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Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a tumor Tumor Inflammation that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%–85% of all primary renal neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors. Most RCCs arise sporadically, but smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity are linked to its development. The disease usually presents asymptomatically. When symptoms finally arise, the tumor Tumor Inflammation has already grown significantly and/or spread to other tissues. The classic clinical triad of RCC is flank pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, hematuria, and a palpable abdominal renal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast, but this triad appears in only about 9% of cases. Affected individuals also commonly present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and/or anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types. Renal cell carcinoma is usually diagnosed via CT scan of the abdomen and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy. Localized cases of RCC are commonly treated and cured with surgery, and advanced cases are treated with a combination of immunotherapy and/or molecular targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy. The long-term prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas for locally advanced or metastatic RCC is often poor.

Last updated: 21 Mar, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Renal cell carcinoma (RCC), also called hypernephroma and renal cell adenocarcinoma, is a type of cancer that originates from the lining of the small tubules of the renal cortex.

Epidemiology

  • Accounts for 80%–85% of all primary renal neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is highest in North America and the Czech Republic:
    • In North America, RCC is responsible for 76,000 new cases and 14,000 deaths each year.
    • In the United States, the incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is highest in the White, Black, Hispanic, and American Indian populations and lowest in the Asian American and Pacific Islander populations.
  • Approximately twice as common in men as in women
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is highest in the 6th to 8th decade of life, with a median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion age of 64.

Etiology

  • Most cases of RCC occur sporadically.
  • Only 4% of cases are associated with a genetic component.
  • Risk factors:
    • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases (associated with a higher incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency and more advanced disease)
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity (risk increases with ↑ BMI BMI An indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese). Obesity)
    • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, especially individuals with cystic Cystic Fibrocystic Change disease of the kidney acquired through dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis
    • Occupational exposure Exposure ABCDE Assessment (e.g., cadmium, asbestos, petroleum by-products)
    • Prolonged ingestion of analgesic combinations (e.g., aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs), NSAIDs NSAIDS Primary vs Secondary Headaches, and acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen)
    • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics: several hereditary diseases have been associated with RCC:
      • Inherited polycystic disease 
      • Von Hippel-Lindau syndrome (approximately 40% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop RCC)
      • Tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor (approximately 5% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop RCC)
      • Hereditary leiomyomatosis and renal cancer syndrome (HLRCC)
      • Hereditary papillary renal cell carcinoma (HPRCC)
    • Cytotoxic Cytotoxic Parvovirus B19 chemotherapy Chemotherapy Osteosarcoma
    • Chronic hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus infection
    • Kidney stones Kidney stones Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis
    • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease

Pathologic Classification

The difference between benign Benign Fibroadenoma and malignant masses in the kidney is determined by histologic criteria. According to the morphology, growth pattern, cell of origin, and histochemical and molecular basis, RCCs are classified into several types:

  • Clear cell (most common) 
  • Papillary
  • Chromophobe 
  • Oncocytic 
  • Collecting duct (very rare)
  • Translocation RCC (very rare)

Clear cell carcinoma

  • 75%–85% of all renal tumors
  • Etiology: 
    • Most commonly sporadic Sporadic Selective IgA Deficiency
    • Genetic mutations Genetic Mutations Carcinogenesis:
      • Deletion of 3p (seen in up to 94% of clear cell tumors)
      • Gain of 5q
      • Monosomy Monosomy The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2n-1. Types of Mutations or partial loss of 14q
    • Genetic pathway alterations:
      • VHL gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
      • PBRM1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
      • BAP1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
      • Inactivation of histone-modifying genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure
      • Ubiquitin-mediated proteolysis pathway
      • Abnormalities in cellular division ( Ras RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis, p53)
  • Pathology/histologic appearance:
    • Arises from clear cells in the proximal tubular epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology
    • Mostly well differentiated
    • Large areas of gray-white necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and foci of hemorrhagic discoloration
    • Can have a trabecular (cordlike) or tubular growth pattern with cells of rounded or polygonal shape and granular or clear cytoplasm
    • May show cystic Cystic Fibrocystic Change and/or solid areas
    • May show cellular atypia Atypia Fibrocystic Change
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas:
    • Depends on the stage at diagnosis
    • Poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas with higher nuclear grade and/or sarcomatoid pattern
Renal clear cell carcinoma with sheet-like, solid clear cells

