INTRODUCTION — Malignant neoplasms involving the kidney may be primary or secondary tumors. Secondary renal neoplasms are usually clinically insignificant and discovered at postmortem examination.
Renal cell carcinomas (RCCs), which originate within the renal cortex, constitute 80 to 85 percent of primary renal neoplasms. Transitional cell carcinomas of the renal pelvis are the next most common (approximately 8 percent). Other parenchymal epithelial tumors, such as oncocytomas, collecting duct tumors, and renal sarcomas, are rare. Nephroblastoma or Wilms tumor is common in children (5 to 6 percent of all primary renal tumors). (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" and "Malignancies of the renal pelvis and ureter".)
The clinical and radiographic presentation of RCC and the methods used for tumor staging, as well as their potential application for screening, will be reviewed here. The prognosis and treatment of RCC are discussed separately. (See "Prognostic factors in patients with renal cell carcinoma".)
CLINICAL MANIFESTATIONS — Patients with RCC can present with a range of symptoms; unfortunately, many patients are asymptomatic until the disease is advanced. At presentation, approximately 25 percent of individuals either have distant metastases or advanced locoregional disease [1].
Patients with localized disease can present with a wide array of symptoms and/or laboratory abnormalities, or they may be diagnosed incidentally. In one review of 309 consecutive patients with RCC, the most common presenting symptoms were hematuria, abdominal mass, pain, and weight loss [2]. In contemporary series, fewer patients have the typical symptoms and there is an increased frequency of incidental diagnosis due to radiologic procedures performed for other indications. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Epidemiology' and "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
This shift in pattern of presentation along with improvements in therapy have contributed to better outcomes in RCC. In a series of 701 patients, those who were diagnosed incidentally had a significantly better disease-specific survival at five years (76 versus 44 percent in those with symptoms) [3]. Multivariate analysis showed that the difference was due to the lower stage and histologic grade at the time of diagnosis. (See "Systemic therapy of advanced clear cell renal carcinoma".)
Symptoms and signs — For patients not diagnosed incidentally, symptoms and signs are generally related to invasion of adjacent structures or distant metastases.
●The classic triad of RCC (flank pain, hematuria, and a palpable abdominal renal mass) occurs in at most 9 percent of patients; when present, it strongly suggests locally advanced disease [2,4].
●Hematuria is observed only with tumor invasion of the collecting system. In an early series, hematuria was observed in almost 40 percent of patients [5]. When severe, the bleeding can cause clots and "colicky" discomfort. Clot formation does not occur with glomerular bleeding; thus, the presence of clots is a significant finding in patients with otherwise unexplained hematuria. (See "Etiology and evaluation of hematuria in adults", section on 'Blood clots'.)
●An abdominal or flank mass, which is associated with lower pole tumors, is more commonly palpated in the thin adult. The mass is generally firm, homogeneous, nontender, and moves with respiration.
●Scrotal varicoceles, the majority of which are left sided, are observed in as many as 11 percent of males with RCC [6]. Varicoceles typically fail to empty when the patient is recumbent. This finding should always arouse suspicion for a kidney tumor that has obstructed the gonadal vein where it enters the renal vein.
●Inferior vena cava involvement can produce a variety of clinical manifestations, including lower extremity edema, ascites, hepatic dysfunction (possibly related to a Budd-Chiari syndrome), and pulmonary emboli.
●Among patients with disseminated disease, signs or symptoms may be due to metastatic tumor; the most common sites of involvement include the lungs, lymph nodes, bone, liver, and brain. In this setting, the diagnosis is often made by biopsy of an accessible metastasis in the setting of a renal mass on abdominal computed tomography (CT). (See "Surveillance for metastatic disease after definitive treatment for renal cell carcinoma", section on 'Sites of metastasis'.)
Paraneoplastic symptoms — Patients with RCC can present with or subsequently develop systemic symptoms or paraneoplastic syndromes [7-9]. In some instances, these may be due to ectopic production of various hormones (eg, erythropoietin, parathyroid hormone-related protein [PTHrP], gonadotropins, human chorionic somatomammotropin, an adrenocorticotropic hormone [ACTH]-like substance, renin, glucagon, insulin) [9].
Anemia — Anemia, which can precede the diagnosis of RCC by several months, has been reported in 29 to 88 percent of patients with advanced disease [6,9-11]. The anemia is often disproportionately severe, can be either normocytic or microcytic, and is frequently associated with iron studies typical of those observed with the anemia of chronic disease. (See "Anemia of chronic disease/anemia of inflammation".)
Hepatic dysfunction — Hepatic dysfunction is an uncommon occurrence in patients with RCC, which is called Stauffer syndrome when it occurs in the absence of liver metastases [12-14]. In a series of 365 patients, 21 percent had a paraneoplastic elevation in serum alkaline phosphatase [14].
