Analyst differential diagnosis of cancer and benign prostatic hyperplasia

Early diagnosis of prostate cancer (PCA) is one of the priority tasks of modern urology and health in General. Currently, in most economically developed countries of Europe prostate cancer comes in second, and in the US in the first place on prevalence among cancers [1]. The attention of researchers to the problem of prostate cancer is associated not only with an increase in the total number of patients, but also with increased mortality from this disease. Thus, among the causes of death of men from cancer prostate cancer ranks second after lung and stomach cancer. Moreover, the characteristic is the rapid growth in the number of newly detected cases of prostate cancer [3]. Recently in the world there is a tendency to identify not only localized prostate cancer in men aged 45 to 75 years, but also in locally advanced cancer stage pT3a–pT3b. This fact indicates either an earlier onset and an aggressive course of the disease, or inadequate implementation of screening programmes for prostate cancer. In favor of the latter assumption according to the data of official statistics on the state of urological morbidity in the Russian Federation, when the average for prophylactic examinations in 2005, prostate cancer was diagnosed in 10.3% of patients (in 2003 from 6.6 per cent in 2004 – 9,8%) and in 21 regions of the Russian Federation prostate cancer by prophylactic examinations not revealed at all [4].

The prostate is anatomically divided into 5 zones: the front part is about 30% and consists mainly of smooth muscle; peripheral, biggest contains 3/5 of the glandular tissue; the Central includes most of the remaining glands; prepostericity fabric plays a key role during ejaculation (the muscle does not allow seed to flow back into the bladder); a transition portion surrounds the urethra, and it is in this area changes, characteristic of an adenoma, or benign prostatic hyperplasia (BPH). The size of the prostate varies with age and increases with age; the average volume of the prostate of an adult male of about 25-30 cm3 [5].

Like seminal vesicles, prostate gland relates to auxiliary sexual glands. The secret that they emit, is a liquid part of the ejaculate, that surrounds the sperm. It consists of glandular and smooth muscle tissue. Many tiny spongy glands have excretory ducts, which merge, forming 15-30 secretory ducts leading out their contents through pin holes in the urethra. Muscle tissue is concentrated in the depths of the gland, around the urethra. During orgasm the muscles of the prostate contract and throw her out the secret in the urethra; at the same time in the urethra, are thrown outthe sperm and the secret of the seminal vesicles.

Ingredients of secret of the prostate gland – transparent, low-acid fluid are numerous and varied. It includes citric acid, phosphatase, spermine, potassium, calcium and zinc. Despite numerous studies, the exact role of prostate secretion in sexual activities is unexplored. Job of the prostate is regulated by male sex hormones coming from the testes are called androgens. The main one is testosterone.

The increase in size of the prostate gland is associated with sexual development: puberty to 20 years it increases in size by 5 times – from 4 to 20 In the next few decades, the most common problem is related to the gland is prostatitis; then, after 50 years, may develop adenoma and prostate cancer. It should be noted that the presence of BPH does not mean that the man has already received his portion of troubles and cancer he can't be, as well as the cure adenoma or prostatitis does not insure against the disease of prostate cancer.

BPH, or what they used to call this disease, prostate cancer remains one of the most common diseases of older men. Today the majority of authors recognize the term "benign prostatic hyperplasia" as the most fully reflecting the morphogenetic nature of the disease.

Diagnosis and treatment of BPH are not only serious medical but a social problem. 95% of men aged 55 to 74 years prostate volume greater than 20 cm3, increasing with age. So, half of men older than 55 years, the volume of the breast becomes more than 30 cm3, each 4th – 40 cm3, and each 8th – 50 cm3. The increase of prostate volume with age is 2% annually, the result of 35 years of iron doubled. Conducted in our country, epidemiological studies indicate a gradual increase in frequency of BPH from 11.3% at age 40-49 years to 81.4% at age 80. Up to 30% of men 40 years of age, surviving up to 80 years, carry surgical treatment for BPH [5].

