Cryotherapy which is also referred to as cryosurgery or cryoablation refers to utilization of very cold temperatures to freeze various cells depending upon the pathology. Cryotherapy has tended to be utilized as treatment of curative intent for localized low-risk and intermediate risk carcinomas of the prostate gland. Cryotherapy has also been utilized for the treatment of post-cryotherapy failure prostate cancers with residual tumour or locally recurrent tumour that is confined to the prostate gland. Cryotherapy has also been utilized for the treatment of locally recurrent prostate cancers or localized prostate cancers that have remained following failure of radiotherapy to the prostate cancer of curative intent or radical prostatectomy of prostate for prostate at times. Because cryotherapy of prostate cancer is a minimally invasive treatment procedure, it can be utilized in the treatment of patients who have localized prostate cancer whose tumours could be treated by means of radical prostatectomy or radiotherapy (external beam radiotherapy or brachytherapy) who are considered not to be medically fit to undergo these procedures because of their co-morbidities. The most common treatment options for the management of localized adenocarcinomas of the prostate gland tend to involve radical prostatectomy or radical radiotherapy. Nevertheless, other treatment options for localized prostate cancer that have been undertaken sporadically include: Radiofrequency ablation of the prostate cancer, High intensity focussed ultrasound scan treatment of prostate cancer, irreversible electroporation of prostate cancer. Cryotherapy of prostate cancer as treatment of curative intent has tended to be published sporadically based upon case reports or case series and there has not been reports of an extensive clinical-trials on cryotherapy of localized adenocarcinoma of the prostate. Furthermore, there is no consensus opinion validated definition of biochemical failure pursuant to treatment of localized prostate cancer by cryotherapy. Nevertheless, one article has reported a prospective study with the undertaking of standardized follow-up protocol in which it a series of 108 patients who were diagnosed as having localized adenocarcinoma of prostate that was staged T1c to T2c were treated by primary cryoablation of curative intent and in which the median follow-up was 61 months.  With regard to the results of this study, the criteria of biochemical recurrence had been unified based upon the American Society for Therapeutic Radiology and Oncology (ASTRO). The end points of the study included:  biochemical progression-free survival (BPFS), cancer-specific survival, as well as overall survival. The complication rates were reported in the study. With regard to the results the biochemical progression-free survival rates were for low-, medium-, and high-risk prostate cancer patients 96.4%, 91.2%, and 62.2%, respectively. The Cancer-specific survival was 98.1%. The overall survival reached 94.4%. The complications that were encountered included incontinence in 5.6% of the patients, urinary tract obstruction in 1.9% of the patients, urethral sloughing in 5.6% of the patients, haematuria in 1.9% of the patients, perineal pain in 11.1% of the patients, and prostatorectal fistula in 0.9% of the patients. Erectile disfunction was found in 98.1% of the patients. The authors concluded that cryotherapy is an effective and minimally invasive treatment for primary carcinomas of the prostate gland in well-selected cases, and the treatment procedure is associated with low surgical risk and good results in terms of biochemical progression-free survival (BPFS), cancer-specific survival, and overall survival. Even though the results of this study had illustrated that the oncology outcome of high-risk prostate cancer was lower than the outcome of low-risk and intermediate-risk prostate cancer more than 60% of patients who had high-risk prostate cancer had biochemical progression-free survival after a median follow-up of 61 months. At the moment cryotherapy is being utilized as treatment of curative option for some low-risk and intermediate (medium) -risk prostate cancer. Cryotherapy of the primary prostate cancer has been utilized for the palliative treatment of some advanced / metastatic prostate cancer which had temporarily ameliorated the general health of few reported patients. In the scenario of persistence of localized low-risk or intermediate- (medium-) risk localized prostate cancer that have persisted following cryotherapy of the prostate cancer, the cancer can be treated by means of either further cryotherapy, radical prostatectomy, radical radiotherapy, HIFU treatment, Irreversible electroporation, and radiofrequency ablation of prostate gland. The complications of erectile / sexual dysfunction, and urinary incontinence / voiding dysfunction following cryotherapy for prostate cancer tends to be more transient in comparison with following radical prostatectomy or radical radiotherapy. It may be that cryotherapy of localized prostate cancer of low-risk, and medium-risk patients may have a slightly inferior long-term oncology outcome in comparison with radical prostatectomy, radical radiotherapy and other minimally invasive treatment options of curative intent but this needs to be further investigated through a large global multicentre treatment comparative study of various treatment options with a long-term follow-up. Nevertheless, cryotherapy of prostate cancer does represent a minimally invasive alternative treatment for localized prostate cancer as treatment of curative intent and it can also be used to treat persistent/locally recurrent prostate cancer following radical radiotherapy and radical prostatectomy. Cryotherapy as treatment option is a safe and effective treatment option for localized low-risk and medium-risk prostate cancer. 

