Renal cell carcinoma

Among malignant tumors of the renal parenchyma the overwhelming majority (85-90%) is the renal cell carcinoma, which develops from the tubular epithelium. The hypothesis of Gravitz, who in 1883 described the so-called hyper-nephritic cancer, about the violation of visceral embryogenesis (in his opinion, the adrenal cells thrown into the tissue of the kidney become a source of the tumor process) is now rejected, and the terms "Gravity tumor", "hyper nephroma" "And" hyper-nephritic cancer "have only historical significance.

[1], [2], [3], [4],

Epidemiology

Sarcoma and other malignant tumors from the connective tissue of the kidney are extremely rare. The frequency of benign neoplasms of the renal parenchyma ranges from 6 to 9%, in other cases, as a rule, there is renal cell carcinoma.

The incidence of renal cell carcinoma depends on age and reaches a maximum of 70 years, men suffer 2 times more often than women. When a kidney tumor is detected in children, a Wilms tumor (nephroblastoma), which in adults, on the contrary, is extremely rare, in 0,5-1% of cases, should be suspected first of all. The frequency of other neoplastic kidney lesions in childhood is extremely low.

Renal cell cancer ranks 10th in terms of incidence among malignant neoplasms of man, accounting for about 3% of all tumors. From 1992 to 1998, the incidence of renal cell carcinoma in Russia increased from 6.6 to 9.0 per 100,000 population. According to some reports, over the past 10 years it has almost doubled. In the structure of mortality from cancer in Russia among men, the frequency of renal cell carcinoma is 2.7%, among women - 2.1%. In 1998, 30,000 cases of renal cell carcinoma were diagnosed in the United States, which killed 12,000 people. The increase in morbidity can be not only true, but also due to a significant improvement in the possibilities of early detection of this disease, the widespread use of ultrasound studies of the kidneys, CT and MRI.

[5], [6], [7], [8], [9]

Causes of the renal cell carcinoma

Despite the huge number of studies devoted to kidney cancer, the cause of renal cell carcinoma is still unclear.

[10], [11], [12], [13], [14]

Risk factors

There are several groups of risk factors that contribute to the development of this disease. To date, it has been proved that smoking tobacco is one of the most significant risk factors for the development of various malignant tumors. The risk of the appearance of renal cell carcinoma in smokers - men and women - increases from 30 to 60% compared with non-smokers. If you quit smoking, the probability of developing the disease decreases, for 25 years after cessation of smoking, the risk of renal cell cancer is reduced by 15%. Renal cell carcinoma is not an occupational disease, although there is evidence of an increased risk in persons engaged in weaving, rubber-rubber, paper production, who have constant contact with industrial dyes, nitroso compounds, oil and its derivatives, cyclic hydrocarbons, asbestos, industrial pesticides and salts of heavy metals.

In most studies, the adverse effect of fat metabolism and excess body weight on the likelihood of developing kidney cancer has been confirmed. Obesity increases its frequency by 20%. In patients with hypertension, the risk of developing renal cell carcinoma increased by 20%. Comparative studies have shown that lowering blood pressure on the background of therapy does not reduce the risk of developing the tumor process. It should be remembered, however, that the neoplasm of the kidney itself contributes to the emergence and progression of arterial hypertension as one of the extrarenal symptoms. Diseases leading to nephrosclerosis (arterial hypertension, diabetes mellitus, nephrolithiasis, chronic pyelonephritis, etc.) may be risk factors for kidney cancer. The close connection of diabetes mellitus with increased blood pressure and obesity makes it difficult to assess the impact of each of these factors. An increased risk of developing renal cell carcinoma in terminal chronic renal failure, especially with prolonged hemodialysis. Injury of the kidney is considered as a reliable risk factor for the development of its tumor. Carried out studies aimed at identifying the risk of cancer in the polycystic, horseshoe-shaped kidney, as well as in hereditary glomerulopathies.

Correlation of the frequency of kidney cancer with excessive consumption of meat was noted. Hydrolysis components, in particular heterocyclic amines, formed during heat treatment of meat have a proven carcinogenic effect. Genetic studies demonstrated the possibility of translocation of chromosomes 3 and 11 in patients with kidney cancer.