In the past decade significantly increased the interest in the problem of prostate cancer. The probability of detecting prostate cancer in men aged 40 to 59 years is 1:78 (up 1.28%), aged 60 to 79 years – 1:6 (15.6 percent). Overall, about 3% of men can die from prostate cancer. This disease is second in terms of mortality among all malignant tumors in Russia and the United States, and these figures are growing steadily [2, 3]. For the period from the late 1970s until the early 1990s, the incidence rates of cancer of the prostate has nearly doubled. How often is prostate cancer found? In the US, he is diagnosed every 3 min every 15 min 1 person dies from it. In 2000 in the United Stateswas 180 400 new cases of prostate cancer, and 31 900 patients died as a result of this disease, in Europe, 200 thousand and 40 thousand respectively. According to the 2014 forecast, the total number of new cases of prostate cancer in the United States will increase to 233 thousand, compared to 2000, more than 29%. That is, the expected mortality rate will be 29 thousand less than in 2000. Interesting is the fact that in 2014 in the USA a total population of 1.9 million prostate cancer patients [8, 9]. The highest rate of increasing incidence and increased detection of prostate cancer in southern Europe (25% every 5 years). Standardized measures of the frequency of prostate cancer detection in Europe of 87.2 cases per 100 thousand men per year and mortality rate of 34.1 per 100 thousand men per year. In the United States, the incidence of clinically significant prostate cancer has a large ethnic and regional differences. Asians in the US have a lower risk of developing prostate cancer or death from it than African Americans (8.7% and a 2.6% vs 9.4% and 4.3%, respectively). Prostate cancer is evaluated differently when the comparison of the frequency of morbidity (mortality) with age, which increases significantly in men older than 40 years (1-2 per 100 thousand men per year to 40 years), reaching a peak by age 80 (1200 per 100 thousand men per year for Asians and 1600 per 100 thousand men per year for African Americans) [3, 7].

So widespread prostate cancer puts him in a number of the most important social issues of our time. We must assume that in our country the situation is no better, although these are alarming statistics, no. This is likely due to the lack of early diagnosis and health education of the population. The majority of patients that come to our clinic, have launched the stage of prostate cancer that does not fully rid them of this disease.

Today prostate cancer is the subject of careful study. Disease practically does not occur before 40 years and becomes increasingly common with each decade of life. Most insidious in this disease that almost no early symptoms. When they appear, to treat prostate cancer it may be too late. For early diagnostics it is important to conduct annual screening. There is an urgent need to develop methods that could provide early detection of the disease and significantly improve the effectiveness of the treatment. Despite many efforts, at least in the near future to expect complete prevention of cancer or radical steps in combating the disease on a common stage, unfortunately, is not necessary. At the moment ways of complete cure of carcinoma of the prostate no. Our hopes are to reduce the number of deaths from prostate cancer based on early diagnosis andeffective treatment of the disease in its initial stages.

The questions arise: how to diagnose prostate cancer, to make a differential diagnosis with BPH?

Histologically determined BPH in most men older than 40 years. First, there is the appearance of stromal nodules in the periurethral region of the transition zone of the prostate. For nodulation immediately glandular hyperplasia. Clinically, the disease manifests itself in different symptoms (table. 1) related to a violation of passage of urine through the lower urinary tract. It must be remembered that these symptoms are not strictly specific for BPH and can occur with prostate cancer or prostatitis, so important are correct methods of examination and diagnosis.

Because unlike BPH prostate cancer usually begins in the peripheral portion of the prostate, the time of onset of symptoms, which the man will notice the stage of the disease can be quite late.

The reasons for voiding are infravesical obstruction and weakening of the function of the detrusor. The basis of obstruction is the prostate increase in size with the gradual narrowing of the lumen of the urethra (the mechanical component) and the increased tone of the smooth muscle fibers of the prostate and posterior urethra (dynamic component).
The first manifestations of the disease include sluggish stream of urine, difficulty and delays the initial phase of urination, the appearance of frequent urination and imperative urge, especially at night. The contractile activity of the bladder remains intact and every time you urinate, the bladder fully emptied. Over time the intensity and frequency of symptoms increase, there are complaints of difficulty urinating, the need to naturopathica and connect the abdominal muscles bladder. However, due to the reduction of the tonus of the detrusor in the lumen of the bladder is a certain amount of urine – residual urine. If the patient does not receive treatment, difficulty urinating gradually becomes constant and predominant symptom, urine flow becomes intermittent, sometimes it stands out in drops. At a full bladder, patients complain of involuntary, uncontrolled release of urine in the urethra. This symptom has received the name of paradoxical ischuria.

