prostatic acinar adenocarcinoma

Definition: An invasive malignant epithelial tumour of the prostate consisting of secretory cells. See also : pseudohyperplastic prostatic adenocarcinoma

Macroscopy

On section, grossly evident cancers are firm, solid, and range in colour from white-grey to yellow-orange, the latter having increased cytoplasmic lipid; the tumours contrast with the adjacent benign parenchyma, which is typically tan and spongy.

Tumours usually extend microscopically beyond their macroscopic border. Gross haemorrhage and necrosis are rare. Subtle tumours may be grossly recognized by structural asymmetry; for example, peripheral zone tumours may deform the periurethral fibromuscular concentric band demarcating the periurethral and peripheral prostate centrally, and peripherally may expand or obscure the outer boundaries of the prostate.

Anterior and apical tumours are difficult to grossly identify because of admixed stromal and nodular hyperplasia.

In general, grossly recognizable tumours tend to be larger, of higher grade and stage, and are frequently palpable, compared with grossly inapparent tumours (usually @<@ 5 mm), which are often nonpalpable, small, low grade and low stage.

Some large tumours are diffusely infiltrative, and may not be evident grossly.

Causes of gross false positive diagnoses include confluent glandular atrophy, healed infarcts, stromal hyperplasia, granulomatous prostatitis and infection.

In countries with widespread PSA testing, grossly evident prostate cancer has become relatively uncommon.

Extraprostatic extension (EPE)

This is defined as invasion of prostate cancer into adjacent periprostatic tissues.

The prostate gland has no true capsule although posterolaterally, there is a layer which is more fibrous than muscular that serves as a reasonable area to denote the boundary of the prostate.

At the apex and everywhere anteriorly in the gland (the latter being the fibromuscular stroma), there is no clear demarcation between the prostate and the surrounding structures.

These attributes make determining EPE for tumours of primarily apical or anterior distribution difficult to establish.

EPE is diagnosed based on tumour extending beyond the outer condensed smooth muscle of the prostate.

When tumour extends beyond the prostate it often elicits a desmoplastic stromal reaction, such that one will not always see tumour with EPE situated in extra-prostatic adipose tissue.

It has been reported that determining the extent of EPE as "focal" (only a few glands outside the prostate) and "established or non focal" (anything more than focal) is of prognostic significance. Focal EPE is often a difficult diagnosis.

Modifications to this approach with emphasis on the "level" of prostate cancer distribution relevant to benign prostatic acini and within the fibrous "capsule" where it exists, has been suggested and claimed to have further value in classifying patients into prognostic categories following radical prostatectomy. More detailed analysis has not been uniformly endorsed.

Microscopy

Adenocarcinomas of the prostate range from well-differentiated gland forming cancers, where it is often difficult to distinguish them from benign prostatic glands, to poorly differentiated tumours, difficult to identify as being of prostatic origin.

A feature common to virtually all prostate cancers is the presence of only a single cell type without a basal cell layer.

Benign prostate glands, in contrast, contain a basal cell layer beneath the secretory cells. The recognition of basal cells on hematoxylin and eosin stained sections is not straightforward.

In cases of obvious carcinoma, there may be cells that closely mimic basal cells. These cells when labeled with basal cell specific antibodies are negative and represent fibroblasts closely apposed to the neoplastic glands.

Conversely, basal cells may not be readily recognized in benign glands without the use of special studies. The histopathology of prostatic cancer, and its distinction from benign glands, rests on a constellation of architectural, nuclear, cytoplasmic, and intraluminal features.

With the exception of three malignant specific features listed at the end of this section, all of the features listed below, while more commonly seen in cancer, can also be seen in benign mimickers of cancer.

Immunochemistry

Prostate specific antigen (PSA)

Following PSA’s discovery in 1979, it has become a useful immunohistochemical marker of prostatic differentiation in formalin-fixed, paraffin-embedded tissue, with both polyclonal and monoclonal antibodies available.

PSA is localized to the cytoplasm of non-neoplastic prostatic glandular cells in all prostatic zones, but is neither expressed by basal cells, seminal vesicle/ejaculatory duct glandular cells, nor urothelial cells.

Because of its relatively high specificity for prostatic glandular cells, PSA is a useful tissue marker expressed by most prostatic adenocarcinomas.

There is frequently intratumoural and intertumoural heterogeneity, with most studies indicating decreasing PSA expression with increasing tumour grade.

PSA is diagnostically helpful in distinguishing prostatic adenocarcinomas from other neoplasms secondarily involving the prostate and establishing prostatic origin in metastatic carcinomas of unknown primary.