The European Association of Urology guidelines on carcinoma of the prostate gland documented that cryotherapy represents a true treatment alternative for patients who have clinically localized carcinoma of the prostate gland [1] [2] The American Association of Urology in 2008 documented a best practice iteration which had confirmed cryotherapy as a valid therapeutic option for both primary as well as recurrent localized carcinoma of the prostate gland. [1] [3] It had been iterated that in 2005 within the United Kingdom, the National Institute of Clinical Excellence had approved utilization of cryotherapy for patients who have adenocarcinoma of the prostate gland, both as a primary therapy as well as salvage therapy pursuant to radiotherapy or hormone treatment. [4] National Institute of Clinical Excellence. Cryotherapy as a primary treatment for prostate cancer. 2005. [4] It has also been documented that in February 2008, the United Kingdom National Institute of Clinical Excellence guidelines on carcinoma of the prostate gland which was released had reversed the aforementioned decision and had suggested that the cryotherapy of prostate cancer should be undertaken within the setting of clinical trials. [1] It has also been stated that because of ongoing debate related to cryotherapy of prostate cancer, a further revision of the NICE guidelines had been made to allow United Kingdom Medical Practitioners to collect data on patients who are treated locally for funding requirements. [1] 

It has been explained that cryotherapy does cause cell death via two principal mechanisms [1] [5] First of all as the temperature does fall, extracellular ice does crystalize which does tend to cause movement of water from the intracellular into the extra-cellular environment after an osmotic gradient. [1] As the temperature continues to fall, intra-cellular ice crystals tend to form, and this does cause direct damage to the intra-cellular organelle system as well as to the cell membrane. [1]  

With regard to the second mechanism, this does relate to platelet aggregation as well as microthrombus formation within small blood vessels and this does tend to emanate in ischaemic change within the tissue area which is supplied by the affected blood vessels. These changes do emanate in the development of coagulative necrosis as well as they do cause a well-demarcated lesion. Furthermore, severe changes of temperature as well as ischaemic changes do induce apoptosis within cells at the periphery of the cryo-lesion. [1] [6] It has been iterated that the effectiveness of cellular destruction does depend upon rapid freezing [1] [7], the lowest temperature that is reached as well as slow thawing. This is stated to be generally achieved via two freeze-thaw cycles to a treat temperature of – 40 degrees centigrade. [1] [5].   

In order to provide treatment of curative intent for the management of localized adenocarcinoma of the prostate gland, either the prostate gland containing the carcinoma should be completely excised through a surgical operation like radical prostatectomy or the tumour cells must be completely destroyed by the treatment option that has been provided and traditionally radical radiotherapy by means of external beam radiotherapy or brachytherapy have tended to be undertaken. Nevertheless, these days other treatment options that are minimally invasive are being undertaken as treatment with an aim of curative intent in various centres in the world but such treatment options are not being regarded as a universally accepted consensus opinion options of treatment. Cryotherapy of prostate cancer is one of the new non-invasive treatment options that are sporadically undertaken in some oncology centres in the world. 

