Kidney cancer

Kidney cancer is the 10th most common malignant neoplasm, and is second only to prostate cancer in terms of its growth rate. The incidence of renal cell cancer peaks at age 70. Men suffer from this disease twice as often as women.

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Epidemiology

Kidney cancer is the most common oncological disease of the kidney tissue. Tumors of the renal pelvis and sarcomas (Wilms tumors) are rare. The latter affect only children, with up to 90% of Wilms tumors diagnosed in patients under 5 years of age.

Every year, 189.1 thousand 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 those infected is 61.4 years, and of those who died is 66 years.

Previously, it was assumed that kidney cancer originated from the adrenal glands, so this category of neoplasms was called hypernephromas. Currently, it is customary to distinguish several types of kidney cancer. The most common (in 70-80% of kidney cancer cases) is the clear cell (non-papillary) type of tumor (clear-cell RCC). It is assumed that clear cell renal cancer arises from the proximal parts of the renal tubules.

Another typical type of kidney cancer (10-15% of cases) is papillary renal carcinoma; many papillary forms of kidney cancer are characterized by a relatively favorable course. Chromophobe tumors make up 5% of kidney cancers and are also characterized by a good prognosis. Carcinomas of the collecting parts of the renal tubules are quite rare (less than 1% of kidney cancer) and represent the most aggressive type of neoplasms in this localization.

Renal cell carcinomas account for approximately 3% of all cancers in adults. The incidence of kidney cancer increases by approximately 2.5% annually. The individual risk of kidney cancer is 0.8-1.4%, depending on gender and the presence of risk factors. The increase in kidney cancer incidence is at least partly due to the widespread introduction of volumetric examination methods (ultrasound diagnostics, computed tomography, nuclear magnetic resonance), which make it possible to detect small, asymptomatic neoplasms. However, the incidence of advanced forms of kidney cancer also continues to increase, which indicates the existence of a “true” increase in incidence.

The highest incidence of kidney cancer is observed in North America and Scandinavia. Rare occurrence of kidney cancer is typical for South America, Asia and Africa. Men suffer from kidney cancer approximately twice as often as women. The peak incidence is at the age of 50-70 years; with a hereditary nature of pathogenesis, kidney cancer can occur much earlier, often in people under 40 years of age.

Worldwide, the incidence of kidney cancer fluctuates between approximately 2.0 and 12.0 per 100,000 people. High rates are typical for developed countries in America and Europe, and low rates are typical for Asia, including Japan, India, and China.

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Causes kidney cancer

A large number of studies have been devoted to kidney cancer, but the etiology of this type of tumor is still unclear. Several groups of risk factors have been identified that contribute to the development of this neoplasm.

Known risk factors can only partially explain variations in the incidence of kidney cancer. The most reproducible data are obtained for smoking: it is assumed that this habit increases the probability of developing the disease by approximately 2 times, with "heavy" smokers being at greatest risk. Kidney cancer is also associated with excess weight. Increased incidence of kidney cancer is observed with the abuse of food of animal origin, while people with a tendency to a vegetarian diet suffer from kidney cancer less often. The risk of the disease increases somewhat with the use of estrogens. Contact with various chemicals, especially at work, can also contribute to the development of kidney cancer.

There is evidence of a relationship between the presence of arterial hypertension and an increased likelihood of tumor development. The risk of kidney cancer increases sharply in terminal stages of renal failure; advances in hemodialysis have made the corresponding clinical situations compatible with life, which has led to the emergence of a new etiologic category of kidney cancer.

Gender and age

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

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Smoking

It has now been proven that tobacco smoking 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 sexes increases from 30 to 60% compared to the non-smoking population.

Moreover, the more cigarettes are smoked daily and the longer the smoking, the greater the probability of developing kidney cancer. When you quit smoking, the probability of developing the disease decreases.

Obesity and overweight

Most studies have confirmed the adverse effect of excess body weight on the likelihood of developing kidney cancer. Obesity increases the incidence of kidney cancer by 20%. This may be due to an increase in the concentration of endogenous estrogens and the biological activity of insulin-like growth factors.

Arterial hypertension

An increase in the risk of kidney cancer development in patients with arterial hypertension by 20% with a history of 5 years or more has been noted. The issue of the influence of antihypertensive drugs on the development of the malignant process is being studied.

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Medicines

Many authors associate the occurrence 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%.

Given the role of obesity as a risk factor, the effect of weight loss drugs on the risk of kidney cancer was assessed. It was found that amphetamine -containing drugs significantly increased the risk of kidney cancer.

