Renal cell carcinoma

Historically, medical practitioners expected a person to present with three findings. This classic triad Other signs and symptom may include haematuria; loin pain; abdominal mass; malaise, which is a general feeling of unwellness; weight loss and/or loss of appetite; anaemia resulting from depression of erythropoietin; erythrocytosis (increased production of red blood cells) due to increased erythropoietin secretion; varicocele, which is seen in males as an enlargement of the pampiniform plexus of veins draining the testis (more often the left testis) hypertension (high blood pressure) resulting from secretion of renin by the tumour; hypercalcemia, which is elevation of calcium levels in the blood; sleep disturbance or night sweats; recurrent fevers; and chronic fatigue. == Risk factors ==

Lifestyle The greatest risk factors for RCC are lifestyle-related: smoking, obesity and hypertension (high blood pressure) have been estimated to account for up to 50% of cases. Occupational exposure to some chemicals such as asbestos, cadmium, lead, chlorinated solvents, petrochemicals and PAH (polycyclic aromatic hydrocarbon) has been examined by multiple studies with inconclusive results. Another suspected risk factor is the long term use of non-steroidal anti-inflammatory drugs (NSAIDs). Finally, studies have found that women who have had a hysterectomy are at more than double the risk of developing RCC than those who have not. Moderate alcohol consumption, on the other hand, has been shown to have a protective effect. Genetics Hereditary factors have a minor impact on individual susceptibility with immediate relatives of people with RCC having a two to fourfold increased risk of developing the condition. Other genetically linked conditions also increase the risk of RCC, including hereditary papillary renal carcinoma, hereditary leiomyomatosis, Birt–Hogg–Dube syndrome, hyperparathyroidism-jaw tumor syndrome, familial papillary thyroid carcinoma, von Hippel–Lindau disease and sickle cell disease. The most significant disease affecting risk however is not genetically linked – patients with acquired cystic disease of the kidney requiring dialysis are 30 times more likely than the general population to develop RCC. == Pathophysiology ==

The tumour arises from the cells of the proximal renal tubular epithelium. There are two subtypes: sporadic (that is, non-hereditary) and hereditary. Both such subtypes are associated with mutations in the short-arm of chromosome 3, with the implicated genes being either tumour suppressor genes (VHL and TSC) or oncogenes (like c-Met). == Diagnosis ==

