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Renal Cell Carcinoma: Symptoms and Diagnostic Workup

• Renal cell carcinoma: Definition and Epidemiology
• Renal cell carcinoma: Pathology
• Renal cell carcinoma: Diagnostic workup
• Renal cell carcinoma: Surgical Treatment
• Renal cell carcinoma: Targeted therapy of advanced disease

Signs and Symptoms of Renal Cell Carcinoma

Asymptomatic disease:

More than 50 % of renal cell carcinomas are discovered incidentally during imaging performed for other conditions.

Classic triad:

Flank pain, hematuria, and a palpable abdominal mass are signs of advanced renal cell carcinoma; the complete triad is rare.

B symptoms:

Night sweats, weight loss, and fever may indicate a high tumor burden.

Symptoms due to metastases:

Cough, shortness of breath, bone pain, neurologic deficits, and jaundice.

Paraneoplastic syndromes:

The likelihood of a paraneoplastic syndrome increases with tumor burden. Improvement after tumor nephrectomy is a favorable sign; persistent or recurrent symptoms may indicate residual or recurrent disease.

Hypercalcemia:

Caused by parathyroid hormone-related peptides, vitamin D activation, prostaglandins, or bone metastases. See serum calcium.

Polycythemia and hypertension:

Caused by erythropoietin and/or renin production (erythropoietin).

Stauffer syndrome:

Reversible hepatic dysfunction (elevated alkaline phosphatase, bilirubin, and transaminases, with abnormal coagulation), probably caused by cytokines such as interleukin 6.

Other syndromes:

Leukemoid reaction, thrombocytosis, Cushing syndrome, hirsutism, and gynecomastia.

Basic Evaluation

The initial evaluation includes a medical history, physical examination, laboratory tests, ultrasound imaging of the kidneys and liver, contrast-enhanced abdominal CT or MRI, and chest staging with CT or chest X-ray for small tumors.

• Medical history and physical examination
• Laboratory tests
• Ultrasound imaging of the kidneys and liver
• Contrast-enhanced abdominal CT or, alternatively, MRI
• Chest CT or chest X-ray for small tumors

Laboratory Tests

Serum creatinine, urinalysis, complete blood count, calcium, liver enzymes, alkaline phosphatase, lactate dehydrogenase, and coagulation tests.

Ultrasound Imaging

Renal cell carcinoma usually appears as a hypoechoic or isoechoic mass, located centrally or peripherally [fig. ultrasound of a large renal cell carcinoma and ultrasound of a small renal cell carcinoma]. Cystic tumors are difficult to assess by ultrasound [fig. cystic renal cell carcinoma]. Suspicious renal masses require contrast-enhanced abdominal CT or, alternatively, MRI. Doppler ultrasound may raise suspicion of venous invasion. The liver should be evaluated for metastases.

Renal ultrasound: large, peripherally growing renal cell carcinoma.

Renal ultrasound in two planes: small, peripherally growing renal cell carcinoma, pT1a (>   <). (1) Liver. (2) Acoustic shadow from the ribs. With kind permission, Dr. med. H. Kempter, Augsburg.

Abdominal CT

Multiphase contrast-enhanced abdominal CT with contrast medium is the imaging method of choice when a renal tumor is suspected [fig. abdominal CT of renal cell carcinoma]. CT helps assess whether nephron-sparing surgery is feasible and plan the surgical approach [fig. cystic renal cell carcinoma]. It can determine the cranial extent of a tumor thrombus [fig. renal cell carcinoma with vena cava thrombus]. Lymphadenopathy with nodes larger than 1 cm is suspicious for lymph node metastasis. In addition to preoperative staging, CT can help estimate function of the contralateral kidney.

Abdominal CT of pT3a renal cell carcinoma: axial image (left) and coronal reconstruction (right), showing advanced left-sided renal cell carcinoma with invasion of the renal vein. With kind permission, Dr. G. Antes, Kempten.

Ultrasound, CT, and gross findings of a large cystic renal cell carcinoma (pT2b G2). Because of its favorable location and the limited overall renal function, the tumor was treated with partial nephrectomy despite its size. With kind permission, J. Menzinger (left and right images) and Prof. Dr. K. Bohndorf (center), Augsburg.

Abdominal CT showing a large vena cava thrombus from a right-sided renal cell carcinoma (left: axial plane; right: coronal plane). The arrow marks the thrombus (left) and its cranial extent (right). With kind permission, Prof. Dr. K. Bohndorf, Augsburg.

Abdominal MRI

Indications include chronic kidney disease, contraindications to iodinated contrast agents, equivocal CT findings, and suspected invasion of adjacent organs or veins. MRI is the preferred method for determining the cranial extent of a vena cava thrombus.

Chest Staging

Chest CT is the most sensitive method for detecting pulmonary metastases and mediastinal lymphadenopathy. In patients with an incidentally detected cT1a tumor, chest CT may be omitted because the risk of pulmonary metastases is low; chest X-ray is a possible minimal evaluation.