PSA is also helpful in excluding benign mimics of prostatic carcinoma, such as seminal vesicle/ejaculatory duct epithelium, nephrogenic adenoma, mesonephric duct remnants, Cowper’s glands, granulomatous prostatitis and malakoplakia.

Whereas monoclonal antibodies to PSA do not label seminal vesicle tissue, polyclonal antibodies have been shown to occasionally label seminal vesicle epithelium.

PSA in conjunction with a basal cell marker is useful in distinguishing intraglandular proliferations of basal cells from acinar cells, helping to separate prostatic intraepithelial neoplasia from basal cell hyperplasia and transitional cell metaplasia in equivocal cases.

A minority of higher grade prostatic adenocarcinomas are PSA negative, although some of these tumours have been shown to express PSA mRNA.

Some prostatic adenocarcinomas lose PSA immunoreactivity following androgen deprivation or radiation therapy.

Prostate specific membrane antigen (PSMA) (membrane bound antigen
expressed in benign and malignant prostatic acinar cells) and androgen receptor may be immunoreactive in some high grade, PSA immunonegative prostatic adenocarcinomas.

Extraprostatic tissues which are variably immunoreactive for PSA, include urethral and periurethral glands (male and female), urothelial glandular metaplasia (cystitis cystitica and glandularis), anal glands (male), urachal remnants and neutrophils.

Extraprostatic neoplasms and tumourlike conditions occasionally immunoreactive for PSA include urethral/periurethral adenocarcinoma (female), bladder adenocarcinoma, extramammary Paget disease of the penis, salivary gland neoplasms in males (pleomorphic adenoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma), mammary carcinoma, mature teratoma, and some nephrogenic adenomas.

Prostate specific acid phosphatase (PAP)

Immunohistochemistry for PAP is active in formalin-fixed, paraffin-embedded tissues. The polyclonal antibody is more sensitive, but
less specific than the monoclonal antibody.

PAP and PSA have similar diagnostic utility; since a small number of prostatic adenocarcinomas are immunoreactive for only one of the two markers, PAP is primarily reserved for cases of suspected prostatic carcinoma in which the PSA stain is negative.

Extraprostatic tissues reported to be immunoreactive for PAP include pancreatic islet cells, hepatocytes, gastric parietal cells, some renal tubular epithelial cells and neutrophils.

Reported PAP immunoreactive neoplasms include some neuroendocrine tumours (pancreatic islet cell tumours, gastrointestinal carcinoids), mammary carcinoma, urothelial adenocarcinoma, anal cloacogenic carcinoma, salivary gland neoplasms (males) and mature teratoma.

 High molecular weight cytokeratins detected by 34βE12 (Cytokeratin-903)

Prognosis and predictive factors

The College of American Pathologists (CAP) have classified prognostic factors into three categories:
 Category I
 Category II
 Category III

 Category I - Factors proven to be of prognostic importance and useful in clinical patient management.

• Factors included in category I, were preoperative PSA, histologic grade (Gleason score), TNM stage grouping, and surgical margin status.

 Category II – Factors that have been extensively studied biologically and clinically, but whose importance remains to be validated in statistically robust studies.

• Category II included tumour volume, histologic type and DNA ploidy.

 Category III – All other factors not sufficiently studied to demonstrate their prognostic value.

• Factors in Category III included such things as perineural invasion, neuroendorcrine differentiation, microvessel density, nuclear features other than ploidy, proliferation markers and a variety of molecular markers such as oncogenes and tumour suppressor genes.

This classification was endorsed by a subsequent World Health Organization (WHO) meeting that focused mainly on biopsy-derived factors.

Serum PSA

PSA is the key factor in the screening for and detection of prostate cancer, its serum level at the time of diagnosis is considered a prognostic marker that stratifies patients into differing prognostic
categories.

Recent reports, however indicate that the prognostic value is driven by patients with high PSA levels, which is significantly associated with increasing tumour volume and a poorer prognosis.

In recent years, however, most newly diagnosed patients have only modestly elevated PSA (between 2 and 9 ng/ml), a range in which BPH and other benign conditions could be the cause of the PSA elevation.

For patients within this category, it was reported that PSA has no meaningful relationship to cancer volume and grade in the radical prostatectomy specimen, and a limited relationship with PSA cure rates.

Following treatment, serum PSA is the major mean of monitoring
patients for tumour recurrence.

Tumour spread and staging

Local extraprostatic extension typically occurs along the anterior aspect of the gland for transition zone carcinomas, and in posterolateral sites for the more common peripheral zone carcinomas.