[15], [16], [17], [18], [19]

Pathogenesis

Distinguish clear-cell (most often), granular-cellular, glandular (adenocarcinoma), sarcoma-like (spindle cell and polymorphic-cellular) renal cell carcinoma. When combined in one drug, they speak of mixed cell carcinoma.

With invasive growth, the tumor can squeeze the organs of the abdominal cavity (liver, stomach, spleen, intestines, pancreas) and sprout in them. In addition to the germination of adjacent organs, hematogenous and lymphogenic metastasis, one of the main pathomorphological features of kidney cancer is its ability to spread as a kind of tumor thrombus through the internal veins into the main trunk of the renal vein, and then into the inferior vena cava until the right atrium.

Hematogenous metastasis occurs in the lungs, the liver, the bones of the skull, spine, pelvis, tubal bones diaphysis, the opposite kidney, the adrenal gland and the brain.

• In hematogenous metastasis in 4% of patients, tumor manifestations are caused by primary metastasis.
• Lymphogenous metastasis is observed along the course of the vessels of the renal peduncle into the para-aortic, aortocaval and paracaval lymph nodes, to the posterior mediastinum. In the kidney can occur neoplasms, which are metastases of cancer of other primary localization: adrenal cancer, bronchogenic lung cancer, stomach, milk and thyroid gland.

In 5% of patients, bilateral renal cell carcinoma is observed. Two-sided kidney cancer is called synchronous if the tumors are diagnosed simultaneously from both sides or no later than 6 months from the time of detection of the primary tumor. In asynchronous bilateral cancer, the tumor of the opposite kidney is diagnosed no earlier than 6 months after the detection of the primary tumor.

[20], [21], [22], [23], [24], [25]

Symptoms of the renal cell carcinoma

Among the clinical symptoms of renal cell carcinoma it is customary to distinguish between the classical triad (hematuria, pain and palpable tumor) and the so-called extrarenal symptoms of renal cell carcinoma. Hematuria can be both macro- and microscopic. Macrogematuria, as a rule total, arises suddenly, initially it is painless, can be accompanied by the departure of vermiform or formless blood clots, suddenly ceases. When clots appear, occlusion of the ureter on the side of the lesion can occur with the appearance of pain resembling renal colic. The tumor is characterized by total macrogematuria, then the appearance of clots in the urine and only then - an attack of pain, in contrast to nephrolithiasis, when there is an initial attack of pain, on the height or against the background of which a visible admixture of blood appears in the urine; In this case, clots are rare. The cause of the emergence of macrogematria in renal cell carcinoma is tumor germination in the cup-and-pelvic system, destruction of the tumor vessels, acute circulatory disturbances in the tumor, as well as venous stasis not only in the tumor, but in the entire affected kidney.

Acute pain on the side of the lesion, reminiscent of renal colic, can be observed with occlusion of the ureter with a blood clot, a hemorrhage into the tumor tissue, and also with the development of an infarction of the uninfected part of the tumor. Constant aching dull pain may be a consequence of impaired urine outflow when the pelvis is contracted by a growing tumor, tumor growth of the renal capsule, paranephric fiber, perineal fascia, adjacent organs and muscles, and as a result of the tension of renal vessels in secondary nephroptosis caused by the tumor.

With palpation of the abdomen and lumbar region, signs characteristic of a kidney tumor (a dense, tuberculous, painless formation) can not always be determined. Palpable formation can be directly a tumor with its localization in the lower segment of the kidney or an unchanged lower segment when the tumor is located in the upper parts of the organ. At the same time, the statement about nephroptosis and the refusal of further diagnosis of neoplasm become a serious mistake. With very large neoplasm, it can descend into the pelvis, occupying the corresponding half of the abdomen. In the case of tumor germination in the muscles and adjacent organs, the infiltration of the renal pedicle, the palpable formation loses its respiratory mobility and the ability to shift in bimanual palpation (a symptom of balloting).

The extrarenal symptoms of renal cell carcinoma are extremely diverse. ON. Mukhin et al. (1995) distinguish the following paraneoplastic reactions in a kidney tumor:

• general symptoms of renal cell carcinoma (anorexia, weight loss, cachexia), sometimes long unrelated to intoxication;
• febrile;
• hematologic;
• disproteinemic;
• endocrinopathic;
• neurological (neuromyopathy);
• cutaneous (dermatoses);
• articular (osteoarthropathies);
• nephrotic.

