prostatic ductal adenocarcinoma

Definition: Subtype of prostatic adenocarcinoma composed of large glands lined by tall pseudostratified columnar cells.

Ductal adenocarcinoma of the prostate is a subtype of adenocarcinoma that has also been termed endometrioid, endometrial, papillary or papillary ductal adenocarcinoma.

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 Prostatic Duct Adenocarcinoma

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Synonyms

Several terms used in the past are no longer appropriate. Endometrial carcinoma was originally used to describe this entity because of its morphologic similarity to endometrium.

This tumour was previously believed to be derived from a Müllerian structure named prostatic utricle. However, subsequent studies on favourable response to orchiectomy, ultrastructural studies, histochemistry and immunohistochemistry have proven the prostatic origin of this tumour. Therefore, the term endometrial or endometrioid carcinoma should not be used.

Prostatic duct carcinoma should be used with caution, because it could also refer to urothelial carcinoma involving prostatic ducts.

Epidemiology

Ductal adenocarcinoma is the most common histological variant of prostatic carcinoma.

The incidence of ductal adenocarcinoma, including both pure ductal and mixed ductal–acinar adenocarcinomas, is 3.2% of all prostatic carcinomas.

Mixed ductal–acinar carcinoma is more common than pure ductal carcinoma.

In pure form, ductal adenocarcinoma accounts for 0.2-0.8% of prostate cancers.

More commonly it is seen with an acinar component.

Etiology

No specific etiologic factors have been defined for this particular type.

Localization

Ductal adenocarcinoma may be located centrally around the prostatic urethra or more frequently located peripherally admixed with typical acinar adenocarcinoma.

Both centrally and peripherally located ductal adenocarcinoma components can be present in the same prostate.

A centrally located adenocarcinoma may also be associated with a peripherally located acinar adenocarcinoma.

Clinical features

Clinically, men with prostatic ductal adenocarcinoma are typically aged 63–72 years (range 41–89 years). Obstruction and haematuria are common clinical manifestations.

The digital rectal examination is usually abnormal and often suspicious for malignancy. Most patients have an elevated serum PSA level. A substantial minority of men with ductal prostatic adenocarcinoma can present with ‘metastatic’ levels of serum PSA in the hundreds to thousands of ng/ml, bone pain, and skeletal metastases.

Clinical stage is more often advanced than in standard acinar carcinomas.

In the largest series to date, of 371 ductal cases, 12% of men with ductal adenocarcinoma presented with distant metastasis versus 4% of men with acinar adenocarcinoma.

The clinical macroscopic appearance of ductal adenocarcinoma by cystoscopy (urethroscopy) is, in many cases, that of an exophytic, villous/polypoid growth, with white fronds of ‘worm-like’ tumour protruding into the urethra at or near the verumontanum. The prostatic urethra can also appear narrowed, nodular, or normal.

Signs and symptoms

Periurethral or centrally located ductal adenocarcinoma may cause haematuria, urinary urgency and eventually urinary retention. In these cases, there may be no abnormalities on rectal examination.

Tumours arising peripherally may lead to enlargement or induration of the prostate. Although ductal adenocarcinoma strongly expresses prostate specific antigen (PSA) immunohistochemically, they are associated with variable serum PSA levels.

Methods of diagnosis

Serum PSA levels may be normal particularly in a patient with only centrally located tumour. In most cases, transurethral resections performed for diagnosis or relief of the urinary obstruction will provide sufficient diagnostic tissue.

Transrectal needle core biopsies may also obtain diagnostic tissue when the tumour is more peripherally located. In addition, areas of ductal adenocarcinoma may be incidentally identified in prostatectomy specimens.

Macroscopy/Urethroscopy

Centrally occurring tumours appear as exophytic polypoid or papillary masses protruding into the urethra around the verumontanum.

Peripherally occurring tumours typically show a white-grey firm appearance similar to acinar adenocarcinoma.

Tumour spread and staging

Ductal adenocarcinoma usually spread along the urethra or into the prostatic ducts with or without stromal invasion.

Other patterns of spread are similar to that of acinar prostatic adenocarcinoma with invasion to extraprostatic tissues and metastasis to pelvic lymph nodes or distal organs.

However, ductal adenocarcinomas appear to have a tendency to metastasize to lung and penis. The metastasis of ductal adenocarcinoma may show pure ductal, acinar or mixed components.

Microscopy

Ductal adenocarcinoma is characterized by tall columnar cells with abundant usually amphophilic cytoplasm, which form a single or pseudostratified layer reminiscent of endometrial carcinoma.