The peripheral zone carcinomas often grow into periprostatic soft tissue by invading along nerves or by direct penetration out of the prostate.

The term "capsule" has been used to denote the outer boundary of the prostate. However, as there is no well-defined capsule surrounding the entire prostate this term is no longer recommended.

Extraprostatic invasion superiorly into the bladder neck can occur with larger tumours, and in advanced cases, this can lead to bladder neck and ureteral obstruction.

Extension into the seminal vesicles can occur by several pathways, including direct extension from carcinoma in adjacent soft tissue, spread along the ejaculatory duct complex, and via lymphvascular space channels.

Posteriorly, Denovillier’s fascia constitutes an effective physical barrier,
and direct prostatic carcinoma spread into the rectum is a rare event.

Metastatic spread of prostatic carcinoma begins when carcinoma invades into lymphvascular spaces. The most common sites of metastatic spread of prostatic carcinoma are the regional lymph nodes and bones of the pelvis and axial skeleton.

The obturator and hypogastric nodes are usually the first ones to be involved, followed by external iliac, common iliac, presacral, and presciatic nodes.

In a few patients, periprostatic/periseminal vesicle lymph nodes may be the first ones to harbour metastatic carcinoma, but these nodes are found in less than 5% of radical prostatectomy specimens.

Metastasis to bone marrow, with an osteoblastic response, is a hallmark of disseminated prostate cancer. The bones most frequently infiltrated by metastatic disease are, in descending order, pelvic bones, dorsal and lumbar spine, ribs, cervical spine, femur, skull, sacrum, and humerus.

Visceral metastatic deposits in the lung and liver are not often clinically apparent, but are common in end-stage disease.

The TNM classification scheme is the currently preferred system
for clinical and pathologic staging of prostatic
carcinoma.

Stages T1a and T1b

 T1 Clinically inapparent tumour not palpable or visible by imaging
 * T1a Tumour incidental histological finding in 5% or less of tissue
resected
 * T1b Tumour incidental histological finding in more than 5% of tissue
resected
 * T1c Tumour identified by needle biopsy (e.g., because of elevated
PSA)

Although the risk of progression at 4 years with stage T1a cancer is low (2%), between 16% and 25% of men with untreated stage T1a prostate cancer and longer (8-10 years) follow-up have had clinically evident progression.

Stage T1b tumours are more heterogeneous in grade, location, and volume than are stage T2 carcinomas.

Stage T1b cancers tend to be lower grade and located within the transition zone as compared with palpable cancers.

The relation between tumour volume and pathologic stage also differs, in that centrally located transition zone carcinomas may grow to a large volume before reaching the edge of the gland and extending out of the prostate, whereas stage T2 tumours that begin peripherally show extraprostatic extension at relatively lower volumes.

This poor correlation between volume and stage is also attributable to the lower grade in many stage T1b cancers.

Stage T2

 T2 Tumour confined within prostate (Tumour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c.)
 * T2a Tumour involves one half of one lobe or less
 * T2b Tumour involves more than half of one lobe, but not both lobes
 * T2c Tumour involves both lobes

Most of the pathological prognostic information obtained relating to clinical stage T2 disease comes from data obtained from analysis of radical prostatectomy specimens.

Pathologic examination of the radical prostatecomy specimen

The key objectives of evaluating the RP specimens are to establish tumour pathologic stage and Gleason score. It is important to paint the entire external surface of the prostate with indelible ink prior to sectioning.

In most centers, the apical and bladder neck margins are removed and submitted either as shave margins en face [with any tumour in this section considered a positive surgical margin (+SM)], or preferably, these margins (especially the apical) are removed as specimens of varying width, sectioned parallel to the urethra, and submitted to examine the margins in the perpendicular plane to the ink. In this method, any tumour on ink is considered to be a +SM.

The extent of sampling the radical prostatectomy specimen varies, only 12% of pathologists responding to a recent survey indicated that they processed the entire prostate. It was reported that a mean of 26 tissue blocks was required to submit the entire prostate and the lower portion of the seminal vesicles.

Cost and time considerations result in many centers using variable partial sampling schemes that may sacrifice sensitivity for detecting positive surgical margins (+SM) or extraprostatic extension (EPE).

Seminal vesicle invasion (SVI)

Seminal vesicle invasion is defined as cancer invading into the muscular coat of the seminal vesicle. SVI has been shown in numerous studies to be a significant prognostic indicator.