The first steps taken to diagnose this condition are consideration of the signs and symptoms, and a medical history (the detailed medical review of past health state) to evaluate any risk factors. Based on the symptoms presented, a range of biochemical tests (using blood and/or urine samples) may also be considered as part of the screening process to provide sufficient quantitative analysis of any differences in electrolytes, kidney and liver function, and blood clotting times. Although this disease lacks characterization in the early stages of tumor development, considerations based on diverse clinical manifestations, as well as resistance to radiation and chemotherapy are important. The main diagnostic tools for detecting renal cell carcinoma are ultrasound, computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the kidneys. Classification Renal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derived from the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes. Array-based karyotyping performs well on paraffin embedded tumours and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumours. The 2004 World Health Organization (WHO) classification of genitourinary tumours recognizes over 40 subtypes of renal neoplasms. Since the publication of the latest iteration of the WHO classification in 2004, several novel renal tumour subtypes have been described: • Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma with smooth muscle stroma • Mucinous tubular and spindle cell carcinoma (MTSCC) In other words, these cancers are not detected usually because they do not cause pain or discomfort when they are discovered. Laboratory analysis can provide an assessment on the overall health of the patient and can provide information in determining the staging and degree of metastasis to other parts of the body (if a renal lesion has been identified) before treatment is given. Urine analysis The presence of blood in urine is a common presumptive sign of renal cell carcinoma. The haemoglobin of the blood causes the urine to be rusty, brown or red in colour. Alternatively, urinalysis can test for sugar, protein and bacteria which can also serve as indicators for cancer. A complete blood cell count can also provide additional information regarding the severity and spreading of the cancer. Complete blood cell count The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells. CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including erythrocyte sedimentation rate (ESR), prothrombin time (PT), activated partial thromboplastin time (APTT) should be considered. Blood chemistry Blood chemistry tests are conducted if renal cell carcinoma is suspected as cancer has the potential to elevate levels of particular chemicals in blood. For example, liver enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are found to be at abnormally high levels. The staging of the cancer can also be determined by abnormal elevated levels of calcium, which suggests that the cancer may have metastasised to the bones. In this case, a doctor should be prompted for a CT scan. Blood chemistry tests also assess the overall function of the kidneys and can allow the doctor to decide upon further radiological tests. Radiology The characteristic appearance of renal cell carcinoma is a solid renal lesion which disturbs the renal contour. It will frequently have an irregular or lobulated margin and may be seen as a lump on the lower pelvic or abdomen region. Traditionally, 85 to 90% of solid renal masses will turn out to be RCC but cystic renal masses may also be due to RCC. However, the advances of diagnostic modalities are able to incidentally diagnose a great proportion of patients with renal lesions that may appear to be small in size and of benign state. Ten percent of RCC will contain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat). Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one. The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features. The main imaging tests performed in order to identify renal cell carcinoma are pelvic and abdominal CT scans, ultrasound tests of the kidneys (ultrasonography), MRI scans, intravenous pyelogram (IVP) or renal angiography. Among these main diagnostic tests, other radiologic tests such as excretory urography, positron-emission tomography (PET) scanning, ultrasonography, arteriography, venography, and bone scanning can also be used to aid in the evaluation of staging renal masses and to differentiate non-malignant tumours from malignant tumours. According to a study conducted by Sauk et al., multidetector CT imaging characteristics have applications in diagnosing patients with clear renal cell carcinoma by depicting the differences of these cells at the cytogenic level. Ultrasound Ultrasonographic examination can be useful in evaluating questionable asymptomatic kidney tumours and cystic renal lesions if computed tomography imaging is inconclusive. This safe and non-invasive radiologic procedure uses high frequency sound waves to generate an interior image of the body on a computer monitor. The image generated by the ultrasound can help diagnose renal cell carcinoma based on the differences of sound reflections on the surface of organs and the abnormal tissue masses. Essentially, ultrasound tests can determine whether the composition of the kidney mass is mainly solid or filled with fluid. However, biopsy tests for molecular analysis to distinguish benign from malignant renal tumours is of investigative interest. Sometimes