RCC patients tend to remain asymptomatic until advanced stages of the disease. The classic symptom triad of flank pain, hematuria and a palpable abdominal mass is presented by less than 10% of affected individuals [10]. Symptoms associated with mRCC largely depend on the affected organ and involvement of adjacent tissue. As these symptoms are identical to symptoms triggered by other neoplasms affecting those organs, they cannot be ascribed to mRCC unless a histopathological analysis of fine-needle aspirates or biopsy specimens has been obtained.

Both RCC and mRCC may provoke symptoms consistent with paraneoplastic syndrome, and those may precede the onset of symptoms due to local mass effects mediated by the primary tumor and metastases. In this context, constitutive symptoms like fever, night sweats and weight loss may be accompanied by endocrine and electrolyte imbalances. Neoplastic tissue has been shown to release interleukins IL-1 and IL-6 as well as tumor necrosis factor-α, and these have been related to enhanced concentrations of acute phase markers like C-reactive protein. Moreover, tumor cells may release parathyroid hormone-related peptide and renin production by the affected kidneys may be increased. This results in hypercalcemia, possibly associated with fatigue, polyuria, polydipsia, and exsiccosis, nausea and vomiting, cardiac arrhythmia,hypertension and altered sensorium. Tumor cells may produce erythropoietin and provoke erythrocytosis. Polycythemia has also been described in mRCC patients. mRCC may be accompanied by amyloidosis, although its pathogenesis remains unclear.

Resection of a localized primary tumor and complete metastasectomy, in case of metastases, generally relieve symptoms of paraneoplastic syndrome. Otherwise, or upon recurrence of fever, night sweats, and weight loss, a thorough workup is required to detect metastases that may have been overlooked before.

As has been mentioned above, RCC does not necessarily provoke clinical symptoms until advanced stages of the disease and the formation of metastases. Nevertheless, RCC may be detected during early stages, incidentally in patients undergoing routine imaging procedures. Due to the tumor's propensity for metastatic spread, diagnostic measures should be taken to rule out the presence of mRCC in these patients. For this computed tomography scans of the thoracic cavity are usually carried out. This technique allows for the visualization of lung metastases and enlarged mediastinal lymph nodes. Similarly, abdomen and pelvis are examined. Here, spread to regional lymph nodes and to hepatic tissue may be observed. Neuroimaging and bone scans are not routinely performed unless clinical symptoms suggest metastases to the brain/bones. With regards to the latter, 18F-NaF-positron emission tomography/computed tomography has recently been proven significantly more sensitive than 99mTc-MDP bone scintigraphy [11]. Essentially, these same techniques are employed to assess the extension of mRCC. Additionally, tumor thrombi may be visualized using sonography or magnetic resonance imaging. As is the case with non-metastatic RCC, confirmation of the tumor type requires histopathological analyses with fine-needle aspirates or biopsy samples.

A thorough physical examination as well as laboratory analyses of blood samples are recommended to identify hematological and biochemical anomalies consistent with paraneoplastic syndrome. Hypercalcemia, hypertension and thromboembolism may contribute to mRCC-related morbidity and may thus require additional, symptomatic therapy. Urine sample analysis may reveal signs of urinary tract infection or hemorrhages.

While partial or total nephrectomy is the treatment of choice for patients diagnosed with non-metastatic RCC, this procedure is not generally recommended for individuals suffering from mRCC. Here, systemic therapy preceded by cytoreductive nephrectomy or followed by resection of any residual tumors should be considered. There are no published guidelines and thus, the choice of an appropriate approach to treatment should be based on the number, location and resectability of metastases as well as on the patient's general condition [12].

With regards to systemic therapy, mRCC are usually resistant to cytotoxic chemotherapy, and cytokines IL-2 and interferon-α have been the mainstays of mRCC treatment for about two decades. Although use of these drugs has been associated with prolonging median survival times, response rates have remained below 20% [13]. Nowadays, monotherapy with IL-2 or interferon-α is no longer recommended for mRCC treatment, unless patient has pulmonary mRCC, clear cell subtype. [10].

More recently, kinase inhibitors axitinib, pazopanib, sorafenib, sunitinib, everolimus, lenvatinib plus everolimus and temsirolimus as well as bevacizumab plus interferon have been approved for mRCC treatment. These compounds are used for targeted cancer therapy if other therapeutic regimens fail to induce a satisfactory response. Sequential application of several compounds has repeatedly been carried out, and the interested reader is referred to an excellent review published recently.[14]. Similarly, the European Association of Urology emphasizes the need for sequential treatment due to insufficient efficacy of monotherapies and reduced tolerability of combined therapy. In general, treatment recommendations are based on prior risk assessment and determination of the histological subtype of RCC. Current guidelines may be revised elsewhere [10], but are likely to be updated in the near future.

Standard therapies are indicated to relieve symptoms associated with paraneoplastic syndrome.

Regular follow-ups are indispensable for an early diagnosis of recurrence.

Despite considerable advances in mRCC therapy, the disease is still associated with high morbidity and mortality. In 2003, median survival times of less than one year have been reported for mRCC patients [8]. According to that same study, less than 20% of affected individuals remained alive two years after diagnosis. However, the outcome varies depending on the organ affected by metastatic spread of RCC and on the resectability of tumors that don't respond to other therapeutic regimens. In this context, complete metastasectomy may increase median survival times to almost five years [9]. Renewed tumor growth is likely after incomplete resection of mRCC and while patients with recurrent pulmonary metastases are often able to undergo another surgery, this does not apply to those suffering from bone metastases [1]. Furthermore, survival times of patients diagnosed with clear cell carcinoma are shorter than those of individuals suffering from papillary and chromophobic neoplasms [3]. To summarize, RCC and mRCC account for about 100,000 deaths each year [4].

