Renal cancer. Contemporary management. Editor John A. Libertino. Springer New York 2013.
2. Natural history of untreated renal masses
Predominantly from the experience of centers applying delayed intervention in select patients with SRMs both on and off formal AS protocols, much has been learned about their natural history. Knowledge of the expected course and behavior of SRMs under observation yields insight into identifying which lesions might be safely observed and which might beneﬁt from routine immediate and deﬁnitive intervention. This ideal classiﬁcation would importantly result in avoidance of overtreatment of lesions with little to no malignant potential. Overall, the data regarding the natural history of untreated SRMs are limited, since historically reﬂexive surgical excision and treatment of SRMs has been routinely performed soon after diagnosis. The majority of existing evidence is comprised of small, retrospective series of selected SRMs monitored with serial abdominal imaging at variable intervals prior to extirpation [19–22] and single institution series investigating outcomes in select patients intentionally managed over the longterm with AS alone [23–36].
Доброкачественные против злокачественных SRM
Recently, the contemporary published literature examining the rates of benign versus malignant lesions in patients with SRMs undergoing immediate treatment was reviewed. The available data included 26 studies published in the past decade and incorporated 27,272 patients from 8 countries. The frequency of benign ﬁndings in SRMs ranged from 7% to 33%, with most studies reporting within a few percentage points of the mean of 14.5% (±5.2%). Histologically, clear cell RCC was identiﬁed in the majority of cases, with a mean of 68.3% (±11.9%). Few studies speciﬁcally examined the diagnostic accuracy of cross-sectional imaging to distinguish between benign and malignant tumors, but the accuracy of currently available methods was reported as low in identiﬁed studies. The association between tumor size and pathological classiﬁcation (benign vs. malignant) was also evaluated in this review. The authors found an inverse relationship between tumor size and benign pathology in 74% (14/19) studies that examined such a relationship and found a statistically signiﬁcant increase in the incidence of clear cell RCC with tumor size in 13 (63%) of the 19 studies. In a recent separate review assessing outcome of SRMs under surveillance, similar results were seen despite the recognized selection bias associated with expectantly managed and untreated masses. Pathologic data were available for 248 patients across 17 studies [19–21, 23–26, 28–36], which conﬁrmed predominantly malignant disease (86.7%) with the majority being low grade (81%). These data highlight that benign renal tumors are common among incidentally detected renal masses (~15% of resected renal tumors) and are more prevalent among small clinical T1a lesions.
Характеристики роста нелеченных SRMs
There are several studies using pooled analytic methods to consolidate institutional data and characterize growth trends in SRMs. A recent pooled analysis of nine single institution retrospective series identiﬁed 234 masses followed for a mean duration of 34 months. Initial tumor diameter was 2.6 cm (range 1.73–4.08), mean growth rate was 0.28 cm/year, and pathologic conﬁrmation was available in 46% (92% were RCC or RCC variant) (Таблица 8.1). A second, more recent, comprehensive systematic literature review identiﬁed 18 studies including 880 patients with 936 SRMs managed by AS that demonstrated consistent ﬁndings (Таблица 8.2).
Таблица 8.1. Мета-анализ истории заболевания наблюдаемых масс-образований
Таблица 8.2. Объединенный анализ небольших новообразований почек, находящихся под активным наблюдением
Summarizing available individual level data from 275 patients (299 SRMs), Smaldone et al. performed a pooled analysis of the six studies that met criteria for inclusion. This analysis revealed a mean age of 66.9 ± 12.3 years (median 69; range 35–88) in 239 patients. The mean maximal tumor diameter and estimated tumor volume at the time of diagnosis were 2.4 ± 1.4 cm (median 2; range 0.2–12) and 17.8 ± 63.9 cm3 (median 4.3; range 0.004–903.7), respectively. At the conclusion of observation, the mean maximal tumor diameter and estimated tumor volume were 3.2 ± 1.7 cm (median 2.8; range 0.9–15) and 34.3 ± 115.9 cm3 (median 11.5; range 0.27–1765.1), respectively. Over the duration of observation (mean of 33.5 ± 22.6 months), this represents a change in diameter of 1.2 cm (0.33 cm/year) and volume of 16.5 cm3 (7.3 cm3/ year). The development of metastatic disease was low in this cohort as only 18 of the 297 patients (2.1%) developed metastatic disease over a mean period of observation of 40.2 months. This provides evidence that the majority of SRMs managed expectantly grow slowly with a very low rate of disease progression over an intermediate time period following diagnosis.
