prostate carcinomas

See also: prostatic adenocarcinoma

Definition: Malignant tumors of the prostate.

Prostate cancer contributes significantly to the overall cancer burden, being the most frequent malignant neoplasia in men.

The number of cases has continuously increased over the past decades, partly due to the higher life expectancy.

An additional factor is the Western lifestyle, characterized by a highly
caloric diet and lack of physical exercise.

Epidemiological data indicates that black people are most succeptable, followed by white people, while Asian people have the lowest risk.

The extent to which prostate cancer mortality can be reduced by PSA screening, is currently being evaluated.

Histopathological diagnosis and grading play a major role in the management of prostate cancer.

Epidemiology

Geographical distribution

Prostate cancer is now the sixth most common cancer in the world (in terms of number of new cases), and third in importance in men.

The estimated number of cases was 513,000 in the year 2000.

This represents 9.7% of cancers in men (15.3 % in developed countries and 4.3% in developing countries).

It is a less prominent cause of death from cancer, with 201,000 deaths (5.6% of cancer deaths in men, 3.2% of all cancer deaths).

The low fatality means that many men are alive following a diagnosis of
prostate cancer – an estimated 1.5 million at 5 years, in 2000, making this the most prevalent form of cancer in men.

In recent years, incidence rates reflect not only differences in risk of the disease, but also the extent of diagnosis of latent cancers both by screening of asymptomatic individuals, and by detection of latent cancer in tissue removed during prostatectomy operations, or at autopsy.

Thus, especially where screening is widespread, recorded ’incidence’ may be very high (in the United States, for example, where it is now by far the most commonly diagnosed cancer in men).

Incidence is very high also in Australia and the Scandinavian countries (probably also due to screening). Incidence rates in Europe are quite variable, but tend to be higher in the countries of northern and western Europe, and lower in the East and South. Prostate cancer remains relatively rare in Asian populations.

Mortality is less affected by the effects of early diagnosis of asymptomatic cancers, but depends upon survival as well as incidence; survival is significantly greater in high-incidence countries (80% in the USA vs. 40% in developing countries).

However, this more favourable prognosis could well be due to more
latent cancer being detected by screening procedures.

Mortality rates are high in North America, North and West Europe, Australia/New Zealand, parts of South America (Brazil) and the Caribbean, and in much of sub-Saharan Africa.

Mortality rates are low in Asian populations, and in North Africa. The difference in mortality between China and the U.S.A is 26 fold (while it is almost 90 fold for incidence).

These international differences are clearly reflected within the United States, where the Black population has the highest incidence (and mortality) rates, some 70% higher than in Whites, who in turn have rates considerably higher than populations of Asian origin (e.g. Chinese, Japanese and Korean males).

Similarly, in São Paulo, Brazil, the risk of prostate cancer in Black males was 1.8 (95% CI 1.4–2.3) times that of White men.

Latent cancers are frequent in older men, and the prevalence greatly exceeds the cumulative incidence in the same population.

Two international studies of latent prostate cancer observed
that prevalence increases steeply with age, but varies much less between populations than the incidence of clinical cancer. The country/ethnic-specific ranking was much the same.

The frequency of latent carcinoma of prostate in Japan is increasing (as with clinical prostate cancer) and may eventually approach the prevalence for U.S. Whites.

Migrants

Migrants from West Africa to England & Wales have mortality rates 3.5 times (95% CI 2.4–5.1) those of the local-born population, and mortality is significantly higher also among migrants from the Caribbean (RR 1.7; 95% CI 1.5–2.0); in contrast, mortality among migrants from East Africa, of predominantly Asian (Indian) ethnicity, are not high.

Migrants from low-risk countries to areas of higher risk show quite marked increases in incidence (for example, Japanese living in the United States).

Some of this change reflects an elimination of the ’diagnostic bias" influencing the international incidence rates.

Localized prostate cancer forms a small proportion of cases in Japan (24%) compared with 66-70% in the U.S.A; incidence in Japan could be 3-4 times that actually recorded if, for example, all transurethral prostatectomy (TURP) sections were carefully examined.

However, rates in Japanese migrants remain well below those in the
U.S. White populations, even in Japanese born in the United States, which suggests that genetic factors are responsible for at least some of the differences between ethnic groups.

Age distribution

The risk of prostate cancer rises very steeply with age. Incidence of clinical disease is low until after age 50, and then increases at approximately the 9-10th power of age, compared with the 5-6th power for other epithelial cancers.

Worldwide, about three-quarters of all cases occur in men aged 65 or more.