prior to the MRI scan, an intravenous injection of a contrasting material called gadolinium is given to allow for a more detailed image. Patients on dialysis or those who have renal insufficiency should avoid this contrasting material as it may induce a rare, yet severe, side effect known as nephrogenic systemic fibrosis. A bone scan or brain imaging is not routinely performed unless signs or symptoms suggest potential metastatic involvement of these areas. MRI scans should also be considered to evaluate tumour extension which has grown in major blood vessels, including the vena cava, in the abdomen. MRI can be used to observe the possible spread of cancer to the brain or spinal cord should the patient present symptoms that suggest this might be the case. Intravenous pyelogram Intravenous pyelogram (IVP) is a useful procedure in detecting the presence of abnormal renal mass in the urinary tract. This procedure involves the injection of a contrasting dye into the arm of the patient. The dye travels from the blood stream and into the kidneys which in time, passes into the kidneys and bladder. This test is not necessary if a CT or MRI scan has been conducted. Renal angiography Renal angiography uses the same principle as IVP, as this type of X-ray also uses a contrasting dye. This radiologic test is important in diagnosing renal cell carcinoma as an aid for examining blood vessels in the kidneys. This diagnostic test relies on the contrasting agent which is injected in the renal artery to be absorbed by the cancerous cells. The contrasting dye provides a clearer outline of abnormally-oriented blood vessels believed to be involved with the tumour. This is imperative for surgeons as it allows the patient's blood vessels to be mapped prior to operation. Staging can follow the TNM staging system, where the size and extent of the tumour (T), involvement of lymph nodes (N) and metastases (M) are classified separately. Also, it can use overall stage grouping into stage I–IV, with the 1997 revision of AJCC described below: Histopathology and prognoses, including renal cell carcinoma and its subtypes The gross and microscopic appearance of renal cell carcinomas is highly variable. Gross examination often shows a yellowish, multilobulated tumor in the renal cortex, which frequently contains zones of necrosis, haemorrhage and scarring. Microscopically, RCC is a heterogeneous group of cancers, made up of several distinct subtypes with different histologic features and clinical outcomes. The most common subtypes are clear cell, papillary, and chromophobe RCC. Sarcomatoid changes (morphology and patterns of IHC that mimic sarcoma, spindle cells) can be observed within any RCC subtype and are associated with more aggressive clinical course and worse prognosis. Clear cell renal cell carcinoma Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, accounting for approximately 75-80% of all cases. The name is derived from the appearance of the tumor cells under a microscope, which look clear or pale due to a high content of glycogen and lipids that dissolves during tissue processing. Pathophysiology and genetics The development of ccRCC is strongly linked to the von Hippel-Lindau (VHL) tumor suppressor gene on chromosome 3p. Inactivation of the VHL gene, through mutation, deletion, or hypermethylation, is the hallmark of ccRCC and is found in over 90% of sporadic (non-inherited) cases. The VHL protein is crucial for targeting hypoxia-inducible factors (HIFs) for degradation. When VHL is inactive, HIFs accumulate, leading to the overexpression of genes that promote tumor growth, angiogenesis (the formation of new blood vessels), and metastasis. This includes vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which have become key targets for therapy. While most cases are sporadic, ccRCC is the primary manifestation of Von Hippel–Lindau disease, a hereditary cancer syndrome that predisposes individuals to tumors in various organs, including the kidneys, brain, and pancreas. It originates from the renal tubular epithelium and is characterized by a papillary or tubulopapillary architecture. Histopathology and classification Microscopically, pRCC tumors feature finger-like projections (papillae) with fibrovascular cores. It is common to find foamy macrophages, psammoma bodies (calcifications), and hemosiderin deposits within the tumor. Historically, pRCC was divided into two subtypes: • Type 1: Characterized by papillae covered with a single layer of small, basophilic cells with scant cytoplasm. These were generally considered to be lower grade and have a better prognosis. • Type 2: Displayed papillae with larger, eosinophilic cells with prominent nucleoli, often arranged in a pseudostratified pattern. These were typically higher grade tumors with a worse prognosis. However, the 2022 World Health Organization (WHO) classification of renal tumors no longer recommends this subtyping. • Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): This syndrome is caused by mutations in the fumarate hydratase (FH) gene. It is associated with a particularly aggressive form of pRCC, as well as cutaneous and uterine leiomyomas. Nuclear grade is believed to be one of the most imperative prognostic factors in patients with renal cell carcinoma. In relation to renal cancer staging, the Heidelberg classification system of renal tumours was introduced in 1976 as a means of more completely correlating the histopathological features with the identified genetic defects. ==Prevention==