At present, one can talk about the pathomorphism of this disease (extrarenal symptoms of renal cell carcinoma have become typical manifestations of renal cell carcinoma), which was largely due to improved diagnosis. In the literature, there have been reports of the development of accurate research methods to maximize early detection of a kidney tumor, which is based on the immunological determination of active peptides responsible for various manifestations of paraneoplastic syndrome. In this regard, a close study of extrarenal manifestations of renal cell carcinoma for the nephrologist internist becomes particularly important.

Extrarenal symptoms of renal cell carcinoma include arterial hypertension, fever, varicocele, anorexia and weight loss up to cachexia. It is believed that, in contrast to classical symptoms (except for hematuria), extrarenal signs allow, with active detection, to approach the early diagnosis of the disease.

At the heart of arterial hypertension, tumors can be caused by thrombosis and compression of renal veins by a tumor or enlarged retroperitoneal lymph nodes. In the absence of these changes, an increase in blood pressure as a result of compression of the intracranial vessels with a tumor with impaired intracinal blood flow is possible. One can not, however, deny the development of pressor agents by a growing neoplasm. Arterial hypertension may have certain nephrogenic features: absence of crises, meager clinical manifestations, accidental detection, resistance to traditional therapy, etc.

The fever in renal cell carcinoma can be different - from a permanent subfebrile condition to high figures. A distinctive feature of the increase in body temperature is the patient's overall satisfactory state, the absence of clinical signs of malaise and intoxication. Sometimes episodes of high fever, on the contrary, are accompanied by a feeling of emotional and physical uplift, euphoria, etc. The cause of fever is likely to be associated with the release of endogenous pyrogens (interleukin-1); infectious nature, as a rule, is absent.

Renal cell carcinoma in men can be accompanied by the appearance of varicose veins of the spermatic cord (varicocele). It is symptomatic in contrast to idiopathic, which occurs in the prepubertal period only on the left and disappears in the horizontal position of the patient. Symptomatic varicocele in a tumor occurs in an adult with no apparent cause, is observed both on the right and on the left, progresses and does not disappear in a horizontal position, because it is associated with compression or tumor thrombosis of the testicle and / or inferior vena cava. The appearance of varicocele in adulthood, as well as the development of varicocele on the right, allow one to suspect a kidney tumor.

Symptoms of Renal Cell Cancer

Symptom	Frequency,%	Frequency of occurrence as the first sign,%	Frequency of isolated manifestation,%
Hematuria	53-58	16-18	10-11
Pain in the lumbar region	44-52	9-14	6-7
Acceleration of ESR	42-48	7-13	4-7
Palpable formation in hypochondrium	38-41	7-10	2-3
Anemia	26-34	2-3	1
Hyperthermia	22-26	12-16	4
Anorexia	14-18	3	1
Arterial hypertension	15-16	10-12	6-8
Pyuria	10-12	2	-
Weight loss	9-14	1	-
Stauffer Syndrome	7-14	1-3	-
Dyspepsia	8-12	4-5	1
Varicocele	3-7	1-2	1
Erythrocytosis	1-2	-	-
Arthralgia, myalgia	1-2	1	-
Hypercalcemia	1	-	-

Some extrarenal symptoms of renal cell carcinoma have not yet been studied to such an extent that it is possible to talk about specific substances associated with their occurrence. Currently, there are persistent searches, including at the genetic level, of the causes that cause extrarenal and paraneoplastic manifestations, in order to identify markers of the tumor process.

In recent years, 25-30% of patients have extremely poor and nonspecific clinical symptoms of renal cell carcinoma or do not have them at all. In prophylactic ultrasound studies or studies with suspicion of liver disease, biliary tract, pancreas, adrenal, spleen, lesion of retroperitoneal lymph nodes, with unclear pains in the abdomen and lumbar region of the kidney, 0.4-0.95% of the examined patients began to detect kidneys. Representations about the more frequent occurrence of renal tumors in the presence of background diseases leading to nephrosclerosis (hypertension, diabetes mellitus, nephrolithiasis, chronic pyelonephritis, etc.), substantiate the urgent need for mandatory ultrasound examination of these patients with the purpose of active early detection of renal cell carcinoma, even with absence of any characteristic complaints.

