade of 3 + 3 = 6; if part of a large circumscribed nodule, grade may be 3 + 2 = 5
Foamy gland (xanthomatous) variant
- PCa with abundant foamy cytoplasm
- Malignant nuclear features not always present, as nuclei may be small and pyknotic
- Presence of infiltrative pattern; may require immunostains
- ISUP recommends discounting foamy cytoplasm and assigning grade based on architecture; most are 3 + 3 = 6 tumors
Mucinous (colloid) adenocarcinoma
- ≥ 25% of resected tumor shows extracellular mucin
- Intraluminal mucinous material does not qualify, and extraprostatic origin must be excluded
- Diagnosis should be made only in resection specimen, as needle biopsy specimen may not show exact proportion of mucinous component
  - In needle biopsy, may be diagnosed as “PCa with mucinous features”
- With strict diagnostic criteria, suggested to have similar features and behavior with conventional PCa
- ISUP recommend to grade irregular cribriform glands floating in mucin as 4 + 4 = 8; no consensus if individual discrete glands in mucin
Signet ring cell variant
- ≥ 25% of resected tumor shows signet ring cell (arbitrary definition)
- Tumor cells contain optically clear vacuoles displacing nuclei and are widely infiltrative
- Associated with typical high-grade PCa
- May be mucin-producing PCa (“mucinous carcinoma with signet ring cells”)
  - Not clear if nonmucinous (mucicarmine negative) signet ring PCa is distinct clinically
- Clinical presentation similar to conventional PCa, with tendency to present at higher stage
PCa with Paneth-cell-like differentiation
- PCa containing neuroendocrine cells with bright eosinophilic cytoplasmic granules resembling Paneth cells of gastrointestinal tract
- Suggested to have favorable prognosis, including those with nests, cords, or single cell morphology
Other rarer variants
- Lymphoepithelioma-like variant
  - As in other organs, characterized by syncytial growth amid dense lymphocytic background
  - No Epstein-Barr virus association
- Oncocytic variant
  - PCa with abundant granular eosinophilic cytoplasm
  - Like other oncocytic tumors, ultrastructurally contains abundant mitochondria
- PCa with stratified epithelium (“PIN-like”)
  - Glands lined by ≥ 2 layers of malignant cells
  - May resemble flat or tufted high-grade PIN but lacks basal cells by immunohistochemistry

Therapy-related Changes

Radiation therapy
- Treated PCa glands usually poorly formed but retain their infiltrative appearance
  - Foamy vacuolated cytoplasm and pleomorphic nuclei; changes vary from mild to marked
  - Marked radiation effect may artifactually produce architecture resembling GS 9 or 10 cancers
  - Luminal features of malignancy may be retained
- Cytologic atypia and pleomorphism more pronounced in benign than malignant glands
- Residual treated PCa with minimal or no radiation effect has higher chance of recurrence
- PAN-CK(AE1/AE3) useful to highlight treated PCa
Hormonal therapy
- Treated PCa may be shrunken glands or single cells
- Glands show xanthomatous cytoplasm, pyknotic and fragmented nuclei, and mucin extravasation
- Empty spaces representing remnants of shrunken glands may be present
- Marked atrophy, basal cell hyperplasia, or squamous metaplasia in adjacent benign glands
- PAN-CK(AE1/AE3) useful to highlight treated PCa

DIFFERENTIAL DIAGNOSIS

General Features

Given broad morphologic spectrum, differential diagnosis for PCa ranges from innocuous benign normal structures to secondary high-grade cancers
PCa most often mimicked by benign prostatic glandular lesions; difficulty enhanced in limited samples (e.g., biopsy)
- Use of ancillary immunohistochemistry helpful in some scenarios
- Pattern-based approach facilitates work-up and judicious selection of adjuvant stains

Atypical Small Acinar Proliferation (ASAP)

Focal atypical glands that are suspicious but quantitatively &/or qualitatively insufficient for diagnosis or exclusion of PCa
Most common differential diagnostic scenario for PCa
Differential diagnosis includes focal PCa and benign glandular lesions
Immunohistochemistry may be helpful
- PCa lacks basal cell staining and often overexpresses AMACR
  - In some cases, definitive diagnosis of PCa is not possible even with a carcinoma staining pattern

SELECTED REFERENCES

1. Gopalan A et al: TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res. 69(4):1400-6, 2009

2. Lopez-Beltran A et al: Lymphoepithelioma-like carcinoma of the prostate. Hum Pathol. 40(7):982-7, 2009

3. Epstein JI et al: The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 29(9):1228-42, 2005

4. Tomlins SA et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 310(5748):644-8, 2005

5. Varma M et al: Morphologic criteria for the diagnosis of prostatic adenocarcinoma in needle biopsy specimens. A study of 250 consecutive cases in a routine surgical pathology practice. Arch Pathol Lab Med. 126(5):554-61, 2002

6. Humphrey PA et al: Pseudohyperplastic prostatic adenocarcinoma. Am J Surg Pathol. 22(10):1239-46, 1998

7. Egan AJ et al: Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol. 21(8):931-5, 1997

8. Nelson RS et al: Prostatic carcinoma with abundant xanthomatous cytoplasm. Foamy gland carcinoma. Am J Surg Pathol. 20(4):419-26, 1996

Tables

Differential Diagnosis for Prostate Carcinoma
Histologic Pattern	Prostate Carcinoma Main	Differential Diagnoses
Small glandular proliferation	Glandular Gleason pattern 3	Crowded benign glands, not otherwise specified
	Atrophic pattern	Simple atrophy
	Post-treatment cancer	Outpouching of high-grade PIN
		Partial atrophy
		Postatrophic hyperplasia (PAH)
		AAH (adenosis)
		Sclerosing adenosis
		Basal cell hyperplasia
		Seminal vesicle epithelium
		Ejaculatory duct
		Cowper glands
		Mesonephric remnants
		Nephrogenic adenoma
		Verumontanum mucosal gland hyperplasia
		Radiation atypia
Atypical large glandular proliferation	Cribriform Gleason patterns 3, 4, and 5	High-grade PIN
	Ductal adenocarcinoma	Urothelial carcinoma involving prostatic ducts and acini
	Pseudohyperplastic pattern	Colorectal carcinoma involving prostate
		Cribriform hyperplasia
		Squamous metaplasia
		Urothelial metaplasia
Infiltrative single cell pattern	Single cell Gleason 5 pattern	Dense inflammation
	Post-treatment carcinoma	Granulomatous prostatitis
		Lymphoma
		Small cell carcinoma
Clear cell pattern	Hypernephroid Gleason pattern 4	Prostatic xanthoma
	Glandular Gleason pattern 3
Oncocytic pattern	Gleason pattern 4	Paraganglion/paraganglioma
		Carcinoid tumor
Poorly to undifferentiated carcinoma	Solid Gleason pattern 5	Urothelial carcinoma
Spindle cell pattern	Sarcomatoid carcinoma	Pseudosarcomatous myofibroblastic proliferation
		Stromal sarcoma
		Leiomyosarcoma
Small cell pattern	Small cell carcinoma	Lymphoma
		Rhabdomyosarcoma