Cryotherapy is a terminology that has been coined for the ablation of tissue through local induction of extremely cold temperatures. Cryotherapy can be utilized both for the primary treatment of localized cancer of the prostate gland and for the salvage treatment of disease refractory to radiotherapy or localized recurrent or residual tumour ensuing other minimally invasive treatments for prostate cancer. Following the finding of a localized recurrent tumour or residual tumour following cryotherapy for a localized prostate cancer, the tumour can still be treated utilizing various treatment options including (a) repeat cryotherapy, (b) salvage radiotherapy, (c) salvage irreversible electroporation of the prostate cancer, (d) salvage High Frequency Focused Ultrasound (HIFU) treatment of the prostate cancer, (e) salvage radical prostatectomy. Because generally cryotherapy is minimally invasive in comparison with radical prostatectomy, patients who have been offered radical prostatectomy as initial treatment of localized prostate cancer can also be offered an alternative treatment option of cryotherapy of the prostate cancer followed by salvage radical prostatectomy or salvage radiotherapy in the event of persistent prostate cancer or residual prostate cancer following cryotherapy of localized prostate cancer of curative intent. Relative contraindications to the undertaking of cryotherapy include previous trans-urethral resection of prostate (TURP) with a large tissue defect, as well as significant symptoms of urinary tract obstruction. A history of abdominoperineal resection for rectal cancer, rectal stenosis, or other major rectal pathology is also a relative contraindication. A pre-procedure serum prostate-specific antigen (PSA) test is pertinent or pivotal for assessing risk and establishing a baseline from which the PSA level can be tracked after treatment. Other pre-procedure laboratory studies include the undertaking of following: (a) Urine culture; (b) Complete blood cell (CBC) count with platelet count; (c) Coagulation tests for example, prothrombin time [PT] and activated partial thromboplastin time [APTT]). Utilization of a cryotherapy system does entail placement of cryoprobes under ultrasound scan-guidance bilaterally in the anteromedial, posterolateral, and posteromedial regions of the gland, to the proximal extent of the prostatic capsule. Some of the complications that tend to ensue cryotherapy of prostate cancer include: the following: (a) Impotence, (b) urinary incontinence, (c) Tissue sloughing, (d) Pelvic and rectal pain, (e) Penile numbness, (f) Rectourethral fistula, (g) Urethral stricture, (h) Hydronephrosis, (i) Small-bowel obstruction, and (j) sloughing from the urethra. It would be recommended that globally Urology and Oncology departments should develop cryotherapy units so that cryotherapy for localized prostate cancer as well as other malignancies could be available as an alternative treatment option for the management of localized adenocarcinoma of prostate gland of curative intent.

Cryotherapy is an option for the primary treatment of localized prostate cancer, along with radical prostatectomy, external beam radiation therapy (EBRT), and brachytherapy. Previous studies and meta-analyses have not found significant differences in the rates of failure between these primary treatments, although cryotherapy was associated with poorer sexual function posttreatment. [1] [2] [3] 

Early cryotherapy systems had significant genitourinary (GU) and gastrointestinal (GI) toxicities, but advances in trans-trans-rectal guidance, urethral warming, and third-generation cryotherapy and the use of focal cryotherapy have decreased treatment-associated side effects and increased rates of use. [1] [4] [5] [6] A review of the national Cryo On-Line Database Registry found a > 1000-fold increase in the use of focal cryotherapy between 1997 and 2007. [7] As the number of patients undergoing primary cryotherapy increases, so too will the number of local recurrences that require salvage treatment. A review of the national Cryo On-Line Database Registry found a > 1000-fold increase in the use of focal cryotherapy between 1997 and 2007. [7] As the number of patients undergoing primary cryotherapy increases, so too will the number of local recurrences that require salvage treatment.

Although it is known that local recurrence can occur in >20% of patients treated with primary cryotherapy, there is a paucity of data on salvage treatments after failure. 

[6] [8] [9] [10] Salvage prostatectomy after cryotherapy has been noted to be extremely difficult because of tissue reaction and fibrosis. [11] 

[12] External beam radiotherapy (EBRT) as an option for salvage treatment has been little evaluated in the literature. [6] [8] [10] 

Of those reports that have been published, the majority have focused on the use of 3-dimensional conformal radiation therapy (CRT) with 2 studies combining 3-dimensional CRT with intensity modulated radiation therapy (IMRT). Recent advances in image-guided radiation therapy utilizing IMRT (IG-IMRT) have been shown to decrease the rates of toxicities in comparison with non–IG-IMRT at the same dose level in the primary treatment of prostate cancer. [13] 

The ensuing summations had been made regarding the approach considerations related to cryotherapy and other miscellaneous facts that need to take into consideration when undertaking cryotherapy to the prostate gland lesions: [14]

Utilization of a cryotherapy system does entail placement of cryoprobes under ultrasonographic guidance bilaterally in the anteromedial, posterolateral, and posteromedial regions of the prostate gland, to the proximal extent of the prostatic capsule.

Cryotherapy does exert its antineoplastic effects through many postulated pathways, including the ensuing: [14]

• Direct cytolysis through extracellular and intracellular ice crystal formation
• Intracellular dehydration and pH changes
• Ischemic necrosis through vascular injury
• Cryoactivation of antitumor immune responses
• Induction of apoptosis

Together with cold-induced damage, additional injury does occur during warming, with osmotic cellular swelling and vascular hyperpermeability. [14] Endothelial damage does lead to platelet aggregation and micro-thrombosis. Histological changes, including necrosis, hyalinization, and inflammation, could persist for at least a year pursuant to treatment, as could residual indolent cancer. [14] Hyalinization might be more prominent in more effectively treated prostates (for example, those with no residual cancer). [15] 

Factors that affect the efficiency of tissue destruction include the following:

• Velocity of cooling
• Nadir temperature
• Duration of freezing
• Velocity of thawing
• Number of freeze-thaw cycles
• Proximity of large blood vessels, which act as heat sinks

In general, a minimum freezing temperature of –40°C (–40°F) maintained for 3 minutes is believed to be necessary for efficient tumour eradication. [16] [17] [18] 

Considering that cryotherapy as treatment of adenocarcinoma of the prostate gland is not available in some Urology and Oncology centres in some parts of the world, there is the likelihood that some clinicians would not be familiar with the treatment of prostate cancer with utilization of cryotherapy. The ensuing article on cryotherapy in the treatment of adenocarcinoma of the prostate gland is divided into two parts: (A) Overview which has discussed miscellaneous general aspects of adenocarcinoma of the prostate gland and cryotherapy and (B) Miscellaneous Narrations and Discussions from Some Case Reports, Case Series and Studies Related to Cryotherapy as a treatment option for Adenocarcinoma of the Prostate Gland. 

To review and update the literature on cryotherapy in the treatment of primary 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 of adenocarcinoma of prostate; Cryotherapy of prostate cancer; cryoablation of adenocarcinoma of prostate. One hundred and seven references were identified which were used to write the article that has been divided into two parts: (A) Overview which has discussed miscellaneous general aspects of adenocarcinoma of the prostate gland and cryotherapy and (B) Miscellaneous Narrations and Discussions from Some Case Reports, Case Series and Studies Related to Cryotherapy as a treatment option for Adenocarcinoma of the Prostate Gland. 

