Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, responsible for approximately 90–95% of cases. It is more common in men (with a male-to-female ratio of up to 2:1). It is most commonly diagnosed in the elderly (especially in people over 75 years of age).
Initial treatment is most commonly either partial or complete removal of the affected kidney(s). Where the cancer has not metastasised (spread to other organs) or burrowed deeper into the tissues of the kidney, the five-year survival rate is 65–90%, but this is lowered considerably when the cancer has spread.
The body is remarkably good at hiding the symptoms and as a result people with RCC often have advanced disease by the time it is discovered. The initial symptoms of RCC often include blood in the urine (occurring in 40% of affected persons at the time they first seek medical attention), flank pain (40%), a mass in the abdomen or flank (25%), weight loss (33%), fever (20%), high blood pressure (20%), night sweats and generally feeling unwell. When RCC metastasises, it most commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones. Immunotherapy and targeted therapy have improved the outlook for metastatic RCC.
RCC is also associated with a number of paraneoplastic syndromes (PNS) which are conditions caused by either the hormones produced by the tumour or by the body's attack on the tumour and are present in about 20% of those with RCC. These syndromes most commonly affect tissues which have not been invaded by the cancer. The most common PNSs seen in people with RCC are: high blood calcium levels, high red blood cell count, high platelet count and secondary amyloidosis.
Signs and symptoms Historically, medical practitioners expected a person to present with three findings. This classic triad is 1: haematuria, which is when there is blood present in the urine, 2: flank pain, which is pain on the side of the body between the hip and ribs, and 3: an abdominal mass, similar to bloating but larger. It is now known that this classic triad of symptoms only occurs in 10–15% of cases, and is usually indicative that the renal cell carcinoma is in an advanced stage. Today, renal cell carcinoma is often asymptomatic, meaning it presents no symptoms, and is commonly detected incidentally during examinations for unrelated medical conditions. The percentage of asymptomatic and incidentally diagnosed RCC cases, particularly smaller tumors, has continued to rise in recent years.
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. It is considered an adenocarcinoma. 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. Upon physical examination, palpation of the abdomen may reveal the presence of a mass or an organ enlargement.
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. Classification of the Common Histological Subtypes of Renal Cell Carcinoma Renal Cell Carcinoma Subtype Frequency Genetic Abnormalities CharacteristicsClear Cell Renal Cell Carcinoma (CCRCC) 60–70% Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs Inactivation of von Hippel–Lindau (VHL) gene by mutation and promoter hypermethylation Gain of chromosome 5q Loss of chromosomes 8p, 9p, and 14q In 2009–2010, five new frequently mutated genes were discovered in CCRCC; KDM6A/UTX, SETD2, KDM5C/JARID1C, and MLL2 CCRCC is derived from the proximal convoluted tubule Most commonly affects male patients in their sixties and seventies Majority of CCRCC arise sporadically Only 2 – 4% of the cases presenting as part of an inherited cancer syndrome Papillary Renal Cell Carcinoma (PRCC) 10–15% Trisomy of chromosomes 7 and 17, loss of chromosome Y in men in sporadic PRCC Trisomy of chromosome 7 in hereditary PRCC Gain of chromosomes 12, 16, and 20 Rare mutations of Met proto-oncogene PRCC is derived from the distal convoluted tubule PRCCs most commonly affect males in their sixties and seventies Less aggressive tumour than clear cell RCC, with 5-year survival rates of 80% to 85%. Majority of tumours occur sporadically, but some may develop in members of families with hereditary PRCC Chromophobe Renal Cell Carcinoma (ChRCC) 3–5% Loss of chromosomes Y, 1, 2, 6, 10, 13, 17, and 21 ChRCC is derived from the cortical collecting duct ChRCC has a much better prognosis than clear cell and papillary RCC, with 5-year survival rate of greater than 90%. Most cases arise sporadically, while some familial cases are associated with Birt–Hogg–Dube (BHD) syndrome Clinical, Pathological and Genetic Features of Uncommon RCC Subtypes Included in the 2004 WHO Classification of RCC Pathology RCC subtype Clinical features Cell/Tissue Characteristics Genetics Prognosis Multilocular Cystic RCC Variant of CCRCC (5% of CCRCC) Mean age 51 years (range 20–76) Male:female = 2–3:1 Clear cytoplasm, small dark nuclei 3p deletion as observed in CCRCC Favorable No local or distant metastasis after complete surgical removal Carcinoma of the Collecting Ducts of Bellini Less than 1% of all renal tumors; arising in the collecting ducts of Bellini Mean age 55 years (range 40–70) Male:female = 2:1 High-grade tumor cells with eosinophilic cytoplasm Variable results: LOH on chromosomes 1q, 6p, 8p,9p, 13q, 19q32 and 21q; c-erB2 amplification associated with unfavorable outcome Poor prognosis 1/3 presenting with metastasis 2/3 patients succumb to the disease within 2 years of diagnosis Medullary Carcinoma Exceedingly rare; almost exclusively in patients with sickle cell hemoglobinopathies or traits Majority are African-Americans Mean age 19 years (5–69) Male:female = 2:1 Haemorrhage and necrosis, high-grade tumour cells with eosinophilic cytoplasm Not well defined Highly aggressive 95% presenting with metastasis Often succumb to the disease within 6 months of diagnosis Xp11.2 Translocation Carcinoma Predominantly affecting children and young adults Accounts for 40% of RCCs in this age group Affects adult patients with a striking female predominance May resemble PRCC Clear and eosinophilic cells Chromosomal translocation involving TFE3 gene on Xp11.2 resulting in overexpression of the TFE3 protein Present at advanced stage, but with indolent clinical course in children Adult patients may pursue more aggressive course Mucinous Tubular Spindle Cell Carcinoma Mean age 53 years (range 13–82) Affects predominantly female patients (male:female = 1:4) incidental finding in most cases Tubules, extracellular mucin and spindle cells Not well defined; Losses involving chromosomes 1, 4, 6, 8, 9, 11, 13, 14, 15, 18, 22 reported; 3p alterations and gain of chromosome 7, and 17 not present Favourable Majority of patients remain disease free after surgical resection Post-Neuroblastoma Renal Cell Carcinoma Mean age of RCC diagnosis is 13.5 years (range 2–35) Eosinophilic cells with oncocytoid features (same as CCRCC) Not well defined; Loss of multiple chromosomal loci observed Similar to other common RCC subtypes
Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology. 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) Multilocular cystic clear cell renal cell carcinoma Tubulocystic renal cell carcinoma Thyroid-like follicular renal cell carcinoma Acquired cystic kidney disease-associated renal cell carcinoma Renal cell carcinoma with t(6;11) translocation (TFEB) Hybrid oncocytoma/chromophobe renal cell carcinoma Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Laboratory tests