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

Diabetes mellitus

There is evidence in the literature of an increased incidence of kidney cancer in patients with diabetes mellitus. The close relationship between diabetes mellitus, 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

The potential pathogenetic significance of hormonal factors in the development of kidney cancer has been proven in animal studies. Sex hormone receptors have been identified in healthy and malignant kidney tissues of animals. However, there is no clear evidence of the adverse effect of estrogens on the risk of kidney cancer in humans.

Diet

Epidemiological studies have shown a correlation between the incidence of kidney cancer and the consumption of meat, plant products, as well as margarine and butter. However, no reliable effect of specific food products on the incidence of kidney cancer has been identified. It is possible that the pathogenetic significance lies not in the original products themselves, but in the substances formed during the cooking process. Heterocyclic amines formed during the heat treatment of meat have a proven carcinogenic effect. According to most authors, the consumption of vegetables and fruits helps reduce the risk of kidney cancer.

Profession

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

Hereditary kidney cancer

Several forms of hereditary pathologies have been described in relation to kidney cancer.

The most well-known is von Hippel-Lindau syndrome. This syndrome is based on a germline mutation in the VHL gene, which was mentioned above. Pathological examination of the kidneys of patients with hereditary damage to one of the VHL alleles allows us to identify hundreds, and sometimes even thousands of loci of malignant transformation. In addition to kidney cancer, carriers of the mutant gene may also have neoplasms of the pancreas, adrenal glands, brain, etc. Despite the fact that von Hippel-Lindau syndrome represents the majority of hereditary forms of kidney cancer, its incidence in the population is relatively low and amounts to 1 in 40,000 people.

Interestingly, many patients with a hereditary form of kidney cancer have a congenital translocation of chromosome 3p detected even during routine cytogenetic testing. Such patients are classified as a separate group, since their VHL gene retains an intact structure and there are no "extrarenal" manifestations of von Hippel-Lindau syndrome.

Hereditary papillary renal cell carcinoma is a rare category of familial cancers caused by a germline activating mutation in an oncogene. The syndrome is caused by a micromutation in the MET oncogene, which encodes a receptor tyrosine kinase. Carriers of the activated MET allele have up to 3,400 microcarcinomas in their kidneys.

Birt-Hogg-Dube syndrome is characterized not only by the appearance of chromophobe renal cancer and oncocytomas, but also by the presence of multiple hair follicle tumors, 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 remain unknown to date.

Another rare type of hereditary disease is a combined predisposition to leiomyomas and renal carcinomas. This syndrome is associated with mutations in the fumarate hydratase gene, which codes for an enzyme in 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 one or another form of this disease.

For clear cell renal cancer, the most characteristic event is the inactivation of the VHL gene (von Hippel - Lindau syndrome). The VHL gene is somewhat unique: it has no homologues in the human genome. It has been established relatively recently that the VHL gene is involved in regulating the biochemical adaptation of the cell to hypoxic conditions. 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 reactions of adaptation to hypoxia even if tissue oxygenation remains at a normal level. As a result, abnormal production of many growth factors is observed, including molecules that promote increased angiogenesis.

Mutational activation of the tyrosine kinase MET is frequently observed in papillary renal cell carcinoma. MET is a membrane receptor; one of the known MET ligands is hepatocyte growth factor. MET is involved in the initiation of proliferative signaling cascades.

Persistent cytogenetic abnormalities have been described for renal cancer. The most typical is the loss of the short arm of chromosome 3. The pathogenetic significance of this phenomenon is at least partly associated with the inactivation of the VHL gene located on chromosome 3p25. It is assumed that other genes located in the same chromosomal locus may also participate in the pathogenesis of renal cancer. In addition to the 3p deletion, some other chromosomal damage is observed in renal cancer. Detection of such cytogenetic features may be important in the differential diagnosis of histological types of renal cancer. For example, papillary renal cancer is characterized by trisomy of chromosomes 7, 16, and 17, as well as the loss of chromosome Y; in chromophobe renal cancer, monosomies of chromosomes 1, 2, 6, and 10 are most often observed.

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Symptoms kidney cancer

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

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Forms

Renal cell tumors:

• clear cell renal cell carcinoma;
• multilocular clear cell renal cell carcinoma;
• papillary renal cell carcinoma;
• chromophobe renal cell carcinoma;
• cancer of the collecting ducts of Bellini;
• medullary renal cell carcinoma;
• cancer with translocation of Xp 11;
• neuroblastoma associated cancer;
• mucinous tubular and spindle cell carcinoma;
• kidney cancer (unclassified);
• papillary adenoma;
• oncocytoma.

Metanephrogenic tumors.

Nephroblastic tumors.

Mesenchymal tumors:

• mixed mesenchymal and epithelial tumors;
• neuroendocrine tumors;
• hematopoietic and lymphoid tumors;
• germ cell tumors.

Metastatic kidney cancer.