Time trends

Time trends in prostate cancer incidence and mortality have been greatly affected by the advent of screening for raised levels of serum Prostate-Specific Antigen (PSA), allowing increasing detection of
preclinical (asymptomatic) disease.

In the USA, prostate cancer incidence rates were increasing slowly up to the 1980’s, probably due to a genuine increase in risk, coupled with increasing diagnosis of latent, asymptomatic cancers in prostatectomy specimens, due to the increasing use of TURP.

Beginning in 1986, and accelerating after 1988, there was a rapid increase in incidence. The recorded incidence of prostate cancer doubled between 1984 and 1992, with the increase being mainly in younger men (under 65) and confined to localized and regional disease.

The incidence rates began to fall again in 1992 (1993 in Black males), probably because most of the prevalent latent cancers in the subset of the population reached by screening had already been detected.

With the introduction of PSA screening, there was also an increase in the rate of increase in mortality, but this was very much less marked
than the change in incidence.

More recently, (since 1992 in White men, 1994 in Black men), mortality rates have decreased.

The contribution that PSA screening and/or improved treatment has made to this decline has been the subject of considerable debate. The increased mortality was probably partly due to mis-certification of cause of death among the large number of men who had been diagnosed with latent prostate cancer in the late 80’s and early 90’s.

The later decline may be partly due to a reversal of this effect; it seems unlikely that screening was entirely responsible.

International trends in mortality have been reviewed by Oliver et al., and in incidence and mortality by Hsing et al.. The largest increases in incidence, especially in younger men, have been seen in high-risk countries, probably partly the effect of increasing detection following TURP, and, more recently, due to use of PSA.

But there have been large increases also in low risk countries; 3.5 x in Shanghai, China, 3.0 x in Singapore Chinese, 2.6 x in Miyagi, Japan, 1.7 x in Hong Kong, between 1975 and 1995.

Only in India (Bombay) does there seem to have been little change (+13%) in incidence.

Some of this increase may be due to greater awareness of the disease, and diagnosis of small and latent cancers.

But it is also probable that there is a genuine increase in risk occurring. This is confirmed by studying changes in mortality.

The increases in rates in the "high risk" countries were much less than
for incidence, but quite substantial nevertheless (15-25%).

In low risk countries, the increase in mortality rates is large, and not much inferior to the changes observed in incidence.

As in the USA, there have been declines in mortality from prostate cancer since around 1988-1991, in several high-risk populations, rather more marked in older than in younger men.

In some of the countries concerned (Canada, Australia), there has been considerable screening activity, but this is not the case in others where the falls in mortality are just as marked (France, Germany, Italy, UK).

There may be a contribution from improvements in treatment which is difficult to evaluate from survival data because of lead-time bias introduced by earlier diagnosis.

Etiology

The marked differences in risk by ethnicity suggest that genetic factors are responsible for at least some of the differences between ethnic groups. Nevertheless, the changes in rates with time, and on migration, also imply that differences in environment or lifestyle are also important. Despite extensive research, the environmental risk factors for prostate cancer are not well understood. Evidence from ecological, case–control
and cohort studies implicates dietary fat in the etiology of prostate cancer, although few studies have adjusted the results for caloric intake, and no particular fat component has been consistently implicated.

There is a strong positive association with intake of animal products,
especially red meat. The evidence from these studies for a protective effect of fruits and vegetables on prostate cancer, unlike many other cancer sites, is not convincing.

There is little evidence for anthropometric associations with prostate cancer, or for a link with obesity. A cohort study of health professionals in the United States, found that differences in the distribution of possible dietary and lifestyle risk factors did not explain the higher risk (RR 1.81) of prostate cancer in Blacks versus Whites.

Genetic factors appear therefore to play a major role in explaining the observed racial differences, and findings of elevated risk in men with a family history of the disease support this.

There is a 5-11 fold increased risk among men with two or more affected first-degree relatives. A similar study involving a population-
based case–control study of prostate cancer among Blacks, Whites
and Asians in the United States and Canada found the prevalence of positive family histories somewhat lower among the Asian Americans than among Blacks or Whites.

It is clear that male sex hormones play an important role in the development and growth of prostate cancers. Testosterone diffuses into the gland, where it is converted by the enzyme steroid 5-alpha
reductase type II (SRD5A2) to the more metabolically active form dihydrotestosterone (DHT). DHT and testosterone bind to the androgen receptor (AR), and the receptor/ligand complex translocates to the nucleus for DNA binding and transactivation of genes which have androgen-responsive elements, including those controlling cell division.

Much research has concentrated on the role of polymorphisms of the genes regulating this process and how inter-ethnic variations in such polymorphisms might explain the higher risk of prostate cancer in men of African descent.