[A] Overview

Definition / general statements [19] 

• Adenocarcinoma is the commonest malignant tumour of the prostate gland
• Adenocarcinoma of the prostate gland affects individuals in every country in the world.
• Adenocarcinoma of the prostate gland originates from prostatic secretory epithelium

Essential features [19]

• The symptoms and clinical examination findings upon assessment of individuals who have adenocarcinoma of the prostate gland as well as other types of prostate cancer tend to be non-specific and would not specifically diagnose adenocarcinoma of prostate specifically with regard to the cell type of tumour. [19] 
• It has been pointed out that the clinical and radiological image features of adenocarcinoma of prostate gland is neither sensitive nor specific for diagnosis of adenocarcinoma of the prostate gland. [19] 
• Adenocarcinoma of the prostate gland is quite often diagnosed by the undertaking of non-targeted needle biopsies of the prostate gland when investigating raised serum prostate specific antigen (PSA) and pathology examination of the prostate biopsy specimen does demonstrate features of the adenocarcinoma of prostate gland.
• Adenocarcinoma of the prostate gland also tends to be diagnosed based upon pathology examination of targeted biopsies of the prostate gland with evidence of the tumour in targeted areas of the prostate gland. [19]
• With regard the adenocarcinoma of the prostate gland, histopathology examination of a specimen of the tumour does tend to demonstrate absence of absence of basal cell layer which is a pathognomonic histological feature of the tumour. [19]
• It has been pointed out that pathognomonic diagnostic features of adenocarcinoma of the prostate gland do include: circumferential perineural invasion, glomerulations as well as collagenous micronodules (mucinous fibroplasia) [19]
• Other histopathology examination features of primary adenocarcinoma of prostate gland include the following: infiltrative architecture of the tumour, nucleolar prominence within the tumour, amphophilic cytoplasm and some intraluminal contents (crystalloids, blue mucin, pink amorphous material) within the tumour. [19]

Terminology

• Some of the utilized terminologies for primary adenocarcinoma of the prostate gland include: [19]

Prostate cancer

• Prostate adenocarcinoma
• Sub-types of prostatic adenocarcinoma that had been described include the ensuing: acinar adenocarcinoma, ductal adenocarcinoma, atrophic adenocarcinoma, pseudo-hyperplastic adenocarcinoma, microcystic adenocarcinoma, foamy gland adenocarcinoma, mucinous adenocarcinoma, signet ring variant of adenocarcinoma, pleomorphic giant cell adenocarcinoma, sarcomatoid adenocarcinoma
• Adenocarcinoma of the prostate gland has also been referred to as prostatic cancer, cancer of the prostate gland. 

Epidemiology

• Second most common cancer and second leading cause of cancer related death in American men (SEER [20] 
• Ninety two percent (92%) of United States of America (U.S.A) cases of adenocarcinoma are diagnosed in men aged who are over 55 years of age; and in 19.5% of men who are aged more than 75 years (SEER data available at [20] 
• Primary adenocarcinoma of prostate gland is found at autopsy in 40% of men who are aged more than 60 years [21] 
• It has been iterated that incidental primary prostate cancer has been reported in about 25% of cystoprostatectomies undertaken for the treatment of urinary bladder cancer [19] [22] 
• It has been pointed out that globally, highest age standardized rates of prostate cancer had been recorded in Oceania, North America, Europe [19] [23] 
• It has also been documented that lower rates of primary adenocarcinoma of the prostate gland had been recorded in developing countries and this may be due to different screening programs and diagnostic pathways
• It has additionally been pointed out that there is a higher incidence of primary adenocarcinoma of the prostate gland in men of African heritage [19] [23] 

Sites

• It has been stated that majority of tumours are multifocal.[24] 
• It has been stated that 75% to 80% of adenocarcinoma of prostate gland are within the posterior / posterolateral peripheral zone of the prostate gland. [19] 
• It has furthermore been stated that about 13% to 20% of primary adenocarcinoma of the prostate gland are within the transition (periurethral) zone [25] [26] 
• It has also been pointed out that majority of clinically significant cancers of the prostate gland do arise within the peripheral zone of the prostate gland which has been sampled by needle biopsies of the prostate gland. [19]
• It has been iterated that transition zone prostate cancer is associated with favourable pathology examination features and better recurrence free survival [19] [27] 
• It has been iterated that adenocarcinoma of the prostate gland less frequently does involve the anterior lobe of the prostate gland most likely due to inadequate sampling using the standard biopsy approach [19] pathology outlines. [28] 

Pathophysiology

It has been pointed out that Germline variants could be associated with an increased risk for the development of prostate adenocarcinoma: [19] 

• Somatic mutations in genes such as ERG, ETV1/4, FLI1, SPOP, FOXA1, IDH1, PTEN, TP53, MYC, CDH1. [29] [30] 
• It has been documented that the most common somatic genomic rearrangement in patients who have adenocarcinoma of the prostate gland is fusion of the androgen regulated gene TMPRSS2 with a member of the ETS transcription family. [30] 

Aetiology

• It has been pointed out that obesity increases the risk for the development of adenocarcinoma of prostate gland [19] [31] 
• It has been summated that non-modifiable risk factors for the development of primary adenocarcinoma of prostate gland include the ensuing: age, race and family history [19] [32]
• Genetic susceptibility has been linked to African heritage [32]
• There is an increased risk for the development of primary adenocarcinoma of the prostate gland with a first degree relative having prostate cancer. [32]
• BRCA2 mutations do increase the risk for the development of prostate cancer by 5-fold; and BRCA2 associated cancers do occur at a lower age and they have worse survival outcomes. [19] [30] [33]
• It has been documented that additional germline variants associated with increased cancer risk do occur in HOXB13. [30] 
• Increased risk of adenocarcinoma of prostate gland does occur in Lynch syndrome. [34]
• It has been pointed out that numerous single nucleotide polymorphisms (SNPs) that have a low to moderate effect on risk / progression had been identified [19] [35] 
• It has been documented that high levels of IGF1 may confer increased risk for the development of adenocarcinoma of the prostate gland [19] [36]
• Clinical features
• It has been stated that primary adenocarcinomas of the prostate gland generally do tend to be asymptomatic unless they are locally advanced or metastatic [19] outlines
• It has also been iterated that quite often primary adenocarcinoma of the prostate gland is diagnosed following investigation of non-specific lower urinary tract symptoms. [19]
• It has been pointed out that in cases of primary adenocarcinoma of prostate gland, digital rectal examinations (DREs) do demonstrate the ensuing findings: the prostate gland may feel normal or may be enlarged / asymmetrical / hard / have a palpable nodule present. [19]

Diagnosis

The ensuing summations have been made regarding some aspects of the diagnosis of primary adenocarcinoma of the prostate gland: [19] 

• Primary adenocarcinoma of the prostate gland generally has tended to be diagnosed by the undertaking of systematic trans-rectal ultrasound scan-guided prostate biopsies
• Trans-perineal needle biopsies of the prostate gland are increasingly utilized due to the fact that it tends to be associated with lower risk of infection
• It has been clearly pointed out that pre-biopsy MRI scan of the prostate that ensued by systematic biopsies of the prostate gland supplemented with targeted biopsies from any radiological abnormality within the prostate gland leads to better identification of clinically significant prostate cancer in comparison with systematic prostate biopsy alone. [37] 
• It has been highlighted that incidental prostate cancer sometimes has been diagnosed in transurethral resection of prostate glands undertaken for lower urinary tract symptoms that had been undertaken to improve voiding that had been presumed to be related to benign prostate hypertrophy but the pathology examination features of the resected specimen demonstrate features of primary adenocarcinoma of the prostate gland. [19] 
• Immunohistochemistry staining studies of specimens of the prostate with utilization of basal cell markers (HMWCK, p63) and AMACR do establish the diagnosis of pure adenocarcinoma of the prostate gland in equivocal cases [19]

It is worth pointing out that other types of immunohistochemistry staining study tumour markers are used to ascertain features of other cell type variants of prostate cancer. 

