Renal cell cancer

SECTION 

6 Renal Tumors

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25

Renal Cell Cancer NITI MADAN AND ROBERT H. WEISS

Introduction Kidney cancer, or renal cell carcinoma (RCC), is the most common malignancy seen in the practice of nephrology. It is one of the relatively few cancers whose incidence is increasing despite our growing knowledge of the associ­ ated risk factors, yet the study of this disease within ne­ phrology pedagogy and continuing education is woefully lacking.1 Although there are many subtypes of RCC, the most common by far is clear cell RCC (ccRCC) and the vast majority of these are characterized by mutations in the von Hippel-Lindau (VHL) gene. Because this subtype is also the most studied, both in the clinic and in the labora­ tory, it will be the major subject of this chapter. Indeed, because of the various genetic and consequent metabolic abnormalities seen in all types of kidney cancer, this dis­ ease has been labeled the “internist’s tumor”2 and “a metabolic disease.”3 Evaluating the various signs and symptoms of the disease in light of its genetics and biology (see later) allows a better understanding of its behavior and provides insight into new therapeutic approaches. After reading this chapter, it is hoped that practicing nephrologists are not only more aware of the biology of RCC, but also un­ derstand the profound effect of its presence in the setting of chronic kidney disease (CKD) and the consequence of its treatment on the incidence and progression of CKD.

have some effect upon cellular metabolism,7 a now com­ monly recognized property of classic oncogenes,8 such as oxygen and/or iron sensing, the tricarboxylic acid (TCA) cycle, glutamine metabolism, and tumor energetics;3 hence the appellation “metabolic disease.”2,5,9 Indeed, ccRCC has also been shown to be characterized by alterations in me­ tabolism, as is evidenced by nonstandard pathways in amino acids degradation, as well as energy production and protection from oxidative stress; this phenomenon of meta­ bolic reprogramming10 was first described by Warburg early in the 20th century11 and has become evident in a variety of malignancies, including RCC. In fact, such find­ ings have been put to use in developing new biomarkers and therapeutic paradigms.3 ccRCC is by far the most common subtype, comprises 70% to 85% of all RCCs, and is one of the most lethal subtypes. The loss of VHL suppressor gene12 is common in ccRCC,13–15 and this mutation, to a large degree, dictates its biological behavior by causing activation of hypoxia pathways even in the absence of true hypoxia and charac­ terizes ccRCC as a malignancy with “Warburg metabolism” (i.e., aerobic glycolysis).11 Activation of downstream events by the VHL system, including neoangiogenesis and para­ neoplastic phenomena, enable ccRCC cells to thrive as their surroundings become progressively more deprived of oxygen.16

Basic Science Considerations

RENAL CELL CARCINOMA IS A METABOLIC DISEASE

The finding that ccRCC is, to a greater extent than other ma­ lignancies, characterized by metabolic reprogramming—in which “normal” metabolism is altered for the benefit of the cancer—has led to advances in therapeutic design, which are based on this finding.3,4 Indeed, many of the paraneo­ plastic effects that are commonly seen with the clinical presentation (Table 25.1) are a result of this altered me­ tabolism. Another characteristic of the varieties of kidney cancer is that most are associated with genetic mutations, which in many cases contribute to the metabolic derange­ ments.5 For these reasons, an understanding of the biologic underpinnings of kidney cancer is essential for anyone who deals with this disease, both in the clinical and research settings.

ccRCC arises from the proximal tubular epithelium and, in its metastatic form, is associated with high mortality. Recent studies involving different genomic platforms,17 also described in proteomic18,19 and metabolomic20 studies, identified a profound metabolic shift in aggressive ccRCCs involving the TCA, pentose phosphate, and phosphoinosi­ tide 3-kinase pathways among others. Additional research has identified reprogrammed pathways in ccRCC, for ex­ ample in both the tryptophan and glutamine metabolic pathways, which have been, or can soon be, exploited for novel therapeutic approaches that have the potential to transform the treatment of this disease.3,20,21 The reader is referred to several recent reviews on this topic.3,4,9,22

BASIC BIOLOGY OF CLEAR CELL RENAL CELL CARCINOMA RCC is the most common malignancy that originates from the renal cortex.6 Each of the known mutated genes from the various subtypes of kidney cancer have been shown to 230

THE BIOLOGY AND RATIONALE OF CURRENT THERAPEUTICS Prior therapeutic approaches exploited the high level of immunogenicity of RCC and used immunotherapy with interferon and interleukin-2 (IL-2), but these were associ­ ated with severe and unpleasant adverse effects with only

25  •  Renal Cell Cancer

Table 25.1  Paraneoplastic Manifestations Are Present in Up to 13%–20% of Patients With Renal Cell Carcinoma Endocrine

Nonendocrine

Hypertension

Kidney failure

Polycythemia

Anemia

Hepatic dysfunction (not caused   by metastasis)

Coagulopathy

Hypercalcemia

Neuropathy and myopathy

Cushing syndrome

Vasculopathy

Glucose metabolism alterations

Amyloidosis

Galactorrhea

modest success. More recently, therapies targeting newly elucidated biochemical pathways have a better response, and fewer adverse effects, and there are even more pipeline therapies based on metabolic reprogramming as with tryp­ tophan23 and arginine24 reprogramming. Most recently, the immune checkpoint inhibitors have shown considerable promise in treating ccRCC and studies are currently under­ way to find optimal combinations use these new drugs.25 However, the marked inter- and intratumoral heterogeneity in ccRCC26 has made it difficult to study this disease as a single entity with respect to therapeutic response. Clinical issues related to the various therapeutic approaches will be discussed in detail later on this chapter.