Investigations for Specific Indications

Transesophageal Echocardiography

Consider when a high vena cava thrombus is suspected and MRI is contraindicated.

Bone Imaging

Bone scintigraphy or whole-body low-dose CT is indicated to detect bone metastases in patients with advanced tumors, elevated alkaline phosphatase, bone pain, or metastases at other sites.

Brain MRI

Contrast-enhanced brain MRI is indicated when brain metastases are clinically suspected. In metastatic disease, it may also be considered before systemic therapy or cytoreductive nephrectomy, because occult brain metastases may change treatment decisions.

PET

PET has no established role in the diagnosis of renal cell carcinoma and is not recommended in current guidelines. It may be considered in selected cases of suspected recurrence or unclear metastatic disease.

Renal Mass Biopsy

Biopsy is indicated for radiologically indeterminate renal masses when renal abscess, lymphoma, or metastasis is suspected; to select patients for active surveillance; or to confirm histology before systemic therapy. False-negative results may occur, particularly with small, cystic, or necrotic tumors. Tumor seeding of the needle tract is rare but has been reported, particularly with papillary tumors.

Genetic Evaluation

Genetic evaluation should be offered to patients younger than 46 years, those with bilateral or multifocal tumors, a positive family history, or clinical or histologic findings suggestive of hereditary renal cell carcinoma. Relevant findings include multifocal papillary or chromophobe/oncocytic tumors, HLRCC syndrome, fumarate hydratase-deficient RCC, and succinate dehydrogenase-deficient RCC.

Screening for Renal Cell Carcinoma

Imaging-based screening is not recommended for the general population because of the low incidence of renal cell carcinoma, the nonspecificity of imaging findings, and the high prevalence of small benign renal tumors. Screening may be appropriate for risk groups, including patients with end-stage renal disease and acquired cystic kidney disease, tuberous sclerosis, von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, and HLRCC syndrome.

Experimental Screening

Urinary aquaporin 1 (AQP1) and perilipin 2 (PLIN2) have shown diagnostic potential in studies (Morrissey et al., 2015).

Differential Diagnosis of a Renal Mass

Inflammatory masses:

Renal abscess, xanthogranulomatous pyelonephritis, infected renal cyst, urogenital tuberculosis, and granulomatous inflammation associated with systemic disease.

Tumors of mature renal parenchyma:

Papillary adenoma, oncocytoma, angiomyolipoma, and renal cell carcinoma.

Tumors of immature renal parenchyma:

Wilms tumor, sarcomas, and other rare pediatric renal tumors.

Tumors of the renal pelvis:

Papillomas, urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma.

Cystic masses:

Simple or complex renal cyst, parapelvic renal cyst, benign multilocular renal cyst, calyceal diverticulum, autosomal recessive or autosomal dominant polycystic kidney disease, von Hippel-Lindau syndrome, tuberous sclerosis, and lymph cysts.

Vascular masses:

Arteriovenous malformation, hemangioma, lymphangioma, and angiomyolipoma.

Neurogenic tumors:

Neuroblastoma, ganglioneuroma, and schwannoma.

Mesenchymal tumors:

Fibroma, fibrosarcoma, lipoma, liposarcoma, leiomyoma, and leiomyosarcoma.

Perirenal masses:

Retroperitoneal sarcomas, teratoma, neuroblastoma, lymphoma, and lymph node metastases, particularly from testicular tumors.

Renal metastases:

Lung cancer, breast cancer, gastrointestinal cancers, malignant melanoma, and lymphoma.

References

DGU; DKG; DKG & Leitlinienprogramm Onkologie Diagnostik, Therapie und Nachsorge des Nierenzellkarzinoms, Langversion 4.02023 https://www.leitlinienprogramm-onkologie.de/leitlinien/nierenzellkarzinom/.

Gold u.a. 1996 GOLD, P. J. ; FEFER, A. ; THOMPSON, J. A.: Paraneoplastic manifestations of renal cell carcinoma.
In: Semin Urol Oncol
14 (1996), Nr. 4, S. 216–22

B. Ljungberg et al., “EAU Guidelines: Renal Cell Carcinoma.” (2024). https://uroweb.org/guidelines/renal-cell-carcinoma/

Morrissey, J. J.; Mellnick, V. M.; Luo, J.; Siegel, M. J.; Figenshau, R. S.; Bhayani, S. & Kharasch, E. D. Evaluation of Urine Aquaporin-1 and Perilipin-2 Concentrations as Biomarkers to Screen for Renal Cell Carcinoma: A Prospective Cohort Study.
JAMA Oncol 2015, 1, 204-212.

Riccabona 2003 RICCABONA, M.: Imaging of renal tumours in infancy and childhood.
In: Eur Radiol
13 Suppl 4 (2003), S. L116–29

  Deutsche Version: Diagnose des Nierenzellkarzinoms

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