When hepatic dysfunction is present, it frequently is associated with fever, weight loss, fatigue, and a poor prognosis [15]. The dysfunction may result from tumor production of cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and possibly interleukin 6 (IL-6) [16-18].
Nephrectomy may result in the amelioration of hepatic dysfunction [12,13]. Recurrent elevations of liver enzymes in such patients may herald local recurrence or distant metastatic disease [14].
Fever — Fever, which occurs in up to 20 percent of patients, is usually intermittent and is frequently accompanied by night sweats, anorexia, weight loss, and fatigue [9,19]. Its origin is unclear [9].
Hypercalcemia — Hypercalcemia occurs in up to 15 percent of patients with advanced RCC and can result from a number of different mechanisms:
●Lytic bone metastases.
●Overproduction of PTHrP [20-23]. Concurrent production of IL-6 may enhance the action of PTHrP [24,25].
●Increased production of prostaglandins that promote bone resorption [26,27]. In such patients, the hypercalcemia can respond to administration of a nonsteroidal anti-inflammatory drug (NSAID), such as indomethacin [26].
The pathogenesis and management of hypercalcemia in patients with malignancy are discussed elsewhere. (See "Hypercalcemia of malignancy: Mechanisms" and "Treatment of hypercalcemia" and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)
Cachexia — As with other tumors, patients with RCC may suffer from significant cachexia [9]. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)
Erythrocytosis — Erythrocytosis occurs in 1 to 5 percent of patients with advanced RCC and appears to be due to constitutive production of erythropoietin [28]. In addition, since the mutated von Hippel-Lindau protein is associated with impaired regulation of hypoxia-induced proteins [29,30], erythrocytosis may be directly related to impaired degradation of hypoxia-inducible transcription factors under normoxic conditions. (See "Regulation of erythropoiesis" and "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)
Secondary (AA) amyloidosis — Secondary (AA) amyloidosis is found in up to 5 percent of patients [31,32]. This finding reflects a chronic inflammatory response as the amyloid fibrils are composed of fragments of the acute phase reactant serum amyloid A protein. (See "Pathogenesis of AA amyloidosis".)
Thrombocytosis — Thrombocytosis is rare in patients with RCC, but its presence is associated with a poor prognosis [33,34]. The underlying mechanism is not firmly established but could be related to IL-6 production by the tumor.
Polymyalgia rheumatica — A syndrome resembling polymyalgia rheumatica has been reported with RCC [35]. In contrast to idiopathic disease, the symptoms do not respond to prednisone but are often corrected by nephrectomy. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)
DIAGNOSTIC EVALUATION — Patients with unexplained hematuria or other symptoms, signs, or findings suggestive of possible RCC must undergo imaging evaluation for the presence of a renal mass. In addition, incidental diagnosis of RCC is becoming more common due to the frequent use of abdominal computed tomography (CT) and/or ultrasonography for evaluation of an unrelated problem. (See "Etiology and evaluation of hematuria in adults" and "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
CT or ultrasonography — The usual first test is abdominal computed tomography (CT) (image 1) or, occasionally, abdominal ultrasound.
Although ultrasonography is less sensitive than CT in detecting a renal mass, it is useful to distinguish a simple benign cyst from a more complex cyst or a solid tumor. The issues surrounding the evaluation of an asymptomatic renal mass or a cyst are discussed in detail separately. (See "Simple and complex kidney cysts in adults" and "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
Summarized briefly, there are three major criteria that allow a simple cyst to be differentiated from a tumor or abscess on ultrasonography (table 1):
●The cyst is round and sharply demarcated with smooth walls
●There are no echoes within the cyst ("anechoic")
●There is a strong posterior wall echo, indicating good transmission through a cyst
If all of these criteria are fulfilled, no further evaluation is necessary since the likelihood of a malignancy is extremely small. If the criteria for a simple cyst by ultrasonography are not satisfied, the patient should undergo CT before and after injection of iodinated contrast. On CT, a simple cyst has a smooth appearance without a clearly delineated wall, has no enhancement with intravascular contrast, and is the density of water. CT urography allows imaging of both the renal parenchyma and the collecting system.
By comparison, thickened irregular walls or septa (image 2) and enhancement after contrast injection are suggestive of malignancy (table 1). (See "Simple and complex kidney cysts in adults", section on 'Bosniak classification of kidney cysts'.)
MRI — Magnetic resonance imaging (MRI) may be useful when ultrasonography and/or CT are inconclusive or if iodinated contrast cannot be administered because of allergy or poor renal function (image 3A-B). MRI is particularly helpful in cases where a neoplasm is diagnosed as it evaluates for tumor growth into the collecting system or the vessels better than the other modalities. (See "Simple and complex kidney cysts in adults", section on 'Category IIF' and "Definitive surgical management of renal cell carcinoma".)