Three mechanisms by which prostate cancer invades the seminal vesicles were described by Ohori et al. as:
 (I) by extension up the ejaculatory duct complex;
 (II) by spread across the base of the prostate without other evidence of EPE (IIa) or by invading the seminal vesicles from the periprostatic and periseminal vesicle adipose tissue (Ib);
 (III) as an isolated tumour deposit without continuity with the primary prostate cancer tumour focus.

While in almost all cases, seminal vesicle invasion occurs in glands with EPE, the latter cannot be documented in a minority of these cases.

Many of these patients had only minimal involvement of the seminal vesicles, or involve only the portion of the seminal vesicles that is at least partially intraprostatic.

Patients in this category were reported to have a favourable prognosis, similar to otherwise similar patients without SVI and it is controversial whether SVI without EPE should be diagnosed.

Lymph nodes metastases (+LN)

Pelvic lymph node metastases, when present, are associated with an almost uniformly poor prognosis in most studies.

Fortunately, however, the frequency of +LN has decreased considerably over time to about 1-2% today. Most of this decrease has resulted primarily from the widespread PSA testing and to a lesser extent from better ways to select patients for surgery preoperatively.

As a consequence of this decline in patients with +LN, some have proposed that pelvic lymph node dissection is no longer necessary in appropriately selected patients.

The detection of +LN can be enhanced with special techniques such as immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR) for PSA or hK2-L, although these tests are not used
in routine clinical practice 1948.

Various prognostic parameters based on the assessment of tumour within the node have been reported. These include Gleason grade, number of positive nodes, tumour volume, tumour diameter, DNA ploidy, and perinodal tumour extension.

In part because of conflicting studies, these nodal parameters are not routinely reported in clinical practice.

In a rare patient, a small lymph node is seen in the periprostatic soft tissue, and may be involved by metastatic prostate cancer, even in the absence of other pelvic lymph node metastases. These patients also have a poor prognosis.

Surgical margin status

Positive surgical margins (+SM) are generally considered to indicate that the cancer has not been completely excised and is an important prognostic parameter following surgery.

Positive margins in a radical prostatectomy specimen may
be classified as "equivocal", "focal", or "extensive", with correspondingly worse prognosis.

The site of the +SM is frequently at the same site as the area of
EPE. However, a +SM may result from incision into an otherwise confined focus of prostate cancer.

A +SM without EPE at the site of the +SM is not infrequently seen, having been reported in from 9-62% of cases of +SM in the literature.

The most common sites of intra-prostatic incision are at the apex and at the site of the neurovascular bundle posterolaterally.

Stage designations to denote a +SM in the absence of EPE anywhere in the gland include stage pT2X and stage pT2+, because extraprostatic tumour at the site of the +SM cannot be excluded.

Most studies suggest a lower risk of progression in men with positive margins as a reflection of capsular incision, as opposed to +SM with EPE.

However, in a series of 1273 patients treated with radical prostatectomy, +SM had an impact on PSA non-progression rate over the spectrum of pathologic stages, including pT2 (confined) cancer.

PSA non-progression rate at 5 years for patients with EPE (pT3a) with
positive +SM was 50%, compared to 80% of patients with EPE and –SM (p@<@0.0005).

A microscopically positive margin at the bladder neck should not be considered as pT4 disease.

Histologic grade (Gleason)

Gleason score on the radical prostatectomy specimen is one of the most powerful predictors of progression following surgery.

Gleason score on the needle biopsy also strongly correlates with prognosis following radiation therapy.

Perineural Invasion

Perineural invasion (PNI) by prostate cancer is seen in radical prostatectomy specimens in 75-84% of cases. Due to the near ubiquitous presence of PNI in radical prostatectomy specimens and studies have not shown radical prostatectomy PNI to be an independent prognostic parameter, this finding is not routinely reported.

One study has noted that the largest diameter of PNI in the radical
prostatectomy was independently related to an increased likelihood of biochemical failure after radical prostatectomy; verification of this result is needed before it can be adopted in clinical practice.

Numerous studies have also evaluated the significance of PNI on cancer in needle biopsy specimens.

Whereas almost all reports have noted an increased risk of EPE in the corresponding radical prostatectomy specimen, there are conflicting data as to whether PNI provides independent prognostication beyond that of needle biopsy grade and serum PSA levels.

It has also been demonstrated that the presence of PNI on the needle
biopsy is associated with a significantly higher incidence of disease progression following radiotherapy and following radical prostatectomy.

As PNI is of prognostic significance and easy to assess histologically, its reporting on needle biopsy is recommended.

Tumour volume

Tumour volume can be measured most accurately with computerized planimetric methods, although a far simpler "grid" method has been described.