The risk of renal cell carcinoma can be reduced by maintaining a normal body weight. == Management ==

of embolic material in a kidney removed because of renal cell carcinoma (cancer not shown). H&E stain. The type of treatment depends on multiple factors and the individual, some of which include the stage of renal cell carcinoma (organs and parts of the body affected/unaffected), type of renal cell carcinoma, pre-existing or comorbid conditions and overall health and age of the person. Every form of treatment has both risks and benefits; a health care professional will provide the best options that suit the individual circumstances. If it has spread outside of the kidneys, often into the lymph nodes, the lungs or the main vein of the kidney, then multiple therapies are used including surgery and medications. RCC is resistant to chemotherapy and radiotherapy in most cases but does respond well to immunotherapy with interleukin-2 or interferon-alpha, biologic, or targeted therapy. In early-stage cases, cryotherapy and surgery are the preferred options. Active surveillance Active surveillance or "watchful waiting" is becoming more common as small renal masses or tumours are being detected and also within the older generation when surgery is not always suitable. In the elderly, patients with co-morbidities, and in poor surgical candidates, this is especially useful. Surgery Different procedures may be most appropriate, depending on circumstances. The recommended treatment for renal cell cancer may be nephrectomy or partial nephrectomy, surgical removal of all or part of the kidney. Most of these small renal masses manifest indolent biological behavior with excellent prognosis. Nephron-sparing partial nephrectomy is used when the tumor is small (less than 4 cm in diameter) or when the patient has other medical concerns such as diabetes or hypertension. Larger and more complex tumors can also be treated with partial nephrectomy by surgeons with an extensive kidney surgery experience. Surgical nephrectomy may be "radical" if the procedure removes the entire affected kidney including Gerota's fascia, the adrenal gland which is on the same side as the affected kidney, and the regional retroperitoneal lymph nodes, all at the same time. It is important to note that the other kidney must be fully functional, and this technique is most often used when there is a large tumour present in only one kidney. In cases where the tumor has spread into the renal vein, inferior vena cava, and possibly the right atrium, this portion of the tumor can be surgically removed, as well. When the tumor involved the inferior vena cava, it is important to classify which parts of the vena cava are involved and to plan accordingly, as sometimes complete resection will involve an incision into the chest with increased morbidity. For this reason, Gaetano Ciancio adapted liver mobilization techniques from liver transplant to address retrohepatic or even suprahepatic inferior vena caval thrombus associated with renal tumors. With this technique, the whole abdominal inferior vena cava is able to be mobilized. This facilitates milking of the tumor down below the major hepatic veins by the surgeon's fingers, bypassing the need for a thoracoabdominal incision or cardiopulmonary bypass. In cases of known metastases, surgical resection of the kidney ("cytoreductive nephrectomy") may improve survival, as well as resection of a solitary metastatic lesion. Kidneys are sometimes embolized prior to surgery to minimize blood loss. Surgery is increasingly performed via laparoscopic techniques. Commonly referred to as key hole surgery, this surgery does not have the large incisions seen in a classically performed radical or partial nephrectomy, but still successfully removes either all or part of the kidney. Laparoscopic surgery is associated with shorter stays in the hospital and quicker recovery time but there are still risks associated with the surgical procedure. These have the advantage of being less of a burden for the patient and the disease-free survival is comparable to that of open surgery. Ideally, percutaneous ablation is restricted to tumours smaller than 3.5 cm and to guide the treatment. However, there are some cases where ablation can be used on tumors that are larger. The primary physical advantage of CIRT is the Bragg peak, a phenomenon where the carbon ions deposit the vast majority of their energy precisely at the tumor site, minimizing damage to surrounding healthy tissues. Biologically, heavy ions have a high linear energy transfer (LET), which causes complex and difficult-to-repair DNA double-strand breaks in cancer cells. This results in a higher relative biological effectiveness (RBE) for killing tumor cells, making it particularly effective against radio-resistant cancers like RCC. The United States, which discontinued its original program in 1993, is re-establishing its capabilities. The first new U.S. facility, at the Mayo Clinic in Florida, is expected to make carbon ion therapy clinically available in 2027 or later. Targeted drugs Cancers often grow in an unbridled fashion because they are able to evade the immune system. Immunotherapy capitalises on this phenomenon and aims to increase a person's immune response to cancer cells. Most of these medications were approved within the past ten years. These treatments are: • Nivolumab • Axitinib • Sunitinib • Cabozantinib • Lenvatinib • Pazopanib • Bevacizumab • Sorafenib • Tivozanib • Temsirolimus • Interleukin-2 (IL-2) has produced "durable remissions" in a small number of patients, but with substantial toxicity. • Interferon-α For patients with metastatic cancer, sunitinib probably results in more progression of the cancer than pembrolizumab, axitinib and avelumab. In comparison to pembrolizumab and axitinib, it probably results in more death, but it may slightly reduce serious unwanted effects. but it is not an approved medication for renal cancer. More medications are expected to become available in the near future as several clinical trials are being conducted for new targeted treatments, including: atezolizumab, varlilumab, durvalumab, avelumab, LAG525, MBG453, TRC105, and savolitinib. Chemotherapy Chemotherapy and radiotherapy are not as successful in the case of RCC. RCC is resistant in most cases but there is about a 4–5% success rate, but this is often short-lived with more tumours and growths developing later. Conversely, neoadjuvant therapy is administered before the intended primary or main treatment. In some cases neoadjuvant therapy has been shown to decrease the size and stage of the RCC to then allow it to be surgically removed. == Metastasis ==

