Renal cell cancer

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

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

Epidemiology

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

The incidence of renal cell carcinoma depends on age and reaches its maximum by the age of 70, men suffer twice as often as women. When a kidney tumor is detected in children, Wilms' tumor (nephroblastoma) should be suspected first, which, on the contrary, is extremely rare in adults - in 0.5-1% of cases. The incidence of other tumor lesions of the kidneys in childhood is extremely low.

Renal cell carcinoma is the 10th most common malignant neoplasm in humans, 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 people. According to some data, it has almost doubled over the past 10 years. In the structure of mortality from oncological diseases in Russia, the incidence of renal cell carcinoma among men is 2.7%, and among women - 2.1%. In 1998, 30,000 cases of renal cell carcinoma were diagnosed in the USA, which caused the death of 12,000 people. The increase in incidence may not only be genuine, but also due to a significant improvement in the possibilities of early detection of this disease, the widespread introduction of ultrasound examinations of the kidneys, CT and MRI.

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

Causes renal cell cancer

Despite the vast amount of research devoted to kidney cancer, the cause of renal cell carcinoma is still unclear.

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

Risk factors

Several groups of risk factors have been identified that contribute to the development of this disease. To date, it has been proven that tobacco smoking is one of the most significant risk factors for the development of various malignant neoplasms. The risk of renal cell carcinoma in smokers - men and women - increases from 30 to 60% compared to non-smokers. When you quit smoking, the likelihood of developing the disease decreases; within 25 years after quitting smoking, the risk of renal cell carcinoma decreases by 15%. Renal cell carcinoma is not an occupational disease, although there is evidence of an increased risk in people employed in weaving, rubber, paper production, having constant contact with industrial dyes, nitroso compounds, oil and its derivatives, cyclic hydrocarbons, asbestos, industrial pesticides and heavy metal salts.

Most studies have confirmed the adverse effect of lipid metabolism disorders and excess body weight on the likelihood of kidney cancer. Obesity increases its incidence by 20%. Patients with arterial hypertension have a 20% increased risk of renal cell carcinoma. Comparative studies have shown that lowering blood pressure during therapy does not reduce the risk of tumor development. However, it should be remembered that a kidney tumor itself contributes to the development and progression of arterial hypertension as one of the extrarenal symptoms. Diseases that lead to nephrosclerosis (arterial hypertension, diabetes mellitus, nephrolithiasis, chronic pyelonephritis, etc.) can be risk factors for kidney cancer. The close relationship between diabetes mellitus, high blood pressure and obesity makes it difficult to assess the impact of each of these factors. An increased risk of renal cell carcinoma has been noted in terminal chronic renal failure, especially in the context of long-term hemodialysis. Kidney trauma is considered a reliable risk factor for the development of a kidney tumor. Research is being conducted to identify the risk of cancer development in polycystic, horseshoe kidneys, and in hereditary glomerulopathies.

A correlation has been noted between the incidence of kidney cancer and excessive meat consumption. Hydrolytic components, in particular heterocyclic amines, formed during heat treatment of meat have a proven carcinogenic effect. Genetic studies have demonstrated the possibility of translocation of chromosomes 3 and 11 in patients with kidney cancer.

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

Pathogenesis

There are clear cell (most common), granular cell, glandular (adenocarcinoma), sarcoma-like (spindle cell and polymorphic cell) renal cell cancer. When they are combined in one preparation, they are called mixed cell cancer.

With invasive growth, the tumor can compress the abdominal organs (liver, stomach, spleen, intestines, pancreas) and grow into them. In addition to the growth of adjacent organs, hematogenous and lymphogenous metastasis, one of the main pathomorphological features of kidney cancer is its ability to spread in the form of a kind of tumor thrombus through the intrarenal veins into the main trunk of the renal vein, and then into the inferior vena cava up to the right atrium.

Hematogenous metastasis occurs to the lungs, liver, bones of the skull, spine, pelvis, diaphysis of tubular bones, the opposite kidney, adrenal glands and brain.

