Renal cancer. Contemporary management. Editor John A. Libertino. Springer New York 2013.
3. Role of percutaneous biopsy and other diagnostic modalities
Traditionally, when renal masses are found on cross-sectional imaging, the diagnosis of malignancy is suspected based on the presence of mass enhancement with intravenous contrast. Contemporary management, including patient counseling and treatment planning, is often delivered in the absence of deﬁnitive pathologic information and based solely on the imaging ﬁndings, despite the expectation that approximately 15% of these presumed RCC lesions are actually benign and less than 30% display aggressive malignant potential. In contrast to other urologic malignancies, where speciﬁc pathologic information from biopsy is applied to predict risk and tumor behavior and subsequently to guide management and treatment, the ability to similarly evaluate a SRMs preoperatively and tailor treatment strategies based on these results remains elusive. While efforts have been made to use preoperative clinical and radiographic variables to predict malignant potential, to date, the clinical utility of noninvasive diagnostic information and predictive models remains limited. Despite the potential suggested beneﬁts of percutaneous renal mass biopsy, this diagnostic procedure has yet to be accepted as a standard component of the evaluation and management of patients with SRMs. A majority of urologists appear to use percutaneous biopsy in selected cases; however, only a small minority do so routinely.
Традиционная роль биопсии объемных образований в почках
Historically, there has been a limited perceived beneﬁt from percutaneous needle biopsy and its subsequent impact on the management of SRMs. The common standard practice has been to treat all SRMs as RCC, and renal mass biopsy was viewed as lacking sufﬁcient sensitivity or accuracy to adequately conﬁrm the preoperative SRMs diagnosis or provide actionable clinical information which alters the need for intervention. However, contemporary biopsy approaches are recognized to have high sensitivity and speciﬁcity for cancer and can clarify the histological diagnosis of a renal mass perhaps affecting clinical decision making. Modern noninvasive imaging and image-guided biopsy techniques of renal masses have improved and can provide an accurate diagnosis in a majority of cases. Traditionally, renal mass biopsy was reserved for the infrequent cases where a renal mass was atypical and suspicious for non-RCC pathology such as lymphoma or infection or in cases of suspected metastasis from another organ to the kidney. Biopsies have also been performed to conﬁrm the diagnosis of a renal primary tumor in the presence of disseminated metastases or unresectable retroperitoneal masses. Otherwise, biopsy has not generally been advocated due to concerns of inaccuracy as well as about safety and risk for needle tract seeding and tumor spillage.
Современная техника биопсии и ее результаты
With historic small-gauge core biopsy needles, renal biopsy exhibited an 81% accuracy rate, with four out of ﬁve biopsies correctly diagnosing a tumor’s pathology. Since the application of larger 18-gauge core needles for tissue procurement and with improvements in immunohistological techniques, percutaneous renal biopsy mass has demonstrated improved accuracy in differentiating benign from malignant histology (>90%) and is safely performed with minimal procedure-related complications. From modern biopsy series, the positive predictive value is reported to be over 95% in cases where a malignancy is detected. In addition, the negative predictive value has been reported to be over 80% in contemporary series with falsenegative rates less than 5% [55, 56]. In a recent contemporary series of 152 biopsies using the 18-gauge core biopsy technique, Maturen et al. reported highly accurate sensitivity (97.7%), speciﬁcity (100%), positive predictive value (100%), and negative predictive values (100%) for malignancy.
Despite these demonstrated improvements in yield, a concern remains that biopsy of smaller tumors can often more frequently return a “nondiagnostic” biopsy result. One series reported their differential yield with biopsy of smaller tumors: tissue was insufﬁcient to make a diagnosis in 37% of tumors <3 cm compared to only 9% of tumors ³3 cm. However, a repeat renal mass biopsy can be performed, which carries with it an equal rate of success as the initial biopsy. An additional recent study that evaluated 345 renal tumors £4 cm (mean diameter 2.5 cm) undergoing percutaneous biopsy reported a diagnostic result in 278 cases (81%) and nondiagnostic result in 67 cases (19%). Solid appearance on imaging and tumor size were associated with a diagnostic result on multivariate analysis. If the ﬁrst biopsy was nondiagnostic, then when a repeat biopsy was performed, a diagnosis was subsequently reached in 83% of cases.