Genomic / molecular genetics studies are now being undertaken in well-equipped and well-resourced centres in the world to provide further information related to adenocarcinoma of prostate gland that would help the multi-disciplinary team to recommend other types of treatment for primary adenocarcinoma of prostate gland especially in cases of a strong family history of prostate cancer as well as a family history of other cancers.

Some prostate cancers are not adenocarcinomas and they would tend not to be associated with raised serum PSA levels due to the fact that they are of stromal origin and in these cases despite the finding of abnormal digital examination findings of the prostate gland, the serum PSA level would be low or normal and an example of such a tumour is prostate stromal sarcoma and this tumour could be associated with raised serum PSA levels when these tumours are associated with a contemporaneously synchronous pure primary adenocarcinoma of the prostate gland within another area of the prostate gland.

Laboratory

The ensuing summations had been made related to various laboratory test findings and recommendations that had been made regarding adenocarcinoma of the prostate gland:

• Raised serum PSA levels generally tend to be associated most cases of adenocarcinoma of the prostate gland. 
• Different serum PSA level cutoffs are being utilized to prompt prostate needle biopsy
• It has been pointed out that age specific serum PSA level cutoffs, serum PSA velocity (rate of change in PSA over time) and serum PSA density (PSA per unit prostate volume - ng/mL/cc) may increase the sensitivity and specificity of serum PSA testing. [38] 
• The United States of America (U.S). Preventative Services Task Force (USPSTF) had recommended against serum PSA based screening for prostate cancer in men who are 70 years and older than 70 years. 
• With regard to men who are aged between 55 years and 69 years, periodic PSA based screening should be an individual choice
• It has been pointed out that screening in this age group does offer a small potential benefit of reducing the chance of death from prostate cancer in some men; nevertheless, many men will experience potential harm [39] 
• The American Urological Association (AUA) does not recommend serum PSA screening in men who are under age 40 years or in men who are aged between 40years and 54 years who are at average risk for the development of adenocarcinoma of prostate gland. 
• For men who are aged between 55 years and 59 years, shared decision making is desirable
• For men who are aged 70 years and over or men with < 10>
• It has been iterated that potential urine biomarker for prostate cancer is PCA3. [30] 

Radiology description

The ensuing summations had been made related to some aspects of radiology imaging in adenocarcinoma of prostate cases: [19] 

• Ultrasound scan (USS) is generally used to guide prostate biopsies and upon ultrasound scan prostate cancer may appear hypoechoic but USS is neither sensitive nor specific for establishing a diagnosis of adenocarcinoma of the prostate gland. 
• Multiparametric Magnetic Resonance Imaging (MRI) scan is commonly used for local tumour staging and MRI scan may also be utilized to identify abnormalities within the prostate gland for targeting at biopsy
• MRI scan abnormalities generally tend to be reported using either PI-RADS (Prostate Imaging - Reporting and Data System) or Likert score. PI-RADS 4 and PI-RADS 5 prostate lesions are biopsied due to the fact that the lesions are regarded to have high risk of adenocarcinoma of the prostate gland and PI-RADS 1 and 2 lesions are regarded to be benign and PI-RADS 3 lesions are observed.
• CT scan is undertaken to identify metastatic disease in lymph nodes
• Isotope Bone scan is used to detect bony metastases
• PET scan is used to identify micro-metastatic disease in selected patients, such as men with raised serum PSA levels after treatment.

Computed Tomography scan of the thorax, abdomen and pelvis (CT TAP) is used for the full staging and follow-up assessment of patients who have undergone treatment of curative intent for adenocarcinoma of the prostate gland. 

Positron Emission Tomography / Computed Tomography (PET/CT) scan is more can detect areas of small metastatic lesions that are not big enough to be identified by CT scan and MRI follow-up scans 

In areas where facilities are not easily available for the undertaking of CT-Scan and MRI Scan, or the patient cannot afford to pay for the cost of CT scan and MRI scan, chest radiograph and ultrasound scan of abdomen and pelvis including the prostate tend to be undertaken in the initial staging and follow-up of patients who have primary adenocarcinoma of the prostate gland.

Laboratory tests 

Urine

Urinalysis, urine microscopy and culture are general tests that tend to be undertaken in patients who manifest with lower urinary tract symptoms which the common symptoms of patients who have primary adenocarcinoma of the prostate gland and generally the results would tend to be normal and if there is any evidence of urinary tract infection, it would be treated appropriately based upon the antibiotic sensitivity pattern of the organism to ensure the patient is well to undergo the appropriate management of the prostate cancer based upon the tumour stage.

Haematology Blood Tests 

Full blood count and INR, are routine tests that tend to be undertaken in cases of primary adenocarcinoma of the prostate and in majority of cases, the results would be within normal range but if there is any evidence of anaemia, it would be investigated and treated accordingly to improve upon the general condition of the patient to enable the patient to go through the appropriate effective treatment. 

Biochemistry Blood Tests 

CRP, Urea and electrolytes, Liver function tests, Bone Profile, and Random blood glucose are routine tests that tend to be undertaken in cases of primary adenocarcinoma of the prostate and in majority of cases, the results would be within normal range but if there is any evidence of an abnormality, it would be investigated and treated accordingly to improve upon the general condition of the patient to enable the patient to go through the appropriate effective treatment. 

Prognostic factors

The prognostic factors associated with primary adenocarcinoma of the prostate gland have been summated to include the following:

• Biopsy Specimen: The prognostic features based upon the pathology examination of the prostate biopsy of the tumour include: The extent of the tumour extent (mm or percentage core involvement), the grade of the tumour (Gleason score and grade group), presence or absence of peri-neural invasion, presence or absence of extra-prostatic extension of the tumour.
• Radical prostatectomy specimen: the tumour size, Gleason score and grade group of the tumour, stage of the tumour, the margin status of the tumour
• Cribriform morphology and intraductal carcinoma associated with invasive prostate cancer are stated to be adverse prognostic indicators for adenocarcinoma of prostate gland. [41] 
• Small cell carcinoma component is stated to be associated with aggressive behaviour and this is treated differently. [19] 
• Some expert groups had recommended incorporating intraductal component of the adenocarcinoma of the prostate gland into the Gleason score while others had recommended reporting it separately in a comment. [42] [43] [44] 

Treatment

The ensuing summations had been made regarding the treatment options of primary adenocarcinoma of the prostate gland: [19]