Polymorphisms in the SRD5A2 genes may provide at least part of the explanation, but more interest is focused on the AR gene, located on the long arm of chromosome X. The AR gene contains a highly polymorphic region of CAG repeats in exon 1, the normal range being 6–39 repeats.

Several studies suggest that men with a lower number of AR CAG repeat lengths are at higher risk of prostate cancer. Blacks in the United States have fewer CAG repeats than Whites, which has been postulated to partly explain their susceptibility to prostate cancer.

Other genetic mechanisms possible related to prostate cancer risk are polymorphisms in the vitamin D receptor gene or in the insulin-like growth factor (IGF) signalling pathway, but there is no evidence for significant interethnic differences in these systems.

Other environmental factors (occupational exposures) or behavioural factors (sexual life) have been investigated, but do not seem to play a clear role.

Localization

Most clinically palpable prostate cancers diagnosed on needle biopsy are predominantly located posteriorly and posterolaterally.

In a few cases, large transition zone tumours may extend into the peripheral zone and become palpable.

Cancers detected on TURP are predominantly within the transition zone.

Nonpalpable cancers detected on needle biopsy are predominantly located peripherally, although 15-25% have tumour predominantly within the transition zone.

Large tumours may extend into the central zone, yet cancers uncommonly arise in this zone.

Multifocal adenocarcinoma of the prostate is present in more than 85% of prostates.

Clinical features

Signs and symptoms

Even before the serum prostate specific antigen test came into common usage over a decade ago, most prostate cancer was asymptomatic, detected by digital rectal examination.

PSA screening has decreased the average tumour volume, and hence further lowered the percentage of cancers that present with symptoms today.

Most cancers arise in the peripheral zone, so that transition zone enlargement sufficient to cause bladder outlet obstruction usually indicates hyperplasia.

However, 8.0% of contemporary transurethral resection specimens disclose carcinoma, and rarely, urinary obstruction results from large-volume periurethral tumour.

Locally extensive cancer is seen less often than in the past but may present with pelvic pain, rectal bleeding or obstruction.

Metastatic prostatic adenocarcinoma can present as bone pain, mainly in the pelvic bones and spinal cord, where it can cause cord compression. However, when bone scan discloses metastasis after diagnosis of a primary prostatic carcinoma, the metastasis is
most often asymptomatic.

Enlarged lymph nodes, usually pelvic, but rarely supraclavicular or axillary (typically left-sided), can sometimes be a presenting symptom.

Ascites and pleural effusion are rare initial presentations of prostate cancer.

Imaging

Ultrasound imaging

Transrectal ultrasound imaging (TRUS) with high frequency transducers is a useful tool for the work-up of patients with a
prostate problem. It enables the operator to evaluate gland volume, as well as delineate and measure focal lesions.

Its primary application, however, remains in image guidance of transrectal prostate biopsies. It has proven to be of limited value for the detection of prostate cancer and the assessment of extraglandular spread due to lack of specificity.

While the majority of early prostate cancers present as hypoechoic lesions in the peripheral zone on TRUS, this sonographic appearance is non-specific, because not all cancers are hypoechoic and not all hypoechoic lesions are malignant.

Sonographic-pathologic correlation studies have shown that approximately 70-75% of cancers are hypoechoic and 25-30% of cancers are isoechoic and blend with surrounding tissues. These cancers cannot be detected by TRUS.

A small number of cancers are echogenic or contain echogenic foci within hypoechoic lesions. The positive predictive value of a hypoechoic lesion to be cancer increases with the size of the lesion, a palpable abnormality in this region and an elevated PSA level.

Overall the incidence of malignancy in a sonographically suspicious lesion is approximately 20-25%. Even with high-resolution equipment many potentially clinically significant cancers are not visualized by TRUS.

A large multicentre study demonstrated that up to 40% of significant cancers were missed by TRUS. In addition, the sensitivity to detect neurovascular bundle invasion has been reported to only be about 66% with a specificity of 78%.

To improve lesion detection the use of colour Doppler US (CDUS) has been advocated particularly for isoechoic lesions or to initiate a TRUS guided biopsy which may not have been performed, thus tailoring the biopsy to target isoechoic yet hypervascular areas of the gland.

Results from these studies are however conflicting due to a problematic overlap in flow detected in cancers, inflammatory conditions or benign lesions.

Newer colour flow techniques such as power Doppler US may be helpful as they may allow detection of slow flow in even smaller tumour vessels.

Other recent developments such as intravenous contrast agents, harmonic imaging and 3-D US have shown a potential role for these US techniques to delineate subtle prostate cancers, assess extraglandular spread or monitor patients with prostate cancer undergoing hormonal treatment.