• In hematogenous metastasis, in 4% of patients, tumor manifestations are caused by primary metastasis.
• Lymphogenous metastasis is observed along the renal pedicle vessels in the paraaortic, aortocaval and paracaval lymph nodes, in the posterior mediastinum. Neoplasms that are metastases of cancer of another primary localization may be found in the kidney: adrenal cancer, bronchogenic lung cancer, stomach, mammary and thyroid gland cancer.

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

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

Symptoms renal cell cancer

Among the clinical symptoms of renal cell carcinoma, it is customary to distinguish the classic triad (hematuria, pain, and a palpable tumor) and the so-called extrarenal symptoms of renal cell carcinoma. Hematuria can be both macro- and microscopic. Macrohematuria, usually total, occurs suddenly, is initially painless, may be accompanied by the passage of worm-like or shapeless blood clots, and suddenly stops. When clots appear, ureteral occlusion may be observed on the affected side with the appearance of pain resembling renal colic. The tumor is characterized by total macrohematuria, then the appearance of clots in the urine, and only then an attack of pain, unlike nephrolithiasis, when an attack of pain initially occurs, at the height or against the background of abatement of which a visible admixture of blood appears in the urine; clots are rare. The cause of macrohematuria in renal cell carcinoma is tumor growth in the renal pelvis, destruction of tumor vessels, acute circulatory disorders in the tumor, as well as venous stasis not only in the tumor, but also in the entire affected kidney.

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

When palpating the abdomen and lumbar region, the signs characteristic of a kidney tumor (a dense, lumpy, painless formation) cannot always be determined. The palpable formation may be the tumor itself if it is localized in the lower segment of the kidney or an unchanged lower segment if the tumor is located in the upper parts of the organ. In this case, the statement about nephroptosis and the refusal to further diagnose the tumor become a serious mistake. If the tumor is very large, it can descend into the pelvis, occupying the corresponding half of the abdomen. In the case of tumor growth into the muscles and adjacent organs, infiltration of the renal pedicle, the palpable formation loses respiratory mobility and the ability to move during bimanual palpation (balloting symptom).

Extrarenal symptoms of renal cell carcinoma are extremely diverse. N.A. Mukhin et al. (1995) identify the following paraneoplastic reactions in renal tumors:

• general symptoms of renal cell carcinoma (anorexia, weight loss, cachexia), sometimes not associated with intoxication for a long time;
• feverish;
• hematological;
• dysproteinemic;
• endocrinopathic;
• neurological (neuromyopathy);
• skin (dermatoses);
• articular (osteoarthropathies);
• nephrotic.

At present, we can talk about the pathomorphosis of this disease (extrarenal symptoms of renal cell carcinoma have become typical manifestations of renal cell carcinoma), which occurred largely due to improved diagnostics. The literature has reported on the development of precise research methods for the earliest possible detection of kidney tumors, 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 is of particular importance for an internist-nephrologist.

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

The basis of arterial hypertension in tumors may be thrombosis and compression of the renal veins by the tumor or enlarged retroperitoneal lymph nodes. In the absence of these changes, an increase in arterial pressure is possible as a result of compression of the intrarenal vessels by the tumor with disturbances in the intrarenal blood flow. However, one cannot deny the production of pressor agents by the growing neoplasm. Arterial hypertension in this case may have certain features of nephrogenic hypertension: absence of crises, scanty clinical manifestations, accidental detection, resistance to traditional therapy, etc.

Fever in renal cell carcinoma can vary - from constant subfebrile to high numbers. A distinctive feature of an increase in body temperature is the general satisfactory condition of the patient, 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 usually associated with the release of endogenous pyrogens (interleukin-1); infectious nature, as a rule, is absent.

Renal cell carcinoma in men may be accompanied by the appearance of varicose veins of the spermatic cord (varicocele). It is symptomatic, unlike idiopathic, which occurs in the prepubertal period only on the left and disappears in the horizontal position of the patient. Symptomatic varicocele with a tumor occurs in an adult without apparent cause, is observed both on the right and on the left, progresses and does not disappear in the horizontal position, since it is associated with compression or tumor thrombosis of the testicular and / or inferior vena cava. The appearance of varicocele in adulthood, as well as the development of varicocele on the right, allow us to suspect a kidney tumor.