Cryotherapy is utilized for the treatment of various conditions in different parts of the body in various countries within the world. It does appear that cryotherapy as primary treatment of localized prostate cancer as well as salvage therapy pursuant to failure or recurrence of adenocarcinoma of the prostate gland tends to be undertaken mostly within the developed countries but not very often in some of the developing countries. Cryotherapy as treatment of curative intent for localized adenocarcinoma as well as salvage therapy for recurrent prostate cancer also tends to be undertaken within regional oncology centres in a number of developed countries and hence many clinicians that work within district hospitals and clinics as well as a number of clinicians who work within district hospitals in some developing countries may not be familiar with cryotherapy as a treatment option for prostate cancer. The ensuing article on cryotherapy as a treatment option for adenocarcinoma of the prostate gland is divided into two parts: (A) Overview which has discussed cryotherapy generally including cryotherapy as treatment for various conditions and (B) Miscellaneous Narrations And Discussions From Some Case Reports, Case Series And Studies Related To Cryotherapy As Treatment Of Curative Intent For Localized Adenocarcinoma Of The Prostate Gland As Well As Salvage Therapy For Failure Of Treatment Or Recurrence Pursuant To Radical Prostatectomy, Radiotherapy / Hormonal Therapy. 

To review and update the literature on Cryotherapy of prostate cancer with a focus on localized low-risk and medium –(intermediate)-risk localized adenocarcinoma of the prostate gland.

Internet data bases were searched including: Google; Google Scholar; Yahoo; and PubMed. The search words that were used included: Cryotherapy; Cryotherapy of prostate cancer, cryotherapy of carcinoma of prostate cancer, cryotherapy of adenocarcinoma of the prostate; carcinoma of prostate; adenocarcinoma of prostate; focal treatment of prostate cancer. One hundred and thirty-six, (136) references were identified which were used to write the article which has been divided into two parts: (A) Overview which contains general discussions on (I) Cryotherapy in general, (II) adenocarcinoma of prostate, (III) cryotherapy of prostate cancer, and (B) Miscellaneous Narrations and Discussions Related to Some Case Reports, Case Series, And Studies Related to Cryotherapy of Prostate Cancer.     

Overview 

Cryotherapy 

Definition and General Statements

Cryotherapy is a terminology that is utilized for the utilization of a freezing chamber which usually tends to be -110 degrees in order to help muscles recover. [8]

It has been stated that cryotherapy tends to be utilized for multiple applications [9] 

It has been documented that “Cryo” is a word which has originated from the Greek language and does mean icy or cold. [8] [10]] 

Cryotherapy does refer to a procedure which exposes the body to temperatures that tend to be colder than minus 200 degrees for about 3 minutes [10] [11] 

It has been documented that the practice of cryotherapy had originated in Japan in the late 1970s when a Japanese rheumatologist utilized cold temperatures for the treatment of his patients’ painful joints [8] [10] [12]

It has also been iterated that cryotherapy is also utilized for the treatment of cancer, in which cold temperatures are utilized to destroy cancer cells. [10] [13] 

Cryotherapy is stated to be at times referred to as cold therapy and it refers to the local or general utilization of low temperature in medical treatment. It has also been pointed out that cryotherapy could be utilized for the treatment of various tissue lesions [1] It has also been documented that the most common utilization of the term cryotherapy does refer to the surgical treatment, which is specifically referred to as cryotherapy or cryoablation and that cryotherapy does refer to the application of extremely low temperature for the purpose of destroying abnormal or diseased tissue and cryotherapy is utilized most often to treat skin conditions  [9] [10] 14] 

It has been documented that cryotherapy tends to be utilized in an effort to relieve muscle pain, sprains, as well as swelling that ensues tissue damage or surgery, [10]

It has been documented that that cryotherapy has tended to be commonly utilized to accelerate recovery in athletes pursuant to exercise for a number of decades as well as cryotherapy does decrease the temperature surface in order to minimize hypoxic cell death, accumulation of oedema, as well as muscle spasms, all of which eventually ameliorate discomfort as well as inflammation [10] [15]