Clinical Presentation RCCs, which originate within the renal cortex, constitute 80% to 85% of primary renal neoplasms. Transitional cell carcinoma of the renal pelvis is the next most common (8%). Other parenchymal epithelial tumors, like oncocyto­ mas, collecting duct tumors, and renal sarcomas are rare. Nephroblastoma or Wilms tumor is common in children. Patients are frequently asymptomatic at presentation and the diagnosis is often made in the renal clinic during imag­ ing for workup of CKD.1 Indeed, approximately one-third of patients have metastatic disease at diagnosis, at which point the prognosis is markedly poor.27 In symptomatic cases, the most common presenting symptoms are flank pain, hema­ turia, a palpable abdominal mass, and weight loss.28,29 The fact that fewer patients are presenting with symptoms and more with radiologic incidental diagnosis may contribute to better outcomes in RCC, as the disease-specific 5-year sur­ vival is better in patients who are diagnosed incidentally, likely because the tumor is less advanced in these cases (76% incidental vs. 44% symptomatic).30 Several online (although unvalidated) “calculators” for renal survival are available, for example: http://www.lifemath.net/cancer/renalcell/ outcome/index.php. There have also been published reports of nomograms and other such tools for calculating survival.31,32 Hematuria is generally observed with tumor invasion into the collecting system. When severe, such bleeding can cause clots and “colicky” abdominal discomfort. Scrotal varicoceles, mostly left-sided, are observed in as many as

231

11% of men with RCC.33 This finding occurs when the tu­ mor obstructs the gonadal vein where it enters the renal vein. Inferior vena cava involvement can produce a variety of symptoms, such as lower extremity edema, ascites, he­ patic dysfunction (Budd-Chiari syndrome), and pulmonary emboli. Metastasis occurs most commonly in lung, lymph nodes, bone, liver, and brain, and in many cases the initial diagnosis of RCC is made via biopsy of accessible metastasis or by finding a renal mass on abdominal imaging. Paraneoplastic syndromes can develop in some patients in the form of systemic symptoms (see Table 25.1)34–36 and can arise from ectopic production of hormones like erythro­ poietin, parathyroid hormone-related protein (PTHrP), gonadotropins, human chorionic somatomammotropin, an adrenocorticotropic hormone (ACTH)-like substance, renin, glucagon, and insulin. Anemia, hepatic dysfunction, fever, cachexia, hypercalcemia, erythrocytosis, thrombocytosis, and AA amyloidosis can also be present. Erythrocytosis occurs because of overproduction of erythropoietin caused by impaired degradation of hypoxia-inducible transcription factors under normoxic conditions.37 Hypercalcemia occurs because of lytic bone lesions, overproduction of PTHrP,38 increased prostaglandins production, and bone resorption. Tumor nephrectomy will naturally correct many of these symptoms, but needs to be undertaken cautiously, especially in patients with CKD (see later).

Screening Screening of asymptomatic individuals is not recom­ mended because of the low prevalence of RCC in the gen­ eral population. However, high risk individuals should undergo periodic screening with abdominal ultrasound, computed tomography (CT), or magnetic resonance imag­ ing (MRI) to detect early disease. Candidates for screening include patients with any of the following conditions:39 1. Prior kidney irradiation39–41 2. Inherited conditions associated with increased inci­ dence of RCC or other renal tumors, including von Hippel-Lindau syndrome and tuberous sclerosis 3. End-stage renal disease (ESRD), especially younger subjects without serious comorbidities, who have been on dialysis for 3 to 5 years, because they can develop acquired cystic disease of the kidney 4. A strong family history of RCC

Diagnosis Patients with signs or symptoms suggestive of RCC should get imaging evaluation for the presence of a renal mass. Historically, patients were diagnosed with RCC after pre­ senting with flank pain, gross hematuria, and a palpable abdominal mass, but this triad is noted only in the minor­ ity of patients with disease. Incidental diagnosis of RCC is becoming more common because of frequent use of radiologic investigations done for unrelated problems, most notably for acute kidney injury (AKI) or hematuria workup in the renal clinic.2 As previously mentioned, unexplained paraneoplastic syndromes can prompt an RCC investigation; this is the origin of the moniker

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SECTION 6  •  Renal Tumors

the internist’s tumor.2 Most paraneoplastic symptoms dis­ appear after tumor resection.42 Typical radiologic features of ccRCC include exophytic growth, intratumoral necrosis or hemorrhage, and high uptake of contrast agents (Fig. 25.1).43 CT is more sensitive

A

B Fig. 25.1  ​Computed tomography scans of clear cell renal cell carcinoma: a solid mass on the right kidney is visualized on these noncontrast scans (Courtesy Dr. Marc Dall’Era, UC Davis).

Nephrectomy

• • • • • • •

Risk factors Baseline CKD Diabetes mellitus HTN Proteinuria Older age Smoking Abnormal nonneoplastic tissue (GS, IF, VS)

in detecting a renal mass, but renal ultrasound is useful in distinguishing a simple benign renal cyst from a more complex cyst or a solid tumor. Criteria for a simple renal cyst include: round shape, sharply demarcated lesion with smooth walls, no echogenicity within the cyst, and hyper­ echoic posterior wall, indicating good transmission through a cyst. By contrast, if the cyst has thickened irregular walls or septa and enhances after intravenous contrast, this suggests further investigation for malignancy. MRI can be helpful if ultrasonography and CT are nondiagnostic or contrast cannot be given. CT or MR angiography is prefer­ able to renal arteriography for preoperative mapping of the vasculature, in preparation for possible nephron-sparing surgery. 18Fluorodeoxyglucose positron emission tomogra­ phy (18FDG-PET) scanning, although useful for screening and staging other malignancies, has been problematic for RCC,44 although newer PET techniques evaluating evi­ dence of metabolic reprogramming such as 18F-glutaminePET, although currently experimental, might ultimately prove more clinically useful.45 Tissue diagnosis can be obtained from total or partial nephrectomy or by biopsy of a metastatic lesion before treatment (see later). Adjacent noncancerous tissue should also be evaluated by the pathologist because con­ current renal disease and even CKD is frequently present in patients with RCC (because of shared risk factors, Fig. 25.2) and in many cases, is undiagnosed. A phone call to the pathologist before total or partial nephrectomy should be done to ensure that the pathologist evaluates the noncancerous kidney tissue for other unsuspected renal diseases (e.g., diabetes, immunoglobulin A nephrop­ athy, thin basement membrane disease), which would allow for optimal long-term management and follow-up of CKD by the nephrologist. Percutaneous biopsy of a small renal mass can be considered if there is a high index of suspicion of metastatic lesion to the kidney, lymphoma, or a focal kidney infection. Biopsy can also be considered if the patient is not a surgical candidate and before initiat­ ing medical treatment. The risk of tumor seeding with RCC biopsy has been largely debunked46 and as such, this technique should be used without hesitation if there is any doubt about the histology, to avoid unnecessary surgery.

New CKD Ischemic injury Loss of nephrons Vascular injury

CKD/ESRD

Progression of CKD

Fig. 25.2  ​New-onset chronic kidney disease (CKD) or progression of CKD and end-stage renal disease may develop following nephrectomy because of nephron loss in patients with underlying risk factors (from2 with permission). GS: glomerulosclerosis; HTN: hypertension; IF: interstitial fibrosis; VS: vascular sclerosis.