Despite the increasing evidence showing the high accuracy of renal mass biopsy in determining a tumor’s histologic subtype, little data exists on the ability of the biopsy to accurately predict a tumor’s grade. Since increasing tumor grade has been shown to be correlated with cancerspeciﬁc survival, pretreatment knowledge of this parameter might signiﬁcantly inﬂuence clinical decision making. In a series of patients on AS undergoing modern renal mass core biopsy, tumor grading was determined in only 63% of patients. Additionally, difﬁculties exist with the accuracy of assigning nuclear grade on a needle biopsy sample, as an underestimation of nuclear grade has been noted in more than half (55%) of patients, likely due to tumor grade heterogeneity.
Despite the renewed interest and consideration of pretreatment percutaneous renal mass biopsy in the management of the SRMs, its indication and role remains controversial. In a recent survey of practice patterns conducted in the United Kingdom, only 34% of urologists reported always using biopsy in the treatment algorithm of indeterminate SRMs, with the remaining respondents reporting either selectively (23%) or never using biopsy (43%) to inform their management decisions. It remains unclear what degree of clinical impact the information from a biopsy has on treatment decisions. Does it justify associated procedural risks and costs? Studies have suggested that biopsy results can signiﬁcantly impact clinical management in 41–60.5% of cases [64,65]. Although limited by selection bias, these ﬁndings have led some to change their practice and recommend an image-guided biopsy of SRMs always be performed before treatment to conﬁrm malignancy, to classify histologic subtype, and to establish tumor grade. While the beneﬁt and use of biopsy has increased and gained traction, it is likely that few urologists would currently recommend a routine biopsy in a young or otherwise healthy patient for whom standard surgical treatment is planned. Biopsy continues to be utilized on a selective basis in patients with absolute or relative indications for surgical resection or having speciﬁc unusual circumstances such as synchronous bilateral lesions.
Potential complications of biopsy are tumor seeding along the needle tract, bleeding, arteriovenous ﬁstula, infection, pneumothorax, and ultimately death. In a large review of more than 16,000 abdominal ﬁne needle biopsies, mortality following renal biopsy was an extremely rare and unlikely event, with an overall mortality rate of 0.031%. Overall, few major complications have been reported in recent series, and the risk of minor complications (<5%) or tumor seeding (<0.01%) with contemporary coaxial biopsy techniques is also low. Clinically signiﬁcant bleeding is uncommon and usually self-limiting, with hemorrhage requiring blood transfusions rarely occurring. In the published literature, only eight cases of tumor seeding have been reported. Analysis of these cases revealed that needle size did not appear to correlate with the risk of seeding, but the risk may increase with the number of needle passes and with use of noncutting needles.
The utility of performing renal biopsy for cystic lesions has repeatedly been questioned. While most cysts can be classiﬁed as benign on imaging, more complex cystic lesions can be malignant over half of the time. Demonstrating the accuracy of biopsy complex cystic lesions, Richter et al. used a combination of FNA and core biopsy on 227 Bosniak II/III lesions to successfully histologically characterize 89%. Of 30 benign cysts diagnosed by FNA, the diagnosis was conﬁrmed by pathological evaluation or by negative imaging at up to 8 years in 97%. However, FNA is not recommended in patients with acquired polycystic disease on dialysis or adult polycystic disease because of the risk of misdiagnosing the papillary hyperplasia that frequently occurs in these cysts with RCC.