Renal clear cell carcinoma:
The tumor Tumor Inflammation consists of sheet-like, solid clear cells. H&E × 100

Image: “Pathological images from patient” by Chen S, Jin B, Xu L, Fu G, Meng H, Liu B, Li J, Xia D. License: CC BY 4.0, cropped by Lecturio.

Papillary carcinoma

  • 10%–15% of cases
  • Etiology: 
    • Most commonly sporadic Sporadic Selective IgA Deficiency (majority associated with trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 7, trisomy Trisomy The possession of a third chromosome of any one type in an otherwise diploid cell. Types of Mutations 17, and the loss of Y in males)
    • MET MET Preoperative Care gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
    • FH gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
  • Pathology/histologic appearance: 
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
Histology of papillary renal cell carcinoma

H&E-stained specimen showing characteristic histology of papillary renal cell carcinoma

Image: “Hematoxylin and Eosin staining of the tumor Tumor Inflammation tissue showing characteristic histology of papillary renal cell carcinoma” by Alanee S, Dynda DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus, Hemmer P, Schwartz B. License: CC BY 4.0

Chromophobe carcinoma

  • 5%–10% of cases
  • Etiology: 
    • Hypodiploid number of chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure
    • Up-regulated KIT oncogene
    • Up-regulated TERT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Pathology/histologic appearance: 
    • Arises from intercalated cells Intercalated cells Tubular System of the collecting ducts
    • Made up of pale, eosinophilic cells arranged in solid sheets around blood vessels
    • Perinuclear halos can be seen
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Favorable prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas (more than clear cell RCC)
    • Possibly due to presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor at an earlier stage
Sarcomatoid chromophobe renal cell carcinoma

Sarcomatoid chromophobe renal cell carcinoma:
a. Microphotograph demonstrating sarcomatoid renal cell carcinoma with giant cell tumors and necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage (H&E x 100) (inset shows giant cell tumor Tumor Inflammation among pleomorphic Pleomorphic Bacteroides cells (H&E x 400))
b. Microphotograph showing chromophobe renal cell carcinoma (arrow) admixed with sarcomatoid areas with bizarre cells and giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis (arrowheads)

Image: “Sarcomatoid renal cell carcinoma coexisting with chromophobe renal cell carcinoma.” by Chakrabarti I, Giri A, Majumdar K, Anuradha DE. License: CC BY 2.0

Oncocytic carcinoma/oncocytomas

  • 3%–7% of cases
  • Etiology: 
    • Genetic abnormalities, including:
      • Loss of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 1 and chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics Y
      • Rearrangement of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 11q13 (contains CCND1 CCND1 Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin d1 is the result of bcl-1 rearrangement, a t(11; 14) translocation, and is implicated in various neoplasms. Lentigo Maligna)
    • Associated with:
      • Birt-Hogg-Dubé syndrome
      • Tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
  • Pathology/histologic appearance: 
    • Arises from intercalated cells Intercalated cells Tubular System of the collecting ducts
    • Composed of oncocytes, well-differentiated neoplastic cells with highly eosinophilic cytoplasm due to numerous mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Favorable prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Behave as benign Benign Fibroadenoma tumors
    • Rarely invasive or metastatic
High-grade oncocytic renal tumor

High-grade oncocytic renal tumor Tumor Inflammation

Image: “High-grade oncocytic renal tumour — high mag” by Nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy. License: CC BY-SA 4.0