It has also been stated that cryotherapy could also involve a range of treatments from the application of ice packs or immersion in ice baths which has generally been referred to as cold therapy, to the utilization of cold chambers. [10]   

It has been iterated that cryotherapy is widely utilized, but there is little evidence as to the efficacy of cryotherapy which had been replicated or demonstrated in large controlled studies. [[new 10]] The long-term side effects of cryotherapy had also not been studied [10] [16] [17] 

It has nevertheless been iterated that: results of a study had concluded that cryotherapy does have a positive impact upon the short-term recovery of athletes as well as cryotherapy had helped in the management of muscle soreness as well as facilitated recovery within the first 24 hours pursuant to a sporting-related activity. It has additionally been iterated that: athletes, who utilized cryotherapy within the first 24 hours for the alleviation of pain had recovered at a faster rate in comparison with athletes who did not utilize cryotherapy pursuant to their sport-related activity [10] [15]

Cryotherapy Chamber 

Partial Body Cryotherapy (PBC). 

It has been documented that there are different types of cryochamber that exist and each chamber does have different mechanisms of action as well as utilization [10] It has been stated that the Partial Body Cryotherapy (PBC) does utilize nitrogen to decrease the temperature. This cryochamber is said to be an individual, tube-shaped enclosure which does cover a person’s body with an open-top in order to keep the head at room temperature. [18] 

The second cryochamber tends to be referred to as the whole-body cryotherapy (WBC) and it does utilize electricity in order to reduce the temperature inside the chamber. In contrast to the first cryochamber, the user fully does enter the electricity operated chamber. [10]

Partial-Body Cryotherapy is stated to be a specific type of low-temperature treatment which is utilized to reduce inflammation as well as painful effects [10] [19] 

It has been iterated that cryotherapy was developed in the 19970s by a rheumatologist from Japan called Toshima Yamaguchi [10] [20] [21] and that cryotherapy had been introduced to Europe, United States of America, as well as Australia in the 1980s [22] [23] The effect of cryotherapy on total antioxidative capacity in patients with active seropositive rheumatoid arthritis. [23]. and 1990s. [24]

Both cryochambers are stated to decrease the skin temperature; however, WBC does reach lower temperatures in comparison with PBC and it might be considered to be more effective. [10] [25]
Mechanism of action

The ensuing summations have been made regarding the mechanism of action related to cryotherapy: [10]]

In scenarios when the body is vulnerable to extreme cooling, the blood vessels tend to be narrowed and they then make less blood to flow to the areas of the swelling. [10]

It has also been iterated that once outside the cryogenic chamber, the vessels do expand, and an increased presence of anti-inflammatory proteins (IL-10) tends to be established within the blood. [10] [26] 

It has also been documented that cryotherapy chamber does entail the exposure of individuals to freezing dry air that is lower than one hundred degrees centigrade (100 °C) for 2 minutes to 4 minutes. [10] [27] 

Main utilizations [10]

Proponents say that cryotherapy may reduce pain as well as inflammation, help with mental disorders, support exercise recovery performance and does improve upon joint function. Cryotherapy chambers belong to the group of equipment that have been associated with sports rehabilitation and wellness.

Weight loss [28]

Reducing anxiety as well as depression [29]

Reduction in the symptoms of eczema [30] 

Cryosurgery 

Medical cryotherapy gun.