Following the sequencing of the human genome and with the evolution of rapid DNA sequencing techniques, medicine continues to move in a “molecular” direction with the goal of providing more individualized diagnostic and therapeutic interventions. The identiﬁcation of molecular biomarkers that could be used to accurately predict aggressive RCC phenotypic features from tissue obtained on percutaneous biopsy specimens would be an ideal means of individualizing treatment strategy to tumor biology. Molecular analysis of biopsy tissue might allow greater clinical beneﬁt beyond that gained from making a histologic diagnosis. Molecular markers of cellular proliferation and apoptosis currently under investigation include Ki-67 (a nuclear antigen that is a marker of active cellular proliferation) [80, 81], p53 (marker of apoptosis) [82, 83], HER-2 (epidermal growth factor), vascular endothelial growth factor (VEGF), bcl-2 (apoptotic inhibitor), cyclin-D1 (cell cycle regulatory molecule), vimentin (epithelial cell adhesion molecule), C-reactive inﬂammatory protein, and carbonic anhydrase IX (cell surface transmembrane enzyme upregulated by hypoxia inducible factor in low oxygen environments), among others. Unfortunately only preliminary data currently exist, and we are not yet able to use this information to determine which patients with SRMs require immediate intervention and which can be safely observed.
Several studies have investigated biomarker activity in lesions initially managed with a period of radiographic surveillance. Fujimoto et al. analyzed argyrophilic nucleolar organizer regions (AgNORs), and proliferating cell nuclear antigen (PCNA) activity in localized tumors ﬁnding tumor doubling time was signiﬁcantly inversely correlated with AgNOR expression and PCNA activity. Using the marker Ki-67 and the transferase-mediated dUTP-biotin nick (TUNEL) assay, Kato et al. measured cell proliferation and apoptosis in 18 patients with localized SRMs. A positive TUNEL ratio was associated with tumor growth rate but not with degree of Ki-67 immunostaining. In an early series investigating growth kinetics of SRMs under observation, Oda et al. observed that the growth rate of incidentally found RCCs varied and that the initial clinical and pathological features did not predict subsequent tumor growth. The authors also examined cell proliferation, apoptosis, and angiogenesis in 16 incidentally found cases of RCC, using the Ki-67 labeling index (KI), apoptotic index (AI), and TUNEL technique. They found that while KI and AI were not associated with each other or tumor growth rates, the KI/AI ratio was strongly correlated with tumor growth rate (r = 0.71; P = 0.01). Unfortunately, the role of biomarkers in the selection and management of patients under AS remains clinically limited. There is an ongoing need to identify both molecular markers that are speciﬁc for malignant or metastatic potential and alternative prognostic tools to help stratify risk in patients presenting with incidentally diagnosed SRMs.
Currently, contrast-enhanced axial imaging (CT or MRI) techniques provide the best evaluation of a renal mass. These modalities are adept at distinguishing most renal cystic lesions from solid masses, evaluating enhancement characteristics, assessing bilateral renal ﬂow and function, and obtaining clinical (radiographic) staging data. These studies provide anatomic detail to optimize treatment and surgical planning. Despite these advantages, existing imaging methods remain limited in the ability to accurately distinguish between benign and malignant solid tumors and cannot characterize the histologic subtype or biology of a tumor or predict its potential future behavior. Nuclear medicine modalities such as positron emission tomography (PET) have the potential to characterize biologic processes at the cellular and subcellular level noninvasively, in addition to providing the macroscopic anatomic detail when correlated with CT or MRI. The use of 2-deoxy-2-[18F]ﬂuoro-D-glucose (18F-FDG) to functionally image malignancies is based on the anticipated altered glycolytic pathway in malignant cells. When used in combination with standard CT, 18F-FDG PET (PET-CT) provides both functional and anatomic tumor data, thereby improving the diagnostic accuracy and tumor localization for a number of solid malignancies versus either modality alone. Unfortunately the initial enthusiasm for the utilization of 18FFDG PET to diagnose, stage, or restage RCC was tempered by the signiﬁcant limitations to its clinical application. A review of available PET/ CT series (small series ranging from 4 to 66 patients) demonstrated poor diagnostic sensitivity (ranging from 32% to 100%) and limited ability to accurately stage patients (ranging from 47% to 75%). A majority of these studies were performed prior to combination scanning which may have inﬂuenced results; however, the reported false-negative results were as high as 68%, severely limiting the utility of 18F-FDG PET for the initial assessment of primary renal masses.