Stages

To determine therapeutic tactics, evaluate the results of treatment and prognosis, the international TNM classification was adopted.

T (tumor) is the primary tumor:

• T1 - tumor up to 7 cm, limited by the kidney and not beyond the renal capsule.
• T2 - a tumor more than 7 cm, bounded by the kidney and not extending beyond the renal capsule.
• T3 - a tumor of any size, sprouting into the paranephric fiber and / or spreading to the renal and lower vena cava.
• T4 - the tumor sprouts the perineal fascia and / or spreads to neighboring organs.

N (nodulus) - regional lymph nodes:

• N0 - lymph nodes are not affected by metastases.
• N1 - metastases in one lymph node and more without taking into account their size.

M (methastases) - distant metastases:

• M0 - there are no distant metastases.
• M1 - distant metastases were detected.

In the clinical course, it is common to distinguish four stages of the cancer process:

• I stage - T1 in the absence of lymph node involvement and distant metastases;
• Stage II - T2 in the absence of lymph node involvement and distant metastases;
• III stage - TK in the absence of lymph node involvement and distant metastases;
• IV stage - any values of T for lesion of lymph nodes and / or detection of distant metastases.

Currently, the issue of the so-called "small" (up to 4 cm) kidney tumor is being discussed; its diagnosis in the first stage of the disease implies a greater success of organ-preserving surgical treatment.

[26], [27], [28], [29], [30], [31]

Diagnostics of the renal cell carcinoma

Diagnosis of renal cell carcinoma is based on clinical signs, laboratory results, ultrasound, X-ray, magnetic resonance, radioisotope studies, as well as data from the histological examination of tissue biopsy specimens of the tumor node, metastases.

Laboratory diagnostics

The laboratory signs include anemia, polycythemia, acceleration of ESR, hyperuricemia, hypercalcemia, Stauffer's syndrome.

It is proved that endogenous pyrogens can release lactoferrin. This glycoprotein is found in most body fluids and in polymorphonuclear leukocytes. It binds bivalent iron, which is one of the main causes of the development of early anemia. It can also be caused by a toxic effect on the red bone marrow with oppression of its function.

If erythrocytosis is detected, then it is necessary to exclude renal cell carcinoma before diagnosing erythremia. Violation of venous outflow from the affected kidney, which may be a consequence of tumor thrombosis of the renal vein, enhances the production of erythropoietin, which stimulates the red germ of hematopoiesis. It should be remembered that such patients may have arterial hypertension on the background of significant blood clotting with changes in hematocrit, slowing of ESR and propensity to thrombosis. In the absence of erythrocytosis, the acceleration of ESR is often observed as a nonspecific sign of many cancers. Hypercalcemia without signs of bone damage is another manifestation of the paraneoplastic process in renal cell carcinoma. Possible causes of its development - the formation of ectopic parathyroid hormone, the effects of vitamin D, its metabolites, prostaglandins, osteoblast activation factor and growth factors.

Stauffer syndrome (1961) consists of an increase in the level of indirect bilirubin and activity of alkaline phosphatase of blood, prolongation of prothrombin time and disproteinemia with an increase in the level of alpha-2 and gamma globulins. In the liver, proliferation of Kupffer cells, hepatic cell proliferation and foci of focal necrosis are observed. It should be remembered that this syndrome is nonspecific, its pathogenesis is not fully understood. Among the possible causes are liver-toxic factor, which is either produced by the tumor itself, or is formed in response to its appearance.

[32], [33]

Ultrasonography

Ultrasound examination is rightly considered to be the simplest and most accessible screening method for the diagnosis of renal cell carcinoma, from which a patient should be examined if there is a suspected kidney tumor. Characteristic features of the tumor process of the renal parenchyma are an increase in the size of the organ, uneven contours, a difference in the echostructure of the revealed formation in comparison with the surrounding intact parenchyma. One of the ultrasound signs of a tumor is the deformation of the renal sinus and the bowl-and-pelvis system. With the central location of the tumor, it pushes and deforms the pelvis and cups surrounding the renal parenchyma while compacting.

