Renal cell cancer





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 associated risk factors, yet the study of this disease within nephrology pedagogy and continuing education is woefully lacking. 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 laboratory, 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 disease has been labeled the “ internist’s tumor ” and “ a metabolic disease .” 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 understand 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.




Basic science considerations


The finding that ccRCC is, to a greater extent than other malignancies, 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. , Indeed, many of the paraneoplastic effects that are commonly seen with the clinical presentation ( Table 25.1 ) are a result of this altered metabolism. Another characteristic of the varieties of kidney cancer is that most are associated with genetic mutations, which in many cases contribute to the metabolic derangements. 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.



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


Basic biology of clear cell renal cell carcinoma


RCC is the most common malignancy that originates from the renal cortex. Each of the known mutated genes from the various subtypes of kidney cancer have been shown to have some effect upon cellular metabolism, a now commonly recognized property of classic oncogenes, such as oxygen and/or iron sensing, the tricarboxylic acid (TCA) cycle, glutamine metabolism, and tumor energetics; hence the appellation “ metabolic disease., , Indeed, ccRCC has also been shown to be characterized by alterations in metabolism, as is evidenced by nonstandard pathways in amino acids degradation, as well as energy production and protection from oxidative stress; this phenomenon of metabolic reprogramming was first described by Warburg early in the 20th century and has become evident in a variety of malignancies, including RCC. In fact, such findings have been put to use in developing new biomarkers and therapeutic paradigms.


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 gene is common in ccRCC, 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 characterizes ccRCC as a malignancy with “Warburg metabolism” (i.e., aerobic glycolysis). Activation of downstream events by the VHL system, including neoangiogenesis and paraneoplastic phenomena, enable ccRCC cells to thrive as their surroundings become progressively more deprived of oxygen.


Renal cell carcinoma is a metabolic disease


ccRCC arises from the proximal tubular epithelium and, in its metastatic form, is associated with high mortality. Recent studies involving different genomic platforms, also described in proteomic , and metabolomic studies, identified a profound metabolic shift in aggressive ccRCCs involving the TCA, pentose phosphate, and phosphoinositide 3-kinase pathways among others. Additional research has identified reprogrammed pathways in ccRCC, for example 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. , , The reader is referred to several recent reviews on this topic. , , ,


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 associated with severe and unpleasant adverse effects with only 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 tryptophan and arginine reprogramming. Most recently, the immune checkpoint inhibitors have shown considerable promise in treating ccRCC and studies are currently underway to find optimal combinations use these new drugs. However, the marked inter- and intratumoral heterogeneity in ccRCC 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 oncocytomas, 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 imaging for workup of CKD. Indeed, approximately one-third of patients have metastatic disease at diagnosis, at which point the prognosis is markedly poor. In symptomatic cases, the most common presenting symptoms are flank pain, hematuria, a palpable abdominal mass, and weight loss. , 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 survival is better in patients who are diagnosed incidentally, likely because the tumor is less advanced in these cases (76% incidental vs. 44% symptomatic). 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. ,


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 11% of men with RCC. This finding occurs when the tumor 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, hepatic 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 ) and can arise from ectopic production of hormones like erythropoietin, 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. Hypercalcemia occurs because of lytic bone lesions, overproduction of PTHrP, 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 recommended because of the low prevalence of RCC in the general population. However, high risk individuals should undergo periodic screening with abdominal ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to detect early disease. Candidates for screening include patients with any of the following conditions:



  • 1.

    Prior kidney irradiation


  • 2.

    Inherited conditions associated with increased incidence 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 presenting with flank pain, gross hematuria, and a palpable abdominal mass, but this triad is noted only in the minority 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. As previously mentioned, unexplained paraneoplastic syndromes can prompt an RCC investigation; this is the origin of the moniker the internist’s tumor . Most paraneoplastic symptoms disappear after tumor resection.