The amount of residual urine was the main criterion for the division of BPH on stage and the indication for surgical treatment. Studies in recent years showed the inconsistency of this approach. It is also important that the same symptom, such as shortness of urination or sensation of incomplete emptying of the bladder, is interpreted extremely sicksubjective and usually do not correspond to objective data. The symptoms of phase accumulation are due to changes in the function of the detrusor and sphincter of the bladder for BPH. An important role in their appearance plays a possible overactive bladder.

Symptoms emptying phase is more dangerous in the prognostic plan and encourage the choice of tactics of surgical treatment. The symptoms of the accumulation phase though, and significantly reduce quality of life, less dangerous and can be eliminated with proper conservative treatment. Complications of the disease, which may occur with BPH and prostate cancer include: hematuria (appearance of blood in the urine), acute urinary retention, secondary formation of bladder stones, chronic renal failure and a variety of inflammation at the background of violations of urodynamics upper and lower urinary tract. At the same time prostate cancer has several symptoms that are not characteristic of BPH, but their appearance usually indicates a late stage of the disease. These symptoms include: pain in the pelvis, the spine and the perineum, the appearance of blood in the ejaculate, weakness, progressive weight loss, and others.

Tactics of treatment of BPH and treatment of prostate cancer are fundamentally different from each other, so it is essential to timely and correctly establish the diagnosis. For this purpose a whole Arsenal of methods of diagnosis. We would like to elaborate on the major ones (Fig. 1).

Digital rectal examination (PRI) (Fig. 2) still remains one of the most important methods of diagnosis of prostate cancer and BPH. WHEN allows to determine the approximate size of the prostate, its configuration, consistency, tenderness, mobility and relation to surrounding tissues. It is conducted also with the aim of identifying tumors of the rectum, chronic prostatitis, and to evaluate tone of the anal sphincter. The nature of tactile sensations can affect the various position of the patient (on the side, the knee-elbow position, etc.), as well as the degree of fullness of the bladder. The specificity in detecting prostate cancer small. Only 26-34% of men with suspicious results WHEN prostate cancer is detected. As a rule, suspected prostate cancer is WHEN the conduct arises only in the later stages of the process, the proportion of false-negative diagnoses reaches 40-60%.

Diagnostic signs of prostate cancer when performing WITH: the asymmetry of the prostate, the presence of seals, sometimes cartilaginous consistency in the form of separate units, or different sizes of infiltrates, often spreading from the prostate towards the seminal vesicles, until they go on the walls of the pelvis.

Standard transabdominal ultrasound of the prostate andthe bladder allows you to determine the size, configuration, and echostructure of the prostate gland, its relationship with the bottom of the bladder, residual urine, the thickness of the bladder wall, presence of bladder stones, tumors.

If the need arises in the differential diagnosis of prostate diseases, more accurate information on differences in the structure of the gland can give the examination of the prostate gland through the rectum – transrectal ultrasound (TRUS). Today it is one of the informative methods of evaluation of the macrostructure of the prostate, detection of nodular formations of cancer. Echographic signs of adenocarcinoma of the prostate are single well-defined foci of decreased echogenicity with multiple hypoechoic areas with blurred boundaries, ISO -, and hyperechoic foci. During germination of the tumor outside the capsule of the prostate on the echograms may be a defect in the capsule and hyperechogenic adipose strips surrounding the prostate gland.