Cryosurgery 

Cryosurgery is a terminology that is utilized for the application of extreme cold in order to destroy abnormal or diseased tissue. The application of ultra-cold liquid does cause damage to the treated tissue as a result of intracellular ice formation. The degree of damage does depend upon the minimum temperature which is achieved and the rate of cooling. [31]

Cryosurgery is utilized to treat a number of diseases and disorders, most especially skin conditions like including warts, moles, skin tags as well as solar keratoses. Liquid nitrogen usually tends to be utilized to freeze the tissues at the cellular level. The procedure tends to be often utilized in view of the fact that it is relatively easy and quick to undertake, and it can be undertaken in the doctor’s surgery, as well as cryosurgery is deemed to be associated with quite a low risk. It has been iterated that if a cancerous lesion is suspected then excision of the lesion rather than cryosurgery might be deemed more appropriate. [32]

Icepack treatment

Ice pack treatment is a treatment of cold temperatures to an injured area of the body. It has been iterated that even though the treatment is extensively utilized, and it had been agreed that Icepack therapy does alleviates symptoms, testing had produced conflicting results about the efficacy of Icepack therapy. [33] [34][35] [36]

An ice pack tends to be placed over an injured area of the body and it is intended to absorb heat of a closed traumatic or oedematous injury by the use of conduction to transfer thermal energy. The physiological effects of cold application do include immediate vasoconstriction with reflexive vasodilatation, decreased local metabolism as well as enzymatic activity, as well as decreased demand for oxygen. Cold does tend to decrease muscle spindle fibre activity and does slow nerve conduction velocity; therefore, it is often utilized to decrease spasticity as well as and guarding of muscle. It is commonly used to alleviate the pain of minor injuries, as well as decrease muscle soreness. It has been stated that the use of ice packs in treatment does decrease the blood flow most rapidly at the beginning of the cooling period, [37] and this does occur as a result of vasoconstriction, the initial reflex sympathetic activity.

It had also been iterated that ice is not commonly utilized preceding rehabilitation or performance because of its known adverse effects to performance including decreased myotatic reflex as well as force production, and a decrease in balance immediately following ice pack therapy for 20 minutes. [38] 

Nevertheless, if ice pack treatment is applied for less than 10 minutes, performance could occur without detrimental effects. It has furthermore been iterated that if the ice pack is removed at this time, athletes tend to be sent back to training or competition directly with no decrease in performance. [39]

Cryotherapy pursuant to total knee replacement 

Total knee replacement (TKR) is a common intervention that tends to be provided for patients who have end-stage osteoarthritis of the knee. Post-operative total knee replacement surgical management does tend to include cryotherapy. Cryotherapy might slightly reduce the amount of blood loss as well as associated pain. Cryotherapy was generally safe and it was not associated with any serious adverse events. Cryotherapy could improve upon the range of movement at the knee in the first one to two weeks pursuant to surgery. Potential benefits of cryotherapy on blood loss, postoperative pain, and range of motion might be too small to justify its utilization, and the quality of the evidence was very low or low for all main outcomes.  For this reason, it was stated that well-designed randomized trials are necessitated to improve upon the quality of the evidence and that the effectiveness of cryotherapy had not been clarified [40].

Cold spray anaesthetics

Freeze spray 

Additional to their utilization in cryosurgery, several types of cold aerosol sprays tend to be utilized to achieve short-term pain relief. Ordinary spray cans that contain tetrafluoroethane, dimethyl ether, or substances that are similar, tend to be utilized to numb the skin preceding or possibly instead of local anaesthetic injections, and preceding other needles, small incisions, sutures, and other procedures. Other products that contain chloroethane are utilized to alleviate sports injuries, similar to ice pack therapy. [10] 

Whole body cryotherapy 

Cryotherapy patients during their preparation of c. 3 minutes. 

