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Renal Cell Carcinoma

(Adenocarcinoma of the Kidneys)

By

Thenappan Chandrasekar

, MD, Thomas Jefferson University

Last full review/revision Jan 2022| Content last modified Sep 2022
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Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent, so the diagnosis is usually suspected based on incidental findings. Diagnosis is confirmed by CT or MRI and occasionally by biopsy. Treatment is with surgery for early disease and targeted therapy, an experimental protocol, or palliative therapy for advanced disease.

RCC, an adenocarcinoma, accounts for 90 to 95% of primary malignant renal tumors. Less common primary renal tumors include transitional cell carcinoma, Wilms tumor Wilms Tumor Wilms tumor is an embryonal cancer of the kidney composed of blastemal, stromal, and epithelial elements. Genetic abnormalities have been implicated in the pathogenesis, but familial inheritance... read more (most often in children), and sarcoma.

In the US, about 76,080 new cases of RCC and other kidney tumors and 13,780 deaths (2021 estimates) occur each year. RCC occurs slightly more often in men (male:female incidence is about 3:2). People affected are usually between 50 and 70 years old. Risk factors include the following:

RCC can trigger thrombus formation in the renal vein, which occasionally propagates into the vena cava. Tumor invasion of the vein wall is uncommon. RCC metastasizes most often to the lymph nodes, lungs, adrenal glands, liver, brain, and bone.

Signs and Symptoms of Renal Cancer

Symptoms usually do not appear until late, when the tumor may already be large and metastatic. Gross or microscopic hematuria is the most common manifestation, followed by flank pain, fever of unknown origin (FUO), and a palpable mass. Other nonspecific symptoms can include fatigue, weight loss, and early satiety. Sometimes hypertension results from segmental ischemia or pedicle compression. Paraneoplastic syndromes Paraneoplastic Syndromes Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastasis. Although the pathogenesis remains unclear, these symptoms may be secondary to substances secreted... read more Paraneoplastic Syndromes occur in 20% of patients. Polycythemia can result from increased erythropoietin activity. However, anemia may also occur. Hypercalcemia is common and may require treatment Treatment Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism, vitamin... read more . Thrombocytosis, cachexia, or secondary amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Amyloidosis may develop.

Diagnosis of Renal Cancer

  • CT with contrast or MRI

Most often, a renal mass is detected incidentally during abdominal or spinal imaging (eg, CT, ultrasonography, MRI) done for other reasons. Otherwise, diagnosis is suggested by clinical findings and confirmed by abdominal CT before and after injection of a radiocontrast agent or by MRI. (See Genitourinary Imaging Tests Genitourinary Imaging Tests Imaging tests are often used to evaluate patients with renal and urologic disorders. Abdominal x-rays without radiopaque contrast agents may be done to check for positioning of ureteral stents... read more .) A renal mass that is enhanced by radiocontrast strongly suggests renal cell carcinoma (RCC). CT and MRI also provide information about local extension and nodal and venous involvement. MRI provides further information about extension into the renal vein and vena cava and has replaced inferior vena cavography. Ultrasonography and intravenous urography may show a mass but provide less information about the characteristics of the mass and extent of disease than do CT or MRI.

Often, nonmalignant and malignant masses can be distinguished radiographically, but sometimes surgery is needed for confirmation. Needle biopsy does not have sufficient sensitivity when findings are equivocal; it is recommended only when the diagnosis would impact treatment choice, such as when there is an infiltrative pattern instead of a discrete mass, when the renal mass may be a metastasis from another known cancer, or sometimes to confirm a diagnosis before chemotherapy or systemic therapy for metastatic renal masses.

Three-dimensional CT, CT angiography, or magnetic resonance angiography is used before surgery, particularly before nephron-sparing surgery, to define the nature of RCC, to more accurately determine the number of renal arteries present, and to delineate the vascular pattern. (See Genitourinary Imaging Tests Genitourinary Imaging Tests Imaging tests are often used to evaluate patients with renal and urologic disorders. Abdominal x-rays without radiopaque contrast agents may be done to check for positioning of ureteral stents... read more .) These imaging techniques have replaced aortography and selective renal artery angiography.

A chest x-ray and liver tests are essential. If chest x-ray is abnormal, chest CT is done. If alkaline phosphatase is elevated, bone scanning is needed. Serum electrolytes, blood urea nitrogen (BUN), creatinine, and calcium are measured. BUN and creatinine are unaffected unless both kidneys are diseased.

Staging

Information from the evaluation makes preliminary staging possible. The TNM (tumor, node, metastasis) system has been recently refined to be precise (see tables AJCC/TNM Staging of Renal Cell Carcinoma AJCC/TNM* Staging of Renal Cell Carcinoma AJCC/TNM* Staging of Renal Cell Carcinoma and TNM Definitions for Renal Cell Carcinoma TNM Definitions for Renal Cell Carcinoma TNM Definitions for Renal Cell Carcinoma ). At diagnosis, RCC is localized in 45%, locally invasive in about 33%, and spread to distant organs in 25% of patients.

Table
Table

Prognosis for Renal Cancer

Five-year survival rates range from about 81% for the American Joint Commission on Cancer (AJCC) stage grouping I (T1 N0 M0) to 8% for stage grouping IV (T4 or M1). Prognosis is poor for patients with metastatic or recurrent renal cell carcinoma (RCC) because treatments are usually ineffective for cure, although they may be useful for palliation.