Symptoms of Renal Cell Carcinoma

Symptom	Frequency, %	Frequency of occurrence as the first symptom, %	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 mass in the 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 the extent that it would be possible to talk about specific substances associated with their occurrence. Currently, persistent searches are underway, including at the genetic level, for the causes that determine extrarenal and paraneoplastic manifestations, with the aim of identifying markers of the tumor process.

In recent years, 25-30% of patients have extremely scanty and non-specific clinical symptoms of renal cell carcinoma or have none at all. During preventive ultrasound examinations or examinations with suspected diseases of the liver, bile ducts, pancreas, adrenal glands, spleen, damage to the retroperitoneal lymph nodes, with unclear pain in the abdomen and lumbar region, kidney tumors began to be detected in 0.4-0.95% of those examined. The idea of a more frequent occurrence of renal neoplasms in the presence of background diseases leading to nephrosclerosis (hypertension, diabetes mellitus, nephrolithiasis, chronic pyelonephritis, etc.) justify the urgent need for mandatory ultrasound examination of these patients for the purpose of active early detection of renal cell carcinoma even in the absence of any characteristic complaints.

Stages

To determine treatment tactics, evaluate treatment results and prognosis, the international TNM classification has been adopted.

T (tumor) - primary tumor:

• T1 - a tumor up to 7 cm in size, limited to the kidney and not extending beyond the renal capsule.
• T2 - the tumor is more than 7 cm, limited to the kidney and does not extend beyond the renal capsule.
• T3 - a tumor of any size that grows into the pararenal tissue and/or extends into the renal and inferior vena cava.
• T4 - the tumor invades the perirenal fascia and/or spreads to adjacent organs.

N (nodulus) - regional lymph nodes:

• N0 - lymph nodes are not affected by metastases.
• N1 - metastases in one or more lymph nodes, regardless of their size.

M (metastes) - distant metastases:

• M0 - no distant metastases.
• M1 - distant metastases detected.

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

• Stage I - T1 in the absence of lymph node damage and distant metastases;
• Stage II - T2 in the absence of lymph node involvement and distant metastases;
• Stage III - TZ in the absence of lymph node damage and distant metastases;
• Stage IV - any T values with damage to the 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 at stage I of the disease suggests greater success of organ-preserving surgical treatment.

[ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ], [ 30 ]

Diagnostics renal cell cancer

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

Laboratory diagnostics

Laboratory signs include anemia, polycythemia, increased ESR, hyperuricemia, hypercalcemia, and Stauffer syndrome.

It has been proven that endogenous pyrogens can release lactoferrin. This glycoprotein is found in most body fluids and in polymorphonuclear leukocytes. It binds divalent iron, which is one of the main causes of early anemia. It can also be caused by toxic effects on the red bone marrow with suppression of its function.

When erythrocytosis is detected, renal cell carcinoma must be excluded before diagnosing erythremia. Impaired venous outflow from the affected kidney, which may be a consequence of tumor thrombosis of the renal vein, promotes increased production of erythropoietin, which stimulates the red germ of hematopoiesis. It should be remembered that such patients may have arterial hypertension against the background of significant blood thickening with changes in hematocrit, slowing of ESR and a tendency to thrombosis. In the absence of erythrocytosis, an accelerated ESR is more often observed as a non-specific sign of many cancerous lesions. Hypercalcemia without signs of bone damage is another manifestation of the paraneoplastic process in renal cell carcinoma. Possible causes of its development are the formation of ectopic parathyroid hormone, the effect of vitamin D, its metabolites, prostaglandins, osteoblast activating factor and growth factors.

