# Histopathologic diagnosis of prostate cancer

A histopathologic diagnosis of prostate cancer is the discernment of whether there is a cancer in the prostate, as well as specifying any subdiagnosis of prostate cancer if possible. The histopathologic subdiagnosis of prostate cancer has implications for the possibility and methodology of any subsequent Gleason scoring. The most common histopathological subdiagnosis of prostate cancer is acinar adenocarcinoma, constituting 93% of prostate cancers. The most common form of acinar adenocarcinoma, in turn, is "adenocarcinoma, not otherwise specified", also termed conventional, or usual acinar adenocarcinoma.

## Sampling

The main sources of tissue sampling are prostatectomy and prostate biopsy.

## Subdiagnoses - overview

| Subdiagnosis | Subdiagnosis | Relative incidence | Relative incidence | Image | Microscopic characteristics | Immunohistochemistry | Gleason scoring |
| Subdiagnosis | Subdiagnosis | Core biopsy | Radical prostatectomy | Image | Microscopic characteristics | Immunohistochemistry | Gleason scoring |
| Acinar adenocarcinoma - 93% | Adenocarcinoma (not otherwise specified/ conventional/ usual acinar) | 77% | 54% | | Collagenous micronodules Glomerulations Further information in section below May be mixed with other subdiagnoses. | Tumorous glands: 34βE12- and p63- (+ in adjacent benign glands) AMACR+ (- in adjacent benign glands) PSA+ (>10 ng/ml) in 60% of cases | As usual |
| Acinar adenocarcinoma - 93% | Foamy gland carcinoma | 17% | 13–23% | | Abundant foamy cytoplasm Nuclei may be small and pyknotic - benign-looking Infiltrative pattern | Foamy cells: PSA+ and CD68− AMACR+ in 68% of cases | Based on architecture, discounting foamy cytoplasms |
| Acinar adenocarcinoma - 93% | Atrophic carcinoma | 2% | 16% | | Glands lined by cells with scant cytoplasm, resembling atrophy Infiltrative growth Usually admixed with non-atrophic components | Tumorous glands: 34βE12- and p63- AMACR+ in 70% of cases | As usual |
| Acinar adenocarcinoma - 93% | Pseudohyperplastic carcinoma | 2% | 11% | | Large-sized or dilated glands Branching and papillary infolding Tall columnar cells Abundant pale to slight granular luminal cytoplasm Nuclei towards basement membrane | Tumorous glands: 34βE12- and p63- AMACR+ in 70–83% of cases | 3+3=6 |
| Acinar adenocarcinoma - 93% | Microcystic carcinoma | | 11% | | Cystic dilatation and rounded expansion of malignant glands Lined by flat cells Intraluminal crystalloids, and wispy blue intraluminal mucin | 34βE12- and p63- AMACR+ | On (usually) adjacent acinar adeocarcinoma |
| Acinar adenocarcinoma - 93% | PIN-like | 1.3% | | | Glands lined by ≥2 layers of malignant cells May resemble flat or tufted high-grade PIN, but lacks basal cells | Tumorous glands: 34βE12- and p63- | Not recommended |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Ductal adenocarcinoma | 3% to 12.7% | 3% to 12.7% | | Large glands and papillary formations, lined by tall columnar cells, often pseudostratified Papillary, cribriform, individual glands, or solid variants Cytoplasm usually amphophilic Nuclei are large and hyperchromatic, with prominent nucleoli | AMACR+ in 77% of cases Usually negative for basal cells stains | |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Intraductal adenocarcinoma | 2.8% | | H&E and CK5/6 | Carcinoma cells spanning entire lumen of ducts and acini At least focal preservation of the basal cell layer | PSA+ AMACR+ Basal cell markers+ | |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Urothelial carcinoma | 0.7 to 2.8% | 0.7 to 2.8% | | Umbrella cells are usually present in low-grade tumors Frequently branching fibrovascular cores Frequently fusing of papillae | | Not recommended |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Small-cell carcinoma | 0.3–2% | 0.3–2% | | Small blue cells with scant cytoplasm High nucleus/cytoplasm ratio "salt and pepper" chromatin Nuclear molding Necrosis of single cells, or geographic Smearing artifacts Half of cases have usual acinar components | | |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Mucinous adenocarcinoma | 0.2% | 0.2% | | ≥25% of tumor shows extracellular mucin Intraluminal mucinous material does not qualify No extraprostatic origin found | Tumorous glands: 34βE12- and p63- PSA+ and CK8/18+ | 4+4=8 for irregular cribriform glands floating in mucin. |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Signet-ring adenocarcinoma | 0.02% | 0.02% | | ≥25% of tumor shows signet-ring cells (widely infiltrative cells with optically clear vacuoles displacing the nuclei) | Tumorous glands: 34βE12- and p63- PSA+ | Not recommended |
| Non acinar (or mixed acinar/ non-acinar) adenocarcinoma | Basal-cell carcinoma | 0.01% | 0.01% | | Basaloid tumor: Scant cytoplasm High nucleus/cytoplasm ratio Irregular or angulated nuclei Euchromatic May have nuclear and cytoplasmic micro-vacuolation Infiltration of adjacent parenchyma BCC-pattern: Variably sized solid nests, cords, or trabeculae Peripheral palisading | p63+ HMCK(34βE12)+ Typically CK20−/CK7+, but CK7− in pure solid basal cell nests Bcl-2+, strongly and diffusely Ki-67 nuclear staining in >20% | Not recommended. |
In uncertain cases, a diagnosis of malignancy can be excluded by immunohistochemical detection of basal cells (or confirmed by absence thereof), such as using the PIN-4 cocktail of stains, which targets p63, CK-5, CK-14 and AMACR (latter also known as P504S).
Other prostate cancer tumor markers may be necessary in cases that remain uncertain after microscopy.

