Histopathologic diagnosis of prostate cancer explained

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.^[1] The most common histopathological subdiagnosis of prostate cancer is acinar adenocarcinoma, constituting 93% of prostate cancers.^[2] The most common form of acinar adenocarcinoma, in turn, is "adenocarcinoma, not otherwise specified", also termed conventional, or usual acinar adenocarcinoma.^[3]

Sampling

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

Subdiagnoses - overview

Subdiagnosis	Relative incidence		Image	Microscopic characteristics
	Radical prostatectomy
Acinar adenocarcinoma - 93%	Adenocarcinoma (not otherwise specified/ conventional/ usual acinar)	77%^[4]	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
	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
	Atrophic carcinoma	2%^[5]	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
	Pseudohyperplastic carcinoma	2%^[6]	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
	Microcystic carcinoma		11%		Cystic dilatation and rounded expansion of malignant glands^[7] Lined by flat cells Intraluminal crystalloids, and wispy blue intraluminal mucin	34βE12- and p63- AMACR+	On (usually) adjacent acinar adeocarcinoma
	PIN-like	1.3%^[8]			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%^[9]			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^[10]	AMACR+ in 77% of cases Usually negative for basal cells stains
	Intraductal adenocarcinoma	2.8%^[11]		H&E and CK5/6	Carcinoma cells spanning entire lumen of ducts and acini^[12] At least focal preservation of the basal cell layer	PSA+ AMACR+ Basal cell markers+
	Urothelial carcinoma	0.7 to 2.8%^[13]			Umbrella cells are usually present in low-grade tumors^[14] Frequently branching fibrovascular cores Frequently fusing of papillae		Not recommended
	Small-cell carcinoma	0.3–2%^[15] ^[16]			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
	Mucinous adenocarcinoma	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.
	Signet-ring adenocarcinoma	0.02%^[17]			≥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
	Basal-cell carcinoma	0.01%^[18]			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.^[2]

Microscopic characteristics

Specific but relatively rare:^[19]

• Collagenous micronodules^[20]
• Glomerulations,^[20] epithelial proliferations into one or more gland lumina, typically a cribriform tuft with a single attachment to the gland wall.
• Perineural invasion.^[20] It should be circumferential^{[21] [22]}
• Angiolymphatic invasion^[20]
• Extraprostatic extension ^[20]

Relatively common and highly specific :^[20]

• Multiple nucleoli
• Eccentric nucleoli^[20]

Less specific findings.

• Mitoses (also seen in for example high-grade prostatic intraepithelial neoplasia (HGPIN) and prostate inflammation).^[20]
• Prominent nucleoli^[20]
• Intraluminal eosinophilic secretion^[20]
• Intraluminal blue mucin^[20]

In uncertain cases, a diagnosis of malignancy can be discarded by immunohistochemical detection of basal cells.^[20]

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.^[23] 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.^[23] It is also unclear whether IDCP could also include tumors with ductal morphology.^[23] 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.^[23] Active surveillance is not appropriate when low-grade invasive cancer is associated with IDCP, as such patients usually have unsampled high-grade prostatic adenocarcinoma.^[23] It is generallyrecommended that IDCP component of IDCP-inv should be included in tumor extent but not grade.^[23] However, there are good arguments in favor of grading IDCP associated with invasive cancer.^[23] WHO 2016 recommends that IDCP should not be graded, but it is unclear whether this applies to both pure IDCP and IDCP-inv.^[23]

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:^[11]