• Preoperative risk stratification of primary adenocarcinoma of the prostate gland is based upon serum PSA level of the patient, the clinical stage of the tumour, biopsy pathology examination parameters of the tumour (the extent of the tumour, the grade of the tumour, cribriform morphology features within the tumour, intraductal carcinoma, presence or absence of perineural invasion)
• Primary treatment options of primary adenocarcinoma of prostate gland are based upon preoperative risk stratification and this has been divided into the ensuing options:
• Active surveillance
• Focal therapy (cryotherapy, high intensity ultrasound)
• Radical prostatectomy
• Brachytherapy
• External beam radiotherapy
• Hormone therapy (e.g., luteinizing hormone releasing hormone [LHRH] analogues, antiandrogens)
• Orchidectomy (rare in contemporary practice)
• Chemotherapy (for metastatic disease)
• Postprostatectomy options: Pursuant to the undertaking of radical prostatectomy whether by open prostatectomy, laparoscopic prostatectomy, or robotic radical prostatectomy, the following tend to be undertaken: 
• Generally, serum PSA monitoring and early salvage therapy if there is rising serum PSA
• Less commonly adjuvant therapy for high stage disease or margin positivity
• Other treatment options that are undertaken by other clinicians and oncologists include: 
• Neoadjuvant or adjuvant Hormonal treatment in association with the undertaking of radical prostatectomy of curative intent for localized adenocarcinoma of the prostate gland. 
• Adjuvant or Neoadjuvant radiotherapy or chemotherapy or chemoradiation 
• Immunotherapy

Other treatment options that tend to be utilized pursuant to the development of localized recurrence of a localized tumour following treatment of curative intent by radiotherapy could entail: salvage prostatectomy, plus or minus chemotherapy and immunotherapy, plus or minus hormonal treatment. 

Treatment of metastatic prostate cancer may entail the undertaking of hormonal treatment, radiotherapy, chemotherapy, plus or minus immunotherapy. 

Treatment of localized back bone pain due to a localized bone metastasis may entail local radiotherapy to the bone metastasis and in cases of back bone metastasis associated with compression of associated nerves and weakness and paralysis of lower limbs, the neuro-surgeons could undertake surgical operation for decompression of the nerves plus use of steroids. Pathological fractures related to bone metastasis may require internal fixation by metallic equipment.

Other treatment options that have been occasionally used to treat few primary adenocarcinomas of the prostate gland as treatment of curative intent or to reduce the size of the tumour to enable further treatment options include the ensuing: 

1. Cryotherapy of the adenocarcinoma of prostate
2. Radiofrequency ablation of the prostate cancer
3. Irreversible electroporation of the prostate cancer.
4. Selective angiography and super-selective embolization of the branch of the artery supplying the prostate tumour to reduce the size of the tumour or to stop bleeding from the tumour in an emergency scenario when there is a well-trained vascular interventional radiologist. 
5. High frequency focused ultrasound (HIFU) therapy of the prostate cancer.
6. In the unlikely event of excessive bleeding from adenocarcinoma of the prostate gland, the bleeding could potentially be treated by means of selective angiography and super-selective embolization of the branch of prostatic artery to the bleeding tumour in an effort to stop the bleeding. 

Gross description

Macroscopy examination of adenocarcinoma of prostate specimen has been summated as follows:

• Upon gross examination often the tumour has tended to be grossly inapparent or not visually identifiable 
• The tumour may form a visible cream mass within the prostate gland 

Microscopic (histopathology examination) description

The microscopy histopathology examination features of primary adenocarcinoma of the prostate gland had been summated as follows: [19] 

• The Gleason grading is based upon the architecture of the tumour found during microscopy examination of the tumour. 
• Gleason grades represent a morphological spectrum from well-formed glands (pattern 3) to increasingly complicated glandular proliferations (pattern 4) to almost no glandular differentiation (pattern 5). [45] 
• Glandular crowding and infiltrative growth pattern of the tumour.
• Nuclear enlargement, nucleolar prominence within the tumour
• Round generally monomorphic nuclei within the tumour
• Amphophilic cytoplasm within the tumour
• Mitoses evidence in the tumour
• Apoptotic bodies present within the tumour
• Stromal desmoplasia within the tumour
• Intraluminal contents: the intraluminal contents of the tumour include: crystalloids, pink amorphous secretions, blue mucin. 
• Glomerulations, collagenous micronodules (mucinous fibroplasia) tend to be seen in the tumour.
• Absence of basal cell layer tends to be seen in the tumour and generally this requires immunohistochemical confirmation. [19] [46]

Cytology description

The role of cytology examination in adenocarcinoma of the prostate gland has been summarized as follows: 

• It has been pointed out that the undertaking of urine cytology for the detection of prostate cancer has a very low sensitivity. [47] 
• Urine cytology is not used clinically with regard to the diagnosis of prostate cancer
• Fine Needle Aspiration (FNA) cytology examination of metastatic prostate cancer to a lymph node may show micro-acinar complexes / cell clusters / single cells with fragile cytoplasm and prominent nucleoli. [48] 
• Immunohistochemistry Staining of Adenocarcinoma of Prostate Gland

Positive staining

Adenocarcinoma of the prostate gland is stated to exhibit positive immunohistochemistry staining features to the ensuing tumour markers: [19]

• PSA
• NKX3.1.
• AMACR (P504S, racemase)
• Prostein (P501S)
• PSMA
• Rare adenocarcinoma of prostate tumours may have exhibit aberrant expression of p63. [49] [50] 

Negative staining

Adenocarcinoma of the prostate gland has been stated to exhibit negative immunohistochemistry staining for the following tumour markers: [19]

• CK 7
• CK 20
• High molecular weight cytokeratins including 34 beta E12, CK 5, CK5/6
• p63
• CDX2
• GATA3
• TTF1 [51] 

Molecular / cytogenetics description 

Summations related to the molecular / cytogenetics features of adenocarcinoma of the prostate gland include the following: [19] 

• Prostate cancer is a heritable disease
• Family history of a first degree relative with prostate cancer does increase the risk for the development of prostate cancer by 2-fold. [52] 
• It has been pointed out that 30% to 40% of familial risk is due to genetic factors. [30] 
• Genetic factors associated with the development of adenocarcinoma of the prostate gland include highly penetrable rare variants and more common low to moderate risk variants. [30] 
• It has been iterated that highly penetrant variants occur in BRCA2 and HOXB13
• It has been documented that more than 280 SNPs had been identified as prostate cancer risk factors. [30] 
• It has been stated that for majority of SNPs, the molecular mechanism of cancer association is generally unknown, as they occur in noncoding regions of the genome [30] 
• It has been documented that somatic mutations occur in genes such as ERG, ETV1/4, FLI1, SPOP, FOXA1, IDH1, PTEN, TP53, MYC, CDH1. [30] [53]                                                   
• It has been pointed out that most common somatic genomic rearrangement is fusion of the androgen regulated gene TMPRSS2 with a member of the ETS transcription family. [30] 
• It has been iterated that somatic mutation profiles of prostate cancer are associated with clinical and pathological outcomes
• There are 7 major subtypes, which are defined by either specific gene fusions of ETS transcription family members (ERG, ETV1, ETV4 and FLI1) or mutations (SPOP, FOXA1, IDH1). [54] 
• It has been pointed out that different subtypes have different molecular profiles, for example.: [54] 
• ETS subset (59% of cases) are enriched in PTEN mutations
• SPOP mutant subset (11%) of cases have distinct somatic copy number alteration profiles, including deletions of CHD1, 6q and 2q

Differential diagnoses of adenocarcinoma of prostate gland

Some of the differential diagnoses of primary adenocarcinoma of the prostate gland have been summarized to include the following: [19] 