Molecules involved in cellular pathways such as cellular oxidative metabolism, DNA synthesis, and tumor hypoxia have been recognized as possible targets for alternative novel nuclear imaging techniques and are currently under development and in the early phases of assessment with RCC [95–97]. Other techniques, such as antibodybased molecular imaging or immuno-PET, may offer a more clinically relevant strategy to improve molecular/biologic imaging in RCC. With the objective of utilizing antibodies having highly selective afﬁnity to cancer-speciﬁc antigens as a means to identify radiographically recognizable molecular targets, immuno-PET offers an exciting strategy to image all types of cancers. With a recognized and speciﬁc molecular target with RCC, enthusiasm for this imaging technique has grown. One such molecular target is carbonic anhydrase IX (CA IX) with its associated antibody G250. Expressed on the cell surface of almost all RCC but not expressed on normal tissues, with the exception of gastric mucosa and larger bile ducts, CA IX is an ideal cancer-speciﬁc target for immuno-PET development. In a phase I study imaging 26 patients with renal masses prior to surgery, radiolabeled G250 immuno-PET (124I-G250-PET/CT) was able to discriminate between ccRCC and non-ccRCC with a high sensitivity (94%) and speciﬁcity (100%) and no serious drug-related adverse events. This led to considerable enthusiasm regarding the potential for the development of a true molecular imaging test for renal cell carcinoma that can yield histologic data in a noninvasive manner. A subsequent multi-institutional phase III study (“REDECT”) was performed and enrolled 202 patients, and results of 124I-G250-PET/CT imaging accurately discriminated ccRCC from non-ccRCC with a much higher sensitivity (86%) and speciﬁcity (87%) compared to conventional multiphase CT imaging. The positive predictive value for clear cell RCC for 124I-G250-PET/CT was 95%, and it was well tolerated with no associated serious adverse events. Preliminary results from the REDECT trial demonstrate that immuno-PET can be used to provide important preoperative diagnostic information that may help guide clinical decision making and direct a patient to optimal therapy.
Прогнозирующие модели и оценка злокачественного потенциала SRM
Recently, several methods of objectively measuring renal mass anatomy have been developed and described, and they are slowly being utilized in regular clinical practice [100–102]. There is increasing evidence to suggest that a relationship may exist between renal mass anatomy and underlying pathology. Using a large prospectively maintained institutional cohort, Kutikov et al. evaluated the relationship between anatomical variables stratiﬁed by R.E.N.A.L. nephrometry score and malignant or high-grade pathologic features at the time of surgical resection. The total nephrometry score and all individual anatomic descriptor components signiﬁcantly differed between tumor histology groups with the exception of the anterior/posterior (A) designation. Papillary and chromophobe tumors had the lowest scores in each attribute indicating that they tended to be small, exophytic tumors with a polar distribution, resulting in low total nephrometry scores that are similar to that of benign lesions. Comparatively, clear cell carcinomas and less common but more aggressive histologic subtypes (collecting duct, sarcomatoid) tended to be large, endophytic, interpolar lesions, thereby having higher total nephrometry scores. Predictive nomograms integrating anatomic tumor attributes with patient’s age and gender were constructed for preoperative prediction of tumor malignant histology (AUC 0.76) and highgrade features (AUC 0.73). This model, which has been validated, represents the most accurate predictive model to date, with accuracy rates (particularly for tumor grade) that rival the results of contemporary percutaneous core biopsy series.