<title>1. INTRODUCTION</title> <p>During the last 20 years, 
the incidence 
of renal cell cancer (RCC) has been steadily increasing (2-3%/year) [##REF##11586189##1##]. This
rise is mostly due to the increase in detection of incidental small renal
masses (SRM ≤ 4 cm) by widespread use of cross-sectional imaging techniques such
as ultrasonography (USG), computed tomography (CT), and magnetic resonance
imaging (MRI). Between 1983 and 2002, the detection of SRM showed almost a three-fold increase for
tumors &lt;2 cm and 2–4 cm,
respectively, whereas the detection rate of 4–7 cm and &gt;7 cm
just rose by 50% and 26%, respectively [##REF##16985252##2##]. Nowadays, more than 50% of all
renal tumors are SRM [##REF##17437434##3##]. The majority of these tumors are asymptomatic and carry a good prognosis
[##REF##10235157##4##]. For open and laparoscopic nephron-sparing surgery (NSS), 5-year
cancer-specific survival rates of 96–100% have been
reported [##REF##10569540##5##, ##REF##17162003##6##].</p> <p>The highest incidence of incidentally
detected SRM is seen in elderly patients [##REF##10235157##4##], who usually present with a number
of comorbidities [##UREF##0##7##–##REF##17669584##9##]. To manage these patients, a variety of treatment
options have evolved in the past several years ranging from radical nephrectomy
to observation for SRM. NSS remains the standard of care for small RCC, but
minimal-invasive therapies and surveillance evolved as alternative treatment options.
Here, we review the literature on surveillance for the management of SRM.</p>
<title>7. CONCLUSIONS</title> <p>Active surveillance is a new management
option for the aged and infirm patient with short-life expectancy. The current
literature contains mostly small, retrospective studies with limited data.
Prior and during followup, renal tumor biopsies are mandatory. Thus, the
authors rather believe in active surveillance than in classical observation.
Imaging alone is inadequate for suggesting the aggressive potential of SRM for
both diagnosis and followup. Current data suggest that a CT or MRI every 3
months in the 1st year, every 6 months in the next 2 years and every year
thereafter, is appropriate for observation.</p> <p>Since not all SRM are harmless, selection
criteria for active surveillance need to be improved. In addition, there is
need for larger studies in order to better outline oncological outcome and followup
protocols.</p>
<p>Recommended by J. Rubio</p> <p>Surveillance is a new management option for small renal masses (SRMs) in aged and
infirm patients with
short-life expectancy. The current literature on surveillance of SRM contains mostly small, retrospective studies with limited data. Imaging alone is inadequate for suggesting the aggressive potential of SRM for both diagnosis and followup. Current data suggest that a computed tomography (CT) or magnetic resonance imaging (MRI) every 3 months in the 1st year, every 6 months in the next 2 years, and every year thereafter, is appropriate for observation. The authors rather believe in active surveillance with mandatory initial and followup renal tumor biopsies than classical observation. Since not all SRMs are harmless, selection criteria for active surveillance need to be improved. In addition, there is need for larger studies in order to better outline oncological outcome and followup protocols. </p>
<title>2. ARE SMALL RENAL MASSES ALWAYS MALIGNANT?</title> <p>Up to 20% of SRM are actually benign [##REF##18343437##10##–##REF##14634382##12##].
Unfortunately, tumor size alone does not appear to be a predictor of benign or
malignant tumor biology. Frank et al. retrospectively examined 2935 solid renal
tumors at all sizes treated over a 25-year period and reported 46.3%, 22.4%, 22%, and 19.9% of
renal lesions lower than 1 cm, 2 cm, 3 cm, and 4 cm to be benign, respectively [##REF##14634382##12##].