Much more information can be obtained by the patient a magnetic resonance imaging (MRI). This method of beam diagnostics, when used in conjunction with a/V enhancement of the prostate, gives the most complete picture of its structure and with high probability allows to suspect the presence of malignant changes. Increasingly popular in the last 2 years is becoming the technique of performing prostate biopsy, which will be discussed below, under simultaneous MRI and TRUS. The capabilities of MRI are increasing rapidly, and due to the wide introduction of more powerful MRI scanners (a 3.0 Tesla vs 1.5 Tesla used until recently) you can get a very accurate picture of the localization of affected tissue, previously contrastirovania special drug. In this zone it is advisable to perform the maximum number of injections biopsy.

There are 3 options to apply the acquired MRI data. The easiest option is perform a biopsy under TRUS control subject MRI data. The second option is the elimination of the MRI-images in the mode "overlay" on the monitor of the ULTRASONIC apparatus at the time of biopsy. Third, the most technologically – conduct 2 studies – ultrasound+MRI in real time when performing the biopsy. Immediately it should be noted that the third option is not available for Russian patients – such equipment in Russia is not licensed.

To the conventional, routine methods of examination of patients, presenting complaints of violation of urination are also include blood and urine tests; uroflowmetry – measurement of maximum speed of flow of urine when urinating natural; much lessperformed radioisotope renography, urodynamic examination.

Since 1987 in the diagnosis of prostate cancer, establishing stage of the process, the evaluation of the effectiveness of treatment is widely used to determine the level of prostate-specific antigen (PSA). This is the most valuable tumor marker, whose determination in serum is necessary for the dynamic monitoring of the course of the adenoma and prostate cancer. IN the prostate, supplemented by ultrasound, can not provide timely diagnosis of prostate cancer, especially in the case of the initial stages of the disease. By its nature, PSA is a glycoprotein (a protein) produced by the secretory epithelium of the prostate. Found that when prostate cancer its level in serum may rise significantly, although this may not always indicate the presence of a malignant process. PSA levels can rise for other reasons, such as BPH, inflammation or infection in the gland, ischemia or infarction of the prostate, and ejaculation before the study. However, the increase in the level of total PSA in the serum of more than 4.0 ng/ml requires further examination. Question the norms of a DOG being actively discussed. It is obvious that there is a level at which the patient would be fully warranted to be free of his prostate cancer. Reducing the level of standards we are able to detect a greater number of cases of prostate cancer, but, on the other hand, much expanding the group of patients falling into the so-called risk group.

Despite the common 4 ng/ml, in practical work, the majority of urologists are increasingly using 2.5 ng/ml as a criterion for rules DOG. Adopted the world programme of early diagnosis of prostate cancer that includes carefully conducted WITH and determination of level of PSA, the analysis should be repeated for all men beginning with 45-50 years. High risk patients who have a family or from the immediate blood relatives have had prostate cancer, screening tests begin at the age of 40. Further, depending on the initial values of PSA, a repeat study 1 p./year or 1 RV/2 years, when PSA levels less than 1 ng/ml through 5 years. Starting from the age of 60, the periodicity of control tests – 1 R/year. An increase in the level of PSA more than 0.75 ng/ml/year – an alarming symptom and requires expanded survey.

For precise diagnosis with increasing PSA levels above the threshold values shown performing prostate biopsy. According to the recommendations of the American and European associations of urology of recent years, receiving increased PSA above the threshold recommended to perform re-analysis after 1-2 weeks., and only after it is received to make a final decision on further tactics of examination. Multifocal transrectala biopsy performed under ultrasound guidance (Fig. 3), is the most reliable way to diagnose prostate cancer. Method biopsy is that with a special high speed automatic needle (called a "biopsy gun") via the rectum under ultrasound taken threadlike pieces of prostate tissue that are subsequently labeled (mapped – definition of the prostate, from which is taken a piece of fabric), and sent to the morphological study. As a rule, biopsy is well tolerated by patients and can be performed without specific analgesia on an outpatient basis. Depending on age, PSA levels and other factors during the biopsy is taken from the standard 12 to 18 pieces of the prostate tissue. When re-biopsy or high volume of prostate biopsy, the number of injections can increase up to 40 or more. In this case we speak of "saturation" biopsy [6].

