Renal cell carcinoma

responsible for 80-85% of all primary renal neoplasms
Transitional cell carcinomas of the renal pelvis are the next most common (8 %)
Other parenchymal epithelial tumors, such as oncocytomas, collecting duct tumors, and renal sarcomas, occur infrequently
Renal medullary carcinoma is a rare form of RCC, seen in sickle cell disease
Nephroblastoma or Wilms tumor occur in children

RCC and 175,000 deaths due to kidney cancer
The incidence of renal cell carcinoma (RCC) varies widely from region to region, with the highest rates observed in the Czech Republic and North America
In the United States, there are approximately 76,000 new cases and almost 14,000 deaths from RCC each year
Epidemiology

RCC occurs predominantly in the sixth to eighth decade of life with median age at diagnosis around 64 years of age
It is unusual in patients under 40 years of age and rare in children
Epidemiology

to cytotoxic agents
Relative resistance to radiotherapy
Variable clinical course for patients with metastatic disease, including anecdotal reports of spontaneous regression

rate
The five-year survival rate of patients with kidney cancer has doubled over the last 60 years, from 34% in 1954 to 62% in 1996 and 75% from 2009 to 2015
This improved survival is mostly due to earlier detection of these tumors at smaller sizes (ie, <4 cm) and curative surgical treatment

with newly diagnosed RCC, excess body weight is associated with a lower stage and lower grade disease
Furthermore, in patients with metastatic disease, RCC is associated with a longer overall survival for those with excess body weight compared with those with normal or below normal body weight
The improved prognosis in these patients may be associated with decreased expression of the fatty acid synthase (FASN) gene

disease of the kidney
Chronic kidney disease, a decreasing estimated glomerular filtration rate (eGFR)
The risk of developing RCC has been estimated to be up to 30 times greater in dialysis patients with acquired polycystic disease of the kidney than in the general population
Among chronic dialysis patients, the incidence of acquired cystic disease is approximately 35-50%, and approximately 6% of these patients eventually develop RCC

to toxic compounds, such as cadmium, asbestos, and petroleum byproducts 
Epidemiologic studies have demonstrated an increased risk for RCC with heavy use of aspirin, nonsteroidal anti inflammatory drugs (NSAIDS), and acetaminophen, although the risk may vary depending on the agent
The prolonged ingestion of analgesic combinations, particularly compounds containing phenacetin (of which acetaminophen is a major metabolite) and aspirin, can lead to chronic renal failure. Such patients are at increased risk for urothelial tumors

use of cytotoxic chemotherapy in childhood for malignancies, autoimmune disorders, or bone marrow transplant conditioning has been associated with the subsequent development of translocation RCC
Chronic hepatitis C infection 
Sickle cell disease — Patients with sickle cell trait and (to a lesser extent) sickle cell disease are at risk for renal medullary carcinoma

history of kidney stones may be associated with both RCC and transitional cell carcinoma of the upper urinary tract
In a meta-analysis that pooled data from almost 63,000 patients with kidney stones, the risk ratio of developing RCC was 1.96 (95% CI 1.24-2.49), and the increased risk appeared to be largely limited to men. The risk ratio for transitional cell carcinoma was 2.14

increased in patients who have been treated for one renal cancer
This increased risk is most pronounced with younger age at the first RCC, suggesting that early onset renal cancer has a genetic component

cancer survivors — At least one study suggests that childhood cancer survivors are at an increased risk for RCC, particularly if they were previously treated with radiotherapy directed at the kidney or with cisplatin

have been described
Factors that favor a hereditary contribution in patients without a clear genetic disease include:
first degree relatives with a tumor
onset before the age of 40
bilateral or multifocal disease
Patients with inherited polycystic disease may have an increased risk of RCC (as well as liver and colon cancer), even in the absence of chronic kidney disease

mutation of VHL gene localized on chromosome 3p, development of clear cell RCC in approximately 35% of individuals
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant disorder
A pathogenic variant in the VHL gene diagnostic for VHL disease is present in approximately 1 in 36,000 individuals

Hereditary cancer kidney syndromes

the middle ear
Serous cystadenomas and neuroendocrine tumors of pancreas
Serous cystadenomas of the epididimus and broad ligament