Рентгенографические характеристики SRM
While SRMs are identiﬁed typically as incidental ﬁndings on body axial imaging, additional detail regarding their nature or estimated behavior is limited. Few radiographic characteristics inform on the risk of SRMs, and generally this information is inadequate to affect the way such lesions are managed. Despite considerable effort towards this goal, we continue to utilize tumor growth, a relatively crude method to predict disease progression, as the most reproducible imaging characteristic on cross-sectional imaging. In recent large series, increase in maximal linear tumor has been shown to correlate with increasing risk of malignant pathology [37, 39, 40], high-grade disease [37, 40, 41], clear cell histology [39, 42], and presence of synchronous metastases [43–45]. In retrospective studies from the Mayo Clinic and Memorial Sloan Kettering Cancer Center encompassing 5,445 patients with surgically treated clinically localized renal masses, increasing tumor diameter has been demonstrated to be associated with increasing rates of malignant pathology as well as high-grade nuclear features [39, 40]. A smaller series comparing 168 renal tumors £3 cm with 119 renal tumors >3–4 cm, smaller lesions were found to display decreased rates of progression to pT3a disease (19.1 vs. 35.7%, p < 0.05), high-grade disease (9.2 vs. 25.5%, p < 0.05), and synchronous metastasis (2.4 vs. 8.4%, p = 0.05). This correlation has been conﬁrmed using population data investigating the relationship between the primary tumor size at presentation and histopathological features. From the Surveillance, Epidemiology, and End Results (SEER) dataset, for each 1 cm increase in size, the probability of ﬁnding a highgrade tumor in 19,932 patients with localized disease increased by 13% (OR 1.13, p < 0.001). While almost 85% of localized RCCs <4 cm were low grade, the authors found that 70% of contained lesions >7 cm were also low-grade lesions; therefore, it is important to note that renal tumors can grow quite large without acquiring the ability to metastasize.
With the knowledge that growth rate can provide insight into malignant potential, the ability to identify features on the initial axial imaging study that predicted future rapid growth would be clinically useful. Unfortunately, despite the ability to measure growth rates accurately, cheaply, and quickly, no discernible CT imaging features have proven sensitive enough to predict a tumor’s future growth rate. Dodelzon et al. recently examined the relationship between growth rate and MR imaging characteristics in patients on active surveillance. Homogeneity on T2-weighted imaging predicted slower growth rate (deﬁned as doubling time greater than 2 years) on multivariate analysis, suggesting initial MR features may have a role in predicting malignant potential for renal lesions being considered for active surveillance.
Despite the data that suggest only a small proportion of renal masses have the ability to display aggressive biology and metastasize early, distinguishing these lesions from more indolent tumors remains a clinical challenge. A single institution tumor registry of 110 patients with biopsy proven synchronous metastatic disease at presentation was compared to 250 controls with clinically localized RCC in a recent study. Larger tumors were more often associated with synchronous metastatic disease compared to smaller lesions (median 8.0 vs. 4.5 cm, p < 0.001) with the odds of synchronous metastasis increased by 22% for each 1 cm increase in tumor size (p < 0.001). Metastatic disease was uncommon (<5%) in patients with tumors less than 3 cm, and no patients with tumors 2 cm or smaller presented with metastatic disease. In a larger series by Nguyen et al. evaluating SEER data, the risk of synchronous metastatic disease was clearly related to initial tumor size and occurred infrequently with small tumors. Despite the data presented, no clear cutoff exists above which one would imminently fear a high risk of synchronous metastases. Largely extrapolated from clinical data in patients with von Hippel-Lindau syndrome, the “3 cm rule” has become an acceptable benchmark as a threshold tumor size below which progression to metastases appears unlikely. This concept is supported from experience with nonfamilial RCC, where SEER data has shown the risk of synchronous metastasis in the setting of SRMs to be extremely low (<5%) in lesions ≤3 cm.