Collecting or Bellini duct tumors

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: very rare
  • Etiology: usually due to genetic abnormalities
  • Pathology/histologic appearance: 
    • Composed of irregular channels Channels The Cell: Cell Membrane 
    • Epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology is very atypical, with a hobnail pattern.
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Poor
    • Commonly associated with metastatic and/or advanced disease
Collecting duct carcinoma

H&E-stained tissue sections demonstrating collecting duct carcinoma

Image: “Hematoxylin and eosin staining of tissue sections from the nephrectomy specimens demonstrating collecting duct carcinoma” by Tazi EM, Essadi I, Tazi MF, Ahellal Y, M’rabti H, Errihani H. License: CC BY 2.0

Translocation renal cell carcinoma

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency
    • Very rare
    • Occurs at a younger age and predominantly in women
  • Etiology: 
    • Due to a fusion of the TFE3, TFEB, or MITF MITF Lentigo Maligna genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure to a number of other genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure, including ASPSCR1, PRCC, SFPQ, and NONO
    • Presents in children with previous chemotherapy Chemotherapy Osteosarcoma, autoimmune disorders, or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow transplant conditioning
  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Much worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas than most other types of RCC because symptoms develop at a later stage
    • Resistant to targeted therapies
Translocation renal cell carcinoma

Translocation renal cell carcinoma, composed of clear cells with voluminous cytoplasm and distinct cell borders showing typical papillary architecture and hyalinized fibrous Fibrous Fibrocystic Change vascular cords

Image: “Translocation renal cell carcinoma” by Kmetec A, Jeruc J. License: CC BY 3.0

Clinical Presentation

Many cases present asymptomatically, leading to further progression of the diseases. Symptoms arise when the tumor Tumor Inflammation has reached a significant size, invaded adjacent structures, or developed distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.

  • Classic triad of flank pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, hematuria, and palpable abdominal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast (present in only 9% of cases)
  • Other symptoms:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
    • Muscle wasting Muscle Wasting Duchenne Muscular Dystrophy
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia 
    • Secondary polycythemia Secondary Polycythemia Polycythemia Vera
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Scrotal varicocele Varicocele A condition characterized by the dilated tortuous veins of the spermatic cord with a marked left-sided predominance. Adverse effect on male fertility occurs when varicocele leads to an increased scrotal (and testicular) temperature and reduced testicular volume. Varicocele, Hydrocele, and Spermatocele, usually left-sided
    • Involvement of the inferior vena cava Inferior vena cava The venous trunk which receives blood from the lower extremities and from the pelvic and abdominal organs. Mediastinum and Great Vessels: Anatomy ( IVC IVC The venous trunk which receives blood from the lower extremities and from the pelvic and abdominal organs. Mediastinum and Great Vessels: Anatomy):
      • Lower-extremity edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
      • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
      • Hepatic dysfunction
      • Pulmonary emboli
    • Paraneoplastic syndrome, which can lead to increased levels of the following hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types:
      • Erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology
      • Parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hormone-related protein
      • Gonadotropins
      • Human placental lactogen
      • Adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones–like substance
      • Renin Renin A highly specific (leu-leu) endopeptidase that generates angiotensin I from its precursor angiotensinogen, leading to a cascade of reactions which elevate blood pressure and increase sodium retention by the kidney in the renin-angiotensin system. Renal Sodium and Water Regulation
      • Glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
      • Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia due to:
      • Lytic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types lesions
      • Parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hormone-related protein
      • Elevated prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids that promote bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types resorption

Diagnosis and Staging

Diagnosis

  • 1st-line: CT scan of the abdomen and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy to show characteristics of RCC, as opposed to a simple renal cyst:
    • Thickened, irregular or smooth wall
    • Septations
    • Enhancement after contrast injection
  • Ultrasonography may also be performed.
  • MRI used if CT and/or ultrasonography inconclusive
  • A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is performed after the imaging diagnosis and must be evaluated for the extent of local invasion and metastatic disease prior to surgery.
Two illustrative cases for selection of roi location

Two illustrative cases for selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions of region of interest (ROI; approximately 1 cm in diameter):
(a) An ROI was placed in the well-enhancing part in left renal clear cell carcinoma in a 37-year-old female patient.
(b) An ROI was placed in left renal cell carcinoma in a 46-year-old female patient.