Typical radiologic features of ccRCC include exophytic growth, intratumoral necrosis or hemorrhage, and high uptake of contrast agents ( Fig. 25.1 ). CT is more sensitive 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 hyperechoic 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 preferable to renal arteriography for preoperative mapping of the vasculature, in preparation for possible nephron-sparing surgery. Fluorodeoxyglucose positron emission tomography ( FDG-PET) scanning, although useful for screening and staging other malignancies, has been problematic for RCC, although newer PET techniques evaluating evidence of metabolic reprogramming such as F-glutamine-PET, although currently experimental, might ultimately prove more clinically useful.




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).




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 concurrent 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 nephropathy, 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 initiating medical treatment. The risk of tumor seeding with RCC biopsy has been largely debunked and as such, this technique should be used without hesitation if there is any doubt about the histology, to avoid unnecessary surgery.




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 (from 2 with permission). GS: glomerulosclerosis; HTN: hypertension; IF: interstitial fibrosis; VS: vascular sclerosis.


In staging RCC, the extent of local and regional involvement 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 preferable. 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. 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.




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 400× (400× photo)


  • B.

    Grade 2: Nucleoli ( arrows ) are conspicuous and eosinophilic at 400× (400× photo)


  • C.

    Grade 3: Nucleoli ( arrow ) are conspicuous and eosinophilic at 100× (100× 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) (100× photo).









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. There are two subtypes, type 1 pRCC and type 2 pRCC, the latter with a worse prognosis.




Fig. 25.4


A. Papillary renal cell carcinoma, type 1 (200×). 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 (200×). 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.)




Chromophobe renal cell carcinoma


This rare (5%) kidney cancer ( Fig. 25.4 ) originates from the collecting duct and is similar to the benign oncocytoma. , 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. Cortical cystic disease can range from simple cysts to complex cysts with increasing risk for malignancy as defined by the Bosniak classification ( Table 25.2 ). However, CKD-associated cystic diseases, including acquired cystic kidney disease (ACKD) and autosomal dominant polycystic kidney disease (ADPKD), have different characteristics from that of the general population and deserve further consideration, as will be discussed in the following sections.



Table 25.2

Bosniak Classification of Cystic Renal Masses














































Septa Wall Solid Enhancement Cyst Size
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, possibly because of the cystic transformation seen in many of these kidneys. The incidence of RCC in the ESRD population ranges from 1% to 7% in various studies, a rate higher than that of the general population, in whom the incidence is 1.6%. Fourfold to fivefold increase in rate of RCC was seen in dialysis patients as compared with the general population. The prognosis of RCC in patients with ESRD-associated renal cystic disease, independent of the renal disease prognosis, is equivalent or better compared 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 dialysis-dependent 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). , Although the presence of ACKD leading to RCC has also been described among transplant recipients (23%), this incidence is far less than that observed in ESRD patients on dialysis (80%), 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. , 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 nephropathy has been associated with lower incidence of ACKD among Japanese dialysis patients. 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. , ,


The appearance and progression of acquired renal cysts may stem from a reparative response to uremic metabolites, chronic acidosis, and ischemia. , Cyst fluid content has been found to be higher in creatinine content, suggesting some filtering or secretory capacity, unlike simple or ADPKD cysts (which have similar cyst and plasma creatinine levels). ACKD cysts often regress after transplantation, once normal filtration is restored. ,


The association of ACKD with both RCC and ESRD may explain causality for the increased risk of RCC in ESRD. 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. , 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, , 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, although in another study, tubulopapillary pathology was also observed (42%). 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. , ,




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. Five-year survival and cancer-specific mortality were markedly 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 characteristics 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 despite the use of powerful immunosuppression drugs, which increase cancer risk in general. , , Most studies have found that the prevalence of native kidney RCC in renal transplant recipients (3%–5%) was no different from nontransplant ESRD population but still 100-fold greater than the general population. ACKD is less commonly described among transplant recipients (23%–33%) but can be as high as 57%, which is still far less than that observed in ESRD patients on dialysis (80%). 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 undergo more frequent surveillance. The 10-year cancer-specific survival of 88% to 95% in transplant recipients is higher than the general population (75%). 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 malignancy risk of most cystic lesions can be assessed using these criteria and prognosis is determined with staging and grading tools (see Table 25.2 ).