Total tumour volume is an important predictor of prognosis and is correlated with other pathologic features. However, in several large series it was not an independent predictor of PSA progression when controlling for the other features of pathologic stage, grade and margins.

These results are different from earlier series, in which many of the patients were treated in the pre-PSA era and had large tumour volumes, which resulted in a strong correlation between tumour volume and prognosis.

Multiple techniques of quantifying the amount of cancer found on needle biopsy have been developed and studied, including measurement of the:
 1) number of positive cores;
 2) total millimeters of cancer amongst all cores;
 3) percentage of each core occupied by cancer;
 4) total percent of cancer in the entire specimen
 5) fraction of positive cores.

There is no clear concensus as to superiority of one technique over the other.

Numerous studies show associations between the number of positive cores and various prognostic variables.

The other widely used method of quantifying the amount of cancer on needle biopsy is measurement of the percentage of each biopsy core and/or of the total specimen involved by cancer.

Extensive cancer on needle biopsy in general predicts for adverse prognosis. However, limited carcinoma on needle biopsy is not as predictive of a favourable prognosis due to sampling limitations.

A feasible and rationale approach would be to have pathologists report the number of cores containing cancer, as well as one other system quantifying tumour extent (e.g. percentage, length).

Lymphovascular invasion in radical prostatectomy (LVI)

The incidence rates of LVI have ranged widely from 14-53%. The differences in incidence rates amongst studies are most likely the result of the use of different criteria for the recognition of LVI.

While most investigators do not recommend the use of immunohistochemistry for verification of an endothelial-lined space, retraction space artefact around tumour may cause difficulty in interpretation of LVI.

Although several studies have found that LVI is important in univariate analysis, only two have reported independent significance in multivariate analysis.

Biomarkers and nuclear morphometry

While the preponderance of studies suggest that DNA ploidy might be useful in clinical practice, a smaller number of studies analyzing large groups of patients have not found ploidy to be independently prognostically useful.

A majority of studies have also demonstrated that overexpression of certain other markers (p53, BCL-2, p21WAF1) and underexpression of others (Rb) is associated with more aggressive prostate cancer behaviour, but further corroboration is necessary before these tests are used clinically.

There are conflicting studies as to the prognostic significance of quantifying microvessel density counts, Ki-67 (proliferation), and chromogranin (neuroendocrine differentiation), p27kip1, Her-2/neu, E-cadherin, and CD44.

Numerous studies have correlated various nuclear measurements with progression following radical prostatectomy.

These techniques have not become clinically accepted in the evaluation of prostate cancer since the majority of studies have come from only a few institutions, some of these nuclear morphometry measurements are patented and under control of private companies, and these techniques are time consuming to perform.

Preoperative and postoperative nomograms

Although there are nomograms to predict for stage prior to therapy,
this and other prognostic factors are best assessed, following pathologic examination of the radical prostatectomy specimen, many of which have been incorporated in a new postoperative nomogram.

The prognostic factors have appreciable limitations when they are
used as stand-alone. However, validation of the several nomograms proposed in the recent times is sometimes lacking whereas comparison for superiority amongst the proposed nomograms has not always been tested. A limitation of these nomograms is that they do not provide predictive information for the individual patient.

Stages T3 and T4

- T3 Tumour extends beyond the prostate (Invasion into the prostatic apex yet not beyond the prostate is not classified as T3, but as T2.)
 * T3a Extracapsular extension (unilateral or bilateral)
 * T3b Tumour invades seminal vesicle(s)

 T4 Tumour is fixed or invades adjacent structures other than sem
inal vesicles: bladder neck, external sphincter, rectum, levator
muscles, or pelvic wall (Microscopic bladder neck involvement at radical prostatectomy should be classified as T3a.)

In general, patients with clinical stage T3 prostate cancer are not candidates for radical prostatectomy and are usually treated with radiotherapy.

Between 50% and 60% of clinical stage T3 prostate cancers have lymph node metastases at the time of diagnosis.

More than 50% of patients with clinical stage T3 disease develop metastases in 5 years, and 75% of these patients die of prostate carcinoma within 10 years.

Distant metastases appear within 5 years in more than 85% of patients with lymph node metastases who receive no further treatment.

In patients with distant metastases, the mortality is approximately 15% at 3 years, 80% at 5 years, and 90% at 10 years.

Of the patients who relapse after hormone therapy, most die within several years.

Prostate biomarkers

 PSA
 Prostatic acid phosphatase (PAP)
 Human glandular kallikrein 2 (hK2)
 Prostate specific membrane antigen (PSMA)