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

Currently, many countries use the classification proposed by the International Union Against Cancer (6th edition), which covers in detail the extent of the tumor process in order to determine treatment tactics. When using the TNM classification, histological confirmation of the diagnosis is mandatory.

T - primary tumor:

Tx - insufficient data to assess the primary tumor;

T0 - the primary tumor is not determined;

T1 - tumor up to 7 cm in greatest dimension, limited to the kidney;

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

T2 - tumor more than 7 cm in greatest dimension, limited to the kidney;

T3 - the tumor extends to large veins or adrenal glands or perirenal tissues, but does not extend beyond Gerota's fascia;

• T3a - tumor invasion of the adrenal gland or pararenal tissue within Gerota's fascia;
• T3b - the tumor extends into the renal vein or inferior vena cava;
• T3c - the tumor extends into the inferior vena cava above the diaphragm;

T4 - tumor extends beyond Gerota's fascia.

N - regional lymph nodes:

• Nx - regional lymph nodes cannot be assessed;
• N0 - no metastases in regional lymph nodes; N1 - metastasis in one lymph node;
• N2 - metastases in more than one regional lymph node.

M - distant metastases:

• Mx - distant metastases cannot be assessed;
• M0 - no distant metastases;
• M1 - distant metastases.

G - histological grading:

• Gx - the degree of differentiation cannot be assessed;
• G1 - highly differentiated tumor;
• G2 - moderately differentiated tumor;
• G3-4 - poorly differentiated/undifferentiated tumor.

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

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Diagnostics kidney cancer

Most often, a kidney tumor is detected by ultrasound. Despite the high diagnostic value of ultrasound, the latter should always be supplemented by CT, the main method for diagnosing volumetric kidney lesions. MRI is performed on 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 renal parenchyma tumors, CT of the abdominal organs, retroperitoneal space and lungs is a mandatory diagnostic procedure aimed at identifying regional and distant metastases. Bone scanning is recommended for patients with corresponding complaints and/or increased activity of alkaline phosphatase in the blood serum. CT of the brain is indicated for patients with neurological symptoms.

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Treatment kidney cancer

Radical nephrectomy remains the gold standard for the treatment of localized and locally advanced renal cancer (T1a-T4N0/+M0). This intervention involves the removal of the kidney en bloc with the adrenal gland and paranephrium within Gerota's fascia in combination with regional lymphadenectomy. Tumor venous thrombosis is an indication for thrombectomy, the technique of which is determined by the length of the thrombus and the degree of its fixation to the intima of the vessel and, in cases of tumor spread to the right heart, to the endocardium.

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

In case of small tumors, organ-preserving operations are used. Obligatory indications for kidney resection are significant decrease/absence of excretory function, hypoplasia/aplasia of the contralateral kidney or bilateral tumor lesion; relative indications are considered to be decreased function of the contralateral kidney, high risk of postoperative acute renal failure, congenital forms of bilateral kidney cancer with a high probability of occurrence of metachronous tumors in the contralateral kidney. Elective indication for organ-preserving intervention is kidney cancer in stage T1a with unchanged contralateral kidney.

Nephrectomy in patients with a tumor smaller than 4 cm can provide relapse-free and long-term survival comparable to the results of radical nephrectomy. The adequacy of nephrectomy with stage Tib for tumors of 4-7 cm is debated. If the tumor is completely removed, the size of the surgical margin (with a distance of more than 1 mm from the tumor) is not associated with a higher probability of local relapse.

Laparoscopic partial nephrectomy may be an alternative to open partial nephrectomy in a limited number of patients and should be performed by a surgeon experienced in such operations. The optimal indications for this type of intervention are small tumors, predominantly located extraparenchymatously.

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

Minimally invasive methods of kidney cancer treatment (radiofrequency ablation, cryo-ablation, microwave ablation, ablation with high-intensity focused ultrasound wave) can serve as an alternative to surgery in carefully selected patients. Ablation can be recommended for patients with small tumors located in the cortex of the renal parenchyma, who have contraindications to surgery, as well as for patients with multiple and/or bilateral tumors. The results of ablative techniques are being studied.

There are no indications for adjuvant therapy after surgical treatment of renal cancer outside the framework of clinical protocols. The effectiveness of adjuvant tumor vaccination using targeted drugs that can potentially improve relapse-free survival, especially in patients with category T3, is being studied. Adjuvant therapy with cytokines (interferon a, interleukin-2) does not affect survival after radical nephrectomy.

Treatment of kidney cancer: disseminated kidney cancer (M+)

Indications for surgical treatment of patients with disseminated renal cancer receiving immunotherapy are defined. All patients with the M+ category and satisfactory somatic status are indicated for nephrectomy. In patients with multiple metastases, nephrectomy is palliative. A meta-analysis of two randomized studies comparing nephrectomy in combination with immunotherapy and immunotherapy alone noted an advantage in the survival of operated patients. The advisability of performing palliative nephrectomy in patients receiving targeted therapy has not been proven and is currently being studied.