It has been stated that an increasing amount of research has been undertaken on the effects of whole-body cryotherapy (WBC) upon exercise, beauty, and health and that results of research had often been inconsistent because the usage of the different types of cryo-chambers, and different periods of treatment. Nevertheless, it had become increasingly clear that WBC does have a positive effect upon muscle soreness and does increase the recovery time after exercise. [19] It had also been documented that some older papers had reported inconsistencies in the effects of whole-body cryotherapy. [10] [24]. It has additionally been iterated that the FDA had pointed out that the effects of whole-body cryotherapy does lack evidence and that whole-body cryotherapy needs to be researched more. [10] [41] 

It has been iterated that cryotherapy is also increasingly being utilized as a non-drug treatment against rheumatoid arthritis, stress, anxiety, chronic pain, multiple sclerosis as well as fibromyalgia. [10] [42].  It has additionally been stated that studies for these, as well as other diseases including Alzheimer’s disease and migraines are being undertaken even though more evidence does become available on the positive effects of Whole-Body Cryotherapy. [10] It has been iterated that the FDA had pointed out that the effects of Whole-Body Cryotherapy, lacks evidence and more research on the topic does need to be researched more. [43] 

It has been explained that cryotherapy treatment does entail the exposure of individuals to extremely cold dry air (below −100 °C) for two to four minutes and that in order to achieve the sub-zero temperatures that are necessitated for WBC, two methods typically tend to be utilized including: liquid nitrogen and refrigerated cold air. It has been explained that during these exposures, individuals do tend to wear minimal clothing, which usually tend to consist of shorts for males, and shorts and a crop top for females. Gloves, a woollen headband covering the ears, and a nose and mouth mask, and furthermore, dry shoes and socks, tend to be commonly worn in order to reduce the risk of cold-related injury. It had been iterated that the first WBC chamber was built in Japan in the late 1970s, and this was introduced to Europe in the 1980s, and it has been utilized in the United States of America (USA) as well as within Australia over the preceding decade. [10] [24]

Adverse effects

It has been iterated that review articles on of whole-body cryotherapy had called for research studies to be undertaken in order to implement active surveillance of adverse events, which had been suspected to have been under-reported. [10] [24] It has been documented that if the cold temperatures are produced by evaporating liquid nitrogen, there is the risk of development of inert gas asphyxiation and also frostbite. [44] [45] Nevertheless, it has been stated that these risks are irrelevant within the electronically operated chambers. [10]

Partial body cryotherapy

With regard to partial body cryotherapy (PBC) devices which also do exist, it has been iterated that if the cold temperatures are produced by evaporating liquid nitrogen, there tends to be the risk of inert gas asphyxiation and also frostbite. [10] [45] 

Definition / general statements related to adenocarcinoma of the prostate gland.

Distribution of Adenocarcinoma of The Prostate Gland: [46]

It has been iterated that 95% of adenocarcinomas of the prostate had tended to be acinar type (of carcinoma and 5% of adenocarcinomas of the prostate gland tend to be ductal type of carcinoma [pathologyoutlines.com new [46]

It has also been documented that 70% of prostate cancers tend to arise from peripheral zone of the prostate gland that is situated on the posterior and lateral aspect of the prostate gland. [pathologyoutlines.com [46]

It has been pointed out that quite often prostate cancer does spare the transition zone of the prostate gland which is situated within the periurethral/anterior zone (TZ) of the prostate gland and that the involvement of the transition zone (TZ) by carcinoma of the prostate gland usually has tended to be the expansion of tumour from the peripheral zone of the prostate gland into the transition zone. [46] 

It has been documented that at radical prostatectomy, greater than 90% (>90%) of the prostate gland has tended to contain tumour but only 65% of the prostate glands have tended to contain prostate cancer tumour anteriorly. [46] 

It has been stated that anterior prostate cancer has tended to be associated with higher volume of prostate cancer tumour as well as resection margin positivity of tumour. [47], even though the oncology outcomes have tended to be similar to the oncology outcomes of posterior prostate cancers. [48]

It has additionally been documented that the finding of prostate cancer tumour within biopsy has tended to entail a tumour that is clinically “significant” if the Gleason score is equal to or higher than 3+4=7 and if the length of the tumour is equal to or higher than 3 mm, within prostatectomy specimens, and the tumour is regarded as significant if the volume of the tumour is equal to or higher than 0.5 cc, or the stage of the tumour is equal to or higher than (≥) pT3a) [49] 