MRI with dynamic gadolinium contrast may be useful in distinguishing papillary or clear cell RCC from other benign and malignant solid renal neoplasms, although the examination does not obviate the need for tissue for diagnosis. In a meta-analysis, contrast enhancement in the corticomedullary phase on MRI diagnosed papillary RCC with a pooled sensitivity of 86 percent (95% CI 68-94 percent) and specificity of 92 percent (95% CI 76-98 percent) [36]. In one large series, clear cell carcinoma was diagnosed with a sensitivity of 85 percent and specificity of 76 percent [37].
Angiography — Catheter-based renal angiography is rarely necessary. If preoperative mapping of the vasculature is required prior to possible nephron-sparing surgery, either CT or MR angiography is preferable.
TISSUE DIAGNOSIS — For patients with localized disease, nephrectomy or partial nephrectomy is used in most cases to obtain tissue for diagnosis of RCC. For patients presenting with metastatic disease who plan to omit or defer cytoreductive nephrectomy, establishing diagnosis via a biopsy of a metastasis is preferred. After the presumptive diagnosis has been made based upon imaging studies, the patient must be evaluated for the extent of local involvement and the presence of metastatic disease prior to surgery. (See 'Staging studies' below.)
In addition to establishing the diagnosis of malignancy, tissue diagnosis provides information about the histopathologic type of RCC, which may have important implications for prognosis and treatment. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Pathology'.)
The role of percutaneous biopsy is more limited, although it may be used for a small renal mass if there is a high index of suspicion for a metastatic lesion to the kidney, lymphoma, or a focal kidney infection. A biopsy can also be used to confirm a diagnosis of RCC in patients who are not surgical candidates, although biopsy of a metastatic lesion, if present, is often preferable. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
STAGING STUDIES
Abdominal CT — The extent of local and regional involvement is determined primarily by abdominal computed tomography (CT), which is extremely accurate in staging RCC. In a retrospective study of 100 RCCs, for example, preoperative CTs were compared with the findings obtained at surgery [38]. The following results were obtained:
●For the detection of renal vein invasion, CT was 78 percent sensitive and 96 percent specific.
●For the detection of metastatic adenopathy, CT was 83 percent sensitive and 88 percent specific.
●For the detection of perinephric invasion, CT was only 46 percent sensitive but was 98 percent specific.
●For the detection of adjacent organ invasion, CT was 100 percent specific.
The sensitivity and specificity of CT for detecting nodal metastasis depend upon the size criterion used to define suspicious nodes. At least some data suggest that approximately 50 percent of patients with radiographically enlarged nodes in the 1 to 2 cm size range do not harbor metastases [39].
The limitations of imaging for the detection of renal vein or perinephric invasion may result in upstaging in patients who undergo nephrectomy. In a series of 1448 patients with clinical T1 lesions, 134 (9 percent) were upstaged to pathologic T3a disease [40]. Patients with pathologic T3a disease had a worse three-year recurrence-free survival compared with those with pathologic T1 disease (76 versus 93 percent).
Other imaging studies — Other imaging studies that may be useful for assessing for distant metastases include bone scan, CT of the chest, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT:
●Bone scan – Bone scan is indicated only in patients with bone pain and/or an elevated serum alkaline phosphatase. In one series, for example, less than 5 percent of such patients had occult bone metastases [41]. Bone scan can be falsely negative since bone metastases are frequently osteolytic rather than osteoblastic.
●Chest CT or radiograph – CT of the chest is useful to evaluate for evidence of pulmonary or mediastinal lymph node metastases. Alternatively, patients with a small renal mass may be offered a chest radiograph. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass", section on 'Definition'.)
●MRI – MRI scanning with gadolinium is superior to CT for evaluation of the inferior vena cava and right atrium when tumor involvement is suspected [42].
●PET/CT – PET scanning has high sensitivity and specificity for the primary lesion. Although PET/CT may be more sensitive than radionuclide scanning for the detection of bone metastases, it is expensive and has limited use for routine staging [43-45].
Pathology
Isolated renal mass — For patients with isolated solid renal masses, resection with either a partial or complete nephrectomy is preferred over biopsy because it provides the diagnosis, pathologic tumor (T) and nodal (N) staging (table 2), and definitive treatment. Preoperative needle biopsies are usually not used for resectable renal lesions because of their low specificity [46] and concerns about tumor seeding of the peritoneum.
Although solid renal masses less than 3 cm were once thought to represent benign adenomas, distinctions based upon size are no longer used, since even small tumors frequently represent carcinomas that will grow over time [47]. Most solid renal masses require a histologic diagnosis; in patients with significant comorbidities, "watchful waiting" might be appropriate. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass" and "Simple and complex kidney cysts in adults".)
Metastatic disease — When metastatic disease is suspected at initial presentation, pathologic confirmation is required prior to starting therapy. Biopsy of a metastatic site is often easier and more informative than biopsy of the primary tumor.
