Kidney Cancer

Kidney cancer ranks 10th in terms of incidence among malignant neoplasms, and in terms of its growth rate is second only to prostate cancer. The incidence of renal cell carcinoma reaches a maximum of 70 years. Men suffer from this nosology 2 times more often than women. 

[1],

Epidemiology

Kidney cancer is the most common oncological disease of kidney tissue. Occasionally there are tumors of the renal pelvis and sarcoma (Wilms tumor, Wilms tumors). The latter affect only children, and up to 90% of Wilms tumors are diagnosed in patients younger than 5 years.

Annually, 189,100 new cases of this disease are registered in the world (2.2% among malignant neoplasms in men and 1.5% in women) and 91.1 thousand deaths. The average age of the sick is 61.4 years, the deceased - 66 years.

Previously, it was assumed that the kidney cancer originates from the adrenal glands, so this category of neoplasms was called hyper nephroma. Currently, it is common to select several types of kidney cancer. Most often (in 70-80% of cases of kidney cancer) there is a clear-cell type of tumor (clear-cell RCC). It is assumed that the light-celled kidney cancer originates from the proximal parts of the renal tubules.

Another typical type of kidney cancer (10-15% of cases) are papillary renal carcinomas; Many papillary forms of kidney cancer are distinguished by relatively safe flow. Chromophobic tumors account for 5% of kidney cancer and are also characterized by a good prognosis. Carcinomas of the collecting departments of renal tubules are quite rare (less than 1% of kidney cancer) and represent the most aggressive variety of tumors of this localization.

Renal cell carcinomas account for approximately 3% of all cancers in adults. The occurrence of kidney cancer increases by about 2.5% per year. The individual risk of kidney cancer is 0.8-1.4%, depending on gender and the presence of risk factors. The increase in the incidence of kidney cancer is at least partly due to the widespread introduction of volumetric research methods (ultrasound diagnostics, computed tomography, nuclear magnetic resonance), which allow to detect small, asymptomatic tumors. However, the frequency of advanced forms of kidney cancer also continues to increase, which indicates the existence of a "true" increase in morbidity.

The highest frequency of kidney cancer is observed in North America and Scandinavia. A rare occurrence of kidney cancer is inherent in the countries of South America, Asia and Africa. Men are ill with cancer of the kidney about twice as often as women. The peak incidence falls on the age of 50-70 years; with the hereditary nature of the pathogenesis of kidney cancer can occur much earlier, often in people younger than 40 years.

In the world, the incidence of kidney cancer varies from about 2.0 to 12.0 per 100,000 people. High indicators are characteristic for developed countries of America and Europe, and low ones for Asia, including Japan, India, and China.

[2], [3], [4], [5], [6]

Causes of the kidney cancer

A large number of studies have been devoted to kidney cancer, but the etiology of this type of tumor is still unclear. There are several groups of risk factors that contribute to the development of this new growth.

Known risk factors can only partially explain the variation in the incidence of kidney cancer. The most reproducible data is obtained with regard to smoking: it is assumed that this habit increases the likelihood of the occurrence of the disease by about 2 times, and the most dangerous are "inveterate" smokers. Kidney cancer is also associated with overweight. An increased incidence of kidney cancer is observed in the abuse of food of animal origin, while people with a propensity for a vegetarian diet are less likely to have kidney cancer. The risk of the disease increases somewhat when using estrogens. Contact with various chemicals, especially in the workplace, can also contribute to the occurrence of kidney cancer.

There are data on the relationship between the presence of  arterial hypertension  and an increased likelihood of developing a tumor. The risk of kidney cancer increases dramatically in terminal stages of kidney failure; the success of hemodialysis made the relevant clinical situations compatible with life, which led to the emergence of a new etiological category of kidney cancer.

Sex and age

The incidence of kidney cancer depends on age and reaches a maximum of 70 years. Men suffer from this pathology twice as often as women.

[7], [8],

Smoking

It has now been proved that smoking tobacco is one of the most significant risk factors for the development of various malignant neoplasms, including kidney cancer. The risk of kidney cancer in smokers of both sex groups increases from 30 to 60% compared with non-smokers.