The cytoplasm of ductal adenocarcinoma is often amphophilic and may occasionally appear clear. In some cases, there are numerous mitoses and marked cytological atypia. In other cases, the cytological atypia is minimal, which makes a diagnosis difficult particularly on needle biopsy.

Peripherally located tumours are often admixed with cribriform, glandular or solid patterns as seen in acinar adenocarcinoma.

Although ductal adenocarcinomas are not typically graded, they are mostly equivalent to Gleason patterns 4.

In some cases comedo necrosis is present whereby they could be considered equivalent to Gleason pattern 5.

In contrast to ordinary acinar adenocarcinoma, some ductal adenocarcinomas are associated with a prominent fibrotic response often including haemosiderin-laden macrophages.

Ductal adenocarcinoma displays a variety of architectural patterns, which are often intermingled:
 Papillary pattern can be seen in both centrally or peripherally located tumours, yet is more common in the former.
 Cribriform pattern is more commonly seen in peripherally located tumours, although they may be also present in centrally located tumours. The cribriform pattern is formed by back-to-back large glands with intraglandular bridging resulting in the formation of slit-like lumens. Individual gland pattern is characterized by single glands.
 Solid pattern can only be identified when it is associated with other patterns of ductal adenocarcinoma. The solid nests of tumour cells are separated by incomplete fibrovascular cores or thin septae.
 Ductal adenocarcinoma must be distinguished from urothelial carcinoma, ectopic prostatic tissue, benign prostatic polyps, and proliferative papillary urethritis.
 One of the more difficult differential diagnoses is cribriform high grade prostatic intraepithelial neoplasia (cribriform HGPIN).
 Some patterns of ductal adenocarcinoma may represent ductal carcinoma in situ.

Microscopically, prostatic duct adenocarcinoma is characterized by pseudostratified columnar epithelium.

The two most common growth patterns are papillary and cribriform. Solid cylinders and comedocarcinoma may also been seen, but it is not possible to classify these configurations as being ductal without an associated papillary and cribriform component.

Single glands of ductal adenocarcinoma are distinctly unusual, and may assume the form of PIN-like adenocarcinoma.

A particularly distinctive finding comprises rounded glandular profiles of cleared tumour cells with central eosinophilic luminal debris.

Glands of ductal adenocarcinoma are often embedded within a fibrotic stroma, which is unusual for small acinar adenocarcinoma.

Mitotic activity in ductal carcinoma is variable, but is higher than in most acinar adenocarcinomas, where it can be difficult to find any mitoses at all.

Recently described rare histological presentations of ductal adenocarcinoma include mucinous/goblet cell, foamy gland, Paneth cell-like neuroendocrine, cystic papillary and micropapillary appearances.

In needle biopsy tissue, papillary and/or cribriform structures are predominant. In one-half of the cases, there is a minor coexisting acinar component, which is most often of a Gleason score of 6 or 7. The percentage of adenocarcinoma that is ductal in needle biopsy tissue correlates with the percentage of ductal cancer in radical prostatectomy tissues: when >50% of the adenocarcinoma is ductal in needle core tissue, then 80% of the corresponding radical prostatectomies have >50% ductal adenocarcinoma.

In radical prostatectomy specimens, the ductal adenocarcinoma is composed of confluent masses of papillary and/or cribriform adenocarcinoma.

The ductal adenocarcinoma is almost always intimately admixed with acinar adenocarcinoma, with the proportion of the tumour showing ductal differentiation ranging from 5% to 100%. Data on the impact of the percentage of the tumour that is ductal are mixed.

Of two recent studies, one found that any proportion of ductal adenocarcinoma was linked to extraprostatic extension,89 whereas the second showed a grade dependence.

Ductal adenocarcinoma admixed with Gleason pattern 3 was more aggressive than Gleason score 7 acinar adenocarcinoma, as long as the ductal component was ≥10% of the tumour.

The presence and proportion of ductal adenocarcinoma were not significant when the Gleason score was 8–10.

It is striking that, in radical prostatectomy specimens, ductal adenocarcinoma is predominantly located in the peripheral zone, with focal extension into the transition zone in only a minority of cases. Ductal adenocarcinoma in radical prostatectomy specimens tends to be of higher pathological stage and larger tumour size than pure acinar adenocarcinoma.

Rare, reported admixtures of ductal adenocarcinoma with other histological types of carcinoma include ductal adenocarcinoma with sarcomatoid carcinoma, mucinous pools, mucinous carcinoma, and urothelial carcinoma.

The histological grade of ductal adenocarcinoma is usually high-grade Gleason pattern 4, but, uncommonly, pattern 3 and pattern 5 can be seen.