Extension of Tumour [46] 

Extra-prostatic extension (EPE) is most common, and has been defined as tumour in contact with extra-prostatic fat

The prostate has a fibromuscular pseudo-capsule that is discontinuous at its apex, bladder base and anteriorly, so the “capsule” is not relevant in staging prostate cancer

Local invasion occurs via seminal vesicles (if tumour infiltrates muscular wall) and bladder base; rarely via prostatic urethra

Rectal invasion is rare due to tough Denonvillier’s fascia which abuts pseudo-capsule; may present as anterior rectal mass, stricture or serosal implants

Seminal vesicle invasion occurs via (a) direct spread along ejaculatory duct complex, (b) spread outside prostate, then into seminal vesicle, (c) isolated deposits of cancer in seminal vesicle with no contiguous primary cancer in the prostate. [50] 

Incidentally detected: [46]

In cysto-prostatectomy specimens for bladder cancer, most studies had reported a 50% rate of incidental prostatic adenocarcinoma; 20% of the tumours were clinically significant [51] 

Epidemiology [46]

It has been stated that adenocarcinoma of the prostate gland accounts for 300,000 cases per year in United States of America and the first most common cancer cause of after skin cancer, as well as it does cause 41,000 deaths per year and adenocarcinoma of the prostate gland is the cause of death after lung cancer. 

It has been documented that 20% of American men tend to be diagnosed as having carcinoma of the prostate gland their lifetimes, as well as 3% die of prostate cancer

It has been stated that the age adjusted incidence of prostate cancer is increasing

It has also been iterated that 99% of individuals who have clinical disease are aged over 50 years.

It has been iterated also that a sizable minority of prostate cancers including those cancers that have been graded as Gleason score 3+3=6 (or less), had been shown almost never to metastasize to the lymph nodes [52] and lately it has been proposed to designate these lesions not even as cancer; however, by the terminology Indolent Lesion of Epithelial Origin (IDLE) [53] 

Nevertheless, majority of pathologists endorse have endorsed that Gleason 3+3=6 cancer is still cancer [54]

, and a variety of surgical and non-surgical management options are now available for low-grade cancer

Low grade or "latent" cancers do comprise of 20% in cancers in men who are in their 50's, and 70% in men in their 70'­s; and usually the pathologist should examine the entire gland to find the tumours. 

It has been iterated that clinical disease and high grade prostatic intraepithelial neoplasia (HGPIN) are more common in African-Americans in comparison with white men; and black men have higher stage prostate cancers at presentation, but the stage-adjusted survival is similar

It has been documented that clinical prostate cancer disease is rare in Asians which does amount to 3 cases to 4 cases per 100,000 versus 50 cases to 60 cases per 100,000 within the United States of American white men; higher rates of prostate care was also found in Scandinavians; and all groups were found to have similar incidence of latent cancers, which had suggested the importance of environmental or other genetic factors

It has also been documented that there tends to be no carcinoma of the prostate gland if prepubertal castration had been undertaken, as well as there tends to be a low incidence of prostate cancer associated with hyperestrogenism (liver cirrhosis)

It has been iterated that carcinoma of the prostate gland is not associated with sexually transmitted disease, smoking, occupational exposure, diet, or nodular hyperplasia

Sites [46]

Prostatic apex is more often involved than the bladder base 

Peripheral zone is more often involved than transition zone or central zone

Posterior peripheral zones are more often involved than anterior / lateral horns of the peripheral zones

But bladder base, transitional / central zone and anterior / lateral horns of peripheral zones are more difficult to sample

Clinical features [46]

It has been stated that with regard to manifestations of carcinoma of the prostate gland, carcinoma of the prostate gland has tended to be detected by means of digital rectal examination (DRE), trans-urethral ultrasound scan images which does miss 30% of carcinomas of the prostate gland that are isolated, or based upon assessments for raised serum levels of prostate specific antigen (PSA) which could be either above 4 ng / dL, or increasing over time. [46]