When revealing voluminous neoplasm, not only its character is assessed, but also its size, localization, depth, prevalence, boundaries, connection with surrounding organs and tissues, possible spreading into large vessels. The use of UZDG significantly helps in solving this problem. Most of the tumor nodes in the kidney are hypervascular, but the lack of an abundance of newly formed vessels does not exclude renal cell carcinoma. Ultrasound examination allows to identify enlarged regional lymph nodes larger than 2 cm.

CT scan

Improvement of diagnostic technologies, the dissemination of computer X-ray research methods with digital image processing, the possibilities of constructing three-dimensional images based on transverse and spiral sections (tomography) in various regimes for detecting contours of organs and formations, their any sections in the program of visualization of blood vessels (angiography), urinary pathways (urography), their combinations significantly changed the nature and sequence of diagnostic measures in patients with a kidney tumor and. The wide possibilities of multispiral X-ray CT with three-dimensional image reconstruction minimized the need for excretory urography and renal angiography in these patients. Computed tomography is now rightly considered to be the main method of visualization of renal cell carcinoma. Her sensitivity in the diagnosis of kidney neoplasms approaches 100%, the accuracy is 95%.

On computer tomograms, kidney cancer is visualized as a deforming cortical layer of the soft tissue knot that can spread into the paranephric fiber and renal sinus with compression or involvement of the bowl-and-pelvic system in the tumor process. The presence of calcicates in the wall of banal solitary cysts should be alarming in terms of possible cancer. Intravenous contrasting helps in doubtful cases: the difference in character and intensity of contrasting in comparison with the externally intact parenchyma is one of the signs of cancer. The increase in diameter, defects in the filling of the renal vein indicate its involvement in the tumor process.

[34], [35]

Magnetic resonance imaging

MRI is an important part of the algorithm for the diagnosis of renal cell carcinoma. This is especially true for patients with renal insufficiency, people with intolerance to radiocontrast iodide preparations, as well as patients who have contraindications to the use of ionizing radiation. The possibility of obtaining a multifaceted image in various planes becomes particularly important when assessing the origin of the primary tumor (kidney, adrenal, retroperitoneal space) when the X-ray CT data are ambiguous. Despite the high resolution, the possibility of multi-axis visualization and evaluation of blood circulation without the use of contrast enhancement, the use of MRI in detecting small tumors is limited due to the similar intensity of the signal of normal parenchyma and renal cell carcinoma both in T1 and T2 modes . However, when using different modes, the informative value of this study is 74-82%, and the accuracy is not inferior to CT.

The undisputed advantage of MRI is a good visualization of the main vessels, which is of great importance for the detection of venous tumor invasion. Even with complete occlusion of the inferior vena cava, a clear visualization of the tumor thrombus and a precise definition of its length without contrast are possible. Therefore, MRI is now considered as a method of choice in the diagnosis of tumor thrombosis and evaluation of its extent, which is invaluable in the development of therapeutic tactics. The informativeness of this study in the diagnosis of metastatic lymph node involvement, unfortunately, has not been adequately studied. Contraindications to MRI - claustrophobia, the presence of an artificial pacemaker, the presence of metal prostheses and surgical clips. Do not forget about the very high cost of this method.

Renal angiography

Until recently, renal angiography was the main method of diagnosis of renal cell carcinoma and a means of developing therapeutic tactics. On arteriograms, a hypervascular tumor node (a symptom of "lakes and puddles"), an expansion of the renal artery and vein on the side of the lesion, defects of filling in the lumen of the veins with tumor invasion was usually determined. Currently, vascular studies of Seldinger's transfemoral access are performed using subtractive (subtraction) techniques with digital processing of X-ray data.

Indications for renal angiography:

• planned resection of the kidney with removal of the tumor;
• a large kidney tumor;
• tumor thrombosis of the inferior vena cava;
• planned embolization of the renal artery.

Excretory urography

Excretory urography is not a method of diagnosing a tumor of the renal parenchyma. On urograms, it is possible to detect an increase in size, deformation of the kidney and the cup-and-pelvis system - indirect signs of volumetric education. Excretory urography is indicated in cases of revealing pathological changes (stones, hydronephrosis, anomalies, effects of the inflammatory process) of the opposite, remaining kidney, also with the alarming results of pharmaco-ultrasound. Restriction of indications to this routine examination is due to the possibility of obtaining all the necessary information for multislice computer and MRI in a special urographic mode.