For mixed ductal–acinar adenocarcinomas, a single Gleason score should be given.

The ductal component is usually of higher grade than the acinar proliferation.

Grade

Ductal adenocarcinomas of the prostate most commonly are composed of either papillary fronds or cribriform structures.

Ductal adenocarcinomas are recognized as being aggressive tumors with most studies showing comparable behavior to acinar cancer with a Gleason score 4+4=8.

The consensus of the panel was that ductal adenocarcinomas should be graded as Gleason score 4+4=8, while retaining the diagnostic term of ductal adenocarcinoma to denote their unique clinical and pathological findings.

This can be achieved by diagnosing such a tumor as “prostatic ductal adenocarcinoma (Gleason score 4+4=8).”

In cases with mixed ductal and acinar patterns, the ductal patterns should be assigned Gleason pattern 4.

The only exceptions to grading ductal adenocarcinoma as Gleason pattern 4 are:
 ductal adenocarcinoma with comedonecrosis.

• Although it has not been specifically studied, ductal adenocarcinoma with comedonecrosis is graded as Gleason pattern 5.

 PIN-like ductal adenocarcinoma

• PIN-like ductal adenocarcinoma consists of individual glands lined by tall pseudostratified columnar cells resembling high grade PIN.
• Its prognosis appears comparable to Gleason pattern 3.

Immunochemistry

Immunohistochemically ductal adenocarcinoma is strongly positive for PSA and PAP. Tumour cells are typically negative for basal cell specific high molecular weight cytokeratin (detected by 34βE12), however, preexisting ducts may be positive for this marker.

The immunophenotype of prostatic ductal adenocarcinoma is similar to that of acinar adenocarcinoma.

Although it is heterogeneous in stain distribution and intensity, immunostains for PSA and PSAP are almost always positive, in both primary and metastatic sites.

However, there are differences between ductal and acinar adenocarcinomas in the Ki67, 34βE12 and AMACR immunoprofiles.

The Ki67 labelling index appears to be higher in ductal adenocarcinomas.

The 34βE12 immunohistochemical reaction with basal cells is different, as basal cells are, by definition, absent in acinar adenocarcinoma, whereas basal cells are observed in the intraductal component of ductal adenocarcinoma.

AMACR can be detected in ductal carcinoma, but at a reduced level.

Molecular biology

At the DNA level, DNA ploidy profiles of ductal adenocarcinoma do not differ substantially from those of acinar adenocarcinoma, but there is a difference in loss of heterozygosity.

Whether the percentage of cases with TMPRSS2–ERG gene rearrangement is different from that in acinar adenocarcinoma is not established.

Finally, the gene expression profiles of acinar and ductal adenocarcinoma are remarkably similar, with only 10–25 gene transcripts (out of thousands) having significantly different expression levels.

No specific gene expression signature can separate ductal from acinar adenocarcinoma. In summary, the molecular differences described here do not currently have diagnostic utility.

Prognosis and predictive factors

Most studies have demonstrated that ductal adenocarcinoma is aggressive. Some reported that 25-40% of cases had metastases at the time of diagnosis with a poor 5-year survival rate ranging from 15-43%.

It is not known whether prognosis correlates with the degree of cytological atypia or growth patterns. Even limited ductal adenocarcinoma on biopsy warrants definitive therapy.

Androgen deprivation therapy may provide palliative relief, even though these cancers are less hormonally responsive than acinar adenocarcinoma.

Ductal adenocarcinoma spreads outside the prostate in the same fashion as pure acinar adenocarcinoma.

The papillary and/or cribriform growths can involve periprostatic soft tissue, seminal vesicles, pelvic lymph nodes, and distant sites, including lung and bone.

Ductal adenocarcinoma appears to have a propensity to metastasize to testis, penis, and lung.

Mixed ductal–acinar adenocarcinomas can penetrate outside the prostate and metastasize as pure ductal adenocarcinoma, pure acinar adenocarcinoma, or mixed ductal–acinar adenocarcinoma.

The outcome for men with prostatic ductal adenocarcinoma is, in most studies, worse than that for men with prostatic acinar adenocarcinoma, probably because of higher stage and grade.

Some patients respond to radical prostatectomy, hormonal therapy, and radiotherapy. In needle biopsy tissue, only the extent of tumour correlated with time to biochemical failure.

Paywall References

 Histological variants of prostatic carcinoma and their significance. Humphrey PA. Histopathology. 2012 Jan;60(1):59-74. PMID: 22212078

 Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma. Amin A, Epstein JI. Am J Surg Pathol. 2011 Apr;35(4):615-9. PMID: 21383610