25  •  Renal Cell Cancer

A

B

C

D

233

Fig. 25.3  ​Clear cell renal cell carcinoma: the World Health Organization/International Society of Urologic Pathologists grading system (recently supplanted Fuhrman nuclear grading). (Courtesy Dr. Morgan Darrow, UC Davis). A.  Grade 1: Nucleoli are absent or inconspicuous at 4003 (4003 photo) B.  Grade 2: Nucleoli (arrows) are conspicuous and eosinophilic at 4003 (4003 photo) C.  Grade 3: Nucleoli (arrow) are conspicuous and eosinophilic at 1003 (1003 photo) D.  Grade 4: Extreme nuclear pleomorphic and/or multinuclear giant cells and/or rhabdoid and/or sarcomatoid differentiation. This photo shows cells with extreme nuclear pleomorphism and rhabdoid features (large eccentric nuclei, large prominent nucleoli, and abundant eosinophilic   cytoplasm) (1003 photo).

In staging RCC, the extent of local and regional involve­ ment is best determined by abdominal CT, which can also detect renal vein invasion, nodal metastasis, perinephric invasion, and adjacent organ invasion. Distant metastases can be detected by bone scan, CT of the chest, MRI, and PET/CT. In addition to radiologic diagnosis, tissue diagnosis provides information about the histopathologic type of RCC and adjacent noncancerous kidney tissue, which has important implications for prognosis and treatment. Biopsy of the metastatic site is often easier and thus may be prefer­ able. If the patient is diagnosed with metastatic disease and therefore requires systemic therapy, most modern drugs for the disease are associated with renal-relevant adverse effects, which are best managed by the nephrologist in concert with the oncologist and/or urologist (see later).

CLINICAL ISSUES WITH RENAL CELL CARCINOMA SUBTYPES Clear Cell Renal Cell Carcinoma The ccRCC histologic subtype is most common (see Fig. 25.3) and is one of the most lethal subtypes.17 It arises from the proximal tubular epithelium and, in its metastatic form, is associated with a high mortality. The large majority of cases of ccRCC are sporadic and only 2% to 3% of ccRCC are linked to hereditary disease, most commonly von Hippel-Lindau syndrome.47

Papillary Renal Cell Carcinoma The second most common subtype, papillary RCC (pRCC), (Fig. 25.4) is also of proximal tubule origin but has been studied less extensively.48 There are two subtypes, type 1 pRCC and type 2 pRCC, the latter with a worse prognosis. Chromophobe Renal Cell Carcinoma This rare (5%) kidney cancer (Fig. 25.4) originates from the collecting duct and is similar to the benign oncocy­ toma.49,50 It is more common in young females and is the least aggressive of all the RCC types, unless characterized by sarcomatous transformation.

Cystic Diseases and Renal Cell Carcinoma The link between cystic disease and RCC was described in the 1800s by Brigidi and Severi.51 Cortical cystic disease can range from simple cysts to complex cysts with in­ creasing52 risk for malignancy as defined by the Bosniak classification53–55 (Table 25.2). However, CKD-associated cystic diseases, including acquired cystic kidney disease (ACKD) and autosomal dominant polycystic kidney dis­ ease (ADPKD), have different characteristics from that of the general population and deserve further consideration, as will be discussed in the following sections.

234

SECTION 6  •  Renal Tumors

A

B

Fig. 25.4  ​A. Papillary renal cell carcinoma, type 1 (2003). Cells arranged in compact tubulopapillary structures. The presence of macrophages with foamy cytoplasm (lower left) is characteristic. The cells of type 1 papillary RCC have pale clear to basophilic cytoplasm and line papillary structures as a single uniform layer. B. Chromophobe renal cell carcinoma (2003). The cells are large with distinct cell borders, are arranged in solid sheets, and have an oncocytic appearance (abundant granular eosinophilic cytoplasm). The nuclei are irregular and have clear perinuclear “halos.” (Photomicrographs courtesy Dr. Morgan Darrow, UC Davis.)

Table 25.2  Bosniak Classification of Cystic Renal Masses Septa

Wall

Solid

Enhancement

Category I Simple benign

No

Hairline thin wall

No

No

Category II

Yes, few hairline   thin septa

Fine calcification

No

Perceived but   nonenhancing

, 3 cm smooth margin

Category II F Minimally complicated

Multiple thin septa, thick   nodular calcification

Thick nodular   calcification

No

Perceived but   nonenhancing

. 3 cm

Category III Complex

Thick irregular or smooth

Thick irregular   or smooth

No

Measurable

. 3 cm

Category IV Malignant

Thick irregular or smooth

Thick irregular   or smooth

Soft tissue   components

Measurable

. 3 cm

Acquired Cystic Kidney Disease and Renal Cell Carcinoma ESRD is associated with a relatively high risk of RCC, pos­ sibly because of the cystic transformation seen in many of these kidneys. The incidence of RCC in the ESRD popula­ tion ranges from 1% to 7% in various studies, a rate higher than that of the general population, in whom the inci­ dence is 1.6%.56–59 Fourfold to fivefold increase in rate of RCC was seen in dialysis patients as compared with the general population.59 The prognosis of RCC in patients with ESRD-associated renal cystic disease, independent of the renal disease prognosis, is equivalent or better com­ pared with the general population. These patients are more likely to have papillary tumors, be younger with a better performance status, have fewer symptoms, smaller tumor size, and lower tumor grade and stage. The development of ACKD has been described among 7% to 22% of CKD patients, but this escalates among dialysisdependent ESRD patients (10%–44% within 1–3 years of onset of renal replacement therapy) and increases further with prolonged duration of dialysis (. 90% after 5–10 years of renal replacement therapy).57,60–62 Although the pres­ ence of ACKD leading to RCC has also been described among

Cyst Size

transplant recipients (23%), this incidence is far less than that observed in ESRD patients on dialysis (80%),57 which is surprising in light of the immunosuppression accompanying transplant. The diagnosis of ACKD is made by the presence of greater than three cysts collectively in both kidneys.60,62 ACKD cysts tend to be smaller in size (typically , 0.6 cm in diameter, but can range up to 2–3 cm) compared with cysts in ADPKD or other cystic diseases. In addition to ESRD duration, risk factors for the development of ACKD, and likely progression to RCC, include male sex, younger age at ESRD onset, and glomerulonephritis as primary kidney disease. Diabetic ne­ phropathy has been associated with lower incidence of ACKD among Japanese dialysis patients.63 Although race and dialysis modality have not been shown to be definitively associated with ACKD incidence, ACKD has been reported to be less common with peritoneal dialysis.56,60,64 The appearance and progression of acquired renal cysts may stem from a reparative response to uremic metabolites, chronic acidosis, and ischemia.56,60 Cyst fluid content has been found to be higher in creatinine content, suggest­ ing some filtering or secretory capacity, unlike simple or ADPKD cysts (which have similar cyst and plasma creati­ nine levels). ACKD cysts often regress after transplantation, once normal filtration is restored.60,65

25  •  Renal Cell Cancer

The association of ACKD with both RCC and ESRD may explain causality for the increased risk of RCC in ESRD.57 Indeed, there are many shared risk factors between CKD and RCC (see Fig. 25.1), which may at least in part explain this association. The annual incidence of RCC in a Japanese ACKD cohort followed for 20 years was 0.151% per year for those on dialysis less than 10 years, and 0.340% per year with dialysis duration for more than 10 years.55,60 pRCC is the predominant histologic subtype among ACKD and dialysis-associated tumors, in contrast to ccRCC, which is typically seen in the general population.