Metastatic renal cell carcinoma (mRCC) is the spread of the primary renal cell carcinoma from the kidney to other organs. Approximately 25–30% of people have this metastatic spread by the time they are diagnosed with renal cell carcinoma. This high proportion is explained by the fact that clinical signs are generally mild until the disease progresses to a more severe state. The most common sites for metastasis are the lymph nodes, lung, bones, liver and brain. Despite this improvement the five-year survival rate for mRCC remains under 10% and 20–25% of patients remain unresponsive to all treatments and in these cases, the disease has a rapid progression. Side effects are quite common with these treatments and include: • Gastrointestinal effects – nausea, vomiting, diarrhea, anorexia • Respiratory effects – coughing, dyspnea (difficulty breathing) • Cardiovascular effects – hypertension (high blood pressure) • Neurological effects – intracranial hemorrhage (bleeding into the brain), thrombosis (blood clots) in the brain • Effects on the skin and mucous membranes – rashes, hand-foot syndrome, stomatitis • Bone marrow suppression – resulting in reduced white blood cells, increasing the risk of infections plus anemia and reduced platelets • Renal effects – impaired kidney function • Fatigue Radiotherapy and chemotherapy are more commonly used in the metastatic form of RCC to target the secondary tumours in the bones, liver, brain and other organs. While not curative, these treatments provide relief for symptoms associated with the spread of tumours. == Prognosis ==

The prognosis is influenced by several factors, including tumour size, degree of invasion and metastasis, histologic type, and nuclear grade. A Korean study estimated a disease-specific overall five-year survival rate of 85%. Taken as a whole, if the disease is limited to the kidney, only 20–30% develop metastatic disease after nephrectomy. More specific subsets show a five-year survival rate of around 90–95% for tumors less than 4 cm. For larger tumors confined to the kidney without venous invasion, survival is still relatively good at 80–85%. For tumors that extend through the renal capsule and out of the local fascial investments, the survivability reduces to near 60%. Factors as general health and fitness or the severity of their symptoms impact the survival rates. For instance, younger people (among 20–40 years old) have a better outcome despite having more symptoms at presentation, possibly due to lower rates spread of cancer to the lymph nodes (stage III). Histological grade is related to the aggressiveness of the cancer, and it is classified in 4 grades, with 1 having the best prognosis (five-year survival over 89%), and 4 with the worst prognosis (46% of five-year survival). Some people have the renal cell cancer detected before they have symptoms (incidentally) because of the CT scan (Computed Tomography Imaging) or ultrasound. Incidentally diagnosed renal cell cancer (no symptoms) differs in outlook from those diagnosed after presenting symptoms of renal cell carcinoma or metastasis. The five-year survival rate was higher for incidental than for symptomatic tumours: 85.3% versus 62.5%. Incidental lesions were significantly lower stage than those that cause symptoms, since 62.1% patients with incidental renal cell carcinoma were observed with Stage I lesions, against 23% were found with symptomatic renal cell carcinoma. If it has metastasized to the lymph nodes, the five-year survival is around 5% to 15%. For metastatic renal cell carcinoma, factors which may present a poor prognosis include a low Karnofsky performance-status score (a standard way of measuring functional impairment in patients with cancer), a low haemoglobin level, a high level of serum lactate dehydrogenase, and a high corrected level of serum calcium. For non-metastatic cases, the Leibovich scoring algorithm may be used to predict post-operative disease progression. Renal cell carcinoma is one of the cancers most strongly associated with paraneoplastic syndromes, most often due to ectopic hormone production by the tumour. The treatment for these complications of RCC is generally limited beyond treating the underlying cancer. == Epidemiology ==

The incidence of the disease varies according to geographic, demographic and, to a lesser extent, hereditary factors. There are some known risk factors, however the significance of other potential risk factors remains more controversial. The incidence of the cancer has been increasing in frequency worldwide at a rate of approximately 2–3% per decade until the last few years where the number of new cases has stabilised. The incidence of RCC varies between sexes, ages, races and geographic location around the world. Men have a higher incidence than women (approximately 1.6:1) and the vast majority are diagnosed after 65 years of age. == History ==

Daniel Sennert made the first reference suggesting a tumour arising in the kidney in his text Practicae Medicinae, first published in 1613. Miril published the earliest unequivocal case of renal carcinoma in 1810. He described the case of Françoise Levelly, a 35-year-old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages of pregnancy. Hypernephroma controversy Following the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma. The pathogenesis of renal epithelial tumours was debated for decades. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphology of small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereas papillary tumours were derived from renal tissue. Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenal origin of renal tumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the term hypernephroma, with its associated adrenal connotation, persisted in the literature. Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure of clear cells from eight renal carcinomas. They found that the tumour cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat. They identified cytoplasmic membranes inserted perpendicularly onto the basement membrane with occasional cells containing microvilli along the free borders. They concluded that these features indicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one of the most debated issues in tumour pathology. == See also ==