At the same time, the more cigarettes are smoked daily and the longer the smoking, the more likely the development of kidney cancer. If you quit smoking, the probability of developing a disease decreases.

Obesity and overweight

In most studies, the adverse effect of excessive body weight on the likelihood of developing kidney cancer has been confirmed. Obesity  leads to an increase in the incidence of kidney cancer by 20%. Perhaps this is due to the increase in the concentration of endogenous estrogens and to the biological activity of insulin-like growth factors.

Arterial hypertension

An increase in the risk of developing kidney cancer in patients with arterial hypertension was noted at 20% with an anamnesis of 5 years or more. The question of the influence of antihypertensive drugs on the development of malignant process is being studied.

[9], [10], [11], [12], [13], [14], [15], [16]

Medications

Many authors associate the appearance of kidney cancer with the use of diuretic drugs. The risk of developing this pathology in patients who received diuretics for various indications is more than 30%.

Taking into account the role of obesity as a risk factor, an assessment was made of the effect of drugs used to reduce body weight on the likelihood of developing kidney cancer. It was found that drugs containing amphetamine significantly increase the risk of developing kidney cancer.

Analgesics containing phenacetin also contribute to the development of a malignant process in the kidney parenchyma.

Diabetes. In the literature, there are data on the increase in the incidence of kidney cancer in patients with diabetes mellitus. The close relationship between diabetes, obesity and hypertension makes it difficult to assess the true impact of each of these diseases on the incidence of kidney cancer.

Reproductive and hormonal factors

Potential pathogenetic significance of hormonal factors in the development of kidney cancer has been proven in animal studies. In healthy and malignant tissues of the kidneys of animals, sex hormone receptors have been identified. However, unequivocal evidence of the adverse effect of estrogens on the risk of developing kidney cancer in humans has not been obtained.

Diet

In epidemiological studies, the correlation of the incidence of kidney cancer with the consumption of meat, plant products, as well as margarine and oil was noted. However, there is no reliable effect of specific food products on the incidence of kidney cancer. Perhaps the pathogenetic value is not the raw materials themselves, but the substances formed during the cooking process. The heterocyclic amines formed during heat treatment of meat have a proven carcinogenic effect. The use of fruits and vegetables, according to most authors, helps reduce the risk of developing kidney cancer.

Profession

Kidney cancer is not an occupational disease. However, the published data on the increased risk of this pathology in persons engaged in weaving, rubber-rubber, paper production, which have contact with industrial dyes, pesticides and heavy metal salts.

Hereditary kidney cancer

Several forms of hereditary pathologies are described with respect to kidney cancer.

The most famous is  von Hippel-Lindau syndrome  (von Hippel-Lindau). At the heart of this syndrome lies the germ mutation in the VHL gene, which was mentioned above. Pathomorphological examination of the kidneys in patients with hereditary damage to one of the VHL alleles makes it possible to identify hundreds and sometimes even thousands of malignant transformation loci. In addition to kidney cancer, neoplasms of the pancreas, adrenal glands, brain, etc. Can also be observed in carriers of the mutant gene. Although von Hippel-Lindau syndrome represents the majority of hereditary forms of kidney cancer, its occurrence in the population is relatively low and is 1 at 40 000 people.

Interestingly, in many patients with a hereditary form of kidney cancer, the congenital translocation of the chromosome 3p is detected even in routine cytogenetic studies. Similar patients are isolated in a separate group, since their VHL gene retains intact structure and there is no "out-of-kid" manifestation of von Hippel-Lindau syndrome.

Hereditary papillary renal carcinoma belongs to a rare category of familial cancers caused by an embryonic activating mutation in the oncogene. The cause of this syndrome is a micromutation in the oncogene MET, which codes for the receptor tyrosine kinase. Carriers of the activated MET allele in the kidneys are detected up to 3400 microcarcinomas.

