Diagnosis of Renal Cell Carcinoma

Many renal masses do not give any sign or symptoms until they reach the late stages and the disease progresses. Already more than 50% of the diagnosis of Renal Cell Carcinoma (RCC) is made incidentally. Most of these incidental diagnoses occur during the non-invasive imaging researches such as ultrasound, which are ordered for various non-specific reasons or abdominal symptoms. [1, 2]

Although the classic triad of flank pain, macroscopic hematuria, and palpable abdominal mass has been reported in patients with aggressive and advanced disease of Renal Cell Carcinoma (RCC), these 3 symptoms may be present in only 6 to 10% of patients at the same time. [3, 4]

Approximately 30% of patients with symptomatic Renal Cell Carcinoma (RCC) may also have paraneoplastic syndromes.   [5]
Some kidney cancer patients present with metastatic disease and have complaints such as cough or bone pain due to metastasis. [6]

In this article, you will be informed about the diagnosis of Renal Cell Carcinoma (RCC) in four main topics: physical examination, laboratory tests, imaging tests and renal biopsy.

1. Physical Examination

When a physician is consulted with metastatic complaints and symptoms suggesting urological or Renal Cell Carcinoma (RCC), the first step is a detailed history and physical examination.
In the anamnesis, the history of smoking and alcohol use, exposure to chemical carcinogens and family history are the subjects that need to be examined in detail.

However, the place of physical examination in Renal Cell Carcinoma (RCC) is extremely limited.

However, some of the findings in the physical examination may be highly motivating to request a radiological examination. For example, during the physical examination, lymphadenopathy or a suspected abdominal mass need to be further evaluated with a number of laboratory and imaging techniques and Renal Cell Carcinoma (RCC) or other malignant masses should be excluded.

Some of the findings that will make it closer to the diagnosis of Renal Cell Carcinoma (RCC) during the physical examination can be listed as follows:

  • Bilateral lower extremity edema and non-reducing varicocele that suggesting venous involvement
  • Palpable abdominal mass
  • Palpable lymphadenopathy

2. Laboratory Investigations

The laboratory investigations include diagnostic tests that can be helpful after anamnesis and physical examination.

The tests frequently requested in the laboratory investigations to confirm or rule out the diagnosis of possible Renal Cell Carcinoma (RCC) are as follows; [6]

  • Serum creatinine
  • Glomerular Filtration Rate (GFR)
  • Complete Blood Count (CBC)
  • Erythrocyte Sedimentation Rate (ESR)
  • Liver Function Tests (LFT)
  • Alkaline Phosphatase (ALP)
  • Lactate Dehydrogenase (LDH)
  • Serum corrected calcium (Ca)
  • Coagulations studies
  • Serum urea
  • Urinalysis

In addition, urinary cytology and, if possible, endoscopic evaluation methods will be very useful for the masses located in the center and holding or invading the collecting system. With these tests, a possible diagnosis of urothelial cancer can also be confirmed or ruled out.

If any of the following conditions exist, split renal function should be determined using renal scintigraphy: [8, 9]

If renal function is impaired as confirmed by increased serum creatinine or severely reduced glomerular filtration rate (GFR).

If renal functions, such as patients with bilateral tumors or having a single kidney, are critically prevented.

Renal scintigraphy is also an additional diagnostic method for patients at risk of future renal failure due to comorbid conditions.

3. Imaging Tests

Many renal tumors are diagnosed during abdominal ultrasound (US) and computed tomography (CT), which have been ordered for other complaints and medical reasons other than kidney. [2]

Renal masses are classified as solid or cystic according to their findings in imaging techniques.

a. The presence of enhancement

When a solid kidney tumor is detected with any imaging technique, the most important criterion for differentiating it from malignant masses is presence of enhancement.[10]

Traditionally, ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) are imaging methods used in the diagnosis of Renal Cell Carcinoma (RCC) and characterization of renal tumors. Contrast-enhanced ultrasound (US) may also be used in some specific cases in some clinics. [11, 12, 13]

b. Magnetic resonance imaging (MRI) and computerized tomography (CT)

Magnetic resonance imaging (MRI) and computerized tomography (CT) are the most widely used and successful methods in the diagnosis and characterization of renal masses. Sections should be taken both before and after the administrating the intravenous contrast agent in order to fully visualize the enhancement during these imaging studies.