Image: “Two illustrative cases for selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions of ROI location” by Scientific Reports. License: CC BY 4.0

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

RCCs vary greatly in the extent of disease at presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor.

  • Localized to the kidney: 65%
  • Regional ( lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy): 17%
  • Metastatic disease: 16%
  • Unstaged: 3%
Table: TNM staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis of renal cell carcinoma
Stage Definition Subdivision
Tumor Tumor Inflammation stage
T0 No evidence of primary tumor Tumor Inflammation
T1 < 7 cm in the greatest dimension, confined to the kidney
  • 1a: < 4 cm
  • 1b: > 4 cm and ≤ 7 cm
T2 > 7 cm in the greatest dimension, confined to the kidney
  • 2a: > 7 cm and ≤ 10 cm
  • 2b: > 10 cm
T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones Extends into major veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins: Histology or perinephric tissues, but not into the adrenal gland or beyond the Gerota fascia Fascia Layers of connective tissue of variable thickness. The superficial fascia is found immediately below the skin; the deep fascia invests muscles, nerves, and other organs. Cellulitis (anterior perirenal fascia Fascia Layers of connective tissue of variable thickness. The superficial fascia is found immediately below the skin; the deep fascia invests muscles, nerves, and other organs. Cellulitis)
T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones Invades beyond the Gerota fascia Fascia Layers of connective tissue of variable thickness. The superficial fascia is found immediately below the skin; the deep fascia invests muscles, nerves, and other organs. Cellulitis and/or into the adrenal gland
Regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
N0 No metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis to regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
N1 Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis to regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
Distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
M0 No distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
M1 Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis to distant lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy and/or organs

Management and Prognosis

Management

  • Localized, nonmetastatic disease requires surgery, which is curative in stages I–III. 
    • Partial nephrectomy
    • Radical nephrectomy
    • Enucleation
    • Thermal ablation
  • Metastatic disease: 
    • If metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis has already developed, the disease is usually unresectable.
    • Immunotherapy with or without molecularly targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy:
      • Nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma plus ipilimumab 
      • Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) plus axitinib 
      • Nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma plus cabozantinib 
      • Molecularly targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy: vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing (VEGF) tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitors (e.g., cabozantinib, lenvatinib plus everolimus Everolimus A derivative of sirolimus and an inhibitor of tor serine-threonine kinases. It is used to prevent graft rejection in heart and kidney transplant patients by blocking cell proliferation signals. It is also an antineoplastic agent. Immunosuppressants, nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Depends on:
    • Type of renal cell carcinoma
    • Extent and size of the tumor Tumor Inflammation at the time of detection
  • Sarcomatoid appearance indicates poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
  • The 5-year survival rate of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with kidney cancer has increased in recent years because of advancements in technology allowing for the detection of more tumors incidentally and at smaller sizes:
    • Localized: 93%
    • Regional: 70%
    • Distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis: 13%
    • Combined survival rate: 75%