[36], [37], [38], [39], [40], [41], [42], [43]

Radioisotopic diagnosis of renal cell carcinoma

Radioisotope methods of kidney research are also not used to diagnose a tumor of the renal parenchyma, but they help in assessing the function of both the affected and healthy kidney.

Ultrasound, computer and MRI can reveal volumetric kidney formation in more than 95% of patients, determine the nature of the disease in 90% of cases, determine the stage of cancer in 80-85% of patients. It should be remembered that none of the diagnostic methods is ideal, different studies can significantly complement and clarify each other. That is why the approach to diagnosis should be individual and complex.

Differential diagnosis

Differential diagnosis of renal cell carcinoma is performed with a solitary cyst, polycystic kidney disease, hydronephrosis, nephroptosis, carbuncle and kidney abscess, pionephrosis, retroperitoneal tumors and other diseases manifested by an increase and deformation of the organ. In addition to the characteristic clinical manifestations and complications of these diseases, ultrasonic data occupies an important place. They allow us to diagnose, by characteristic signs, solitary cysts and polycystosis, to dilute the cup-and-pelvis system to suspect a hydronephrosis transformation for subsequent refinement by routine radiopaque studies. Carbuncle and kidney abscess have a corresponding clinical picture. Doubts in the liquid or dense content of volumetric education - indications for its puncture under ultrasound control, the study of its contents (general clinical, bacteriological, cytological), if necessary with the subsequent introduction of a contrast medium for cystography.

Corresponding history, the presence of annular calcification, eosinophilia, positive specific reactions are the basis of differential diagnosis with echinococcosis of the kidney. In the overwhelming majority of cases, ultrasound diagnosis of renal cell carcinoma and other studies do not allow us to judge the nature of the tumor. An exception is renal angiomyolipomas, which are hyperechoic in ultrasound research, and with CT have a fat tissue density.

[44], [45], [46], [47], [48], [49], [50], [51]

Treatment of the renal cell carcinoma

Operative treatment of renal cell carcinoma is the only method that allows one to count on the cure or prolongation of the life of a patient with renal cell carcinoma. The patient's age should not be the determining factor in the choice of treatment. Of course, the severity of concomitant diseases, and the severity of intoxication, as well as potential blood loss, should be taken into account.

The operation of choice today is rightly considered removal of the kidney - a radical nephrectomy with removal of the affected kidney with a single block of paranephric fiber and fascia in combination with regional and juxtaregionic lymphadenectomy.

In view of the possible presence of macroscopically not metastatic changes in the lymph nodes, it is necessary to remove the cellulose containing the lymphatic apparatus. For the right kidney, this is pre-, retro-, latero- and aortocaval fiber from the feet of the diaphragm to the bifurcation of the aorta, for the left - preterolateral and retroaortal tissue.

In recent years, organ preservation operations have become more widespread. Absolute indications for them are cancer of a single or both kidneys, cancer of one with a pronounced functional inconsistency of another kidney and signs of chronic kidney failure. In recent years, more extensive laparoscopic surgery has been introduced.

Radiation therapy does not have a significant effect on the outcome of renal cell carcinoma. Chemotherapy does not affect the kidney tumor and is used for pulmonary metastases. The effectiveness and features of immunotherapy with the use of interferon preparations, as a new method of treatment of renal cell carcinoma, are now being studied.

Dispensary supervision

Follow-up examinations of patients operated on for renal cell carcinoma should be performed for the first 3 years every 4 months, every 6 months for 5 years, then once a year for life.

[52], [53], [54], [55]

Forecast

The five-year survival rate after successful organ-preserving surgeries for a kidney tumor today exceeds 80%. It certainly depends on the timely detection of the disease. According to the urological clinic of the Moscow Medical Academy. THEM. Sechenov, with a tumor size of up to 4 cm, 5-year survival is 93.5% (after nephrectomy - 84.6%), with dimensions from 4 to 7 cm - 81.4%.

[56], [57]