Renal cell carcinoma (RCC) originates from proximal renal tubular epithelium. The etiology of the tumor is still largely unknown, but a series of risk factors have been identified [2]:

• Cigarette smoking
• Western-style diet
• Overweight/obesity
• Lack of exercise
• Diabetes mellitus
• Hypertension
• Medical history of urinary tract infection
• In women, parity and oophorectomy
• Occupational and environmental exposure to chloroacetate, trichloroethylene, vinyl chloride
• Mutations of genes encoding for glutathione S-transferases
• Von Hippel–Lindau Disease, Birt-Hogg-Dubé syndrome

Some of these factors are mutually dependent, e.g., people adhering to a Western-style diet may be more prone to obesity. Evidence regarding the etiological role of gene variants is scarce, but patients carrying certain gene defects may be more susceptible to RCC after exposure to carcinogenic agents. To date, it is not known whether individual risk factors predispose for certain subtypes of RCC, namely clear cell, papillary, chromophobic and collecting duct RCC. Clear cell RCC are associated with a worse prognosis than papillary and chromophobic RCC, and this fact may be due to an increased propensity for metastatic spread in the former [3].

RCC accounts for more than 90% of kidney tumors and approximately 3% of malignancies detected in adult patients [4]. The worldwide incidence of RCC has been estimated to 209,000 in 2006, while more than 300,000 new cases have been diagnosed in 2012 [5]. Although these values do not necessarily indicate a drastic increase in case numbers - disagreements may merely be owing to methodological differences - worldwide incidence rates have been reported to have increased by up to 3% per decade [4]. Higher incidence rates in developed countries may be ascribed to the aforementioned risk factors being more prevalent in the respective geographical regions [5]. People of all races and both genders may develop mRCC, although men are affected about twice as often as women. The disease is most commonly diagnosed in patients aged 40-60 years. Development of mRCC by young patients is often related to hereditary disorders predisposing for tumor growth.

About a fourth of affected individuals present with metastatic renal cancer at the time of diagnosis.Distant metastases are most commonly located in the lungs (in more than 50% of mRCC cases), bones and liver (each more than 30%), and brain (about 5% of mRCC). Furthermore, mRCC may affect adrenal glands,thyroid, pancreas, skin and spinal cord as well as other tissues. These values imply that majority of mRCC patients suffer from multiple sites of mRCC. In fact, solitary metastases are encountered in only 5% of individuals diagnosed with mRCC [4].

RCC tumor cells may spread through blood vessels - primarily through renal veins and inferior vena cava - as well as the lymphatic system. Tumor thrombi may form within those vessels and in fact, such complications may be observed in up to 10% of mRCC patients [6]. mRCC have been shown to invade venous walls, although case reports on metastatic spread to venous vessels are rare. Nevertheless, tumor thrombi constitute reservoirs of tumor cells that may induce recurrence after treatment of mRCC. Administration of sunitinib may further increase the likelihood of thromboembolic events [7].

Because smoking is a major risk factor for kidney cancer and mRCC, patients should be advised to stop tobacco consumption. Additionally, adherence to a healthy diet lowers the individual risk of overweight/obesity and related pathologies like diabetes mellitus and hypertension. If dietary adjustments are combined with regular exercise, patients may not only prevent renal neoplasms, but also a wide variety of other disease entities. Exposure to carcinogens should be reduced as much as possible, although evidence regarding a direct correlation between such substances and mRCC has not yet been provided.

People diagnosed with von Hippel-Lindau disease or other disorders known to predispose for tumor growth should be offered regular examinations. This may help to detect RCC in the early stages prior to metastatic spread.

Renal cell carcinoma (RCC) is the most common type of malignant tumor affecting the kidneys. RCC accounts for about 3% of malignancies diagnosed in adult patients and it has been estimated that more than 200,000 people develop RCC each year. About half of those patients develop metastatic renal cell carcinoma (mRCC). This condition may either be diagnosed at the time of detection of the primary tumor or at any time later, possibly after an apparently successful treatment of kidney cancer [1]. RCC most commonly metastasizes to regional lymph nodes, lungs, bones, liver and adrenal glands, but occasional metastasis to other organs has also been reported. While bone and brain metastases usually provoke clinical symptoms, this does not apply to the primary tumor, lymph node or pulmonary metastases. Patients suffering from RCC remain asymptomatic until advanced stages of the disease and the initial spread to lymph nodes or lungs may not be noted either. Consequently, wide-spread mRCC is more commonly detected than solitary metastases, and this condition negatively affects the patient's response to therapy, the resectability of tumor tissue and the associated prognosis.

Renal cell carcinoma is the most common malignancy originating from the kidney's tubular epithelium. The tumor is characterized by aggressive growth and propensity for metastatic spread. Additionally, patients do not typically develop any symptoms until advanced stages of the disease and thus, many suffer from metastatic renal cell carcinoma (mRCC) at the time of diagnosis. mRCC most commonly affects lymph nodes, lungs, bones, liver and brain, but may also be encountered in other organs. While non-metastatic tumors may be resected, surgical removal of tumor tissue is a major challenge if multiple organs are compromised. Consequently, mRCC patients often have to undergo systemic therapy. The prognosis of an individual patient depends on a variety of factors, namely on the organ(s) compromised by mRCC, the resectability of tumors that do not respond to other therapeutic regimens and on the tumor's histopathological properties. Recently, several compounds have been approved for mRCC treatment, and they may prolong survival times.

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