Ductal adenocarcinoma of the prostate : a morphological, immunohistochemical and genetic study

Ductal adenocarcinoma of the prostate (DAC) is the second most common prostate cancer subtype. Patients with DAC often present at an advanced clinicopathological stage, with or without metastases. Patients have a high rate of extraprostatic extension, seminal vesicle invasion, a shortened time to biochemical recurrence as well as regional and distant metastases. The diagnosis of DAC continues to challenge pathologists half a century after its discovery. Histologically, DAC is an adenocarcinoma with papillary, cribriform, glandular or mixed architecture. The epithelium is tall, columnar, pseudostratified and the nuclei elongated with high-grade features. Our aim was to characterize the entity of DAC by morphology, immunohistochemistry and genetic analyses to provide better understanding and tools for diagnosis.

The prognostic significance of histopathological features of DAC were analyzed. Classic DAC shows tall, columnar, pseudostratified epithelium, elongated nuclei and papillary, glandular and/or cribriform architecture. The tumors may lack elongated nuclei or classical architecture and still have similar prognosis, which justifies their classification as DAC. However, cases with only stratified, high grade nuclei had better prognosis and should not be considered DAC. The reproducibility of the DAC diagnosis was evaluated among international experts on prostate pathology. The most useful diagnostic feature of DAC was papillary architecture while nuclear and cellular features were less important. The most common differential diagnoses to DAC included intraductal prostate cancer, acinar adenocarcinoma and high-grade PIN. The immunohistochemical profile of DAC showed overlap with staining patterns of acinar adenocarcinomas, but differences consistent with the more aggressive phenotype of DAC were noted, such as a higher expression of Ki-67, p53 and p16. The immunohistochemical profile of DAC was also compared with that of adenocarcinomas of non-prostatic origin.

To diagnose the site of origin of metastases may be challenging as DAC resembles some other adenocarcinomas morphologically. The expression of cytokeratins and intestinal markers in DAC were not specific and may lead to diagnostic errors if not combined with prostate specific markers. In men with adenocarcinoma of unknown primary, the threshold for applying prostate specific immunomarkers should be low even when the morphology suggests a non-prostatic origin. The genetic profile of DAC was analyzed by sequencing and was found to be similar to that of advanced and/or metastatic acinar adenocarcinoma of the prostate. This can explain the aggressive behavior of this prostate cancer subtype and may also offer targets for future tailored therapies.

List of scientific papers

I. Seipel AH, Wiklund F, Wiklund NP, Egevad L. Histopathological features of ductal adenocarcinoma of the prostate in 1,051 radical prostatectomy specimens. Virchows Archiv. April 2013, volume 462, pages 429-36.
https://doi.org/10.1007/s00428-013-1385-5

II. Seipel AH, Delahunt B, Samaratunga H, Amin M, Barton J, Berney DM, Billis A, Cheng L, Compérat E, Evans A, Fine SW, Grignon D, Humphrey PA, MagiGalluzzi C, Montironi R, Sesterhenn I, Srigley JR, Trpkov K, van der Kwast T, Varma M, Zhou M, Ahmad A, Moss S, Egevad L. Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists. Histopathology. August 2014, volume 65, pages 216-27.
https://doi.org/10.1111/his.12382

III. Seipel AH, Samaratunga H, Delahunt B, Wiklund F, Wiklund NP, Lindberg J, Grönberg H, Egevad L. Immunohistochemical profile of ductal adenocarcinoma of the prostate. Virchows Archiv. November 2014, volume 465, pages 559-65.
https://doi.org/10.1007/s00428-014-1636-0

IV. Seipel AH, Samaratunga H, Delahunt B, Wiklund NP, Clements M, Egevad L. Immunohistochemistry of ductal adenocarcinoma of the prostate and adenocarcinomas of non-prostatic origin: A comparative study. APMIS. April 2016, volume 124, pages 263-70.
https://doi.org/10.1111/apm.12504

V. Seipel AH, Whitington T, Delahunt B, Samaratunga H, Wiklund P, Grönberg H, Lindberg J, Egevad L. Genetic Profile of Ductal Adenocarcinoma of the Prostate. [Submitted]