Polycystic Kidney Disease and Renal Cell Carcinoma The prevalence of RCC in ADPKD appears to be no greater than that in the general population according to small case series and observational studies,39,66–69 although there is some controversy in the literature on this subject. As in the general population, the histologic diagnosis of RCC in ADPKD tends to be ccRCC in a recent case series,67 although in another study, tubulopapillary pathology was also observed (42%).68 RCC in ADPKD presents at a younger mean age (50–60 years) than spontaneous RCC, but often with advanced disease where a third of patients have bilateral kidney involvement or metastatic disease. The diagnosis in these patients may be delayed because of the complexity of diagnostic images in the presence of multiple benign cysts in ADPKD. Symptomatic diagnosis rather than incidental discovery of RCC is more common in this select population.66,67,69

Prognosis of Renal Cell Carcinoma in End-Stage Renal Disease The prognosis of RCC in the ESRD population is equivalent or better compared with the general population.70–74 Five-year survival and cancer-specific mortality were mark­ edly better in ESRD as compared to the general population. In ESRD, the majority of patients (87%) were incidentally diagnosed, and these patients had more favorable charac­ teristics like younger age, better performance status, fewer symptoms, smaller tumor size, lower tumor grade and stage, and were more likely than the general population to have papillary histology. The higher survival in ESRD group is attributed to the incidental finding, thus leading to earlier diagnosis.

Acquired Cystic Kidney Disease, Renal Cell Carcinoma, and Renal Transplantation Screening for RCC in renal transplant candidates who have ESRD is controversial and not currently recommended de­ spite the use of powerful immunosuppression drugs, which increase cancer risk in general.57,75,76 Most studies have

235

found that the prevalence of native kidney RCC in renal transplant recipients (3%–5%) was no different from non­ transplant ESRD population but still 100-fold greater than the general population.77–79 ACKD is less commonly de­ scribed among transplant recipients (23%–33%) but can be as high as 57%,80 which is still far less than that observed in ESRD patients on dialysis (80%).57 As expected, RCC is more common in transplant patients with ACKD than those without ACKD. In general, transplant patients have much better prognosis than nontransplant ESRD and the general population because more such individuals are diagnosed at a younger age, have smaller tumor size and less metastatic disease, more are at stage T1, papillary subtype and un­ dergo more frequent surveillance. The 10-year cancerspecific survival of 88% to 95% in transplant recipients is higher than the general population (75%).81 Five-year cancer-specific survival in transplant patients was 97% as compared with the nontransplanted ESRD group of 77%. The overall patient and graft survival between those with and without RCC have been comparable. Given the minimal gain of life expectancy, screening for ACKD in the entire ESRD population is not recommended. However, screening may be considered in younger, healthier patients. The ma­ lignancy risk of most cystic lesions can be assessed using these criteria and prognosis is determined with staging and grading tools (see Table 25.2).54 Clinical judgment and risk analysis should be applied in determining the benefit of RCC screening. Although survival did not reportedly improve with ACKD screening, according to a decision analysis performed in dialysis pa­ tients,75 screening among potential transplant recipients in our opinion seems quite reasonable, given the noninvasive­ ness of the imaging. Furthermore, a more favorable prog­ nosis in the transplant candidate population group than in a dialysis group in general (which was the focus of that study) suggests that screening may be more beneficial in the former group because of younger age at diagnosis, earlier discovery of tumor (better prognostic characteris­ tics, stage and size), and longer life expectancy. However, in the ESRD population with a high risk for RCC, the benefit of periodic screening has not been established.

TUMOR NODE METASTASIS STAGING Tumor node metastasis (TNM) staging for RCC was first established in 1997 by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer, and was most recently updated in 2017 (Table 25.3).82 T-staging (T1-T4) is classified by the extent and size of the tumor, which differentiates cancer-specific survival. T1 tu­ mors are limited to the kidney and are 7 cm or smaller; T2 tumors are larger than 7 cm but totally within the kidney; T3 tumors extend beyond the kidney, but within Gerota’s fascia, and may involve neighboring veins (renal vein or inferior vena cava); and T4 tumors invade Gerota’s fascia or extend to the ipsilateral adrenal gland. T1-T2 are further subdivided according to renal mass size, and T3 is subdivided depending on venous involvement. T-staging imposes the greatest discrimination of 5-year cancerspecific survival, where T1a tumors have survival as high as 98%, which declines to 10% with stage T4. Nodal invasion minimally alters outcomes, but distant metastases

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SECTION 6  •  Renal Tumors

Table 25.3  Kidney Cancer Tumor, Node, Metastasis Staging American Joint Committee on Cancer Union for International Cancer Control 2017 Primary Tumor (T) T Category

T Criteria

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1a

Tumor , 4 cm in greatest dimension, limited to kidney

T1b

Tumor . 4 cm but , 7 cm in greatest dimension, limited to kidney

T2a

Tumor . 7 cm in greatest dimension, limited to kidney

T2b

Tumor . 10 cm, limited to kidney

T3a

Tumor extends into renal vein, branches, invades pelvicalyceal system and perirenal/renal sinus fat but not beyond Gerota’s fascia

T3b

Tumor extends into the vena cava below the diaphragm

T3c

Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava

T4

Tumor invades beyond Gerota’s fascia including contiguous extension into the ipsilateral adrenal gland

Regional lymph nodes (N) N category

N criteria

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph node(s)

Distant metastasis (M) M category M0

No distant metastasis

M1

Distant metastasis

Prognostic Stage Groups When T is…

When N is…

When M is…

Stage is….