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

[ 31 ], [ 32 ]

Ultrasound examination

Ultrasound examination is rightfully considered the simplest and most accessible screening method for diagnosing renal cell carcinoma. It should be the first method of examining a patient if a kidney tumor is suspected. Characteristic signs of a tumor process in the renal parenchyma are an increase in the size of the organ, uneven contours, and a difference in the echostructure of the detected formation compared to the surrounding intact parenchyma. One of the ultrasound signs of a tumor is deformation of the renal sinus and the calyceal-pelvic system. If the tumor is located centrally, it displaces and deforms the pelvis and calyces, while the surrounding renal parenchyma becomes denser.

When a volumetric neoplasm is detected, not only its nature is assessed, but also its size, localization, depth, prevalence, boundaries, connection with surrounding organs and tissues, and possible spread to large vessels. The use of ultrasound Doppler imaging significantly helps in solving this problem. Most tumor nodes in the kidney are hypervascular, but the absence of an abundance of newly formed vessels does not exclude renal cell carcinoma. Ultrasound examination allows one to detect enlarged regional lymph nodes larger than 2 cm.

Computer tomography

Improvement of diagnostic technologies, distribution of computer X-ray examination methods with digital image processing, possibilities of constructing three-dimensional images based on transverse and spiral sections (tomography) in various modes for detection of contours of organs and formations, their any sections in the program of visualization of blood vessels (angiography), urinary tract (urography), their combinations have significantly changed the nature and sequence of diagnostic measures in patients with kidney tumors. Wide possibilities of multispiral X-ray CT with three-dimensional reconstruction of images have reduced to a minimum the need for excretory urography and renal angiography in these patients. Currently, computed tomography should rightfully be considered as the main method of visualization of renal cell carcinoma. Its sensitivity in diagnostics of kidney tumors approaches 100%, accuracy is 95%.

On CT scans, kidney cancer is visualized as a soft tissue node that deforms the cortex, which can spread into the paranephric tissue and renal sinus with compression or involvement of the calyceal-pelvic system in the tumor process. The presence of calcifications in the wall of common solitary cysts should be alarming in terms of possible cancer. Intravenous contrast helps in doubtful cases: the difference in the nature and intensity of contrast in comparison with the externally intact parenchyma is one of the signs of cancer. An increase in the diameter, filling defects of the renal vein indicate its involvement in the tumor process.

[ 33 ], [ 34 ]

Magnetic resonance imaging

MRI plays an important role in the diagnostic algorithm for renal cell carcinoma. This is especially true for patients with renal failure, individuals with intolerance to radiopaque iodine preparations, and patients with contraindications to the use of ionizing radiation. The ability to obtain a multi-plane image in different planes is of particular importance when assessing the origin of the primary tumor (kidney, adrenal gland, retroperitoneal space), when X-ray CT data are ambiguous. Despite the high resolution, the ability to multi-axial visualization and assess blood circulation without contrast enhancement, the use of MRI in detecting small tumors is limited due to the similar signal intensity of normal parenchyma and renal cell carcinoma in both T1 and T2 modes. However, when using different modes, the information content of this study is 74-82%, and the accuracy is not inferior to CT.

The indisputable advantage of MRI is good visualization of the main vessels, which is of great importance for detecting venous tumor invasion. Even with complete occlusion of the inferior vena cava, clear visualization of the tumor thrombus and precise determination of its extent without contrast are possible. Therefore, MRI is now considered as the method of choice in diagnosing tumor thrombosis and assessing its extent, which is of invaluable importance in developing treatment tactics. The informativeness of this study in diagnosing metastatic lesions of the lymph nodes, unfortunately, has not been sufficiently studied. Contraindications to MRI are claustrophobia, the presence of an artificial pacemaker, the presence of metal prostheses and surgical staples. One should not forget about the very high cost of this method.

Renal angiography

Until recently, renal angiography was the main diagnostic method for renal cell carcinoma and a means of developing treatment tactics. Arteriograms usually revealed a hypervascular tumor node (the "lakes and puddles" symptom), dilation of the renal artery and vein on the affected side, and filling defects in the lumen of the veins with tumor invasion. Currently, vascular studies using transfemoral access according to Seldinger are performed using a subtraction (subtraction) technique with digital processing of X-ray data.