Birt-Hogg-Dube syndrome is characterized not only by the appearance of chromophobic kidney cancer and oncocyte, but also by the presence of multiple tumors of the hair follicles, as well as bronchopulmonary cysts, often accompanied by pneumothorax. The BHD gene associated with this syndrome is located on the short arm of chromosome 17. The functions of the BHD gene are by now unknown.

Another rare type of hereditary disease is the combined predisposition to leiomyomas and renal carcinomas. This syndrome is associated with mutations in the fumarate-hydratase gene, which encodes the enzyme of the Krebs cycle.

Pathogenesis

A distinctive feature of the molecular portrait of kidney cancer is the ability to identify the main genetic event in the pathogenesis of a particular form of the disease.

For light-cell kidney cancer, the most characteristic event is the inactivation of the VHL gene (von Hippel-Lindau syndrome). The VHL gene is to a certain extent unique: it does not have homologues in the human genome. Relatively recently it was found that the VHL gene participates in the regulation of the biochemical adaptation of the cell to the conditions of hypoxia. In particular, the VHL protein interacts with the alpha subunits of the so-called. Hypoxia-Inducible Factors (HIFI, HIF2), which regulate the transcription of a number of genes involved in the processes of providing the cell with oxygen. When VHL is inactivated, the cell triggers adaptation reactions to hypoxia even if tissue oxygenation is maintained at a normal level. As a result, anomalous production of many growth factors is observed, including molecules that promote increased angiogenesis.

In the papillary kidney cancer, a mutational activation of tyrosine kinase MET is often observed. MET is a membrane receptor; one of the known ligands of MET is the growth factor of hepatocytes. MET participates in the initiation of proliferative signaling cascades.

Stable cytogenetic abnormalities are described for kidney cancer. The most common is the loss of the short arm of chromosome 3. The pathogenetic significance of this phenomenon is at least partly due to the inactivation of the VHL gene located on chromosome Sp25. It is assumed that other genes located in the same chromosomal locus can participate in the pathogenesis of kidney cancer. In addition to the 3p deletion, some other chromosomal lesions are observed in kidney cancer. Identification of such cytogenetic features may be important in the differential diagnosis of histological types of kidney cancer. For example, papillary kidney cancer is characterized by trisomy of chromosomes 7.16 and 17, as well as loss of chromosome Y; with chromophobic kidney cancer, monosomies of chromosomes 1, 2, 6 and 10 are most often observed.

[17], [18]

Symptoms of the kidney cancer

Symptoms of kidney cancer, described earlier, occur in 15% of patients (pain, macromembria and palpable tumor), is now rare. The appearance of varicocele is noted in 3.3% of patients, arterial hypertension - in 15%, the syndrome of compression of the inferior vena cava (edema of the legs, varicocele, dilatation of the subcutaneous veins of the stomach, deep vein thrombosis of the lower extremities, proteinuria) due to tumor thrombosis and enlarged lymph nodes 50% of patients. Kidney cancer is characterized by a wide variety of paraneoplastic symptoms, which include arterial hypertension, erythrocytosis,  hypercalcemia, hyperthermia, amyloidosis, the development of liver failure in the absence of its metastatic lesion (Staubert's syndrome). The appearance of visceral metastases causes the development of the corresponding symptoms. Signs of late stages - anemia, high ESR, loss of appetite, weight loss, weakness.

[19], [20]

Forms

Renal cell tumors:

• light-celled kidney cancer;
• multilocular light-celled kidney cancer;
• papillary kidney cancer;
• chromophobic kidney cancer;
• cancer of the collecting ducts Bellini;
• medullary kidney cancer;
• cancer with translocation Xp 11;
• cancer associated with neuroblastoma;
• mucous tubular and spindle cell carcinoma;
• kidney cancer (unclassified);
• papillary adenoma;
• oncocytoma.

Metanephrenic tumors.

Neuroblastic tumors.

Mesenchymal tumors:

• mixed mesenchymal and epithelial tumors;
• neuroendocrine tumors;
• hematopoietic and lymphoid tumors;
• germinogenno-cellular tumors.

Metastatic kidney cancer.