T1

N0

M0

I

T1

N1

M0

III

T2

N0

M0

II

T2

N1

M0

III

T3

NX, N0

M0

III

T3

N1

M0

III

T4

Any N

M0

IV

Any T

Any N

M1

IV

including ipsilateral adrenal gland invasion worsens prog­ nosis considerably.83 More recently, renal sinus fat involve­ ment has been found to be associated with lower survival.84 Composite prognostic staging (I-IV) summarizes the TNM findings. Tumors with stage I-II have kidney limited lesions only. The prognostic stage is elevated to III when there is any nodal involvement regardless of kidney size or T-staging, and is escalated to stage IV when Gerota’s fascia invasion, adrenal gland, or distant metastasis occurs. Grading, in contrast to staging, guides prognosis based on nuclear features. Of the grading systems, the World Health Organization/International Society of Urologic Pathologists grading system has supplanted the older Fuhrman categorization and is most universally used for prognostic assessment despite some limitations. The

nuclear size, irregularity, and nucleoli prominence differen­ tiate RCC into 4 grades (see Fig. 25.3). Five-year cancerspecific survival is highest for grade 1 (51%–93%), and lowest in grade 4 (10%–28%).83 Although this grading system is reliably used for ccRCC, it has not been adequately validated for pRCC or chromophobe RCC subtypes.84,85 Independent of TNM staging, higher grade and larger tumor size predict poorer survival, with histologic subtype also playing a role. The most common and sporadic form of RCC, ccRCC (60%–90% prevalence vs. 6%–14% for papillary, and 6%–14% for chromophobe), has inferior outcomes as compared with pRCC or chromophobe RCC.85 Other features, such as the presence of sarcomatoid or rhabdoid (eccentric large nuclei and eosinophilic cyto­ plasm) differentiation and microscopic coagulative tumor

25  •  Renal Cell Cancer

necrosis, add to the worse prognosis. Sarcomatoid differen­ tiation, seen in only 4% of all RCCs, reflects extreme dedif­ ferentiation and is associated with a dismal prognosis. All tumors with a sarcomatoid component were classified as nuclear grade 4.86 Each 10% increase in sarcomatoid changes is associated with a 6% increased risk of death from RCC and with poor survival. Cancer-specific survival rates at 2 and 5 years after nephrectomy were 33.3% and 14.5%, respectively. The presence of distant metastases at the radical nephrectomy and histologic tumor necrosis were significantly associated with death from RCC among patients with sarcomatoid RCC. Patients with ccRCC (con­ ventional) and chromophobe RCC were more likely to have tumors with a sarcomatoid component (5.2% and 8.7%, respectively) compared with patients with pRCC (1.9%). Rhabdoid differentiation is even rarer with similarly poor survival.83,84 Various integrated staging systems based on variables often including TNM staging, tumor size, clinical symptoms, histologic subtype, grading, and other prognostic pathologic findings have been devised and can be used to predict out­ comes both preoperatively and postoperatively. Accuracy of these tools are high for RCC recurrence (66%–80%), distant metastases (78%–85%), and RCC cancer-specific survival (64%–89%). Such algorithms are particularly helpful for patients with advanced disease (metastatic RCC) who are in the highest mortality range and therefore are poorly differ­ entiated by TNM staging alone. Therapeutic effectiveness of choice of antineoplastic treatment (cytokine or targeted therapy) has been examined using these staging systems to select optimal treatment regimens.83,87

Treatment The nephrologist, although traditionally excluded in this area, should play a significant role in the management of renal masses.2 More than half of patients are diagnosed with RCC incidentally, and often in the renal clinic, and many have CKD in addition to RCC because of shared risk factors (see Fig. 25.1). The evolution of both medical and surgical treatment for this “nephrologist’s tumor”2 is cur­ rently occurring rapidly, and input of the nephrologist in treatment decisions, especially (but not only) when CKD becomes part of the equation, is essential.

GENERAL PRINCIPLES FOR RENAL CELL CARCINOMA MANAGEMENT (FIG. 25.5) Surgical Management The initial approach is based on extent of disease, patient’s age, and comorbidity. Surgery by radical or partial nephrec­ tomy remains the mainstay of curative treatment for patients who present with early stage RCC. However, a sig­ nificant proportion of patients develop metastatic disease after RCC surgery, which results in high mortality, and these individuals generally require systemic therapies. The incidence of metastasis depends on tumor stage and grade. In those individuals who present late with advanced and metastatic disease, the overall clinical course of RCC varies; approximately 50% of patients survive less than 1 year and

237

10% survive for more than 5 years. Surgery is curative in the majority of patients who have localized disease; however, surgical treatment with radical or partial ne­ phrectomy is based upon the extent of disease, patient age, and comorbidities. In selected patients with resectable primary tumor and a concurrent single metastasis, surgical resection of metastasis plus radical nephrectomy can be curative. In patients with small renal masses, advanced CKD, and who are high-risk surgical candidates, ablative therapies can be considered. Partial Nephrectomy Before surgery, laboratory data need to be obtained for risk assessment for CKD. Partial nephrectomy is useful for preser­ vation of kidney function,89–91 as a nephron sparing proce­ dure, and should be considered for all patients. The goal of partial nephrectomy is to completely remove the primary tumor, while preserving the maximal amount of healthy renal tissue. Partial nephrectomy is indicated for patients with T1 tumor with normal contralateral kidney, and in pa­ tients with a solitary kidney or those with conditions that affect kidney function. Minimizing nephron mass loss, for small renal masses in particular, should be prioritized with either partial nephrectomy or thermal ablation to lower the risk of CKD or its progression. Partial nephrectomy has equivalent/comparable oncologic and overall survival and greater renal preservation. Data were pooled from systematic review and meta-analysis of partial versus radical nephrec­ tomy. According to pool estimates, partial nephrectomy cor­ related with a 19% risk reduction in all-cause mortality, 29% risk reduction in cancer specific mortality, and 61% risk reduction in severe chronic kidney disease. For these reasons, it is nephrologist’s role to advocate for the partial nephrec­ tomy approach in all referred patients with small renal masses (<4 cm) and no metastasis. Although such a survival benefit was not clearly seen in the sole randomized controlled trial, the European Organization for Research and Treatment of Cancer study, renal protection was apparent, with fewer reaching estimated glomerular filtration rate less than 60 mL/min/1.73 m2 after partial nephrectomy versus radical nephrectomy.91,92 The American Urological Association recommends nephrology referral for high CKD risk patients including those with known CKD, including proteinuria, with diabetes mellitus, or poor blood pressure control, a rec­ ommendation with which we concur.93 Nephrectomy scoring systems (radius, exophytic or endo­ phytic, nearness to collecting system or sinus, anterior or posterior, and location relative to polar lines [R.E.N.A.L] and preoperative aspects and dimensions used for anatomic classification [PADUA]) have been proposed to predict the complexity of the partial nephrectomy procedure and to predict perioperative outcomes according to anatomic and topographic tumor characteristics.94,95 The PADUA and RENAL nephrometry assign numerical values to a focused set of morphologic variables readily ascertainable with con­ ventional contrast material–enhanced CT or MRI, such as tumor size and location. Overall, the performance of these metrics has been deemed favorable, with multiple studies demonstrating predictive strength with respect to operative complications. Laparoscopic and robot-assisted partial nephrectomy are the main alternatives to classic open partial nephrectomy.