In the prospective randomized multicenter EORTC 30904 study, comparing nephron-sparing
surgery with nephrectomy in patients with resectable RCC, 11.6% of the 541
surgically removed tumors (≤5 cm) were benign [##REF##17140723##13##] and among the 100 lesions
(mean diameter 2.8 cm) on which Gill et al. [##REF##12796646##14##] performed laparoscopic partial
nephrectomy 30% were identified as benign. In a recent report by Remzi et al. [##REF##16890647##11##]
that reflects the renal tumors of today, renal tumors of ≤2 cm, 2-3 cm, 3-4 cm
were reported to be benign in 24.6%, 20.4%, and 16.0%, respectively, without
any correlation to tumor size (<italic>P</italic> = .66). In another series of 1208 SRM,
the frequency of benign lesions in the tumor size ranges 0.1–1.0, 1.1–2.0, and
2.1–3.0 was 15%, 14%, and 14%, respectively. However, the incidence of benign
lesions decreased significantly in tumors measuring 3.1–4.0 cm (8%, <italic>P</italic> = .001)
[##REF##18343437##10##].</p> <p>Benign lesions (oncocytomas, low-fat angiomyolipomas)
are still difficult to differentiate from RCC's even with today's advanced
imaging modalities. In a recent study by Remzi et al. [##REF##17437434##3##], only 17% of all
benign lesions were correctly identified as benign on preoperative CT and 43%
of patients who were assessed incorrectly on preoperative CT's underwent
unnecessary radical surgery. There are only a few studies pointing out the
success of differentiating low-fat AML from RCC with nonroutine special imaging
studies [##REF##14990834##15##].</p> <p>In addition to initial tumor size, growth
rate of tumors on surveillance is also not a reliable predictor of histology.
In their review, Chawla et al. compared initial tumor size and the observed
growth rate between oncocytomas and RCC variants. Of the 76 tumors, 12% were
oncocytomas and the remaining 88% were RCC. At first presentation, mean tumor
sizes were 2.00 ± 0.99 (median 1.50, ranging from 1 to 3.9) and 2.21 ± 1.5 cm
(median 2.0, ranging from 0.20 to 12.0) in oncocytomas and RCC's, respectively,
(<italic>P</italic> = .59). The mean growth rate of oncocytomas and RCC variants did not
differ statistically (0.05 ± 0.67, median 0.16, ranging from 1.62 to 0.62, and
0.35 ± 0.41 cm yearly, median 0.35, ranging from 0.42 to 1.6, respectively, <italic>P</italic> = .15)
[##REF##16406965##8##]. Thus growth rate after opting for surveillance strategy is not an ideal
parameter to further initiate surgical treatment [##REF##14634382##12##–##REF##12796646##14##].</p> <title>3. ARE SMALL RENAL CELL CARCINOMAS HARMLESS?</title> <p>In their study, Remzi et al. [##REF##16890647##11##] retrospectively
analyzed 287 SRMs that were defined to be ≤4 cm by preoperative CT scans and
subsequently underwent surgery. About 80% of these lesions were malignant. Tumors
were stratified into three groups according to their largest diameter, defined
as ≤2 cm, 2.1 to 3.0 cm and 3.1 to 4.0 cm. They were also grouped into two
groups of ≤3 cm and 3.1 to 4 cm. There was a significant correlation between
tumor size and Fuhrman grade. Two (4.2%), four (5%), and twenty five (25.5%) cases
of RCC 2 cm or less, 2.1 to 3 cm, and 3.1 to 4 cm in diameter had Fuhrman grade
G3/4, respectively, (<italic>P</italic> = .0007). but there was no statistical difference
in Fuhrman grades G3/4 between those ≤2 and 2.1 to 3 cm (<italic>P</italic> = .847),
whereas the difference between ≤3 cm and 3.1 to 4 was statistically significant
(<italic>P</italic> = .0023). Advanced stage (pT3a or greater) was documented in two
(4.2%), 12 (14.9%) and 35 (35.7%) cases for RCC diameter ≤2 cm, 2.1 to 3.0 cm
and 3.1 to 4 cm, respectively, (<italic>P</italic> = .0023). At least pT3a stage showed no
statistical difference between ≤2 cm and 2.1 to 3 cm group (<italic>P</italic> = .172)
whereas the difference between ≤3 cm and 3.1 to 4 cm groups was statistically
significant (<italic>P</italic> = .0007). Among the 287 patients, 14 present with distant
metastases, 10 of which being among the 119 tumors within the 3.1 to 4 cm group
(8.4%) and the remaining four among the 168 tumors of ≤3 cm group (2.4%) (<italic>P</italic> = .0045).