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

Notes and References

1. Li J, Wang Z . The pathology of unusual subtypes of prostate cancer . Chin. J. Cancer Res. . 28 . 1 . 130–43 . February 2016 . 27041935 . 4779761 . 10.3978/j.issn.1000-9604.2016.01.06 .
2. Baig. Faraz A.. Hamid. Amna. Mirza. Talat. Syed. Serajuddaula. Ductal and Acinar Adenocarcinoma of Prostate: Morphological and Immunohistochemical Characterization. Oman Medical Journal. 30. 3. 2015. 162–166. 1999-768X. 10.5001/omj.2015.36 . 26171121 . 4459157 . free.
3. Web site: Prostatic Adenocarcinoma. Stanford University School of Medicine. 2019-10-30. 2019-09-11. https://web.archive.org/web/20190911145728/http://surgpathcriteria.stanford.edu/prostate/adenocarcinoma/classification-lists.html. dead.
4. Numbers for usual acinar adenocarcinoma do not include mixed patterns with other types.
5. Number refers to sporadic atrophic pattern adenocarcinoma.
6. Humphrey. Peter A. Variants of acinar adenocarcinoma of the prostate mimicking benign conditions. Modern Pathology. 31. S1. 2018. 64–70. 0893-3952. 10.1038/modpathol.2017.137. 29297496 . free.
7. Yaskiv. Oksana. Cao. Dengfeng. Humphrey. Peter A.. Microcystic Adenocarcinoma of the Prostate: A Variant of Pseudohyperplastic and Atrophic Patterns. The American Journal of Surgical Pathology. 34. 4. 2010. 556–561. 0147-5185. 10.1097/PAS.0b013e3181d2a549. 20216381 . 24149412 .
8. Zhou. Ming. High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate. Modern Pathology. 31. S1. 2018. 71–79. 0893-3952. 10.1038/modpathol.2017.138. 29297491 . free.
9. Liu T, Wang Y, Zhou R, Li H, Cheng H, Zhang J . The update of prostatic ductal adenocarcinoma . Chin. J. Cancer Res. . 28 . 1 . 50–7 . February 2016 . 27041926 . 4779765 . 10.3978/j.issn.1000-9604.2016.02.02 .
10. Web site: Prostatic Ductal Adenocarcinoma. Robert V Rouse. Stanford University School of Medicine. 2012-01-06.
11. Magers. Martin. Kunju. Lakshmi Priya. Wu. Angela. Intraductal Carcinoma of the Prostate: Morphologic Features, Differential Diagnoses, Significance, and Reporting Practices. Archives of Pathology & Laboratory Medicine. 139. 10. 2015. 1234–1241. 0003-9985. 10.5858/arpa.2015-0206-RA. 26414467 . free.
12. Roberts. Jordan A.. Zhou. Ming. Park. Yong Wok. Ro. Jae Y.. Intraductal Carcinoma of Prostate: A Comprehensive and Concise Review. Korean Journal of Pathology. 47. 4. 2013. 307–315. 1738-1843. 10.4132/KoreanJPathol.2013.47.4.307. 24009625 . 3759629. free.
13. Grignon. David J. Unusual subtypes of prostate cancer. Modern Pathology. 17. 3. 2004. 316–327. 0893-3952. 10.1038/modpathol.3800052. 14976541 .
14. Web site: Papillary Urothelial (Transitional Cell) Carcinoma. Stanford University School of Medicine. Robert V Rouse. Original posting/updates: 10/20/12, 12/29/12
15. 0.3–1%: Page 77 in:Book: Beltran, Antonio . Pathology of the prostate : an algorithmic approach . Cambridge University Press . Cambridge, United Kingdom New York, NY . 2017 . 978-1-108-18565-3 . 1011514854 .
16. 0.5-2%: Kumar. Kishore. Ahmed. Rafeeq. Chukwunonso. Chime. Tariq. Hassan. Niazi. Masooma. Makker. Jasbir. Ihimoyan. Ariyo. Poorly Differentiated Small-Cell-Type Neuroendocrine Carcinoma of the Prostate: A Case Report and Literature Review. Case Reports in Oncology. 11. 3. 2018. 676–681. 1662-6575. 10.1159/000493255. 30483097 . 6243899 . free.
17. Wang. Jue. Wang. Fen Wei. Hemstreet. George P.. Younger Age Is an Independent Predictor for Poor Survival in Patients with Signet Ring Prostate Carcinoma. Prostate Cancer. 2011. 2011. 1–8. 2090-3111. 10.1155/2011/216169. 22110982 . 3216005. free.
18. Ninomiya. Sahoko. Kawahara. Takashi. Iwashita. Hiromichi. Iwamoto. Genta. Takamoto. Daiji. Mochizuki. Taku. Kuroda. Shinnosuke. Takeshima. Teppei. Izumi. Koji. Teranishi. Jun-ichi. Yumura. Yasushi. Miyoshi. Yasuhide. Asai. Takuo. Uemura. Hiroji. Prostate Basal Cell Carcinoma: A Case Report. Case Reports in Oncology. 11. 1. 2018. 138–142. 1662-6575. 10.1159/000487389. free.
19. "Rare" here refers to prevalence at least in core biopsies.
    -Cruz. Andrea O.. Santana. Amanda L. S.. Santos. Andréia C.. Athanazio. Daniel A.. Frequency of the morphological criteria of prostate adenocarcinoma in 387 consecutive prostate needle biopsies: emphasis on the location and number of nucleoli. Jornal Brasileiro de Patologia e Medicina Laboratorial. 2016. 1676-2444. 10.5935/1676-2444.20160018. free.
20. Cruz. Andrea O.. Santana. Amanda L. S.. Santos. Andréia C.. Athanazio. Daniel A.. Frequency of the morphological criteria of prostate adenocarcinoma in 387 consecutive prostate needle biopsies: emphasis on the location and number of nucleoli. Jornal Brasileiro de Patologia e Medicina Laboratorial. 2016. 1676-2444. 10.5935/1676-2444.20160018. free.
21. Web site: Prostatic Adenocarcinoma. Stanford Medical School. Robert V Rouse MD. 2019-10-30. 2019-09-11. https://web.archive.org/web/20190911035244/http://surgpathcriteria.stanford.edu/prostate/adenocarcinoma/. dead. Last update 2/2/16
22. Glands adjacent to and indenting nerves is not sufficient as a diagnostic criterion by itself. Glands partially surrounding a nerve is an indication of carcinoma.
    - Web site: Prostatic Adenocarcinoma. Stanford Medical School. Robert V Rouse MD. 2019-10-30. 2019-09-11. https://web.archive.org/web/20190911035244/http://surgpathcriteria.stanford.edu/prostate/adenocarcinoma/. dead. Last update 2/2/16
23. Varma. Murali. Delahunt. Brett. Egevad. Lars. Samaratunga. Hemamali. Kristiansen. Glen. Intraductal carcinoma of the prostate: a critical re-appraisal. Virchows Archiv. 474. 5. 2019. 525–534. 0945-6317. 10.1007/s00428-019-02544-6. 30825003 . 6505500 . free.
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