238

SECTION 6  •  Renal Tumors

RCC

Metastatic Histopathology Clinical parameters Genomics Precision normograms

Localized

Small tumors < 3 cm Biopsy Histopathology Genomics

Large tumors > 3 cm Biopsy or surgery Histopathology Genomics

Clinical parameters

Clinical parameters

Low-risk • Active surveillance

High-risk • Partial nephrectomy preferred

Candidate for surgery • Partial nephrectomy if solitary kidney or has risk of CKD Vs • Radical nephrectomy if lymph node or IVC or renal vein involvement

Operable 1. Nephrectomy and metastatectomy if advanced disease 2. Cytoreductive nephrectomy to remove primary tumor

High-risk Not candidate for surgery • systemic therapy, palliative care • Immunotherapy • Targeted therapy

Inoperable

Single targeted therapy Multiple targeted therapy Single immunotherapy Multiple immunotherapies Oligo-metastasectomy Targeted + immunotherapy Personalized vaccination Active surveillance

Fig. 25.5  ​Treatment algorithm for renal cell carcinoma (RCC). CKD, Chronic kidney disease; IVC, inferior vena cava.

Laparoscopic technique should be reserved for small tumors and with no complexity features. Hematuria, perirenal hematoma, and urinary fistulas are most common compli­ cations, and less frequent issues include AKI and infection.96 Radical Nephrectomy Classical radical nephrectomy consists of removal of the affected kidney, perirenal fat tissue, adrenal gland, and re­ gional lymph nodes. However, if the tumor is smaller than 5 cm and is located at the inferior pole, the adrenal gland can be spared. The regional lymph node dissection is re­ served for patients with clinically positive nodes detected either by CT or during the surgical procedure. Radical ne­ phrectomy should be considered for a patient with multiple small tumors and in cases where the tumor extends into vasculature. The laparoscopic approach for radical ne­ phrectomy is currently performed for stage I and stage II tumors, whereas an open surgical approach remains the gold standard for the treatment for more complex cases. The robot-assisted approach can be considered as a poten­ tial alternative to open surgery in cases with venous tumor thrombus.

Cytoreductive Nephrectomy As mentioned earlier, many RCCs are silent until the disease is locally advanced and therefore unresectable or metastatic. In these cases systemic therapy with immunotherapy, mo­ lecularly targeted agents, and surgery and radiation, all might have a role depending upon extent of disease, sites of involvement, and other patient-specific factors. Many centers offer cytoreductive nephrectomy in metastatic disease, if there is a substantial disease volume at the primary site, but only a low burden of metastatic disease. The median overall survival is 17.1 months in cytoreduc­ tive nephrectomy cases versus 7.7 months in the noncyto­ reductive nephrectomy group, even while they receive systemic targeted therapies.97

Active Surveillance and Ablative Therapies Active surveillance or ablative procedures, like cryotherapy and radiofrequency ablation, can be considered in patients with small renal masses who are not surgical candidates, for example elderly patients, those with CKD or other competing health risks, and limited life expectancy. No definite surveillance protocol exists, but the most common

25  •  Renal Cell Cancer

approach is to perform renal ultrasonography or MRI every 3 months for 1 year and then every 6 months for a year and then annually thereafter. Intervention should be consid­ ered for tumor growth to greater than 3 to 4 cm or by more than 0.4 to 0.5 cm per year.98 Active surveillance is an op­ tion for patients with small asymptomatic lesions. Adjuvant Therapy Adjuvant systemic therapy has not been shown to have a role after complete surgical resection outside of a formal clinical trial. Sunitinib, an antiangiogenic kinase inhibitor, has been approved for adjuvant therapy based on improve­ ments in disease-free survival compared with placebo in high-risk disease,99 but the phase 3 trial failed to show sur­ vival benefit and was associated with significant toxicity. Radiation therapy (RT) is helpful mainly for bone metas­ tases, brain metastases, and painful recurrences in the renal bed. Although RCCs are characterized as radioresistant tu­ mors, conventional and stereotactic RT is frequently useful to treat a single or limited number of metastases. In these settings, the utility of RT is similar to that in metastases from other tumor types. RT has been used as an adjuvant therapy following nephrectomy in patients at high risk of local recurrence but its role in this setting remains unproven and is generally discouraged.100,101

Systemic Therapy The evolution of drugs for metastatic RCC in recent years is illustrated in Table 25.4 with terminology aptly described.102 The so-called “Dark Age” was before 2005 and median sur­ vival was 15 months. Then followed the “Modern Age” (2005–2014) and median survival improved to 30 months with newer drugs. Currently, in the “Golden Age,” the me­ dian survival is expected to be 5 years. The ultimate goal of the future “Diamond Age” is long-term survival.102 The current therapies are associated with various adverse events, which are shown in Table 25.5. Immunotherapy: Interleukin 2, Interferon-Alpha Cytokines, such as interferon-alpha and high-dose IL-2, that enhance antitumor immune activity have been used since the 1990s to treat metastatic RCC. Both these drugs benefit only a small subset of patients with intrinsic favor­ able disease biology and are associated with substantial