This study showed a high-aggressive
potential of SRM beyond 3 cm, and thus not all SRM are actually harmless [##REF##16890647##11##].</p> <p>Klatte et al. [##REF##18343437##10##] investigated 1208
patients with SRM, of whom 88% had RCC. Mean tumor size (±SD) was 2.9 (±0.9) cm. In their study, cancer-specific survival of small nonmetastatic (NX/N0M0)
RCC was 96% and 91% after 5 and 10 years, respectively. There was a 7% chance
of RCC recurrence post nephrectomy at 5 years. Independent prognostic factors
of cancer-specific survival were ECOG performance status, T stage, presence of
metastatic disease, and Fuhrman nuclear grade. This study pointed out that
there is a small but not insignificant number of patients who recur after
curative surgery for SRM.</p> <p>Measuring tumor diameters by sequential
imaging modalities are also not reliable, so when choosing surveillance as an
option the cut-off diameter should be set well. As stated above, SRM with a
tumor diameter below 3 cm on CT seems to fit better for surveillance than larger tumors. In
addition to size, patients with concomitant invasion of the perirenal fat
(clinical T3a) on cross-sectional imaging should be excluded from a
surveillance protocol, since T3a tumors are at a higher risk of RCC-specific
death [##REF##18343437##10##].</p> <p>In their study, Minardi et al. warn
against the possibility of recurrence and death in patients even with low-grade RCC's. They
report on 48 patients with pT1a clear cell RCC who underwent NSS. After a
median followup of 2 years, 3.9% had died of metastatic RCC. Thus even small
lesions can metastasize [##REF##16145371##16##].</p> <title>4. NEW TREATMENT OPTIONS</title> <p>Nowadays, NSS is the standard treatment
for SRM, which is related to the minimal impairment of renal function and
excellent cancer-specific survival rates either in open and laparoscopic NSS of
about 96–100% after 5 years [##REF##10569540##5##, ##REF##17162003##6##].</p> <p>Recently minimal invasive therapy
modalities such as radiofrequency ablation (RFA), High-intensity focused
ultrasound (HIFU) and cryotherapy emerged as potential treatment options for
clinically localized RCC for SRM with promising short-term results [##REF##12892573##17##].
Effective renal cryoablation has been achieved by open and laparoscopic
approaches as well as by percutaneous image-guided techniques. Percutaneous RFA has been
successfully performed under ultrasound, CT, or MRI guidance [##REF##18280512##18##]. Many studies
report excellent cancer-specific survival rates of 90–100% [##REF##18280512##18##, ##REF##16725292##19##], however
most of the series do not describe the underlying tumor entity (e.g.,
benign/malignant), have small number of patients treated and a short followup.
Additionally Klingler et al. recently reported that skipping (up to 24%) was a
major problem in RFA [##REF##17437433##20##]. It is well known from series of open NSS that the
time to recurrence is in mean over 5 years, thus a followup of one or two
years, which is reported in most series is insufficient to show oncological
safety [##REF##10569540##5##, ##REF##17441921##21##]. In a recent meta-analysis on RFA, cryoablation, and
surveillance, the risk of recurrence was 7.45 and 18.23 higher for cryoablation
and RFA, compared to NSS. Additionally this meta-analysis showed that NSS,
ablation, and surveillance are viable strategies for SRMs based on short-term
and intermediate term oncological outcomes [##REF##18280512##18##]. However, a significant
selection bias currently exists in the clinical application of these techniques
with regard to patient age and tumor size. Although long-term data have
demonstrated excellent outcomes for NSS, extended oncological efficacy remains
to be established for ablation and surveillance strategies. While current data
demonstrate a significantly higher incidence of local tumor progression
following cryoablation and RFA, no significant differences in progression to
metastatic RCC were seen regardless of treatment modality [##REF##18280512##18##]. These data
suggest an overtreatment bias for SRMs, thus nowadays a new treatment strategy is “surveillance:
treatment by initial observation with serial imaging with delayed treatment for
progression” gains popularity as a management option for SRMs.</p> <title>5. ACTIVE SURVEILLANCE IN WHOM,
HOW AND WHEN?</title> <title>5.1. Natural history</title> <p>The natural history of SRM is not well
known due to their early removal after diagnosis in most of the cases. There
are only few insights on the natural history of SRMs.</p> <p>In one of the important studies regarding
surveillance Bosniak and colleagues retrospectively examined the followup
images of 40 incidentally detected renal masses (&lt;3.5 cm). After an average
of 3.8 years, 26 tumors were removed. Of these 26 removed masses, 22 (84.6%)
were histologically confirmed as RCC. The overall mean linear growth rate for
all tumors was 0.36 cm per year. None of the patients developed metastasis [##REF##7480724##22##].</p> <p>In one study, 13 patients with SRM who
were either too old (median patient age was 69 years) or no candidates for
surgery were followed with abdominal imaging for a median of 42 months. The
growth rate was highly variable. Most SRM grew at a low rate or not at all [##REF##10992354##23##].