Clinical classification of kidney cancer according to TNM (IUCN, 2003)

Currently, in many countries, use the classification proposed by the International Anti-Cancer Union (6th edition), detailing the prevalence of the tumor process in order to determine therapeutic tactics. When using the TNM classification, histological confirmation of the diagnosis is mandatory.

T - primary tumor:

Tx - insufficient data to estimate the primary tumor;

T0 - primary tumor is not detected;

T1 - tumor up to 7 cm in the largest dimension, bounded by the kidney;

• T1a - tumor 4 cm or less;
• T1b - tumor more than 4 cm, but less than 7 cm;

T2 - tumor more than 7 cm in the largest dimension, bounded by the kidney;

TK - the tumor extends to large veins or over-the kidneys or perineal tissues, but does not extend beyond the fascia of Herota;

• TZa - tumor invasion of the adrenal gland or paranephric fiber within the fascia of the Herota;
• ТЗb - the tumor extends into the renal vein or inferior vena cava;
• ТЗс - the tumor extends into the inferior vena cava above the diaphragm;

T4 - the tumor extends beyond the fascia of Herota.

N - regional lymph nodes:

• Nx - regional lymph nodes can not be evaluated;
• N0 - no metastases in the regional lymph nodes; N1 - metastasis in one lymph node;
• N2 - metastases in more than one regional lymph node.

M - distant metastases:

• Mx - distant metastases can not be evaluated;
• M0 - no distant metastases;
• M1 - distant metastases.

G - histological gradation:

• Gx - the degree of differentiation can not be estimated;
• G1 is a highly differentiated tumor;
• G2 - moderately differentiated tumor;
• G3-4 is a low-grade / undifferentiated tumor.

Grouping by stages: Stage I T1 N0 M0 Stage 11 T2 N0 M0 Stage 111 T3 N0 M0 Tl, T2, T3 N1 M0 Stage IV T4 N0, N1 M0 Any T N2 M0 Any T Any N M1.

[21], [22], [23]

Diagnostics of the kidney cancer

Most often, the kidney tumor is detected with  ultrasound. Despite the high diagnostic value of ultrasound, the latter should always be supplemented with CT scan by the main method of diagnosing volumetric kidney formations. MRI is performed by patients with an allergy to iodine-containing contrast agents, chronic renal failure, tumor thrombosis of the inferior vena cava, and to confirm bone metastases. When examining patients with tumors of the renal parenchyma CT of the abdominal cavity, retroperitoneum and lungs, an obligatory diagnostic procedure aimed at identifying regional and distant metastases. Bone scans are recommended to patients with appropriate complaints and / or increased serum alkaline phosphatase activity. CT scan of the brain is indicated in patients with neurological symptoms.

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Treatment of the kidney cancer

Radical nephrectomy remains the gold standard for the treatment of localized and locally advanced kidney cancer (T1a-T4N0 / + M0). This intervention implies the removal of the kidney with a single block of the adrenal and paranephrine within the fascia of Gerota in conjunction with regional lymphadenectomy. Tumor venous thrombosis is an indication for thrombectomy, the technique of which is determined by the extent of the thrombus and the degree of its fixation to intima of the vessel and, in cases of tumor spreading to the right heart, to the endocardium.

Laparoscopic radical nephrectomy has become the standard for the treatment of patients with categories T1a-T2, allowing to comply with all oncological principles, but associated with less trauma than open surgery.

With small tumors, organ-preserving surgeries are used. Obligatory indications for kidney resection significant decrease / absence of excretory function, hypoplasia / aplasia of the contralateral kidney or bilateral tumor damage; relative indications are a decrease in the function of the contralateral kidney, a high risk of postoperative acute renal failure, congenital forms of bilateral renal cancer with a high likelihood of metachronous tumors in the contralateral kidney. Elective indication for organ-preserving intervention is renal cancer in stage T1a with unaltered contralateral kidney.

Resection of the kidney in patients with a tumor less than 4 cm is capable of providing a disease-free and long-term survival comparable to the results of radical nephrectomy. The question of the adequacy of resection of the kidney with Tib stage with a tumor size of 4-7 cm is discussed. If the tumor is completely removed, the size of the surgical margin (for an indentation from the tumor more than 1 mm) is not associated with a greater likelihood of occurrence of local recurrence.

