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Renal Cell Carcinoma

(Adenocarcinoma of the Kidneys)

By

J. Ryan Mark

, MD, Sidney Kimmel Cancer Center at Thomas Jefferson University

Last full review/revision Sep 2019| Content last modified Sep 2019
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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 73,820 new cases of RCC and other kidney tumors and 14,770 deaths (2019 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.

Symptoms and Signs of Renal Cell Carcinoma

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. 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 Cell Carcinoma

  • CT with contrast or MRI

Most often, a renal mass is detected incidentally during abdominal imaging (eg, CT, ultrasonography) 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 Genitourinary Imaging Tests .) 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 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 for metastases.

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 Genitourinary Imaging Tests .) 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 and TNM Definitions for Renal Cell Carcinoma TNM Definitions for Renal Cell Carcinoma 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 ). At diagnosis, RCC is localized in 45%, locally invasive in about 33%, and spread to distant organs in 25%.

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Prognosis for Renal Cell Carcinoma

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 Cell Carcinoma

  • For early renal cell carcinoma (RCC), surgical treatment

  • For advanced RCC, palliative therapies or experimental protocols

Curative treatments

Radical nephrectomy (removal of kidney, adrenal gland, perirenal fat, and Gerota fascia) is standard treatment for localized RCC and provides a reasonable chance for cure. Results with open or laparoscopic procedures are comparable; recovery is easier with laparoscopic procedures. Nephron-sparing surgery (partial nephrectomy) is possible and appropriate for many patients, even in patients with a normal contralateral kidney if the tumor is < 4 to 7 cm. 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. Nonsurgical destruction of renal tumors via freezing (cryosurgery) or thermal energy (radiofrequency ablation), often percutaneously, are not currently recommended as primary treatment. They are being done in highly selected patients, but long-term data about efficacy and indications are not yet available.

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.

Radiation therapy is no longer combined with nephrectomy; however, stereotactic body radiation therapy for small renal masses is being explored.

Adjuvant use of systemic 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 (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 .

Palliative treatments

Palliation can include nephrectomy, tumor embolization, and possibly external beam radiation 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 metastatic in bone.

For some patients, 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).

The newest available systemic therapies for metastatic RCC that has progressed on targeted therapy are nivolumab and pembrolizumab. These monoclonal antibodies against PD-1 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. Nivolumab was shown to prolong overall survival by 5.4 months (25.0 vs 19.6 months; P < 0.002) when compared to everolimus in patients with advanced RCC who had been treated with one or more tyrosine kinase inhibitors (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 . Combination nivolumab/ipilimumab has recently been shown to have a superior overall survival compared to sunitinib in patients with previously untreated intermediate and poor risk metastatic RCC (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 . Likewise, combination pembrolizumab/axitinib outperformed sunitinib by improving overall survival, progression-free survival, and objective response rate across all risk groups (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 . Both of these combinations are now used in the first line for patients with metastatic kidney cancer.

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 (5) 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 .

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 and liver tests.

  • Treat most localized RCC by radical nephrectomy.

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

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