Differential Diagnosis

  • Benign Benign Fibroadenoma renal tumor Tumor Inflammation:
    • Angiomyolipoma Angiomyolipoma A benign tumor containing vascular, adipose, and muscle elements. It occurs most often in the kidney with smooth muscle elements (angiolipoleiomyoma) in association with tuberous sclerosis. Tuberous Sclerosis: appears on imaging as an enhancing mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast containing macroscopic fat and no calcifications. Small angiomyolipomas with minimal fat are difficult to characterize on imaging and often require further evaluation. Associated with tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor, especially if bilateral. 
    • Metanephric adenoma: rare, benign Benign Fibroadenoma lesions that are more common in women than in men. Often discovered incidentally, but can present with pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, hematuria, or a palpable mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast. Can be difficult to differentiate on histology from papillary RCC or epithelial-predominant Wilms tumor Tumor Inflammation.
  • Metastatic disease: cancer from another source that spreads to the kidney. Metastatic disease often presents with multiple renal lesions with borderline enhancement and widespread metastatic disease.
  • Lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum: hematologic malignancy Malignancy Hemothorax that can involve the kidney. Percutaneous biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma should be done to differentiate lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum from RCC. Renal involvement in hematologic malignancies is found at autopsy in about ⅓ of terminal lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum or leukemia patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. Renal involvement should be suspected in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with massive retroperitoneal Retroperitoneal Peritoneum: Anatomy lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, or lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy elsewhere in the body or in atypical retroperitoneal Retroperitoneal Peritoneum: Anatomy regions. 
  • Renal abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease or focal pyelonephritis Pyelonephritis Pyelonephritis is infection affecting the renal pelvis and the renal parenchyma. This condition arises mostly as a complication of bladder infection that ascends to the upper urinary tract. Pyelonephritis can be acute or chronic (which results from persistent or chronic infections). Typical acute symptoms are flank pain, fever, and nausea with vomiting. T Pyelonephritis and Perinephric Abscess: a variety of infectious Infectious Febrile Infant and inflammatory conditions can mimic RCC, including acute and chronic pyelonephritis Pyelonephritis Pyelonephritis is infection affecting the renal pelvis and the renal parenchyma. This condition arises mostly as a complication of bladder infection that ascends to the upper urinary tract. Pyelonephritis can be acute or chronic (which results from persistent or chronic infections). Typical acute symptoms are flank pain, fever, and nausea with vomiting. T Pyelonephritis and Perinephric Abscess and renal abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease. Axial Axial Computed Tomography (CT) imaging often shows perineal inflammatory changes. Clinical symptoms, such as chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, flank pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, or pyuria Pyuria The presence of white blood cells (leukocytes) in the urine. It is often associated with bacterial infections of the urinary tract. Pyuria without bacteriuria can be caused by tuberculosis, stones, or cancer. Urinary tract infections (UTIs) aid in the diagnosis. Renal mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma or aspiration with drain placement can aid in the diagnosis. Serial imaging to demonstrate the resolution of the mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast may also be required after the treatment.

References

  1. American Cancer Society. Key statistics about kidney cancer. https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html
  2. American Cancer Society. What is kidney cancer? https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.htm
  3. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. (2020). Cancer stat facts: kidney and renal pelvis cancer. https://seer.cancer.gov/statfacts/html/kidrp.html
  4. Choueiri, T.K. (2020). Prognostic factors in patients with renal cell carcinoma. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/prognostic-factors-in-patients-with-renal-cell-carcinoma
  5. George, D., Jonasch, E. (2021). Systemic therapy advanced clear cell renal carcinoma. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/systemic-therapy-of-advanced-clear-cell-renal-carcinoma
  6. Motzer, R.J. (2018). Renal cell carcinoma. In Jameson, J., et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=2129&sectionid=192016249
  7. Pierorazio, P.M., Campbell, S.C. (2021). Diagnostic approach, differential diagnosis, and management of a small renal mass. UpToDate. Retrieved Feb 17, 2021, from https://www.uptodate.com/contents/diagnostic-approach-differential-diagnosis-and-management-of-a-small-renal-mass
  8. Richie, J.P. (2021). Definitive surgical management of renal cell carcinoma. UpToDate. Retrieved Feb 17, 2021, from https://www.uptodate.com/contents/definitive-surgical-management-of-renal-cell-carcinoma
  9. Atkins, M.B. (2020). Clinical manifestations, evaluation, and staging of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/clinical-manifestations-evaluation-and-staging-of-renal-cell-carcinoma
  10. Atkins, M.B., Choueiri, T.K. (2021). Epidemiology, pathology, and pathogenesis of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-renal-cell-carcinoma
  11. Atkins, M.B. (2021). Overview of the treatment of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-renal-cell-carcinoma

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