toxicity of flu-like adverse events, particularly with highdose IL-2,103 so their use is limited. In addition, such therapies may enhance the intrinsic antiimmunity of many RCCs.23 Targeted Therapy Targeted therapy, which is becoming increasingly essential for RCC treatment, affects the cancer’s specific genes, proteins, metabolism, or the tissue environment that con­ tributes to cancer growth and survival. These treatments block the growth and spread of cancer cells, while generally limiting damage to healthy cells. Given the highly vascular nature of RCCs, it is not surprising that several therapies are available to exploit this feature. Most ccRCCs have mutations in the VHL gene that cause the cancer to appear hypoxic and thus overproduce vascu­ lar endothelial growth factor (VEGF), a growth factor that causes neoangiogenesis. Most tyrosine kinase inhibitors (TKIs) block VEGF and other chemical signals that promote the development of new blood vessels (angiogenesis). Ap­ proved agents are sorafenib, sunitinib, pazopanib, axitinib, lenvatinib, and cabozantinib.104–109 The anti-VEGF TKIs sunitinib, pazopanib, and the combination of bevacizumab and interferon-alpha are approved first-line options, whereas axitinib and cabozantinib are approved as secondline options. The anti-VEGF monoclonal antibody, bevaci­ zumab, is approved for use with interferon-alpha.110,111 The mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus are approved in the secondline setting and the first-line setting in patients with poor risk status.112,113 Checkpoint Inhibitor Immunotherapy Immunotherapy targets the immune system to recognize and eradicate cancer cells. Modern immunotherapy has focused on “checkpoint” proteins, such as cytotoxic T-lymphocyteassociated-protein-4 (CTLA-4) and programmed death-1 protein (PD-1), which are receptors on the surface of immune cells that act like a brake, or checkpoint, preventing the development of autoimmunity.114 CTLA-4 receptor has homology to the T-cell activator molecule CD-28 and prevents T-cell activation by outcompeting CD-28 for its ligand.115 The binding of PD-1 with programmed death ligand (PDL-1) results in T-cell anergy.116

Table 25.4  The Evolution of System Therapy for ccRCC 1992–2004 Dark Age

2005 Modern Age

2006 Modern Age

2007 Modern Age

2008 Modern Age

Drug

Immunotherapy . Interferon-alpha 1

Sorafenib TKIs

Sunitinib

Temsirolimus (mTORC1) inhibitors

Everolimus   (mTORC1) inhibitors

Drug

2. High-dose IL-2

Year

2009 Modern Age

2010 Modern Age

2012 Modern Age

2015-2025 Golden Age

After 2025 Diamond Age

Bevacizumab and   Interferon-alpha

Pazopanib TKIs

Axitinib TKIs

TKIs: Cabozantinib Lenvatinib

Drug combinations Vaccinations

CPIs: Nivolumab

Drug sequences

Year

Drug Drug

239

CPI, Checkpoint inhibitor; IL-2, interleukin 2; mTORC1, mammalian target of rapamycin complex 1; TKI, tyrosine kinase inhibitor.

240

SECTION 6  •  Renal Tumors

Table 25.5  Adverse Events Associated With Systemic Therapy for Clear Cell Renal Cell Carcinoma Adverse Events

Sorafenib (TKIs)

Sunitinib (TKIs)

Pazopanib (TKIs)

Gastrointestinal

11 Diarrhea

11 Diarrhea

11 Diarrhea

Hypertension

11

11

11

11 Hand-foot

11 Hand-foot

11 Hand-foot

Hepatic

Bevacizumab 1 IFNalpha (anti-VEGF)

11

11

Renal Proteinuria Skin

11

Respiratory Cardiovascular Infections Bleeding

11

Endocrine

Adverse Events

Temsirolimus (mTOR inhibitor)

Everolimus (mTOR inhibitor)

Nivolumab (Checkpoint inhibitors) PD-1

Hepatic

11

Gastrointestinal

11 Colitis

Ipilimumab (Checkpoint inhibitors) CTLA4

Hypertension Renal

AIN, hyponatremia

Podocytopathy AIN, hyponatremia

Proteinuria Skin

11 Stomatitis

Respiratory

11 Stomatitis

11

11 Pneumonitis

11 Pneumonitis

11 Hyperglycemia, hypercholesterolemia

11

Cardiovascular Infections Bleeding Endocrine

11 11 Hyperglycemia, hypercholesterolemia

AIN, Acute tubulointerstitial nephritis; CTLA4, cytotoxic T-lymphocyte-associated-protein-4; IFN, interferon; mTOR, mammalian target of rapamycin; PD-1, programmed death 1 protein; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Immune checkpoint inhibitors (CPIs), monoclonal anti­ bodies that target inhibitory proteins, such as CTLA-4, PD-1, and PDL-1,117 represent a novel immunotherapy. CPIs enhance tumor killing by blunting the braking mecha­ nism that blocks T-cell activation, thereby augmenting the immune response. Although CPIs are considered the most innovative and promising agents in the treatment of can­ cer,118,119 their pathophysiology is still not fully understood, but may be similar to that of autoimmune disease, wherein activated lymphocytes target self-antigens. Antibodies against PDL-1 include avelumab and atezoli­ zumab and antibodies against PD-1 include nivolumab and pembrolizumab. PD-1 negatively regulates T-cell func­ tion and its ligand PDL-1 is highly expressed by cancer cells. Blockade of this PD-1–PDL-1 axis promotes T-cell activation and immune killing of the cancer. Ipilimumab, an antibody and which binds CTLA4, thus promotes T cell activation.120,121 Combination therapies of anti-VEGF

(axitinib and bevacizumab) and checkpoint inhibitors (nivolumab) are also used. By the end of 2014, nivolumab122,123 and pembroli­ zumab, both PD-1 inhibitors, also were approved. Nivolumab was approved in the United States and the European Union after the CheckMate 025 RCT showed an overall survival benefit compared with everolimus in patients who have failed therapy with sunitinib and pazopanib. However, the response rate was only 25% and most patients did not have significant tumor shrinkage. Immune-related adverse events complicate the use of CPIs. Their pathophysiology may be similar to that of autoimmune disease, wherein activated lymphocytes target self-antigens.124 The most specific immune-related adverse effects of ipilimumab are colitis, hypothyroidism, and hypophysitis. Adverse events associated with pem­ brolizumab and nivolumab are pneumonitis and hypo­ thyroidism.124

25  •  Renal Cell Cancer

241

CPI-related renal toxicity is not common. AKI and hypo­ natremia, are the most frequently reported renal events.125 Acute tubulointerstitial nephritis (AIN) is the most com­ mon pathophysiology of AKI, and the nephrologist should be aware of this complication, because it generally responds to steroids and drug withdrawal.125–128 The overall inci­ dence of AKI was 2.2%, and occurred more frequently in patients who received combination therapy with ipilim­ umab and nivolumab (4.9%) than patients who received monotherapy. The incidence of grade III or IV AKI, defined as an increase in creatinine greater than threefold above baseline, an increase in creatinine to a level greater than 4.0 mg/dL, or need for renal replacement therapy, was 0.6%.127 A recent metaanalysis analyzed eight randomized clinical trials involving CPIs, amounting to 4070 patients. All grade immune-related renal toxicity ranged from 0.7% to 6%, whereas high-grade immune-related renal toxicity ranged from 0% to 2%.128

renal replacement therapy, necessitates permanent dis­ continuation of the drug.136

MECHANISM OF RENAL INJURY

First-Line Systemic Therapy Immunotherapy with CPIs and molecularly targeted therapies are the primary systemic modalities for the management of patients whose disease is not controlled by definitive locoregional therapy.142 If the combination of nivolumab and ipilimumab is not available then anti­ angiogenic targeted therapy (pazopanib and sunitinib) are the preferred agents. A recently published trial143 showed an efficacy and overall survival benefit of two CPIs used concurrently, nivolumab plus ipilimumab, over sunitinib in the first-line treatment of intermediate or poor-risk advanced ccRCC.