It has been iterated that there is some evidence which does favour the utilization of serum prostate specific antigen (PSA) that is higher than 2.5 ng / dL, as a cut-off point for prostate biopsies to miss fewer prostate cancers, particularly with regard to men who are older than 60 years. [46] [55]

Diagnosis [46]

It has been stated that these days, diagnosis of carcinoma of the prostate gland has most often been made based upon pathology examinations of specimens of needle biopsies of the prostate gland and on rare occasions diagnosis of carcinoma of the prostate gland has been made upon pathology examinations of trans-urethral resection of prostate (TURP) specimens. [pathology outlines.com [46]

Considering that trans-vesical prostatectomy and retropubic prostatectomies are undertaken in some parts of the world because of enlarged prostate glands associated with lower urinary tract symptoms for pre-operative diagnosis of benign prostate biopsies, on rare occasions some of the prostatectomy specimens could be found to contain areas of adenocarcinoma of the prostate gland. [46]

Reporting standards [pathologyoutlines.com [46]

With regard to the standard of reporting of prostate biopsies by pathologists, it has been iterated that in a sample of prostate biopsy specimen from a single vial, the pathologist should report the fraction of cores that are involved by cancer [56] the percentage of each core than contain cancer [57] and the length (in mm) of tumour on needle biopsy cores [58] all of these do tend to carry important prognostic value [59]

All reports on prostate cancer should list the fraction of cores or core fragments that contain cancer, and at least either the percentage of individual core involvement or the length of the tumour (in mm or cm)

Many commercial urological pathology laboratories and individual pathologists do tend to report both percentage of tumour and the length of tumour

When there are intervening areas of benign prostate within the core biopsy, the tumour tends to be designated as multifocal or discontinuously involving the core, and one of those two terms should appear in the diagnosis

Urine cytology:

With regard to utilization of urine cytology in the process of assessing prostate gland for the diagnosis of prostate gland the following points should be understood: [46] 

Urine cytology has not been used since 1980s and urine cytology has been largely replaced by automated spring loaded 18-gauge biopsy

Urine cytology is not useful for prostate cancer screening because it is difficult to identify well differentiated tumours with utilization of urine cytology, and that it is easier for poor/moderately differentiated tumours of the prostate gland.

Core biopsy of prostate [46]

High grade adenocarcinoma of the prostate gland versus high grade urothelial carcinoma:    It has been pointed out that specimens of adenocarcinoma of adenocarcinoma of the prostate gland do contain oval nuclei with smooth borders; fine, powdery, evenly distributed chromatin; large nucleolus (if present), no significant pleomorphism [60]

normal seminal vesicle cells tend to be atypical and do simulate carcinoma but they tend to exhibit positive staining for MUC6 (MUC6+) [61] 
Transurethral resection of prostate (TURP) specimens:

It has been stated that with regard to the finding within a TURP specimen of the prostate gland, this could either indicate an extensive spread by conventional adenocarcinoma of the prostate gland or central carcinoma of the prostate gland. [pathologyoutlines.com [46]

It has been recommended by Humphrey et al. that with the finding of prostate cancer in TURP specimens, complete sampling should be undertaken for patients who are younger than age 60 years [62] 

With regard to the finding of prostate cancer in patients who are older than 60 years of age, random sampling of 8 blocks of the TURP specimen should be undertaken by the pathologist [63] 

or 10 blocks (Humphrey book) can be undertaken; and if cancer is detected, then complete submission would be needed. [46]

It has also been recommended that if only high-grade PIN is found in the TURP specimen then the pathologist should embed all the tissue as well as obtain deeper levels. [46]

Frozen section diagnosis:

With regard to frozen section specimens related to the assessment of prostate cancer, the ensuing recommendations have been made for pathologists to undertake: [46] 

Pathologists should look for architectural disarray or perineural invasion of the tumour.

With regard to lymph node frozen section/imprints, pathologists should be aware of the fact that 10