• Benign prostate tissue which upon microscopy examination demonstrates the following features:
• Pale cytoplasm
• Corpora amylacea
• No other intraluminal contents
• Basal cell marker immunoreactivity
• Prostate atrophy which upon microscopy examination demonstrates the following features:
• Lobular architecture
• Scant cytoplasm
• Basal cell marker immunoreactivity
• Adenosis of Prostate which upon microscopy examination demonstrates the following features:
• Lobular architecture
• Basal cell marker immunoreactivity (often scattered)
• Atypical small acinar proliferation (ASAP) which upon microscopy examination demonstrates the following features:
• Small size
• Lack of significant cytological atypia, including a lack of macronucleoli
• High-grade prostatic intraepithelial neoplasia (HGPIN) which upon microscopy examination demonstrates the following features:
• Less architectural atypia
• Maintained basal cells
• Post-atrophic hyperplasia which upon microscopy examination demonstrates the following features:
• Some glands atrophic
• Basal cell marker immunoreactivity (often scattered)
• Partial atrophy which upon microscopy examination demonstrates the following features:
• Atrophic glands with abundant lateral pale cytoplasm
• Irregularly distributed nuclei
• Basal cell marker immunoreactivity (often scattered)
• Radiation Atypia which upon microscopy examination demonstrates the following features:
• Glandular atrophy
• Nuclear irregularity and pleomorphism
• Atypical stromal cells
• Basal cell marker immunoreactivity
• Urothelial carcinoma which upon microscopy examination demonstrates the following features:
• Nuclear irregularity and pleomorphism
• Hyaline dense eosinophilic cytoplasm
• Desmoplastic stromal reaction
• Immunoreactivity for urothelial markers (GATA3, CK7, p63)
• No expression of prostatic immunomarkers (PSA, PSAP, NKX3.1)

Cryotherapy [55] 

The ensuing iterations had been made regarding an overview of cryotherapy: [55]

• Cryotherapy, which is sometimes referred to as cold therapy, is the local or general utilization of low temperatures in medical therapy. 
• Cryotherapy may be utilized to treat a variety of tissue lesions. [56] 
• The most prominent utilization of the term refers to the surgical treatment, which is specifically known as cryotherapy or cryoablation. Cryosurgery is a terminology which is used for the application of extremely low temperatures to destroy abnormal or diseased tissue and is used most commonly to treat skin conditions.
• Cryotherapy is utilized in an effort to relieve muscle pain, sprains and swelling after soft tissue damage or surgery. For many decades, cryotherapy has been commonly used to accelerate recovery in athletes following their exercise. Cryotherapy decreases the temperature of tissue surface to minimize hypoxic cell death, oedema accumulation, and muscle spasms, all of which ultimately alleviate discomfort and inflammation of individuals. [57]
• Cryotherapy could be a range of treatments from the application of ice packs or immersion in ice baths which is generally known as cold therapy, to the use of cold chambers.
• While cryotherapy is widely utilized, there is little evidence as to its efficacy that has been replicated by or demonstrated in large controlled studies. 
• The long-term side effects of cryotherapy had also not been studied. [58] [59]
• Nevertheless, cryotherapy is stated to be important in that individuals should note that a number of studies had shown a possible association between cryotherapy and adverse effects. The adverse events associated with cryotherapy had been documented to include the risk of frostbite, superficial nerve palsies, Raynaud’s phenomenon, cold urticaria and delayed regeneration. [55] 
• The potential harm of cryotherapy had raised doubts regarding its utilization and effectiveness which had led to guidance against the use of cryotherapy. [60] Nevertheless, a study which had been undertaken had concluded that cryotherapy had had reported a positive impact upon the short-term recovery of athletes. Cryotherapy helped to manage muscle soreness and facilitate recovery within the first 24 hours following a sport-related activity. It was stated that athletes who utilize cryotherapy within the first 24 hours to alleviate pain had recovered at a faster rate than athletes who did not use cryotherapy after their sport-related activity. [57]
• Even though there are many positive effects of cryotherapy in athletes' short-term recovery, in recent years, there had been much controversy regarding whether cryotherapy is actually beneficial or might be causing the opposite effect. 
• While inflammation which occurs post-injury or from a damaging exercise might be detrimental to secondary tissue, it is beneficial for the structural and functional repair of the damaged tissue. In view of this, some researchers are now recommending that ice should not be used so as not to delay the natural healing process following an injury. 
• The original RICE (rest, ice, compression, elevation) method was rescinded due to fact that the inflammatory response is necessary for the healing process, and this practice might delay healing instead of facilitating it. 
• Animal studies had also shown that a disrupted inflammatory stage of healing may lead to impaired tissue repair and redundant collagen synthesis. [61] 
• Furthermore, if undertaken regularly post-exercise, cryotherapy could have a negative effect upon muscle mass, strength gains, and rate of muscle protein synthesis. This is due to the fact that cryotherapy does blunt the chronic skeletal muscle adaptations from resistance training exercises. It has been stated that these harmful effects could be easily avoided by not using cryotherapy during an athlete's training season or pre-season phase. [61]

[B] Miscellaneous Narrations and Discussions from Some Case Reports, Case Series, And Studies Related to Cryotherapy for The Management of Primary Adenocarcinoma of The Prostate Gland.

Izawa et al. [62] undertook a study to determine the long-term disease-specific survival (DSS) and disease-free survival (DFS) rates after salvage cryotherapy for locally recurrent adenocarcinoma of the prostate and to identify pre-treatment factors that have an impact upon DSS and DFS. Izawa et al. [62] stated that between July 1992 and January 1995, 131 patients who had received definitive radiotherapy treatment (XRT) had undergone salvage cryotherapy for locally recurrent adenocarcinoma of the prostate gland. Izawa et al. [62] stated that they had defined cryotherapy failure as an increasing post-cryotherapy serum prostate-specific antigen (PSA) level of > 2 ng/mL above the post-cryotherapy nadir, a positive prostate biopsy, or radiography image evidence of metastatic disease. Izawa et al. [62] studied clinical variables to determine whether there was an association with the DSS and DFS. Izawa et al. [62] summarized the results as follows:

• The median follow-up was 4.8 years. 
• The 5-year DSS rates were 87% for patients who had a pre-cryotherapy Gleason score < 8>
• The 5-year DFS rates were 57% for patients with a pre-cryotherapy serum PSA level of < 10>
• The 5-year DSS rates for patients with a pre-XRT clinical stage of T1 to T2 and those with a clinical stage of T3 to T4 were 94% and 72%, respectively (P.0041). The 5-year DFS rates for these groups were 90% and 69%, respectively (P.0057). 

Izawa et al. [62] made the following conclusions:

• Androgen-independent local recurrences, Gleason score, and pre-XRT clinical stage were important factors that had an impact upon DSS and DFS. 
• The subset of patients cured by salvage cryotherapy seems to be small, and patient selection is important. 