VHL-associated tumours

the VHL gene
VHL protein, the product of the VHL gene, is a tumor suppressor protein that performs a number of important cellular functions
Mutation in the VHL gene causes accumulation of HIF1A and HIF2A factors (substrates for the product of the VHL gene) and increased levels of erythropoietin, vascular endothelial growth factor (VEGF), and other growth factors, providing a stimulus for tumor growth

cancer syndrome in which affected individuals are at risk for the development of type 1 papillary renal cell carcinomas
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome in which affected family members have cutaneous and uterine leiomyomas, and/or papillary type 2 RCCs

genetic disorder characterized by fibrofolliculomas (benign tumors arising in hair follicles), pulmonary cysts, pneumothorax, kidney tumors
The renal tumors are usually of the chromophobe type, but they can exist as hybrids with other cell types (clear cell, oncocytic)
This disorder is associated with mutations in the FLCN gene, which codes for folliculin

(10%)
Chromophobe tumors (≤5%)
Oncocytomas (5–10%)
Collecting duct or Bellini duct tumors (<1%)
Translocation carcinoma (<1%)

a more indolent clinical course
Oncocytomas are considered benign neoplasms
Collecting duct carcinomas, which are thought to arise from the collecting ducts within the renal medulla, are rare but often very aggressive
Medullary carcinoma has histopathologic and clinical features similar to those of collecting duct carcinoma, associated with sickle cell trait

>80% of patients who develop metastases
Clear cell tumors arise from the epithelial cells of the proximal tubules and usually show chromosome 3p deletions
Deletions of 3p21–26 (where the VHL gene maps) are identified in patients with familial as well as sporadic tumors

cell RCC
VHL gene encodes a tumor suppressor protein that is involved in regulating the transcription of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and a number of other hypoxia-inducible proteins
Inactivation of VHL leads to overexpression of these agonists of the VEGF and PDGF receptors, which promote tumor angiogenesis and tumor growth

VHL mutations in common, different portions of the primary tumor and different metastatic sites may have wide variation in genetic lesions
This tumor heterogeneity may underlie the emergence of treatment resistance

RCC (52% of cases), other genes are implicated as well
PBRM1 in 40% of cases
SETD2 in 15% of cases
BAP1 in 15% of cases
These three genes, all part of the chromatin remodeling/histone methylation pathway, are also located on the short arm of chromosome 3p
Mutations in BAP1 have been linked to shorter survival in renal cancer
In a subset of clear cell RCCs, alterations have been found in components of the mammalian target of rapamycin (mTOR) pathway, spurring the study of mTOR inhibitors in renal cancer

subtype
Type 1 papillary RCC tumors are associated with MET pathway dysregulation, and patients can present with indolent disease and have a more favorable prognosis

c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor, activates a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion

by sporadic gene mutations (such as those involving 1p-, 3p-, or +5q) or germline mutations in the fumarate hydratase gene, which is associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. These patients typically present with more aggressive disease and have a less favorable prognosis

Anemia
Varicocele

abdominal renal mass) occurs in at most 9% of patients; when present, it strongly suggests locally advanced disease
An abdominal or flank mass (associated with lower pole tumors).
The mass is generally firm, homogeneous, nontender, and moves with respiration
Physical exam

11 % of men with RCC. Varicocele typically fail to empty when the patient is recumbent. This finding should always arouse suspicion for a kidney tumor that has obstructed the gonadal vein where it enters the renal vein
Inferior vena cava involvement can produce lower extremity edema, ascites, hepatic dysfunction and pulmonary emboli
Physical exam

discovered from the initial presentation of a paraneoplastic syndrome
Hypercalcemia
Non metastatic hepatic dysfunction (Stauffer’s syndrome)
Acquired dysfibrinogenemia
Erythrocytosis (is noted at presentation in only ~3% of patients)
Anemia, a sign of metastatic disease, is more common

on a radiologic imaging
Widespread use of radiologic cross-sectional imaging procedures (computed tomography [CT], ultrasound, magnetic resonance imaging [MRI]) contributes to earlier detection of renal mass
The increasing number of incidentally discovered low-stage tumors has contributed to an improved 5-year survival for patients with RCC and increased use of nephron-sparing surgery (partial nephrectomy)

abdomen and pelvis
Chest radiograph
Urine analysis
Urine cytology
CT chest, If metastatic disease is suspected from the chest radiograph
MRI is useful in evaluating the inferior vena cava in cases of suspected tumor involvement or invasion by thrombus, or when intravenous contrast administration given with CT is prohibited by impaired renal function

differential diagnosis of a renal mass includes RCC, cysts, benign neoplasms (adenoma, angiomyolipoma, oncocytoma), inflammatory lesions (pyelonephritis or abscesses), and other primary or metastatic cancers
Less common malignancies that may involve the kidney include transitional cell carcinoma of the renal pelvis, sarcoma, lymphoma, and Wilms’ tumor
Differential diagnosis of renal mass

staging system
Stage I tumors are ≤7 cm in greatest diameter and confined to the kidney
Stage II tumors are >7 cm and confined to the kidney

staging system
Stage III tumors extend through the renal capsule but are confined to Gerota’s fascia (IIIa), or involve a single hilar lymph node (N1)
Stage IV disease includes tumors that have invaded adjacent organs or involve multiple lymph nodes or distant metastases

