Ductal adenocarcinoma of the prostate (DAC) is an aggressive histological subtype of prostate cancer (PCa). DACs account for up to 12% of all prostate tumors, with the majority occurring as mixed tumors with the more common acinar adenocarcinoma of the prostate.^1,2 However, they can also rarely occur as pure DAC tumors in 0.8%.² Although DACs frequently involve the prostatic ducts, the term “ductal PCa” describes its histological architecture.² Classically, DACs have tall pseudostratified columnar epithelium with elongated nuclei and abundant amphophilic cytoplasm with a papillary or a cribriform pattern with back-to-back glands with slit-like lumens.² DACs are generally classified as Gleason 4+4 or higher grade based on their histological patterns, reflected by the aggressive clinical course.² As the presence of a DAC component in a prostate tumor confers poor outcomes,³ early identification and treatment of these tumors are essential.

The diagnosis of DAC can be difficult, as most patients present with lower serum PSA levels compared to acinar adenocarcinoma and the majority have an impalpable tumor on a digital rectal examination.² DACs originate from the peripheral zone, and a large proportion (almost 50%) tend to grow centrally, involving the transition zone.¹ As such, patients often present with obstructive symptoms, and the diagnosis of DAC is made frequently on transurethral prostatectomy specimens.²

One of the key differential diagnoses of DAC is intraductal carcinoma (IDC-P). IDC-P is generally a high-grade adenocarcinoma within the large ducts and retains its basal membrane layer, in contrast with DAC.⁴ Although DAC morphology can overlap with IDC-P,⁴ these are biologically separate entities that behave very differently. The variations in the ductal patterns, inadequate samples on biopsy, and inter-reader variability can add further complexity to the histological diagnosis of DAC.⁵ Therefore, adequate sampling of these tumors is essential for enhancing the histological diagnosis. DACs have characteristic multiparametric magnetic resonance imaging (mpMRI) features derived from their histological characteristics, such as intermediate T2 signal, well-defined margin, lobulation, and/or hypointense rim, and restricted diffusion and contrast enhancement.⁶ These mpMRI features can prompt the diagnosis of DAC, allowing these tumors to be targeted and biopsied appropriately.

The diagnosis of DAC also has several implications in treatment planning for localized disease. Most “clinically localized” DACs have advanced pathological stage at radical prostatectomy, with up to 93% of patients upstaged to pT3 and 27% pN1 disease.² As most DACs are not prostate-specific membrane antigen (PSMA) avid, pelvic lymph node dissection is critical when performing a radical prostatectomy.² Nerve spare is also cautioned with DAC, as reflected by the high positive margin rates (up to 67%) and extraprostatic disease seen with these tumors.² Traditionally, DACs were thought to be unresponsive to radiation therapy, and most patients were offered radical prostatectomy as the optimal therapy for DAC. However, recent series demonstrate patients undergoing radiation therapy have similar outcomes to radical prostatectomy.³ Nevertheless, both radical prostatectomy and radiation therapy are less efficacious compared to patients undergoing these therapies for high-risk acinar adenocarcinoma.³ Patients with DAC had a much higher risk of developing metastases compared to matched patients with high-risk acinar adenocarcinoma after radical prostatectomy (21% vs 5%, p <0.001) or radiation therapy (26% vs 9%, p <0.001).³ Therefore, multimodal therapies are often necessary for treating patients with DAC.

Up to 68% of men with DAC present with metastatic disease, often with visceral metastases and other unusual sites (such as the penis and testes) at lower PSA levels compared to acinar adenocarcinomas.^2,7 As 44% of patients who underwent definitive therapy for DAC developed recurrences in their lungs, CT of the chest is essential as part of routine surveillance.⁷ Studies demonstrate that most DACs are PSMA positron emission tomography (PET) nonavid,⁸ as illustrated in the Figure. Therefore, CT and fluorodeoxyglucose PET may be better diagnostic imaging modalities for detecting distant DAC metastases.

Figure. A, classic mpMRI characteristics of DAC seen in a 62-year-old man who underwent a radical prostatectomy for DAC with a PSA of 4.7 ng/ml. The white arrow denotes the ductal prostatic tumor, a well-defined lesion with a hypo-intense margin and an intermediate T2 signal. This tumor also demonstrated restricted diffusion and contrast enhancement on mpMRI (not shown). B, PSMA PET scan of the same patient demonstrating no PSMA uptake in the ductal tumor.

Although DAC and acinar tumors have a similar clonal origin,⁹ the DAC phenotype diverges to develop a genomic landscape resembling that of castrate-resistant PCa even in its early, localized, hormone-naïve stages.^3,10 Despite expressing the androgen receptor, DACs have a poor response to androgen deprivation therapy due to these intrinsic androgen resistance pathways.³ This explains why other systemic therapies, including platinum- or taxane-based chemotherapy, also have poor efficacy in treating DAC.⁷ As such, understanding the biology of DAC to develop targeted therapies is vital.

Recent studies have provided insights into the genomics of DAC, demonstrating mutations in the DNA damage repair pathways, WNT pathway and PI3K pathways. Interestingly, DACs have the highest reported rates of DNA damage repair mutations (49%) compared to any other cancer, with 31% homologous recombinant somatic gene mutations (including 18% BRCA2 and 10% ATM) and 20% germline mutations.¹⁰ Therefore, DAC provides a unique, enriched disease for targeted PARP inhibitor therapy. Combination therapies may also be effective in DAC, as 10% of patients who received combination neoadjuvant systemic therapies achieved complete pathological downstaging at radical prostatectomy and did not develop metastases.³

As DACs have significant clinical and therapeutic implications, emphasis should be on identifying PCa cases with a DAC component and move away from the current paradigms of pure vs mixed DACs or the percentage of DAC in a tumor. Better diagnostic tools, including biomarkers and imaging, are much needed in the diagnosis of DACs, as the traditional diagnostic tools of PSA and digital rectal examination have little yield. Lastly, understanding the biology of DAC is critical in developing neoadjuvant therapies, and multi-institutional efforts are needed to test these therapies, given the rarity of this lethal disease.