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 patients, screening among potential transplant recipients in our opinion seems quite reasonable, given the noninvasiveness of the imaging. Furthermore, a more favorable prognosis 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 characteristics, 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 ). T-staging (T1-T4) is classified by the extent and size of the tumor, which differentiates cancer-specific survival. T1 tumors 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 cancer-specific 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 including ipsilateral adrenal gland invasion worsens prognosis considerably. More recently, renal sinus fat involvement has been found to be associated with lower survival. 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.



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


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 differentiate RCC into 4 grades (see Fig. 25.3 ). Five-year cancer-specific survival is highest for grade 1 (51%–93%), and lowest in grade 4 (10%–28%). Although this grading system is reliably used for ccRCC, it has not been adequately validated for pRCC or chromophobe RCC subtypes. ,


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. Other features, such as the presence of sarcomatoid or rhabdoid (eccentric large nuclei and eosinophilic cytoplasm) differentiation and microscopic coagulative tumor necrosis, add to the worse prognosis. Sarcomatoid differentiation, seen in only 4% of all RCCs, reflects extreme dedifferentiation and is associated with a dismal prognosis. All tumors with a sarcomatoid component were classified as nuclear grade 4. 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 (conventional) 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. ,


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 outcomes 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 differentiated 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. ,




Treatment


The nephrologist, although traditionally excluded in this area, should play a significant role in the management of renal masses. 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” is currently 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 nephrectomy remains the mainstay of curative treatment for patients who present with early stage RCC. However, a significant 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 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 nephrectomy 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.




Fig. 25.5


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


Partial nephrectomy


Before surgery, laboratory data need to be obtained for risk assessment for CKD. Partial nephrectomy is useful for preservation of kidney function, as a nephron sparing procedure, 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 patients 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 nephrectomy. According to pool estimates, partial nephrectomy correlated 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 nephrectomy 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 m 2 after partial nephrectomy versus radical nephrectomy. , 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 recommendation with which we concur.


Nephrectomy scoring systems (radius, exophytic or endophytic, 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. , The PADUA and RENAL nephrometry assign numerical values to a focused set of morphologic variables readily ascertainable with conventional 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. Laparoscopic technique should be reserved for small tumors and with no complexity features. Hematuria, perirenal hematoma, and urinary fistulas are most common complications, and less frequent issues include AKI and infection.


Radical nephrectomy


Classical radical nephrectomy consists of removal of the affected kidney, perirenal fat tissue, adrenal gland, and regional 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 reserved for patients with clinically positive nodes detected either by CT or during the surgical procedure. Radical nephrectomy should be considered for a patient with multiple small tumors and in cases where the tumor extends into vasculature. The laparoscopic approach for radical nephrectomy 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 potential 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, molecularly 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 cytoreductive nephrectomy cases versus 7.7 months in the noncytoreductive nephrectomy group, even while they receive systemic targeted therapies.


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 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 considered for tumor growth to greater than 3 to 4 cm or by more than 0.4 to 0.5 cm per year. Active surveillance is an option 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 improvements in disease-free survival compared with placebo in high-risk disease, but the phase 3 trial failed to show survival benefit and was associated with significant toxicity.


Radiation therapy (RT) is helpful mainly for bone metastases, brain metastases, and painful recurrences in the renal bed. Although RCCs are characterized as radioresistant tumors, 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. ,


Systemic therapy


The evolution of drugs for metastatic RCC in recent years is illustrated in Table 25.4 with terminology aptly described. The so-called “Dark Age” was before 2005 and median survival 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 median survival is expected to be 5 years. The ultimate goal of the future “Diamond Age” is long-term survival. The current therapies are associated with various adverse events, which are shown in Table 25.5 .


Mar 16, 2020 | Posted by in NEPHROLOGY | Comments Off on Renal cell cancer

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