Computed tomography and magnetic resonance imaging

Cross-sectional imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have not proven valuable because of low sensitivities to detect and stage prostate cancer.

MRI is sometimes reserved for staging of patients with biopsy proven prostate cancer. The combined use of MRI and proton MRI-spectroscopy imaging (MRSI) is currently being evaluated for staging of prostate cancer.

These techniques however, also appear to have limitations for
imaging of microscopic disease. Knowledge obtained from MRSI may provide insight into the biological behaviour of prostate cancer, such as tumour aggressiveness and extra-prostatic extension.

Plain film radiography and nuclear medicine

Skeletal radiography (bone survey) is an insensitive method to screen for bony metastases and should be reserved to confirm skeletal abnormalities in patients with positive bone scintigraphy.

Bone scintigraphy (radionuclide bone scans) provides the most sensitive method for detecting bone metastases. Upper urinary tract obstruction may also be identified on bone scintigraphy obviating the need for intravenous urography.

Monoclonal antibody radioimmunoscintigraphy (prostate specific membrane antigen-PMSA) chelated to Indium111 (Prostacint®, Cytogen Corporation, Princeton, N.J.) has shown promise to detect microscopic metastatic deposits in regional and distant sites.

However, due to limited positive predictive values reported (50-62%) its use in combination with PSA, histologic grade and clinical staging is recommended to provide increased predictive information.

Another new development in the field of nuclear medicine is positron emission tomography (PET), which allows in vivo-characterization of tumours and may have implications for the evaluation of patients with prostate cancer in the future.

Laboratory tests

 Prostate specific antigen (PSA)
 

WHO histological classification of tumours of the prostate

 prostatic epithelial tumors

• prostatic glandular tumors
  • prostatic adenocarcinoma (prostatic acinar adenocarcinoma) ICD-0:8140/31
    • prostatic atrophic adenocarcinoma
    • prostatic pseudohyperplastic adenocarcinoma
    • prostatic foamy adenocarcinoma
    • prostatic colloid adenocarcinoma ICD-0:8480/3
    • prostatic signet ring adenocarcinoma ICD-0:8490/3
    • prostatic oncocytic adenocarcinoma ICD-0:8290/3
    • prostatic lymphoepithelioma-like adenocarcinoma ICD-0:8082/3

• • prostatic carcinoma with spindle cell differentiation (prostatic spindle cell carcinoma) : (carcinosarcoma, sarcomatoid carcinoma) ICD-0:8572/3

• • prostatic intraepithelial neoplasia (PIN)
  • prostatic intraepithelial neoplasia, grade III (PIN III) ICD-0:8148/2
  • prostatic ductal adenocarcinoma ICD-0:8500/3
    • prostatic cribriform adenocarcinoma ICD-0:8201/3
    • prostatic papillary adenocarcinoma ICD-0:8260/3
    • prostatic solid adenocarcinoma ICD-0:8230/3

• prostatic urothelial tumors
  • prostatic urothelial carcinoma ICD-0:8120/3

• prostatic squamous tumors
  • prostatic aadenosquamous carcinoma ICD-0:8560/3
  • prostatic squamous cell carcinoma ICD-0:8070/3

• prostatic basal cell tumors
  • prostatic basal cell adenoma ICD-0:8147/0
  • prostatic basal cell carcinoma ICD-0:8147/3

 prostatic neuroendocrine tumors

• prostatic endocrine differentiation within adenocarcinoma ICD-0:8574/3
• prostatic carcinoid tumour ICD-0:8240/3
• prostatic small cell carcinoma ICD-0:8041/3
• prostatic paraganglioma ICD-0:8680/1
• prostatic neuroblastoma ICD-0:9500/3

 prostatic prostatic stromal tumors

• prostatic stromal tumour of uncertain malignant potential ICD-0:8935/1
• prostatic stromal sarcoma ICD-0:8935/3

 prostatic mesenchymal tumors

• prostatic leiomyosarcoma ICD-0:8890/3
• prostatic thabdomyosarcoma ICD-0:8900/3
• prostatic chondrosarcoma ICD-0:9220/3
• prostatic angiosarcoma ICD-0:9120/3
• prostatic malignant fibrous histiocytoma ICD-0:8830/3
• prostatic malignant peripheral nerve sheath tumour ICD-0:9540/3
• prostatic hemangioma ICD-0:9120/0
• prostatic chondroma ICD-0:9220/0
• prostatic leiomyoma ICD-0:8890/0
• prostatic granular cell tumour ICD-0:9580/0
• prostatic hemangiopericytoma ICD-0:9150/1
• prostatic solitary fibrous tumour ICD-0:8815/0

 prostatic mematolymphoid tumors

• prostatic lymphoma
• prostatic leukemia

 prostatic miscellaneous tumours

• prostatic cystadenoma ICD-0:8440/0
• prostatic nephroblastoma (Wilms tumour) ICD-0:8960/3
• prostatic malignant rhabdoid tumour ICD-0:8963/3
• prostatic Germ cell tumors
  • prostatic Yolk sac tumor ICD-0:9071/3
  • prostatic seminoma ICD-0:9061/3
  • prostatic embryonal carcinoma & teratoma ICD-0:9081/3
  • prostatic choriocarcinoma ICD-0:9100/3