II disease
15–20% with stage III
15–20% with stage IV

I
74% for stage II
53% for stage III
8% for stage IV

survival rates when designing a clinical trial
Prognostic model, developed by investigators at Memorial Sloan Kettering Cancer Center, incorporated five factors shown to correlate with worse survival in advanced renal cell carcinoma:
poor performance status
high serum lactate dehydrogenase
high serum calcium
low hemoglobin concentration
<1-year interval from diagnosis to treatment
Patients with zero risk factors had significantly longer median survival (30 months) than those with one or two risk factors (14 months) and those with three to five risk factors (5 months)

tumors and selected cases of stage III disease is radical or partial nephrectomy
A radical nephrectomy involves en bloc removal of Gerota’s fascia and its contents, including the kidney, the ipsilateral adrenal gland in some cases, and adjacent hilar lymph nodes
Open, laparoscopic, or robotic surgical techniques may be used to perform radical nephrectomy

cava (stage III disease) does not preclude resection even if cardiopulmonary bypass is required
If the tumor is resected, half of these patients have prolonged survival

patients who have impaired renal function or only one kidney, depending on the size and location of the lesion
A nephron-sparing approach can also be used for patients with bilateral tumors
Partial nephrectomy techniques are applied electively to resect small masses
Treatment of localized RCC

kidney disease and is associated with increased risks of cardiovascular morbidity and mortality
When compared with radical nephrectomy, partial nephrectomy can achieve preserved renal function, and reduced frequency of late cardiovascular events
Treatment of localized RCC

not improve outcome, even in cases with a poor prognosis
Adjuvant trials with sunitinib, an orally administered antiangiogenesis inhibitor, do not consistently show a benefit in prolonging time to relapse following nephrectomy
Adjuvant therapy
Adjuvant therapy with pembrolizumab (monoclonal antibodiy directed against programmed cell death 1 protein PD-1 ) of patients at high risk of recurrent RCC following nephrectomy or following complete resection of primary and metastatic lesions extended disease free survival versus placebo

nodes, liver, bone, and brain
These tumors may follow an unpredictable and protracted clinical course

Treatment of metastatic RCC

may occur in patients who relapse after nephrectomy in a solitary site that is removed
Indications for nephrectomy with metastases at initial presentation are to alleviate pain or hemorrhage of a primary tumor
Treatment of metastatic RCC

metastases
The types of radiotherapy most commonly used are external beam therapy and stereotactic radiotherapy
In select cases, stereotactic ablative radiotherapy to a metastatic site may result in local control with relatively minimal toxicity
Treatment of metastatic RCC

immunology and oncology have been linked since the late 19th century, when the surgeon William Coley reported that injection of killed bacteria into sites of sarcoma could lead to tumor shrinkage
Treatment of metastatic RCC

results in spontaneous and dramatic remissions in metastases, particularly in the lungs
These observations were followed by the clinical demonstration of antitumor activity with the cytokine interleukin 2 (IL-2) and interferon alfa (IFNa), although only a minority of patients derived major clinical benefit
Cytokine therapy with IL-2 or interferon-α producd regression in 10–15% of patients
IL-2 produced durable complete remission in a small proportion of cases with high levels of toxicity
Treatment of metastatic RCC

trials established a role for antiangiogenic therapy
These trials separately evaluated two orally administered antiangiogenic agents, sorafenib and sunitinb, that inhibited receptor tyrosine kinase signaling through the VEGF and PDGF receptors
Both showed efficacy as second-line treatment following progression during or after cytokine treatment

in RCC and correlates with microvessel density, a measure of the extent of angiogenesis1
After activation of HIF, VEGF is upregulated and binds to its receptor (VEGFR) on endothelial cell surfaces2,3
This promotes endothelial cell migration and proliferation – vital for the development of new tumour-induced blood vessels1–3
VEGF and VEGFR have proven to be attractive molecular targets for novel therapies for RCC because they play key roles in tumor angiogenesis