In a subsequent study, 32 renal masses &lt;4 cm (25 solid masses, 7 complex
cysts) which were found in 29 patients were managed by surveillance. During a
median followup of 27.9 months (range: 5.3–143.0 months)
serial abdominal imaging was performed at least three times on each mass. The
average growth rate was low and it did not show any statistical difference from
zero growth (<italic>P</italic> = .09; 95% confidence interval, −0.005–0.2 cm per year)
and was not associated with either initial size (<italic>P</italic> = .28) or mass type (<italic>P</italic> = .41).
Seven masses (22%) reached 4 cm in greatest dimension after 12–85 months of followup.
Eight masses (25%) doubled their volumes within 12 months. Overall, 11 masses
(34%) fulfilled one of these two criteria of rapid growth. Nine tumors were
removed surgically after an average of 3.1 years of followup either due to
surgeon's concern or patient's anxiety. No progression to metastatic disease
was observed [##REF##14770429##24##].</p> <p>There are a certain number of other
retrospective studies investigating the natural history of SRM. Commonly these
authors render surveillance as a possible safe option for patients with short-life
expectancies or patients who are unfit for surgery. Unfortunately these studies
accrued a limited number of patients and had short followup 
durations [##REF##11683965##25##–##REF##14665856##29##]. In
their review, Rendon and Jewett [##REF##16414497##30##] conclude active surveillance as a viable and
safe option for the patient with a short-life expectancy or within
well-controlled clinical trials. They also point out the necessity of close
interval followups using imaging techniques every 3 months for the 1st year,
every 6 months for the next 2 years and once every year thereafter.</p> <p>In a meta-analysis by Chawla et al. [##REF##16406965##8##], 234
SRM under surveillance were included. Mean lesion size at presentation was 2.60 cm (median 2.48, ranging from 1.73 to 4.08). Lesions were observed for a mean followup
of 34 months (median 32, ranging from 26 to 39 in all series combined). The
mean growth rate was 0.28 cm per year (median 0.28, ranging from 0.09 to 0.86)
and only 1% of the patients developed metastatic disease. In 46% of the cases
(131 out of 286), a
pathological confirmation was available, which showed RCC in 92% (120 of 131).
Among RCC, a mean growth rate of 0.40 cm yearly (median 0.35, ranging from 0.42
to 1.6) was observed. Lesion size at presentation did not correlate with growth
rate (<italic>P</italic> = .46). Serial radiographic data alone were insufficient to
predict the true natural history of SRM and patients concomitant diseases
should also be taken into consideration when deciding for active surveillance.</p> <p>Kouba et al. [##REF##17222611##31##] reported short-term
outcomes of patients under surveillance. A total of 43 patients with 46 renal
masses underwent planned expectant management of enhancing solid or cystic
(Bosniak IV) renal masses. 74% of patients had tumor growth with a mean
(median) growth rate of 0.70 (0.35) cm per year during a mean followup of 36
months. There were no significant symptoms, disease progression or cancer-specific
death. Four patients (10%) died of other causes. 13 out of 43 patients
underwent surgical intervention after a mean delay of 12 months. Initial tumor size showed
no significant difference in the intervention and nonintervention group (3.1 cm
2.6 cm, resp., <italic>P</italic> = .4504) and there was also no correlation between growth rate
and tumor size. Delayed intervention did not appear to adversely impact
pathological outcomes. The authors consider surveillance for SRM as a
reasonable option for appropriately selected patients, especially the elderly
and those with competing co-morbidities.</p> <p>These data suggest that active
surveillance is an option in elderly patients with severe comorbidities or
patients, who are not willing to undergo surgery. Excellent patient compliance
and close followup with contrast enhanced CT or MRI is mandatory.</p> <title>5.2. Limitations</title> <p>Imaging alone is inadequate on defining
management in patients with SRMs. Punnen et al. observed inter- and
intraobserver variability in measuring tumor diameter (±0.3 cm in diameter).