Pisters et al. [63] undertook a phase I/II study to evaluate the efficacy and complications of salvage cryotherapy as a treatment option for locally recurrent prostate cancer following full dose radiotherapy and/or systemic therapy. Pisters et al. [63] compared the efficacy of single and double freeze-thaw cycles using posttreatment prostate specific antigen (PSA) levels and prostate biopsies as end points. Pisters et al. [63] reported that a total of 150 patients with locally recurrent prostate cancer following radiotherapy, hormonal therapy and/or systemic chemotherapy underwent salvage cryotherapy using a single free thaw cycle which included 71 men, with a mean follow-up of 17.3 months or double-free thaw cycle which comprised of 79 men, who had a mean follow-up of 10.0 months. Pisters et al. [63] measured serum PSA approximately every 3 months postoperatively and they repeated sextant biopsies 6 months postoperatively. Pisters et al. [63] assessed the complications by retrospective chart review and a mailed quality of life survey. Pisters et al. [63] summarized the results as follows:

• Overall, 45 patients that amounted to 31% of the patients had persistently undetectable serum PSA. 
• Patients who had a history of radiation therapy only who underwent a double freeze-thaw cycle had a higher negative biopsy rate which was 93% versus 71%, p <0>
• The main complications of salvage cryotherapy were urinary incontinence which occurred in 3% of the patients, obstructive symptoms which occurred in 67%, impotence which occurred in 72% of the patients and severe perineal pain which occurred in 8% of the patients.

Pisters et al. [63] made the ensuing conclusions:

• Salvage cryotherapy does impact local tumour control as evident by the high frequency of negative posttreatment biopsies. 
• A double freeze-thaw cycle does appear more effective than a single cycle. 
• Like salvage prostatectomy, salvage cryotherapy does cause significant morbidity.

Rodriguez et al. [64] stated that published data about cryotherapy for prostate cancer (PC) treatment had been based upon case series with a lack of clinical trials and the inexistence of a validated definition of biochemical failure. Rodriguez et al. [64] undertook a prospective study with standardized follow-up protocol in their institution. Rodriguez et al. [64] undertook a prospective study of a series of cases including 108 patients who were diagnosed with localized PC at clinical stage T1c-T2c which had been treated by primary cryoablation and who had a median follow-up of 61 months. Rodriguez et al. [64] unified the criteria of biochemical recurrence according to the American Society for Therapeutic Radiology and Oncology (ASTRO). End points were biochemical progression-free survival (BPFS), cancer-specific survival, and overall survival. The rate of complications was reported. Rodriguez et al. [64] summarized the results as follows: 

• The BPFS for low-, medium-, and high-risk patients was 96.4%, 91.2%, and 62.2%, respectively. Cancer-specific survival was 98.1%. 
• The overall survival had reached 94.4%. 
• The complications included incontinence in 5.6%, urinary tract obstruction in 1.9%, urethral sloughing in 5.6%, haematuria in 1.9%, perineal pain in 11.1%, and prostate-rectal fistula in 0.9%. 
• Erectile disfunction was found in 98.1% of the patients. 
• Rodriguez et al. [64] concluded that cryotherapy is an effective and minimally invasive treatment for primary PC in well-selected cases, with low surgical risk and good results in terms of BPFS, cancer-specific survival, and overall survival.

Chad and Katz edited by Gill [5] stated the following: 

• Minimally invasive options to treat low-risk prostate cancer are more desirable than radical therapy. 
• Technological improvements in cryotherapy had increased its use, and long-term data on its efficacy are emerging. 

Chad and Katz, Gill editor. [5] discussed contemporary data on cryotherapy with specific focus on studies using the newest technology. Chad and Katz, Gill editor, [5] made the ensuing iterations. 

• With respect to biochemical recurrence rates, cryotherapy had appeared to be as effective treatment for low-risk prostate cancer as other treatment modalities.
• The definition of recurrence had remained problematic, even though contemporary studies had been more consistently using both the American Society for Therapeutic Radiation Oncology and Phoenix criteria. 
• Erectile dysfunction rates are universally high after whole-gland cryoablation, but incontinence and urethrorectal fistula rates had appeared to be low with third-generation cryo systems. 
• Focal cryotherapy had encouraging short-term efficacy in terms of biochemical disease-free survival rate for unifocal disease, and rates of erectile dysfunction were dramatically lower than those seen with whole-gland cryoablation.

Chad and Katz, edited by Gill et al. [5] made the ensuing summations:

• Cryosurgery has a promising role to play in primary and salvage treatment of select prostate cancer patients. 
• Focal cryotherapy for unilateral disease does offer the added benefit of minimal adverse effects. 
• Long-term data were emerging to support cryosurgery, and large multi-centre databases had been developed to answer questions regarding optimal treatment outcomes and patterns.

[65] Alexandre de la Taille, Omar Hayek, Mitchell C Benson, Emilia Bagiella, Carl A Olsson, Marie Fatal, Aaron E Katz,

De la Taille et al. [65] stated that cryotherapy of the prostate represents a potential treatment option for localized recurrent prostate cancer after radiotherapy. De la Taille et al. [65] reported their experience and evaluated the predictive factors for prostate-specific antigen (PSA) recurrence. De la Taille et al. [65] reported that between October 1994 and April 1999, 43 patients had undergone salvage cryoablation. They also stated that all of the patients had biopsy-proven recurrent prostate cancer without seminal vesicle invasion, negative bone scans, and negative lymph node dissection. The patients had received 3 months of combined hormonal therapy preceding their cryosurgery. Biochemical recurrence-free survival (bRFS) was defined by de la Taille et al. [65] as a serum PSA value less than 0.1 ng/mL. The results of the study were summarized by de la Taille et al. [65] as follows:

• The complications had included incontinence which occurred in 9% of the patients, obstruction which had occurred in 5% of the patients, urethral stricture which had occurred in 5% of the patients, rectal pain which had occurred in 26% of the patients, urinary infection which had occurred in 9% of the patients, scrotal oedema which had occurred in 12% of the patients, and haematuria which had occurred in 5% of the patients. 
• The mean follow-up was 21.9 months and this had ranged between 1.2 months to 54 months. 
• Twenty-six patients that amounted to 60% of the patients had reached a serum PSA nadir of less than 0.1 ng/mL, 16 patients which amounted to (37% of the patients had a serum PSA of less than 4 ng/mL, and 1 patient that amounted to 3% of the patients had a serum PSA of less than 10 ng/mL. 
• The bRFS rate was 79% at 6 months and 66% at 12 months. The bRFS rate was higher for patients who had an undetectable post-cryotherapy serum PSA than for patients who did not reach a serum PSA of less than 0.1 ng/mL which amounted to 73% versus 30%, P = 0.0076. 
• Utilizing multivariate analysis, a serum PSA nadir greater than 0.1 ng/mL was an independent predictor of PSA recurrence. 

De la Taille et al. [65] made the following conclusions:

• Current salvage cryotherapy of the prostate could result in undetectable serum PSA levels with low morbidity. 
• Their data had supported the current safety and efficacy profile. 
• They believed that cryotherapy is a viable option in the treatment of patients who have biopsy-proven local failure after radiation therapy for prostate cancer.
• Further refinements in technique and equipment might enhance cryosurgical results.

