Sensitivity and specificity of biopsy
Several studies have evaluated sensitivity, specificity, and accuracy of renal mass biopsy in diagnosing malignancy; however, their results vary considerably by patient population, biopsy guidance-modality, needle size, and tumor type. A recent meta-analysis among studies published after 2001 found that accuracy was 96%, rate of false negatives was 0.6%, and rate of false positives was 0%.12
The sensitivity of biopsy for small masses (≤3 cm) is lower than for large masses.15 Sensitivity is limited by false-negative results, which are due to failure to properly target a small mass or sampling of a necrotic center in a large tumor.15
Biopsy is not only useful in de- termining malignancy versus benignity, but also in diagnosing histology and grade, as these may affect prognosis and management, especially in patients being considered for nephron-sparing surgery or percutaneous ablation. Advances in pathology, including immunohistochemistry and cytogenetic techniques, have improved the accuracy of subtype determination in renal mass biopsy. Overall accuracy in subtype identification has been reported to be as high as 94%.12 FISH and polymerase chain reaction (PCR) can be used to aid in differentiation between subtypes of RCC.
This is especially useful in differentiation between oncocytoma and chromophobe RCC, as they may coexist as a hybrid tumor. Hale’s colloidal iron stain can also be helpful in this setting. The immunocytochemical and cytogenetic profiles of the various subtypes of RCC are increasingly better described. DNA microarrays have been used to measure the expression levels of large numbers of genes simultaneously and can be used to differentiate subtypes of RCC based on mRNA expression. For example, high CA9 expression is seen in clear-cell RCC, AMACR in papil- lary RCC, and CLCNKB in chromo- phobe RCC and oncocytoma.16 Fur-ther research using this technology will improve our algorithm for subtype determination.
Higher grade portends worse prognosis. Chromophobe, collecting duct, renal medullary, and unclassified RCC are designated as high or low grade.
Fuhrman nuclear grading is used for clear cell and papillary RCC. It is based on nuclear charac- teristics, including size, contour, and nucleoli without consideration for mitotic activity. Renal tumors are commonly hetero- geneous, so there is concern that Fuhrman nuclear grade identification based on a small sampling may be misleading. In two large series, nuclear grade was determined correctly at biopsy in 70% (17) and 84% (18) of cases. Grade accuracy can be improved by grouping tumors into “low grade” (Fuhrman I-II) and “high grade” (Fuhrman III-IV).
Specific indications for biopsy
The rise in incidental detection of small (cT1a) renal masses has brought new attention to the debate about renal mass biopsy. Radiologically, it is difficult to distinguish between benign and malignant small renal cortical neoplasms. When stratified by size there is a direct correlation between benignity and size of the mass,8 with a high percentage of small renal cortical neoplasms being benign.
Among those that are malignant, a significant number are low grade and likely indolent.15 This is why biopsy before jumping to treatment, especially in older patients with comorbidities, is so important. Unfortunately, the sensitivity of biopsy of small renal masses has been found to be lower than that of biopsy of 4-6 cm renal masses, 84% vs. 97%,19 although more recent papers looking only at small renal masses have found higher sensitivity. Subtype determination is also less accurate in small as compared with larger masses;12 however, with the use of IHC, accuracy of subtype determination has been reported as high as 93%.20< /p>
Pre- and post-ablative biopsy
With the increasing use of ablative technologies for renal masses, tissue sampling prior to percutaneous or laparoscopic ablation has emerged as an indication for renal mass biopsy. Ablative technologies such as cryotherapy, radiofrequency ablation, and more recently, microwave ablation and extracorporeal high-intensity focused ultrasound ablation, are being used on small solid renal tumors.
Pre-ablation biopsy in combination with imaging findings is the only way to determine if these small masses are benign or malignant. In two recent meta-analyses, biopsy of the masses occurred in only 62.2% to 88% of ablations.21,22 Thus a number of patients, some of whom likely have benign lesions, are being empirically treated based on imaging without tissue evidence. A benign diagnosis can avoid subjecting patients to the risks of an ablative procedure and prevents years of unnecessary imaging and follow-up visits as well as the patient anxiety associated with a cancer diagnosis.
From a societal perspective, benign determinations on biopsy can avoid the healthcare costs of unnecessarily treating incidentally discovered small renal masses. From a research perspective, without tissue diagnosis of malignancy, treatment efficacy of ablation may be overestimated if benign lesions are included in the data.
Biopsy may also be used to assess the success of ablation. Although typically this is done with contrast-enhanced CT with lack of enhancement indicating the absence of tumor recurrence, lack of enhancement does not completely rule out the presence of viable tumor cells, particularly with radiofrequency ablation technologies.23 Oxidative stress stains may be a valuable addition in assessing biopsy results after ablation.24< /p>
Biopsy of indeterminate cystic renal masses
A number of landmark reviews have described the radiological features of benign and malignant cystic masses.1,25 The Bosniak classification is based on imaging and used to guide the clinical management of renal cysts. Bosniak type I are simple cysts; type II are minimally complex with thin septations and fine calcifications or uniformly high attenuation cysts <3cm. Type IIF cysts are minimally complex but require follow up because of an increased number of septations or thicker calcifications. This category also includes hyperdense cysts >3cm in diameter. Indeterminate cystic renal masses (Bosniak type III) have thick or irregular septa and a thickened or irregular cyst wall. Bosniak type IV cysts contain enhancing solid tissue components adjacent to but independent of the cyst wall or septa.
Type III and IV cysts are typically managed surgically, as they cannot be classified on the basis of imaging findings alone and can only be categorized after surgical removal and complete pathologic assessment. At the time of resection, however, the prevalence of benign masses among type III cysts has been reported to be as high as 41%.26
Benign indeterminate cystic renal masses are usually complicated cysts with inflammatory changes, and biopsy shows inflammatory cells, renal epithelial cells, and fibrous tissue. Atypical cells may also be seen making it impossible to rule out RCC. Aspiration of cyst fluid may be helpful. Clear fluid is generally assumed to be benign and hemorrhagic fluid malignant.
There are, however, reports of RCC from which clear fluid was aspirated27 and only 15%-20% of bloody cysts are malignant at resection.28 In spite of its limitations, percutaneous biopsy has been used to aid in management of indeterminate cystic masses with those determined to be malignant undergoing definitive treatment and those determined to be benign being observed. Those that are observed are typically considered to be benign if they demonstrate no growth at one year,16,27 although it is important to recognize that some cancers may be extremely slow growing and no interval of time can be used to definitively diagnose a mass as benign.
A recent study retrospectively analyzed the pathology and outcomes of small renal mass biopsy, with special attention paid to those patients who underwent repeat biopsy for nondiagnostic results.29 Of the 345 biopsies performed initially, 67 (19.4%) were nondiagnostic. Repeat biopsy was performed in 12 of the 67 nondiagnostic cases, leading to diagnosis in 10 (83.3%), with two of those masses being benign.29