Tumor volume is exponentially related to tumor diameter, and thus inaccuracy of
measuring tumor diameters is related to a greater error (inter- and
intraobserver variability for tumor volume 2.515 mm<sup>3</sup> 
and 2.075 mm<sup>3</sup>,
resp.) [##REF##17085106##32##].</p> <title>5.3. Role of renal tumor biopsy</title> <p>There have been serious suspicions in the
past about needle-core biopsies of renal masses regarding complications, tumor
seeding, and wrong sampling. Due to advances in application techniques and help
of imaging guidance, the results of needle biopsies have improved
significantly. Fine-needle aspiration (18-gauge or thinner) and core biopsies
of renal masses are now much safer than before and they can even be applied in
an outpatient setting with low morbidity rates [##REF##10210375##33##–##REF##16709793##36##].</p> <p>Today the success rate of obtaining
tissue and their pathologic interpretation are excellent [##REF##18061339##37##]. Neuzillet et al.
[##REF##15076280##34##] were able to obtain adequate material for histological examination from
96.6% out of 88
patients that underwent Helical-CT-guided percutaneous fine-needle biopsy. 62 patients whose
biopsy examinations indicated RCCs were treated surgically (radical or partial
nephrectomy). The postoperative evaluation revealed a 92%-sensitivity rate of
biopsy in predicting malignancy and tumor subtype. The results also showed no
false-positive cases, no track seeding, and no complications.</p> <p>Schmidbauer et al. [##REF##18061339##37##] published a
prospective study on 78 patients with SRMs who underwent 18-gauge core biopsy
under computed tomography (CT)-fluoroscopic guidance. In addition, using the
same sheath, fine-needle aspiration was taken in 44 patients and analyzed
cytologically. The renal masses were subsequently removed surgically and
evaluated histologically. The results showed a sensitivity of 93.5% and 90.6%,
for core biopsy and fine-needle aspiration for the detection of renal cell
carcinoma (RCC), respectively; Fuhrman grade was correctly predicted in 76% and
28% and the correct histologic subtype identified 91% and 86%, respectively.
Cytology from fine-needle aspiration revealed a sensitivity of 100% and 75% in
detecting malignant and benign lesions, respectively. Two of the SRMs'
diagnosed as oncocytomas on core biopsy were revealed to be hybrid tumors with
scattered areas of oncocytomas and chromophobe RCC on histological evaluation.</p> <p>These data suggest that before opting for
surveillance a sufficient renal tumor mass biopsy should be performed to
further guide followup.</p> <title>6. WHO AND HOW?</title> <p>According to many authors, active
surveillance is a feasible option especially for elderly and unfit patients.