Computerized tomography (CT) of kidney

In computerized tomography (CT), images are compared before and after administration of contrast agent according to the values called Hounsfield units (HU). A change of fifteen or more between these units called Hounsfield shows contrast enhancement. [14]

Although computerized tomography (CT) or magnetic resonance imaging (MRI) scans can accurately diagnose Renal Cell Carcinoma (RCC), they cannot reliably distinguish between oncocytoma and fat-free angiomyolipoma (AML) from the malignant renal tumors. [15, 16, 17, 18]

The most important topics that an abdominal computed tomography scan contributes to clinicians are: [20]

  • Conditions of adrenal glands and other solid organs
  • Functions and morphology of the contralateral kidney
  • Enlargement or hypertrophy of locoregional lymph nodes (LN)
  • Extension or spread of primary tumor
  • Venous involvement

Contrast-enhanced abdominal computerized tomography (CT) scanning is particularly useful in selected cases where information about renal vascular circulation is needed. [21, 22]

If the information provided with the computerized tomography (CT) scan is not enough, contrast-enhanced ultrasound (CEUS) can be considered as further investigation option and characterization of renal masses can be achieved. [23]

Magnetic resonance imaging (MRI) of kidney

Magnetic resonance imaging (MRI) may provide additional information about venous involvement, especially for tumor thrombus extending to the inferior vena cava, which cannot be clearly visualized on computerized tomography (CT) scan. [24, 25]

In addition, magnetic resonance imaging is indicated in patients with allergies to computerized tomography (CT) intravenous contrast agents and in pregnant patients without renal failure. [26, 27]

Advanced magnetic resonance imaging (MRI) techniques, which are developed as diffusion-weighted and perfusion-weighted, can provide important contributions in the evaluation of renal masses. [28]

Magnetic resonance imaging (MRI) may be the first choice in the diagnosis of complex renal cysts which are in the Bosniak IIF-III classification. In cases with these cysts, the sensitivity and specificity of computed tomography (CT) are low as 36% and 76%, respectively.

In addition, contrast-enhanced ultrasound (CEUS) has the highest rates and values as 100% sensitivity, 97% specificity and 100% negative predictive value. [29]

Young patients who are uncomfortable with radiation exposure from computerized tomography, which are frequently taken, may also be referred to magnetic resonance imaging (MRI).

However, it should be noted that the data about the relationship between radiation exposure from computed tomography (CT) that are taken for diagnostic purposes and the development of secondary cancers is extremely limited. [30]

c. Other investigations

Apart from magnetic resonance imaging (MRI) and computed tomography (CT), a number of additional imaging techniques may be preferred in selected Renal Cell Carcinoma (RCC) patients. The two most important ones are renal arteriography and inferior venacavography.

Isotope renogram and evaluation of total renal functions are important, in patients who have any signs of impaired renal function, in order to make a correct decision of treatment.

Positron-emission tomography (PET) is an imaging technique that is not recommended for Renal Cell Carcinoma (RCC) patients.

d. Evaluation of metastasis

Routine computed tomography (CT) is recommended to evaluate the metastasis of kidney cancer because the lung is one of the organs most commonly metastasized by Renal Cell Carcinoma (RCC). In addition, computed tomography is the most appropriate method for performing chest staging. [31, 32]

On the other hand, routine bone imaging is not recommended at the time of diagnosis for bones, which are another common site of metastasis. Because according to medical literature, bone metastasis, if present, gives symptoms such as bone pain at the time of diagnosis of Renal Cell Carcinoma (RCC). [33, 34]

However, bone scan, brain computerized tomography (CT) and magnetic resonance imaging (MRI) can be ordered for a number of specific clinical or laboratory findings, and even for a number of symptoms. [35, 36]

e. Bosniak classification

Bosniak classification divides renal cysts into 5 classes according to computerized tomography (CT) images. Thus, malignancy risks of cysts can be estimated. In addition, this classification provides access to recommended treatment methods for each category.

Bosniak ClassificationRadiological FeaturesRecommended Treatment
ISimple benign cyst with a hairline-thin wall without septa, calcification, or solid components. Same density as water and does not enhance with contrast medium.Bening / Watchful waiting
IIBenign cyst that may contain a few hairline-thin septa. Fine calcification may be present in the wall or septa. Uniformly high-attenuation lesions < 3 cm in size, with sharp margins without enhancement.Bening / Watchful waiting
IIFThese may contain more hairline-thin septa. Minimal enhancement of a hairline-thin septum or wall. Minimal thickening of the septa or wall. The cyst may contain calcification, which may be nodular and thick, with no contrast enhancement. No enhancing soft-tissue elements. This category also includes totally intra-renal, non-enhancing, high attenuation renal lesions > 3 cm. Generally well-marginated.Follow-up, up to five years. Some are malignant.
IIIThese are indeterminate cystic masses with thickened irregular walls or septa with enhancement.Surgery or active surveillance – see Chapter 7. Over 50% are malignant.
IVClearly malignant containing enhancing soft-tissue components.Surgery. Most are malignant.