In patients with a previously diagnosed nonrenal malignancy, metastatic disease is more likely than a new primary RCC. If the renal mass is nonenhancing and there is clinical evidence of progression of the nonrenal malignancy, biopsy confirmation may be unnecessary [48].
●Is there a role for upfront cytoreductive nephrectomy in staging? – The role of upfront cytoreductive nephrectomy is evolving in the era of effective treatments such as checkpoint inhibitor immunotherapy and antiangiogenic agents for patients with metastatic RCC (algorithm 1).
In general, initial cytoreductive nephrectomy may be indicated in select patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)-favorable or low-intermediate risk features (ie, no or one risk factor) (table 3). Palliative cytoreductive nephrectomy may also be indicated in those experiencing symptoms from the primary tumor (eg, pain, intractable hematuria). Further details on the approach to cytoreductive nephrectomy and supporting randomized trial data in patients with metastatic clear cell RCC are discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Cytoreductive nephrectomy' and "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Palliative nephrectomy'.)
For those with IMDC-high-intermediate or poor risk features (≥2 risk factors) (table 3), initial systemic therapy is indicated, and a decision about cytoreductive nephrectomy should be delayed until more information about disease responsiveness and treatment tolerability is available. (See "Systemic therapy of advanced clear cell renal carcinoma" and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)
TNM STAGING SYSTEM — The eighth (2017) Tumor, Node, Metastasis (TNM) staging system is used for staging all histologic variants of RCC. This system is supported by both the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) [49]. These TNM criteria use the anatomic extent of disease to define prognostic stage groups. (See "Prognostic factors in patients with renal cell carcinoma".)
The TNM system is shown in the table (table 2). In this system, tumors limited to the kidney are classified as T1 or T2 based upon size. T3 tumors extend into the renal vein or perinephric tissues but not beyond the Gerota fascia, while T4 tumors extend beyond the Gerota fascia, including direct extension into the ipsilateral adrenal gland. Nodal and distant metastases are simply classified as absent or present.
SOLID RENAL MASSES — The optimal management of solid renal parenchymal masses is incompletely understood and relies upon both the ability of imaging studies to identify simple renal cysts and the likelihood of the lesion to exhibit clinically malignant behavior. The evaluation and initial management of a patient with a solid renal mass are discussed separately. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
SCREENING — Screening of asymptomatic individuals is not recommended because of the low prevalence of RCC in the general population. However, individuals at high risk for the development of RCC should undergo periodic monitoring with abdominal ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) to detect early disease [50].
Candidates for screening include patients with any of the following conditions:
●Inherited conditions associated with an increased incidence of RCC or other renal tumors, including Von Hippel-Lindau syndrome and tuberous sclerosis. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Renal manifestations of tuberous sclerosis complex" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)
●End-stage kidney disease, especially younger subjects without serious comorbid diseases who have been on dialysis for three to five years or more.
●A strong family history of RCC. (See "Hereditary kidney cancer syndromes".)
●Prior kidney irradiation.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Renal cell carcinoma (kidney cancer) (Beyond the Basics)")
SUMMARY
●Clinical manifestations – Patients with renal cell carcinoma (RCC) can present with a range of symptoms due to the tumor itself (eg, mass, pain), invasion of the urinary tract (eg, hematuria), paraneoplastic syndromes, or the presence of metastases. In addition, RCC is more frequently being diagnosed incidentally as a consequence of increased use of imaging procedures for other reasons. (See 'Clinical manifestations' above.)
●Diagnostic evaluation – Patients with symptoms, signs, or other findings suggestive of RCC should undergo evaluation for the presence of a renal mass. Abdominal computed tomography (CT) or ultrasound can confirm the presence of a mass, distinguish RCC from a benign cyst, and assess the extent of disease. (See 'Diagnostic evaluation' above.)
●Approach to a solitary small renal mass – In the setting of a solitary small renal mass, imaging studies cannot reliably distinguish a benign renal tumor from RCC. Thus, it is generally recommended that lesions other than simple cysts be resected. (See "Diagnostic approach, differential diagnosis, and management of a small renal mass".)
●Staging – The tumor, node, metastasis (TNM) staging system, which is based upon the extent of the primary tumor and the presence or absence of regional lymph node involvement or distant metastases, is used for staging all histologic variants of RCC (table 2). This staging system correlates with prognosis and provides important information for patient management. (See 'TNM staging system' above and 'Tissue diagnosis' above and 'Staging studies' above and "Prognostic factors in patients with renal cell carcinoma".)
●Screening for individuals at high risk for RCC – Individuals thought to be at increased risk for the development of RCC should undergo routine screening with abdominal ultrasound, CT, or magnetic resonance imaging (MRI). (See 'Screening' above.)