Laparoscopic resection of the kidney may be an alternative to open resection in a limited number of patients and it should be performed by a surgeon who has experience of such operations. Optimal indications for interventions of this type are small tumors that are primarily extraparenchymatous.

The use of laparoscopic access is associated with less trauma and a good cosmetic effect, but leads to an increase in the time of ischemia and an increase in the frequency of surgical complications. The oncological radicality of these interventions corresponds to open resection, long-term results are in the study stage.

Minimally invasive methods of treatment of kidney cancer (radiofrequency ablation, cryoablation, microwave ablation, ablation with a high-intensity focused ultrasonic wave) can serve as an alternative to the surgical method in carefully selected patients. Ablation can be recommended for patients with small tumors located in the cortical layer of the kidney parenchyma, which has contraindications to surgical intervention, as well as patients with multiple and / or bilateral tumors. The results of ablative techniques are being studied.

Indications for adjuvant therapy after the operative treatment of kidney cancer outside the scope of clinical protocols there. The effectiveness of adjuvant tumor vaccination is studied using targeted drugs potentially capable of improving disease-free survival, especially in patients with category T3. Adjuvant therapy with cytokines (interferon a, interleukin-2) does not affect survival after a radically performed nephrectomy surgery.

Kidney Cancer Treatment: Disseminated Kidney Cancer (M +)

Indications for surgical treatment of patients with disseminated kidney cancer receiving immunotherapy were determined. All patients with a M + category having a satisfactory somatic status are shown to perform nephrectomy. In patients with multiple metastases, nephrectomy is palliative. In a meta-analysis of two randomized studies comparing nephrectomy in combination with immunotherapy and only immunotherapy, the survival benefit of operated patients was noted. The feasibility of performing palliative nephrectomy in patients receiving targeted therapy has not been proven and is currently being studied.

In the case of solitary or single metastases, their prompt removal allows the patient to be cured. The complete removal of all metastatic foci improves the clinical prognosis for disseminated kidney cancer. Removal of metastases is recommended for patients with a limited number of tumor sites, the possibility of their radical rapid removal and good somatic status. Removal of metastases should also be performed by patients with residual tumor and removable foci that reacted to previous immunotherapy.

Despite the lack of resistance to kidney cancer,  radiation therapy  can be used in case of metastases in the brain and bone lesions. Since it is able to significantly reduce the symptomatic manifestations of the above-mentioned localizations.

Renal cell adenocarcinoma is characterized by overexpression of the gene for multiple drug resistance, the product of which is responsible for removing toxic substances from the cell, including cytostatics. In this regard, kidney cancer is chemically resistant.

Clinical observations of spontaneous regression and detection of cytotoxic T-lymphocytes in patients with kidney cancer in peripheral blood, as well as populations of mononuclear cells infiltrating the tumor, served as a theoretical basis for treating renal cell carcinoma as an immunogenic tumor whose treatment can be based on immune modulation. Until recently, immunotherapy played a leading role in the treatment of common forms of kidney cancer. The standard of treatment was therapy with the use of interferon-2a and interleukin-2.

The total response to immunotherapy with interferon a varies from 10 to 20%. Accounting for an average of 15%, a full-2%. The duration of remission in the vast majority of patients is low and is 6-10 months, but in 5-7% of patients with a full response to treatment it is possible to achieve a long-term remission. Despite the sufficient experience of using interferon a in disseminated kidney cancer, the optimal dose and regimens for its administration have not been determined. The use of single doses of interferon a less than 3 million IU reduces effectiveness. And an increase in a single dose of this cytokine of more than 10 million ME does not give any advantages. The most common mode of interferon therapy is a-6 million ME subcutaneously. 3 times a week, long.