The mechanism of CPI-induced AIN is as yet not com­ pletely understood, but it has been speculated that there are two possible mechanisms. First, CTLA-4 and PD-1 pathways normally operate to limit autoimmunity and interference with these pathways can lead to un­ wanted immune effects. PD-1 signaling limits T-cell medi­ ated inflammatory injury, and PD-1 knockout mice spon­ taneously develop interstitial nephritis and lupus-likeglomerulonephritis.129,130 Second, CPI-induced AIN may be caused by the loss of tolerance to endogenous kidney antigens, as opposed to the delayed-type hypersensitivity response characteristic of more conventional AIN.131 Patients can have hematuria (16%), new or worsened hypertension (11%),127,132 and subnephrotic range pro­ teinuria. Nephrotic syndrome is a rare finding only associ­ ated with ipilimumab.133,134 Increased serum creatinine and pyuria are the only clinical clues in a large majority of cases. As with traditional AIN, white blood cell casts are only rarely seen. CPI-induced AIN has a more hetero­ geneous time course from drug exposure to the develop­ ment of AKI. It could be 3 to 64 weeks based on the drug used.127,132 Also there are extrarenal immune adverse effects seen with these drugs. Pathologic diagnosis by renal biopsy is definitive, and reveals tubulitis and interstitial inflammation, consisting of activated lymphocytes, mac­ rophages, and eosinophils.127,135 Noncaseating granulo­ matous interstitial nephritis may also occur.127

MANAGEMENT OF CHECKPOINT INHIBITORSINDUCED ACUTE TUBULOINTERSTITIAL NEPHRITIS First, the CPI should be discontinued, then if necessary, immunosuppression including high-dose steroids, Myco­ phenolate Mofetil, and potentially, tumor necrosis factor alpha inhibitors can be used.128 Later, the patient can be given the same or an alternate CPI if renal function is stable after initial discontinuation.127 Development of grade 3 or 4 toxicity, defined as AKI with increase in cre­ atinine more than threefold above baseline, an increase in creatinine to a level more than 4.0 mg/dL, or need for

HYPONATREMIA Ipilimumab can cause hyponatremia from hypocortisolemia via immune-related injury to the pituitary gland. Loss of ACTH-secreting corticotrophs leads to a loss of corticotropinreleasing hormone that causes adrenal insufficiency. Studies show that upon drug withdrawal, MRI findings of hypophysitis resolved after treatment with hydrocorti­ sone.137,138 The PD-1 inhibitors (nivolumab, pembrolizumab) are also associated with thyroid dysfunction.139 Hypophysitis is also seen with nivolumab but the incidence is less than 1%.139,140 Another adverse effect reported for nivolumab is adrenalitis resulting in primary adrenal failure presenting with hyponatremia, which has failed to resolve with hydro­ cortisone but responded to fludrocortisone.141

Second-Line Therapy The standard of care for systemic treatment of RCC is rap­ idly changing because of the advent of new drugs and re­ sults of clinical trials. As of this writing, there is less general agreement regarding patients who have progressed on firstline therapy with CPI immunotherapy. Treatment with VEGF TKI will be the next option. Options include axitinib, cabozantinib, sunitinib, and pazopanib. Patients who have progressed following immunotherapy and one or two courses of antiangiogenic therapy may benefit from alter­ native VEGF or mechanistic mTOR targeted agent. Nivolumab is approved for use after failure of VEGF TKI therapy; however, nivolumab has been shown to have about a 20% overall response rate in this setting. For those who respond, the response can be durable in some cases. Axitinib and cabozantinib, both next-generation multi­ kinase inhibitors, are also approved for use after progres­ sion on pazopanib/sunitinib. The mTOR inhibitors also are approved for use in the second-line setting (and in fact there is one trial that suggests a benefit to giving lenva­ tinib, another multikinase inhibitor, with everolimus in this setting), but they are generally used more in the thirdline setting. At this point it is unclear how to treat patients after pro­ gression on CPI therapy. None of the VEGF TKIs, such as cabozantinib or axitinib, or the mTOR inhibitors, were stud­ ied in patients who had previously received nivolumab therapy, but this is usually the next step. Clinical trials are currently underway.

242

SECTION 6  •  Renal Tumors

Key Points n

n

n

n

Clear cell renal cell carcinoma (ccRCC) is a metabolic disease characterized by many examples of metabolic reprogramming. ccRCC is often asymptomatic at presentation and is often accompanied by paraneoplastic phenomena, which can aid in its diagnosis. ccRCC is frequently discovered during the workup of other kidney diseases. New therapeutic approaches have recently been intro­ duced, including immune checkpoint inhibitors and therapies based on metabolic reprogramming.

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243

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243.e1

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Abstract Renal cell carcinoma (RCC) is the malignancy seen most commonly in the clinical practice of nephrology. The most common subtype by far, clear cell RCC (ccRCC), is one of the relatively few malignancies that is increasing in incidence, and RCC is one of the cancers which is characterized by metabolic reprogramming, hence it is known as a metabolic disease. RCC is often asymptomatic at presentation and is commonly detected by nephrologists in the process of work­ ing up other diseases, such as acute kidney injury or ob­ struction, often by the observation of paraneoplastic phe­ nomena. In addition, RCC is frequently discovered in an advanced form, such that many patients have metastases at the time of diagnosis, a finding which is associated with a

markedly poor prognosis. Thus the practicing nephrologist needs at least a rudimentary understanding of this disease. In this chapter, we consider surgical, as well as medical treatment, with an emphasis on the very recent and evolv­ ing approaches from a medical, as well as surgical stand­ point, including novel treatments related to immune modu­ lation, which may soon change the landscape of treatment of this disease.

Keywords Metabolic disease, immunotherapy, paraneoplastic, ne­ phrectomy, kinase inhibition, metastatic