4. Linehan WM, et al. Cancer of the Kidney: Introduction. In: DeVita VT, et al, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, PA. Lippincott, Williams & Watkins; 2011:1161–82: Ch 93

1. Banumathy G, Cairns P. Cancer Biol Ther 2010;10:658–64;
2. Pili R, et al. Cancer of the Kidney. In: Niederhuber JE, et al, eds. Abeloff’s Clinical Oncology. 5th ed. 2014:1416–44.e5:Ch 82;
3. Rini BI, et al. Lancet 2009;373:1119–32;

efficacy for sunitinib with an acceptable safety profile
This trial resulted in a change in the standard first-line treatment from interferon to sunitinib
Treatment of metastatic RCC

5-year renal cancer survival rates over the past decades (50% in the mid-1970s, 57% in the late 1980s, and 74% for 2005−2012) can be attributed to widespread imaging leading to earlier discovery of tumors, the new agents are likely playing a an important role

tyrosine kinase inhibitors; the antiangiogenic bevacizumab (bevacizumab is a recombinant, humanized monoclonal antibody which binds to vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, Flt-1 and KDR; VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels), mTOR inhibitors temsirolimus and everolimus; nivolumab that inhibits PD-1…

first-line phase III trial
Efficacy was similar, and there was less fatigue and skin toxicity, resulting in better quality-of-life scores for pazopanib compared with sunitinib, but different profile of adverse effects, liver toxicity more frequent

tumors
Nivolumab, cabozantinib, and lenvatinib plus everolimus were compared to everolimus in randomized trials and showed that patients lived longer with each of these agents compared to patients treated with everolimus
Patients may benefit from the sequential use of agents following progression on first line therapy

treatment of metastatic RCC
Monoclonal antibodies directed against programmed cell death 1 protein PD-1 (nivolumab, pembrolizumab)
Monoclonal antibodies that binds to programmed death ligand 1 (PD-L1) (avelumab)
Anti cytotoxic T-lymphocyte antigen 4 (CTLA-4 ) (ipilimumab)

protein expressed on T cells, B cells, and NK cells
Programmed cell death 1 (PD-1) is an inhibitory molecule that binds to the PD-1 ligand (PD-L1) and PD-L2
PD-L1 is expressed on the surface of multiple tissue types, including many tumor cells, as well as hematopoietic cells; PD-L2 is more restricted to hematopoietic cells
Additional cells such as NK cells, monocytes, and dendritic cells also express PD-1 and/or PD-L1

promotes peripheral T effector cell exhaustion, and promotes conversion of T effector cells to Treg cells
Additional cells such as NK cells, monocytes, and dendritic cells also express PD-1 and/or PD-L1

that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding to its receptor

Immunotherapy

blocking of ligands PD-L1 and PDL-2 from interaction with PD-1 to help to restore T-cell response

Immunotherapy

programmed death ligand 1 (PD-L1) to selectively prevent the interaction between the programmed cell death-1 (PD-1) and B7.1 receptors, while still allowing interaction between PD-L2 and PD-1

Immunotherapy

to the cytotoxic T-lymphocyte associated protein 4, which is a down-regulator of T-cell activation pathways
Blocking CTLA-4 allows for enhanced T-cell activation and proliferation

T-cell function, resulting in improved anti-tumor responses in metastatic RCC

with systemic therapy as initial treatment. The decision to start systemic therapy and the selection of agent(s) depend on disease-related symptoms, patient comorbidities, and tumor risk stratification. Listed treatments are preferred options, although alternative agents that are not listed may also be effective. Clinical trials are encouraged if available. Select patients may be candidates for cytoreductive nephrectomy prior to initiation of immunotherapy
RCC: renal cell carcinoma; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; KPS: Karnofsky performance status; LLN: lower limit of normal; ULN: upper limit of normal.
* Patients with limited disease on imaging are usually asymptomatic. However, the decision to treat must take into account multiple factors, including rate of growth, location of tumor (eg, proximity to vital organs with potential for damage), and symptoms.
¶ For those who are ineligible for or choose to forego initial treatment with immunotherapy combinations, regardless of risk category, we offer antiangiogenic therapy with vascular endothelial growth factor (VEGF) inhibitors. The preferred agent depends on risk stratification and patient comorbidities
Δ For patients with good-risk, asymptomatic disease who desire a more aggressive management approach, options include sunitinib or pazopanib

Approach to initial systemic therapy in patients with metastatic clear cell RCC