Treatment of Renal Cancer

  • For early renal cell carcinoma (RCC), surgical treatment, active surveillance, or thermal ablation

  • For advanced RCC, palliative therapies or experimental protocols

Curative treatments

Radical nephrectomy (removal of kidney, perirenal fat, Gerota fascia +/- ipsilateral adrenal gland) is standard treatment for localized RCC and provides a reasonable chance for cure. Results with open or minimally invasive procedures are comparable; recovery is generally easier with minimally invasive procedures. Nephron-sparing surgery (partial nephrectomy) is possible and appropriate for many patients. Partial nephrectomy is gaining popularity because it results in a lower incidence of chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more Chronic Kidney Disease than radical nephrectomy. It is the standard of care for clinically staged T1a tumors (cT1a, < 4 cm) and should be considered in patients with T1b or T2 tumors and those with absolute indications for nephron preservation (eg, bilateral renal masses, CKD, solitary kidney). Radical nephrectomy should be considered in patients with a normal contralateral kidney, normal kidney function, and more advanced primary tumors (cT1b through cT4). Nonsurgical destruction of renal tumors via freezing (cryosurgery) or thermal energy (radiofrequency ablation), often percutaneously, should be considered for tumors smaller than 3 cm. For small renal masses, active surveillance (with delayed intervention) should be considered a first-line treatment option, particularly if active treatments pose risks and/or patients have significant comorbidities. Decision making for treatment is complex and multifactorial and typically involves shared decision-making (1 Treatment references Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more ).

For tumors involving the renal vein and vena cava, surgery may be curative if no nodal or distant metastases exist.

If both kidneys are affected, partial nephrectomy of one or both kidneys is preferable to bilateral radical nephrectomy if technically feasible.

Adjuvant use of targeted therapy after surgery has failed to prolong survival in multiple clinical trials, yet improvements in disease-free survival seen in patients taking adjuvant sunitinib in S-TRAC led to its approved use following resection in high-risk patients (2 Treatment references Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more ). Its use has been limited. The KEYNOTE-564 study (3 Treatment references Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more ) showed robust increases in disease-free survival in patients treated with pembrolizumab as an adjuvant therapy for surgically treated RCC patients at high risk of recurrence.

Palliative treatments

Palliation can include nephrectomy, tumor embolization, external beam radiation therapy and systemic therapy. Resection of metastases offers palliation and, if metastases are limited in number, prolongs life in some patients, particularly those with a long interval between initial treatment (nephrectomy) and development of metastases. Although metastatic RCC is traditionally characterized as radioresistant, radiation therapy can be palliative when RCC is oligometastatic, particularly to the bone.

Systemic therapies were the mainstay of management of patients with metastatic RCC. Drug therapy reduces tumor size and prolongs life. About 10 to 20% of patients respond to interferon alfa-2b or IL-2, although the response is long-lasting in < 5%. Many targeted therapies have shown efficacy for advanced tumors: sunitinib, sorafenib, bevacizumab, pazopanib, cabozantinib, axitinib, and lenvatinib (tyrosine kinase inhibitors) and temsirolimus and everolimus, which inhibit the mammalian target of rapamycin (mTOR).

However, the newest available systemic therapies for metastatic RCC are immune checkpoint inhibitors (ICI). These monoclonal antibodies against PD-1 or PD-L1 work by blocking the PD-1/PD-L1 interaction between tumor cells and infiltrating T-cells, thus blocking PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. For favorable and intermediate or poor risk RCC, first-line treatments are combination therapies (ICI +/- targeted therapy or a 2nd ICI) ; combinations include axitinib + pembrolizumab, cabozantinib + nivolumab, levantinib + pembrolizumab, and ipilimumab + nivolumab.

Other treatments are experimental. They include stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more , other interleukins, anti-angiogenesis therapy (eg, thalidomide), and vaccine therapy. Traditional chemotherapeutic drugs, alone or combined, and progestins are ineffective.

Cytoreductive nephrectomy before systemic therapy is controversial now that CARMENA (Clinical Trial to Assess the Importance of Nephrectomy), a randomized phase III trial comparing cytoreductive nephrectomy followed by sunitinib and sunitinib alone showed survival was not worse when treating with sunitinib alone (4 Treatment references Renal cell carcinoma (RCC) is the most common renal cancer. Symptoms can include hematuria, flank pain, a palpable mass, and fever of unknown origin (FUO). However, symptoms are often absent... read more ); however, that trial was criticized for its patient selection.

The current recommendations are to consider cytoreductive nephrectomy in patients with any of the following criteria:

  • The bulk of the disease burden in the kidney

  • Symptomatic bleeding or pain from the primary tumor

  • Presence of a paraneoplastic tumor

  • Excellent performance status with normal contralateral kidney function

Increased knowledge of genetic subtypes of RCC is leading to evolving management recommendations that are more specific.

Treatment references

Key Points

  • RCC, an adenocarcinoma, accounts for 90 to 95% of primary malignant renal tumors.

  • Symptoms (most often gross or microscopic hematuria) usually do not develop until the tumor is large or metastatic, so incidental discovery is common.

  • Diagnose RCC by MRI or contrast-enhanced CT and do a chest x-ray, blood tests (including liver tests) to complete staging.

  • Treat most localized RCC by surgery, active surveillance or thermal ablation.

  • Treat advanced RCC with combination immunotherapy, targeted drug therapies, interferon alfa-2b or IL-2, palliative radiation, and/or surgery

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