The overall efficacy of interleukin-2 is 15% with a total and partial remission rate of 7% and 8%, respectively. Optimal doses of interleukin-2 are not known; the most common mode is 125-250 IU / kg subcutaneously. 3 times a week, long. The greatest effectiveness of the drug is observed with intravenous administration, but it is associated with a high incidence of severe complications and even lethality associated with its toxicity.

The factors of unfavorable prognosis for disseminated kidney cancer, which include somatic status (Karnovsky index <80%), are singled out. High LDH activity (1.5 times higher than normal), hypercalcemia (corrected calcium more than 10 mg / L), anemia (Hb less than 13 g / L) and time from primary diagnosis to systemic treatment less than a year. Based on the results obtained, a prognostic model of MSKCC was developed that identifies a group of poor (more than three risk factors, a median survival of 6 months). Moderate (1-2 risk factors, median survival - 14 months) and a favorable prognosis (no risk factors, median survival - 30 months). Standard cytokine therapy is highly effective in the group of good prognosis. Is ineffective in patients with moderate and ineffective in patients with poor prognosis.

The combination of cytokines (interferon a and interleukin-2) and cytostatic drugs (fluorouracil, vinblastine, cyclophosphamide, doxorubicin) and retinoids does not lead to an increase in treatment effectiveness.

A better understanding of the immunology of tumors has led to the creation of a fundamentally new generation of vaccines using dendritic cells. The latter are the most potent antigen-presenting cells that present the tumor antigen in combination with the proteins of the main histocompatibility complex of the first class to cytotoxic lymphocytes and activate the latter. Discovery of tumor-associated antigen G250. Specific for the kidney cancer present in 85% of the tumor observations and the release of an associated peptide recognized by cytotoxic T lymphocytes has given a new impetus to the creation of C250-peptide vaccines that are actively studied.

A fundamentally new approach is the use of monoclonal antibodies to the G250. Labeled with radioactive  ¹⁵¹ J, which actively accumulate in kidney tumors and can be used both for diagnostic and therapeutic purposes. Genetic modification of antitumor vaccines makes it possible to increase their effectiveness. Introduction ex vivo into the genome of tumor cells of certain polynucleotide sequences allows them to acquire the ability to produce various cytokines, which causes an increase in their immunogenicity. It is noted that vaccines that stimulate the production of granulocyte-macrophage colony-stimulating factor induce the formation of an immune response against the anti-coagulant tumors.

One of the most promising areas of immunotherapy for solid tumors resistant to other types of treatment is allogeneic stem cell transplantation, which causes a graft-versus-host reaction. In this case, non-myeloablative techniques are used, which make it possible to provide immunosuppressive action sufficient for carrying out allogeneic transplantation without inhibiting the recipient's own hematopoiesis. The frequency of clinically pronounced effect of such treatment in patients with disseminated kidney cancer reaches 53%. The main limiting factor is high toxicity, leading to a lethality in 12-30% of observations.

The emergence of effective targeted drugs causes gradual revision of approaches to the treatment of disseminated kidney cancer. For renal cell carcinoma, mutations of the VHL (Van Gippel-Lindau) gene are characteristic, which leads to the activation of tumor pathogenesis along the path of the endothelial growth factor. In this regard, drugs that block angiogenesis, lead to a delay in tumor growth in renal adenocarcinoma.

Forecast

Kidney cancer is characterized by a rather poor prognosis: 5-year survival is observed only in 40% of patients with kidney tumors, while in other urological tumors (tumors of the prostate, bladder) this figure is around 20%. Such statistics are related to the fact that the only effective method of treating kidney cancer is surgical. Kidney cancer is practically not sensitive to either traditional chemotherapy or radiotherapy. Sometimes the kidney cancer retains a certain immunogenicity, which explains the existence of spontaneous remissions and even regressions of the disease, and also in some cases allows observing the impressive effectiveness of treatment with high doses of interleukin-2 (IL-2).

The five- and ten-year survival of patients on kidney cancer of all stages is 61.5 and 46.6%, respectively. The most important factors of survival prognosis are categories T, N, M, histological variant and degree of tumor anaplasia, ploidy of DNA and mitotic index, as well as a number of molecular factors.

[25], [26], [27], [28]