Indications for renal angiography:

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

Excretory urography

Excretory urography is not a diagnostic method for renal parenchyma tumors. Urograms can reveal an increase in size, deformation of the kidney and the renal pelvis - indirect signs of a volumetric formation. Excretory urography is indicated in cases of pathological changes (stones, hydronephrosis, anomalies, consequences of the inflammatory process) of the opposite, remaining kidney, as well as in case of alarming results of a pharmacoultrasound examination. The limitation of indications for this routine examination is due to the possibility of obtaining all the necessary information with multispiral computed tomography and MRI in a special urographic mode.

[ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ]

Radioisotope diagnostics of renal cell carcinoma

Radioisotope methods of kidney examination are also not used to diagnose renal parenchymal tumors, but they help in assessing the function of both the affected and healthy kidneys.

Ultrasound, CT and MRI allow to detect volumetric kidney formations in more than 95% of patients, to establish the nature of the disease in 90% of cases, to 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 diagnostics should be individual and comprehensive.

Differential diagnosis

Differential diagnostics of renal cell carcinoma is performed with solitary cyst, polycystic kidney disease, hydronephrosis, nephroptosis, carbuncle and renal abscess, pyonephrosis, retroperitoneal tumors and other diseases manifested by enlargement and deformation of the organ. In addition to the characteristic clinical manifestations and complications of these diseases, ultrasound data certainly play an important role. They allow diagnosing solitary cysts and polycystic disease based on characteristic signs, and suspecting hydronephrotic transformation based on dilation of the renal pelvis and calyces for subsequent clarification by routine X-ray contrast studies. Carbuncle and renal abscess have a corresponding clinical picture. Doubts about the liquid or dense contents of a volumetric formation are indications for its puncture under ultrasound control, examination of its contents (general clinical, bacteriological, cytological), if necessary, with subsequent introduction of a contrast agent for cystography.

The corresponding anamnesis, the presence of ring-shaped calcification, eosinophilia, positive specific reactions are the basis for differential diagnostics with renal echinococcosis. In the vast majority of cases, ultrasound diagnostics of renal cell carcinoma and other studies do not allow us to judge the nature of the tumor. The exception is renal angiomyolipomas, which are hyperechoic in ultrasound examination and have adipose tissue density in CT.

[ 43 ], [ 44 ], [ 45 ], [ 46 ], [ 47 ], [ 48 ]

Treatment renal cell cancer

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

The operation of choice today is rightfully considered to be kidney removal - radical nephrectomy with removal of the affected kidney as a single block with paranephric tissue and fascia in combination with regional and juxtaregional lymphadenectomy.

Taking into account the possible presence of undetectable macroscopic metastatic changes in the lymph nodes, it is necessary to remove the tissue containing the lymphatic apparatus. For the right kidney, this is the pre-, retro-, latero- and aortocaval tissue from the crura of the diaphragm to the bifurcation of the aorta; for the left kidney, this is the pre-, latero- and retroaortic tissue.

In recent years, organ-preserving surgeries have become more widespread. Absolute indications for them are considered to be cancer of a single or both kidneys, cancer of one kidney with pronounced functional failure of the other kidney and signs of chronic renal failure. In recent years, the most gentle laparoscopic surgeries have been more widely introduced.

Radiation therapy has no significant effect on the outcome of renal cell carcinoma. Chemotherapy does not affect the kidney tumor and is used for lung metastases. The effectiveness and features of immunotherapy using interferon drugs, as a new method of treating renal cell carcinoma, are currently being studied.

Outpatient observation

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

[ 49 ], [ 50 ], [ 51 ], [ 52 ]

Forecast

Five-year survival after successful organ-preserving operations for kidney tumors today exceeds 80%. It certainly depends on timely detection of the disease. According to the urology clinic of the Moscow Medical Academy named after I.M. Sechenov, with tumor sizes up to 4 cm, 5-year survival is 93.5% (after nephrectomy - 84.6%), with sizes from 4 to 7 cm - 81.4%.

[ 53 ], [ 54 ]