Because active surveillance is a new concept, large studies with appropriate followup
are still missing. Which patients should undergo active surveillance? What
should be our followup intervals? What is the cut-off tumor diameter? What should
be the limit for annual growth? In order to precisely answer these questions,
larger numbers of studies are required. In some centers, renal masses below the
limit of 3-4 cm in diameter are considered to be at low risk of metastasis [##REF##11435822##38##, ##REF##10210376##39##].</p> <p>The authors believe that low-grade tumors
measuring &lt;3 cm could enter an active surveillance protocol. Prior and during followup, renal
tumor biopsies are mandatory. Biopsies should be assessed by the same
pathologist to exclude interobserver
variations, especially in grading. High-grade tumors, sarcomatoid features,
collecting duct, and unclassified RCC have to be excluded because of their
known unfavorable outcomes. Additionally, young and/or healthy patients are no
good candidates for active surveillance because of lacking long-term data
(see ##TAB##0##Table 1##).</p> <p>For followup, Rendon et al. suggested CT
or MRI every 3 months in the 1st year, every 6 months for the next 2 years and
every year thereafter [##REF##16414497##30##], however, there are no oncological outcome data that
support this approach. Again, repeated biopsies of the mass have to be
performed in certain intervals. Tumors that exceed 3 or 4 cm or which double in
volume in &lt;12 months need further intervention [##UREF##0##7##, ##REF##18343437##10##, ##REF##16890647##11##], for example,
surgery or ablation.</p> <p>These short-interval followups may have a
negative impact on patient compliance. Another downside of active surveillance
is the patient's anxiety. The knowledge of living with a tumor and “not doing
anything about it” is also a psychological burden on the patient.</p>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Possible inclusion and exclusion criteria
for active surveillance of SRM.</p></caption><table frame="hsides" rules="groups"><tbody><tr><td align="left" rowspan="1" colspan="1">
<italic>Inclusion:</italic>
</td></tr><tr><td align="center" colspan="1" rowspan="1">
<hr/>
</td></tr><tr><td align="left" rowspan="1" colspan="1">(1) Benign lesion on renal tumor biopsy</td></tr><tr><td align="left" rowspan="1" colspan="1">(2) Aged and infirm patient</td></tr><tr><td align="left" rowspan="1" colspan="1">(3) Tumor size &lt;3 cm on
cross-sectional imaging</td></tr><tr><td align="left" rowspan="1" colspan="1">(4) Chromophobe RCC, low-grade, on renal
tumor biopsy</td></tr><tr><td align="left" rowspan="1" colspan="1">(5) Chromophobe-oncocytic hybrid tumor on
renal tumor biopsy</td></tr><tr><td align="left" rowspan="1" colspan="1">(6) Willingness of the patient to undergo
regular CT or MRI scans and repeated biopsies (good compliance)</td></tr><tr><td align="center" colspan="1" rowspan="1">
<hr/>
</td></tr><tr><td align="left" rowspan="1" colspan="1">
<italic>Exclusion:</italic>
</td></tr><tr><td align="center" colspan="1" rowspan="1">
<hr/>
</td></tr><tr><td align="left" rowspan="1" colspan="1">(1) Young and healthy patient</td></tr><tr><td align="left" rowspan="1" colspan="1">(2) Sarcomatoid features </td></tr><tr><td align="left" rowspan="1" colspan="1">(3) Collecting duct or unclassified RCC</td></tr><tr><td align="left" rowspan="1" colspan="1">(4) Evidence of 
≥T3a disease on
cross-sectional imaging</td></tr><tr><td align="left" rowspan="1" colspan="1">(5) High grade</td></tr><tr><td align="left" rowspan="1" colspan="1">(6) Symptomatic lesions</td></tr><tr><td align="center" colspan="1" rowspan="1">
<hr/>
</td></tr><tr><td align="left" rowspan="1" colspan="1">
<italic>Unclear:</italic>
</td></tr><tr><td align="center" colspan="1" rowspan="1">
<hr/>
</td></tr><tr><td align="left" rowspan="1" colspan="1"> (1) Low grade clear-cell RCC </td></tr><tr><td align="left" rowspan="1" colspan="1">(2) Low-grade papillary RCC </td></tr><tr><td align="left" rowspan="1" colspan="1">(3) Multifocal RCC </td></tr><tr><td align="left" rowspan="1" colspan="1"> (4) Hereditary RCC</td></tr></tbody></table></table-wrap>
[{"label": ["7"], "surname": ["Volpe", "Jewett"], "given-names": ["A", "MAS"], "article-title": ["The natural history of small renal masses"], "italic": ["Nature Clinical Practice Urology"], "year": ["2005"], "volume": ["2"], "issue": ["8"], "fpage": ["384"], "lpage": ["390"]}]
Adv Urol. 2008 Aug 12; 2008:196701