Ghafar et al. [65] stated that cryosurgical ablation of the prostate had been reported to be a potential treatment for radioresistant clinically localized prostate cancer. Ghafar et al. [65] reported their experience with the safety and efficacy of salvage cryosurgery using the argon based CRYOCare system (Endocare, Inc, Irvine, California. Ghafar et al [65] stated that between October 1997 and September 2000, 38 men who had a mean age of 71.9 years had undergone salvage cryosurgery for recurrent prostate cancer after the radiotherapy they had undergone failed. All of the patients had biochemical disease recurrence, which they had defined as an increase in prostate specific antigen (PSA) level of greater than 0.3 ng. /ml. above the post-radiation serum PSA nadir. Subsequently prostate biopsy was noted to be positive for cancer. Pre-cryosurgery bone scan had demonstrated no evidence of metastatic disease. In addition, these patients received 3 months of neoadjuvant androgen deprivation therapy before cryotherapy. Ghafar et al. [65] summarized the results as follows:

• The serum PSA nadir was 0.1 or less, 1 or less and greater than 1 ng./ml. in 31 patients that amounted to 81.5%, 5 patients which amounted to 13.2% and 2 patients which amounted to 5.3% of the patients, respectively. 
• Biochemical recurrence-free survival calculated from Kaplan-Meier curves was 86% at 1 year and 74% at 2 years. 
• The reported complications included rectal pain in 39.5% of cases, urinary tract infection in 2.6%, incontinence in 7.9%, haematuria in 7.9% and scrotal oedema in 10.5%. 
• The rate of rectourethral fistula, urethral sloughing and urinary retention was 0%.

Ghafar et al. [65] made the following conclusions:

• Their study outcome had supported cryosurgery of the prostate as safe and effective treatment in patients in whom radiation therapy fails.
• Utilizing the CRYOCare machine had resulted in a marked decrease in complications.

Pisters et al. [66] undertook a study to identify clinical pretreatment factors associated with early treatment failure after salvage cryotherapy. Pisters et al. [66] reported that between 1992 and 1995, 145 patients had undergone salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Pisters et al. [66] defined treatment failure as an increasing post-cryotherapy serial prostate-specific antigen (PSA) level of more than or equal to 2 ng/mL above the post-cryotherapy nadir or as a positive posttreatment biopsy. Pisters et al. [66] evaluated the following factors as predictors of treatment failure: tumour stage and grade at initial diagnosis, type of prior therapy, stage and grade of locally recurrent tumour, number of positive biopsy cores at recurrence, and pre-cryotherapy PSA level. Pisters et al. [66] summarized the results as follows:

• Among patients who had a prior history of radiotherapy therapy only, the 2-year actuarial disease-free survival (DFS) rates were 74% for patients who had a pre-cryotherapy serum PSA of less than 10 ng/mL and 28% for patients who had a pre-cryotherapy serum PSA of more than 10 ng/mL, P < .00001. 
• The DFS rates were 58% for patients who had a Gleason score of less than or equal to 8 recurrence and 29% for patients who had a Gleason score greater than or equal to 9 recurrence, P < .004. 
• Among patients who had a pre-cryotherapy serum PSA of less than 10 ng/mL, the DFS rates were 74% for patients who had a prior history of radiotherapy only and 19% for patients with a history of prior hormonal therapy plus radiation therapy, P < .002.

Pisters et al. [66] made the following conclusions:

• Patients failing initial radiotherapy with a serum PSA level of more than 10 ng/mL and Gleason score of the recurrent cancer more than or equal to 9 were unlikely to be successfully salvaged. 
• Patients who had failing initial hormonal therapy and radiotherapy were less likely to be successfully salvaged than patients failing radiation therapy only.

Loening et al. [67] reported cryosurgical destruction of primary adenocarcinoma of the prostate gland which was undertaken through the perineal route in 215 patients during a 12-year period. The average age of the patients was 66 years. The stage of the disease had varied from B to D. With regard to 74% of the patients, Loening et al. [67] did not find any clinical evidence of tumour within the prostatic fossa pursuant to the cryotherapy. Few of the patients needed to undergo trans-urethral surgery and none of the patients needed repeated trans-urethral resections of prostate for obstructive symptoms. Loening et al. [67] stated that this experience had suggested that local destruction of carcinoma of the prostate gland can be achived with little morbidity as well as mortality.

Grampass et al. [68] undertook a study to evaluate the potential for salvage radical prostatectomy after failure of transrectal ultrasound (TRUS)-guided percutaneous cryosurgical ablation of the prostate. An additional purpose of the study was to determine the accuracy of intraoperative TRUS to delineate the extent of freeze destruction that results from cryosurgery. Grampass et al. [68] reported that six patients with biopsy-confirmed, Stage T3 prostate cancer had undergone salvage radical prostatectomy 3 months to 10 months after failing prostate cryosurgery. Zones of freeze destruction (resolving coagulative necrosis) and residual adenocarcinoma were mapped on the coverslips of whole-mount sections. Grampass et al. [68] compared histologically proven zones of freeze destruction correlating to successfully treated prostatic tissue to the hypoechoic ice ball treatment zones seen on intraoperative TRUS images. Grampass et al. [68] summarized the results as follows: 

• The whole mounts were found to contain necrotic areas of cryo-destruction which appeared much smaller than predicted by intraoperative ultrasound. 
• Each of the cases were also found to have contained residual viable adenocarcinoma.
• All of the patients were alive and clinically free of localized disease 0.5 months to 12 months after salvage radical prostatectomy.

Grampass et al. [68] made the following conclusions:

• Salvage radical prostatectomy does offer an effective treatment option in patients who have failed trans-perineal cryosurgery of the prostate. 
• Intraoperative TRUS had predicted that the entire prostate would show freeze destruction. 
• Whole-mount analysis; nevertheless, had revealed areas of remaining unaffected adenocarcinoma and normal prostatic parenchyma. 
• TRUS, therefore, had overestimated the area of prostatic tissue destroyed by extreme cold. This finding had challenged the assumption that the entire prostate is lethally frozen when its boundaries are included within the hypoechoic ice ball witnessed on TRUS.

Mouraviev and Polascik [69] stated that with the recent introduction of novel, minimally invasive procedures for the treatment of prostate cancer, cryotherapy had become a feasible option as a viable alternative treatment option to traditional radical surgery and radiotherapy. In this review we update recent data concerning the basic science of cryobiology, technical trends, oncologic results and complications of this procedure. Mouraviev and Polascik [69] stated that as a result of better understanding of tumour cryo-destruction at a molecular level, refinements in cryo-techniques and improved patient selection, the results of cryotherapy were becoming more promising. In addition, the dramatic decrease in the number of complications following modern cryotherapy had led to a better quality of life, which might be a preferable option, especially for elderly patients with comorbidities. Current trends towards nerve-sparing and focal cryoablation are also discussed. Recent advances in cryobiology had opened up new opportunities to apply cryotherapy in combination with chemotherapy or radiotherapy for patients with intermediate or high-risk cancers. Mouraviev and Polascik [69] stated that potential directions for future developments in cryosurgery do include concepts to reduce side effects such as minimizing cryodamage of the neurovascular bundles (nerve-sparing procedure), and focal ablation of a specific tumour site in patients in whom saturation biopsy supports unifocal prostate cancer.

Wake et al. [70] stated that cryosurgical ablation of the prostate had recently become recognized as a therapeutic option in the treatment of localized adenocarcinoma of the prostate. To assess the efficacy of cryoablation in this disease process several centres had instituted treatment protocols. Wake et al. [70] reported that their overall series had included 117 ultrasound-scan guided percutaneous trans-perineal cryoablations performed on 104 patients who had localized adenocarcinoma of the prostate. The follow-up of the patients had consisted of digital rectal examinations and measurement of serum prostate specific antigen levels at 3-month intervals following the cryosurgery. In addition, prostate biopsies were obtained 3 months to 6 months postoperatively.