In case of solitary or single metastases, their surgical removal allows to cure the patient. Complete removal of all metastatic foci improves the clinical prognosis in disseminated renal cancer. Removal of metastases is recommended for patients with a limited number of tumor foci, the possibility of their radical surgical removal and good somatic status. Removal of metastases should also be performed in patients with residual tumor and foci accessible for removal that responded to previous immunotherapy.

Despite the heteroresistant nature of kidney cancer, radiation therapy can be used to treat brain metastases and bone lesions, as it can significantly reduce symptomatic manifestations in the above-mentioned locations.

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

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

The overall response to interferon-a immunotherapy ranges from 10 to 20%. On average, it is 15%, and complete - 2%. The duration of remission in the vast majority of patients is short and is 6-10 months, but in 5-7% of patients with a complete response to treatment, long-term remission can be achieved. Despite sufficient experience in the use of interferon-a in disseminated kidney cancer, the optimal doses and regimens for its administration have not been determined. The use of single doses of interferon-a less than 3 million IU reduces the effectiveness. And increasing the single dose of this cytokine to more than 10 million IU does not provide any advantages. The most common regimen for interferon-a therapy is 6 million IU subcutaneously. 3 times a week, for a long time.

The overall efficacy of interleukin-2 is 15% with complete and partial remission rates of 7 and 8%, respectively. Optimal doses of interleukin-2 are unknown; the most common regimen is 125-250 IU/kg subcutaneously. 3 times a week, for a long time. The greatest efficacy of the drug is observed with intravenous administration, but this is associated with a high frequency of severe complications and even mortality associated with its toxicity.

There are factors of unfavorable prognosis in disseminated renal cancer, which include somatic status (Karnofsky index <80%), high LDH activity (1.5 times the norm), hypercalcemia (corrected calcium more than 10 mg/l), anemia (Hb less than 13 g/l) and the time from the primary diagnosis to the start of systemic treatment of less than a year. Based on the obtained results, the MSKCC prognostic model was developed, which distinguishes a group of poor (more than three risk factors, median survival is 6 months), moderate (1-2 risk factors, median survival is 14 months) and favorable prognosis (no risk factors, median survival is 30 months). Standard cytokine therapy is highly effective in the good prognosis group. It is ineffective in patients with moderate and ineffective in patients with poor prognosis.

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

A better understanding of tumor immunology has led to the creation of a fundamentally new generation of vaccines using dendritic cells. The latter are the most powerful antigen-presenting cells, presenting tumor antigen in a complex with proteins of the major histocompatibility complex class I to cytotoxic lymphocytes and activating the latter. The discovery of the tumor-associated antigen G250, specific for kidney cancer, present in 85% of observations in the tumor, and the isolation of the associated peptide recognized by cytotoxic T-lymphocytes, gave a new impetus to the creation of C250-peptide vaccines, which are being actively studied.

A fundamentally new approach is the use of monoclonal antibodies to G250, labeled with radioactive ¹⁵¹ J, which actively accumulate in kidney tumors and can be used for both diagnostic and therapeutic purposes. Genetic modification of antitumor vaccines makes it possible to increase their effectiveness. Ex vivo introduction of certain polynucleotide sequences into the genome of tumor cells allows them to acquire the ability to produce various cytokines, which increases their immunogenicity. It is noted that vaccines stimulating the production of granulocyte-macrophage colony-stimulating factor induce the formation of an immune response against weakly immunogenic 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. Non-myeloablative techniques are used, which provide an immunosuppressive effect sufficient for allogeneic transplantation without suppressing 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 mortality in 12-30% of cases.

The emergence of effective targeted drugs forces us to gradually reconsider approaches to the treatment of disseminated renal cancer. Renal cell cancer is characterized by mutations of the VHL (Van Hippel-Lindau) gene, which leads to the activation of tumor pathogenesis along the endothelial growth factor pathway. In this regard, drugs that block angiogenesis lead to a delay in tumor growth in renal adenocarcinoma.

Forecast

Kidney cancer has a rather poor prognosis: 5-year survival is observed in only 40% of patients with kidney tumors, while for other urological neoplasms (prostate, bladder tumors) this figure is around 20%. Such statistics are due to the fact that the only effective method of treating kidney cancer is surgery. Kidney cancer is practically insensitive to either traditional chemotherapy or radiotherapy. Sometimes kidney cancer retains a certain immunogenicity, which explains the existence of spontaneous remissions and even regressions of the disease, and in some cases allows us to observe the impressive effectiveness of treatment with high doses of interleukin-2 (IL-2).

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

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