• prostatic clear cell adenocarcinoma ICD-0:0/3
• prostatic Melanoma ICD-0:8720/3

 prostatic metastatic tumours
 prostatic tumors of the seminal vesicles

 prostatic epithelial tumors

• prostatic adenocarcinoma ICD-0:8140/3
• prostatic cystadenoma ICD-0:8440/0

 prostatic mixed epithelial and stromal tumors

• prostatic malignant mixed epithelial and stromal tumors
• prostatic benign mixed epithelial and stromal tumors

 prostatic mesenchymal tumours

• prostatic leiomyosarcoma ICD-0:8890/3
• prostatic angiosarcoma ICD-0:9120/3
• prostatic liposarcoma ICD-0:8850/3
• prostatic malignant fibrous histiocytoma ICD-0:8830/3
• prostatic solitary fibrous tumour ICD-0:8815/0
• prostatic hemangiopericytoma ICD-0:9150/1
• prostatic leiomyoma ICD-0:8890/0

 prostatic miscellaneous tumours

• prostatic choriocarcinoma ICD-0:9100/3
• prostatic male adnexal tumour of probable Wolffian origin

 prostatic metastatic tumors

TNM classification of carcinomas of the prostate

T – Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
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)
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
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.)

Note: There is no pT1 category because there is insufficient tissue to assess the highest pT category.

N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Note: Metastasis no larger than 0.2cm can be designated pN1mi

M – Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)

G Histopathological grading
GX Grade cannot be assessed
G1 Well differentiated (Gleason 2-4)
G2 Moderately differentiated (Gleason 5-6)
G3–4 Poorly differentiated/undifferentiated (Gleason 7-10)

Stage grouping

Stage I T1a N0 M0 G1
Stage II T1a N0 M0 G2, 3–4
T1b, c N0 M0 Any G
T1, T2 N0 M0 Any G
Stage III T3 N0 M0 Any G
Stage IV T4 N0 M0 Any G
Any T N1 M0 Any G
Any T Any N M1 Any G

See also

 Cancer
 Tumors

References

 Targeted therapy in prostate cancer. Corcoran NM, Gleave ME. Histopathology. 2012 Jan;60(1):216-31. PMID: 22212088

 Prostate cancer and inflammation: the evidence. Sfanos KS, De Marzo AM. Histopathology. 2012 Jan;60(1):199-215. PMID: 22212087

 Anatomy of the prostate revisited: implications for prostate biopsy and zonal origins of prostate cancer. Fine SW, Reuter VE. Histopathology. 2012 Jan;60(1):142-52. PMID: 22212083

 Staging of prostate cancer. Cheng L, Montironi R, Bostwick DG, Lopez-Beltran A, Berney DM. Histopathology. 2012 Jan;60(1):87-117. PMID: 22212080

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

 Diagnosis of limited adenocarcinoma of the prostate. Epstein JI. Histopathology. 2012 Jan;60(1):28-40. PMID: 22212076

 The impact of the 2005 International Society of Urological Pathology (ISUP) consensus on Gleason grading in contemporary practice. Zareba P, Zhang J, Yilmaz A, Trpkov K. Histopathology. 2009 Oct;55(4):384-91. PMID: 19817888

 Pitfalls in the diagnosis of prostatic cancer: retrospective review of 1791 cases with clinical outcome. Berney DM, Fisher G, Kattan MW, Oliver RT, Møller H, Fearn P, Eastham J, Scardino P, Cuzick J, Reuter VE, Foster CS; Trans-Atlantic prostate group. Histopathology. 2007 Oct;51(4):452-7. PMID: 17880526

 Diagnostic utility of immunohistochemistry in morphologically difficult prostate cancer: review of current literature. Varma M, Jasani B. Histopathology. 2005 Jul;47(1):1-16. PMID: 15982318

 Pre-neoplastic lesions of the prostate. Parkinson MC. Histopathology. 1995 Oct;27(4):301-11. PMID: 8847060