It is important to emphasize that in the interpretation of biopsy results is of great importance the experience of the pathologist who performs the study. At our clinic for over 10 years functioning in the histology laboratory performing every day dozens of such studies. Good equipment and expertise – the key to the accuracy of the result. Sometimes the resulting material is insufficient for the formulation of the final diagnosis. In this case, resort to more sophisticated research at the genetic level, immunohistochemical [7]. One of the possible findings of a pathologist may be the presence of prostatic intraepithelial neoplasia (PIN) or atypical proliferation (ASAP). The presence of these changes (cancer they are not) necessitates a repeat biopsy from a greater number of points after 1-6 months. after the first biopsy. The most frequent indications for prostate biopsy: presence of change of the results DURING and/or increasing the level of PSA in the blood serum.

Many articles in recent years suggests that the implementation of a giant number of biopsies throughout the world leads to the detection of numerous cases of so-called clinically insignificant cancer." Evaluation criteria of clinical significance are different, but the General principle is that such cancer, if it has not been identified and continued to grow slowly, would not represent a threat to the health of the patient and would not be a threat to his life. To differentiate these patients on the "doripenem stage" – not an easy task. An even more difficult task is to understand which of the identified crayfish is a threat to the patient, and what – not. One of the criteria of "insignificance" is the identity of the patient group low risk: stage of disease – no more than Т2а, scorea Gleason score – 3+3=6, no more than 2 biopsy of columns from one half of the prostate contain cancer cells on the total area of tissue not more than 5%, the patient is more than 65 years of age and the PSA level is not more than 10. Obviously, the slightest error in the interpretation of data, histological studies immediately changes the prognosis of the disease. Also controversial remains the question of the adequacy of collection of material for biopsy – no one can guarantee that the study appears the most malignant portion of the tumor.

For the objectivization of our knowledge about the tumor many researchers try to use alternative biomarkers. Their popularity is still low, and the cost of tests is very significant. Most of them are not yet available in Russia, but, discussing the possibility of differential diagnosis of prostate cancer, not to talk about them today is impossible. In addition to studies on the DOG to determine the necessity of biopsy can be used to test the index definition prostate health (Prostate Health Index PHI). If a biopsy has not given a clear result or observed the presence of PIN and ASAP, for making decisions about re-biopsy can be used ПСА3-and test ConfirmMDx. The last of the diagnostic tests "catches" the proximity of malignant changes in the distance of a few millimeters by the analysis of biochemical indicators of benign tissue obtained during biopsy. It should be noted that the cost of these tests is quite high and the accuracy is far from 100%. On the other hand, the obvious advantage of their use is to reduce the number of so-called "unnecessary biopsies", which is not only beneficial for health, but also helps to relieve patients from unnecessary suffering. The need for such searches is obvious: in 2013 the United States made 19 million studies to determine the level of PSA. 4.7 million cases PSA level was increased – made more than 1.3 million biopsies revealed 241 thousand new cases of prostate cancer and mortality from this disease was only 28 thousand people [9]. There is a need for more personalized and informed approach to determining the indications for prostate biopsy.

A separate area of the laboratory diagnosis of prostate cancer is to attempt a biochemical evaluation of the degree of "clinical significance" or, in other words, the malignancy of prostate tumors. What kind of tumor requires immediate active treatment and which will not develop and will not cause their host any inconveniences during the long years? The most popular tests to answer this question are the OncotypeDX®, and Prolaris® and Decipher®. These new diagnostic systems combine the results of the analysis of the clinical picture and outcomesdisease data detailed immunohistochemical and biochemical studies obtained during biopsy of the prostate tissue. While this is only the first experimental steps toward laboratory diagnosis "clinical significance" and "grade" prostate cancer. Their widespread introduction – the nearest future. While they are used only in certain medical centers and laboratories in the US and Europe, generally accepted standards they are not.

In any case, in identifying a cancer patient requires further investigation to determine the tumor stage and further treatment tactics. This is at least the means to perform MRI of small pelvis with contrast and radioisotope study of the bones of the skeleton, especially in patients with a PSA level exceeding 20 ng/ml.

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