4. Renal biopsy

Percutaneous renal tumor biopsy is an important diagnostic tool in tumors that cannot get a certain diagnosis of Renal Cell Carcinoma (RCC) with radiologic imaging techniques.
Percutaneous renal biopsy is also used for the determination of histology in patients with small masses and in whom treatment is planned with ablative surgery (AS). Thus, the most appropriate medical and surgical treatment strategy for metastatic diseases can be selected. [37, 38]

However, renal biopsy is not indicated for fragile patients with comorbidities. Regardless of the histology of the tumor, only consideration for these patients is watchful waiting (conservative management).

Due to the extremely high diagnosis rates of imaging techniques developed until today, renal tumor biopsy is not mandatory in patients with contrast-enhancing masses who will undergo surgical treatment.

a. Core and fine needle aspiration (FNA) biopsy

Percutaneous biopsy can be performed under general anesthesia as needle core biopsy or fine needle aspiration (FNA). Both biopsy methods can be performed with computerized tomography (CT) or ultrasound (US) guidance with similar diagnostic yield. [39, 40]

The use of an 18-gauge needle for core biopsy of these methods offers the lowest morbidity and the tissues that sufficient for diagnosis. In addition, coaxial technique should use used for multiple tumor biopsies to prevent potential tumor seedings. [41, 42]

While core biopsies are used to characterize renal masses, the combination with the fine needle aspiration method increases accuracy.

b. A meta-analysis of kidney biopsy

According to a meta-analysis performed in total 5228 patients by the Panel, on the performance and complications of renal tumor biopsy, needle core biopsies were found as more accurate than fine needle aspiration (FNA) biopsies. [43]

According to other studies in the medical literature, large tumor size, solid pattern and exophytic location are among the other factors that require core biopsy. [44]

Core biopsies in specialized and experienced centers on kidney cancer may have a high diagnostic yield, specificity and sensitivity for the diagnosis of potential malignancy.

According to the meta-analysis conducted by the Panel, the sensitivity of diagnostic core biopsies in detecting malignancy is 99.1% and the specificity is 99.7%.[43]

However, although core biopsies have high sensitivity and specificity rates, approximately 0.22% and 6% of them are non-diagnostic. [42, 45]

If radiological images are suspicious for malignancy, while core biopsy is non-diagnostic, surgical exploration should be considered. It is also known that repeated biopsies are diagnostic in approximately 83 to 100% of cases. [44, 46]

c. Accuracy of renal biopsy

The ability of renal biopsies to determine the histopathological type of the mass is extremely good. The concordance between histology of renal tumor, renal tumor biopsy result and surgical specimen obtained after partial or radical nephrectomy has approximately rate of 90.3%. [43]

However, it is somewhat difficult to determine the grade of the tumor in core biopsies. According to the data in the medical literature, the accuracy for nuclear grading was 62.5%, while with starting the use of the simplified two-tier system it recently reached the rate of 87%. [43]

The ideal location of the core biopsy and the number of ideal number of tissues to be removed have not been determined. However, at least 2 good quality cores must be obtained and sampling from necrotic areas should be avoided in order to increase diagnostic accuracy. [47, 48]

In order to avoid necrosis in the central regions, especially in large tumors, peripheral biopsies will have a better diagnostic yield. [49]

Especially in T2 tumors according to Tumor Node Metastasis (TNM) classification, the diagnostic values of multiple core biopsies taken from at least 4 separate contrast-enhancing areas were found to be higher. Sarcomatoid changes are more easily detectable and diagnostic yield is higher in these techniques, without increasing complication rates. [50]

For more information about the staging and Tumour Node Metastasis (TNM) Classifications of Renal Cell Carcinoma, you can read:
Staging and Classification Systems of Renal Cell Carcinoma

d. Biopsy of cystic renal mass

If the patient has a cystic renal mass, the diagnostic yield and accuracy of core biopsies are low, because of that, they are not sufficient alone. However, if the cyst is a Bosniak IV cyst, meaning it contains a solid compartment, core biopsies may be preferred. [39, 43]

Especially in complex cystic lesions, the combination of core biopsy and fine needle aspiration (FNA) techniques provide complementary and accurate results. [51, 52]

e. Complications and result

As a result, percutaneous biopsies have low morbidity. In addition, the tumor seeding in the needle is an anecdote.

According to the data collected from the studies in the medical literature, subcapsular or perinephric hematomas that spontaneously resolve may occur in approximately 4.3% of cases. However, clinically significant bleeding is extremely rare and they are usually self-limiting. [43]


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