Wake et al. [70] summarized the results as follows: 

• Out of 63 patients who had undergone initial cryosurgery and follow-up biopsy 47 patients that amounted to 75 percent of the patients had negative findings.
• Out of the 16 patients with positive biopsies 10 consented to undergo a second cryosurgical ablation, and 7 of these patients subsequently had negative follow-up biopsies. Therefore, their disease-free rate at 3 months after 1 or 2 cryosurgical procedures was 95 percent. 
• A total of 46 protocol patients in their series completed 12 months of evaluation and 40 of the patients that amounted to 87 percent of the patients had no evidence of disease. 
• This same cohort had shown only minimal disease progression, with disease-free rates of 96, 93, 87 and 87 percent at 3, 6, 9 and 12 months, respectively. 
• Major complications were infrequent.

Wake et al. [70] made the following conclusions:

• At 1-year follow-up their clinical experience had shown cryoablation of the prostate to be an effective therapy in select cases of prostatic adenocarcinoma. 
• Long-term efficacy is still in question but, based upon current disease-free rates, this therapeutic modality merits continued clinical investigation.

Ellis [71] described the technique and recent experience incorporating cryosurgery into our community practice for primary treatment of localized prostate cancer. Ellis [71] reported that between December 2000 and December 2001, a total of 93 patients had undergone targeted cryoablation for localized prostate cancer. Ellis [71] reported that out of the 93 patients, 18 had failed radiotherapy, and cryotherapy was undertaken as salvage therapy. The remaining 75 patients underwent targeted cryoablation of the prostate as primary therapy. A single urologist using an argon-based cryoablation system undertook the procedure. Cryoprobes and thermos-sensors were placed under transrectal ultrasound guidance through a trans-perineal route. A double freeze-thaw cycle was utilized with anterior-to- posterior probe operation. Strategically placed thermos-sensors were utilized to monitor and control the freezing, and a warming catheter was used to protect the urethra. Ellis [71] stated that they achieved a nadir serum prostate-specific antigen (PSA) level of ≤0.4 ng/mL in 84% of the entire population they had studied which included 63 patients out of the 75 patients. Post-surgery complications were noted to be minimal. Incontinence had developed in 4 patients, as did post-suprapubic catheter removal urinary retention. Erectile dysfunction was noted to have developed in 28 of 34 patients who were potent pre-operatively, with 6 out of the 34 patients regaining potency pursuant to surgery. No rectourethral fistula formation had occurred. Urethral sloughing was found in 5 patients, 1 of whom had developed a scrotal abscess during the treatment of the sloughing. Ellis [71] concluded that the use of cryoablation of the prostate for the treatment of localized adenocarcinoma of the prostate is feasible and it can easily be transferred from the pioneering centres to the community hospitals without sacrificing safety or efficacy.

Shelley et al. [72] stated the following:

• Prostate cancer is a common cancer in elderly men and in some prostate cancer will prove fatal. 
• Standard treatments for localized prostate cancer disease include surgery entailing radical prostatectomy, radiotherapy and active monitoring. 
• New emerging therapy options are being evaluated with the aim of reducing the complication rate associated with standard therapies, as well as developing an effective treatment. One such modality of treatment is cryotherapy, a procedure which does introduce probes directly into the prostate tumour and kills the malignant cells by a freezing process.

Shelley et al. [72] undertook a review of the literature which was aimed to evaluate the relative clinical and economic benefits of cryotherapy compared to standard therapies for the primary treatment of localized prostate cancer. The search of Shelley et al. [72] included an electronic search of MEDLINE from 1996 to December 2006, plus EMBASE (Exerpta Medica Database), the Cochrane library, ISI Science Citation Index, Database of Abstracts and Reviews of Effectiveness (DARE), and LILACS to identify all relevant published randomized trials of cryotherapy for localized prostate cancer. Cancerlit→ and HealthSTAR databases were searched to their final date. Handsearching of relevant journals was undertaken. Shelley et al. [72] reported that only published randomized trials which had compared the effectiveness of cryotherapy with radical prostatectomy, radiotherapy or active monitoring for the primary treatment of men with localized prostate cancer were eligible for inclusion in this review. Shelley et al. [72] extracted data from eligible studies, and included study design, participants, interventions and outcomes. Primary outcome measures were biochemical disease‐free survival, disease‐free survival and treatment‐induced complications. Secondary outcomes included disease‐specific survival, overall survival, quality‐of‐life outcome measures and economic impact measures. Shelley et al. [72] summarized the results as follows: 

• There were no randomized trials found that compared cryotherapy with other therapies for the primary treatment of localized prostate cancer. 
• All studies they had identified were case series. 
• In order to indicate the level of the available evidence, studies which had evaluated cryotherapy as a primary therapy, with the use of transrectal ultrasound guidance and urethral warming in at least 50 patients who had localized prostate cancer, and a minimum of one year follow up, were reviewed. 
• Eight case series were identified that had complied with these criteria; two were retrospective studies. 
• The patients who were recruited had totalled1483) and they had an age range from 41 years to 84 years, stages T1 = 0 to 43%, T2 = 24 to 88%, T3 = 1 to 41%, and T4 = 0 to 14% of tumours. The mean pre-operative serum PSA level had ranged from 9.7 to 39 ng/mL, with Gleason scores < 7>

Shelley et al. [72] made the following conclusions:

• Cryotherapy does offer a potential alternative to standard therapies for the primary treatment of localized prostate cancer. 
• However, the poor quality of the available studies has made it difficult to determine the relative benefits of this modality. 
• Randomized trials are required to fully evaluate the full potential of cryotherapy in men with this disease. 
• Patients who select cryotherapy as their therapeutic option should be made fully aware of the reported efficacy, complications and the low‐grade evidence from which these data had been derived.

Cresswell et al. [73] presented the early results of the use of third-generation cryotherapy in primary and recurrent prostate cancer at one United Kingdom (UK) centre. Cresswell et al. [73] reported that over a 14-month period, 51 patients had undergone cryotherapy for prostate cancer. In 31 patients, cryotherapy was used as the primary treatment and in 20 patients, cryotherapy was used as a salvage treatment after radiotherapy or hormone ablation. Cresswell et al. [73] collected data prospectively and the median follow-up was 9 months. Cresswell et al. [73] summarized the results as follows: 

• The serum prostate-specific antigen (PSA) level had decreased to <0>
• A higher Gleason grade and serum PSA levels were associated with a poorer outcome. 
• No patient developed a fistula, 4

• Available information on published that has revealed that cryotherapy is an effective treatment and minimally invasive, with low surgical risk, low morbidity, with good results in the long follow-up in terms of survival, biochemical recurrence, cancer-specific survival and overall survival. 
• Cryotherapy is a valid technique that has at times been used for the treatment of organ-confined tumours and preferably in low- and intermediate-risk groups. It is a safe alternative for patients with high surgical risk or contraindication for radiotherapy, with a low rate of complications. 
• Cryotherapy can be repeated in case of biochemical relapse after histological confirmation of local recurrence or evidence of persistence of prostate cancer after initial treatment of cancer by cryotherapy.
• Cryotherapy of prostate cancer can also be undertaken as salvage therapy following evidence of persistence of the tumour or localized recurrence following previous radiotherapy, or irreversible electroporation of localized prostate cancer. 
• Salvage radiotherapy of curative intent or salvage radical prostatectomy can be undertaken for recurrence or persistence of localized prostate cancer following initial treatment of curative intent of the prostate cancer by cryotherapy. 

None.