## Acinar adenocarcinoma

These constitute 93% of prostate cancers.

### Microscopic characteristics
#### Specific but relatively rare

* Collagenous micronodules
* Glomerulations, epithelial proliferations into one or more gland lumina, typically a cribriform tuft with a single attachment to the gland wall.
* Perineural invasion. It should be circumferential
* Angiolymphatic invasion
* Extraprostatic extension
* Glomerulation.

#### Relatively common and highly specific

* Multiple nucleoli
* Eccentric nucleoli
* Acinar adenocarcinoma with multiple nucleoli.
* Acinar adenocarcinoma with double and eccentric nucleoli.

#### Less specific findings.

* Mitoses (also seen in for example high-grade prostatic intraepithelial neoplasia (HGPIN) and prostate inflammation).
* Prominent nucleoli
* Intraluminal eosinophilic secretion
* Intraluminal blue mucin
* Adenocarcinoma with two mitoses in reactive epithelium.
* Acinar adenocarcinoma with intraluminal blue mucin.
In uncertain cases, a diagnosis of malignancy can be discarded by immunohistochemical detection of basal cells.
* Atrophy is a differential diagnosis to prostate cancer. This example shows gradually increasing simple atrophy from left to right, H&E stain. Crowding and angulation may mimic that of adenocarcinoma, but there is nuclear basophilia rather than atypia, and occasional basal cells can still be seen.
* Also, seminal vesicle glands may mimic prostatic adenocarcinoma by crowded glands with enlarged hyperchromatic and irregular nuclei, but will have inconspicuous nucleoli and coarse refractile golden brown lipofuscin granules.

## Intraductal carcinoma

Intraductal carcinoma of the prostate gland (IDCP), which is now categorised as a distinct entity by WHO 2016, includes two biologically distinct diseases. IDCP associated with invasive carcinoma (IDCP-inv) generally represents a growth pattern of invasive prostatic adenocarcinoma while the rarely encountered pure IDCP is a precursor of prostate cancer. The diagnostic criterion of nuclear size at least 6 times normal is ambiguous as size could refer to either nuclear area or diameter. If area, then this criterion could be re-defined as nuclear diameter at least three times normal as it is difficult to visually compare area of nuclei. It is also unclear whether IDCP could also include tumors with ductal morphology. There is no consensus whether pure IDCP in needle biopsies should be managed with re-biopsy or radical therapy. A pragmatic approach would be to recommend radical therapy only for extensive pure IDCP that is morphologically unequivocal for high-grade prostate cancer. Active surveillance is not appropriate when low-grade invasive cancer is associated with IDCP, as such patients usually have unsampled high-grade prostatic adenocarcinoma. It is generally recommended that IDCP component of IDCP-inv should be included in tumor extent but not grade. However, there are good arguments in favor of grading IDCP associated with invasive cancer. WHO 2016 recommends that IDCP should not be graded, but it is unclear whether this applies to both pure IDCP and IDCP-inv.
* Intraductal carcinoma of the prostate with an infiltrative growth pattern may be morphologically difficult to distinguish from invasive cancer. One focus shows comedonecrosis (arrow), morphologically suggesting Gleason pattern 5 invasive carcinoma (a haematoxylin and eosin, b CK5/6)
* Intraductal carcinoma of the prostate with very patchy basal cells identified by immunohistochemistry. At least some of the glands lacking basal cell immunoreactivity represent intraductal rather than invasive carcinoma (a haematoxylin and eosin, b CK 5/6)
Ductal adenocarcinoma may have a prominent cribriforming architecture, with glands appearing relatively round, and may thereby mimic intraductal adenocarcinoma, but can be distinguished by the following features:
Differences between ductal and intraductal adenocarcinoma :
| Feature | Ductal adenocarcinoma | Intraductal adenocarcinoma |
| True fibrovascular cores in micropapillary architecture | Present | Usually absent |
| Cribriform lumens | Lined by pseudostratified, columnar cells | Punched out lumens lined by cuboidal cells |
| Basal cell markers | Usually negative | Usually positive |

## Further workup

Further workup of a diagnosis of prostate cancer includes mainly:
* Gleason score
* Prostate cancer staging