# Multifocal Renal Cell Carcinoma:  Clinicopathologic Features and Outcomes for Tumors≤4 cm

Authors: Paul L. Crispen; Christine M. Lohse; Michael L. Blute
Journal: Advances in Urology
 (2008)

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## Abstract

A significant increase in the incidental detection of small renal tumors has been observed with the routine use of cross-sectional abdominal imaging.  However, the proportion of small renal tumors associated with multifocal RCC has yet to be established. Here then, we report our experience with the treatment of multifocal RCC in which the primary tumor was ≤4 cm. In our series of 1113 RCC patients, 5.4% (60/1113) had multifocal disease at the time of nephrectomy. Discordant histology was present in 17% (10/60) of patients with multifocal RCC. Nephron sparing surgery was utilized more frequently in patients with solitary tumors. Overall, cancer-specific, and distant metastasis-free survival appeared to be similar between multifocal and solitary tumors.  These findings are consistent with previous series which evaluated multifocal RCC with tumors >4 cm. With the known incidence of multifocality RCC, careful inspection of the entire renal unit should be performed when performing nephron sparing surgery.


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## Body

## 1. Introduction

The routine use of cross-sectional abdominal imaging has led to a significant increase in the
diagnosis of renal cell carcinoma (RCC) [1, 2]. An estimated 51000 new
cases of cancer of the kidney and renal pelvis were diagnosed in 2007, with the
vast majority representing RCC [3]. While the preponderance of patients
with sporadic RCC will have solitary tumors, 4–20% of patients
will have multifocal RCC at the time of diagnosis [4–9]. This is in contrast to
patients with hereditary forms of RCC, such as von Hippel-Lindau,
Birt-Hogg-Dubé, and hereditary papillary renal carcinoma, who typically have
multifocal disease at the time of presentation [10–12]. Whether a patient with
multifocal RCC has sporadic or hereditary disease, treatment decisions are
based on balancing the preservation of renal function with oncologic efficacy.
This is especially true in the case of small (≤4 cm) renal tumors,
which are often amenable to nephron sparing surgery (NSS) [13, 14].Although several previous series have reported on the incidence of multifocality (Table1), there are
limited data on the incidence and outcomes of patients with small (≤4 cm) sporadic multifocal RCC. Here then, we review our experience with the
management and outcomes of patients with multifocal sporadic RCC in which the
primary tumor size was ≤4 cm.Table 1
Incidence of multifocal RCC in prior series. ccRCC = clear
cell renal cell carcinoma; pRCC = papillary renal cell carcinoma; NA = not available.
AuthorYearTotal PatientsMultifocal (%)Median Tumor≤4 cm (%)Size (cm)Richstone2004107157 (5.3)5.016%Dimarco20042373101 (4.3)4.5 ccRCCNA4.0 pRCCLang200425537
(14.5)NA12.9%Junker200237261 (16.4)NANAKarayiannis20025610 (17.8)7.530%Schlichter200028148 (17.1)NANABaltaci200010322 (21.4)7.524.1%Wunderlich199926036 (13.9)NANA


## 2. Materials and Methods

We studied 1113 patients treated with radical nephrectomy or NSS for sporadic,
pNX/pN0, pM0 RCC ≤4.0 cm between 1970 and 2004. Of these, 1053
(94.6%) patients had a solitary, unilateral RCC. The remaining 60 (5.4%)
patients had unilateral multifocal RCC. Patients with bilateral disease at time
of presentation were excluded from analysis.
Clinical and pathologic variables were compared between patients with
multifocal and solitary tumors. Clinical variables evaluated included patient
age, gender, symptoms at presentation, ECOG performance status, and type of
surgery. Pathologic features evaluated included 2002 primary tumor classification,
histologic subtype, nuclear grade, presence of histologic necrosis, and
sarcomatoid differentiation. Histologic subtype was assigned following the
recommendations of the 1997 Union Internationale Contre le Cancer and American
Joint Committee on Cancer workshop on the classification of RCC [15]. For the 60 patients with
multifocal RCC, pathologic characteristics of the largest tumor were
summarized, with the exception of histologic subtype. All pathologic specimens were reviewed by a single urologic
pathologist. Patient followup data are obtained and maintained through our
nephrectomy registry. Information on patients who do not follow up at our
institution is obtained by a registered nurse via outside medical records,
patient/physician correspondence, or death certificates. Fewer than 3% of the
patients in the Nephrectomy Registry have been lost to follow up.Clinical and pathologic features between the multifocal and solitary groups were
compared using Wilcoxon rank sum, chi-square, and Fisher’s exact tests.
Overall, cancer-specific and distant metastases-free survivals were estimated
using the Kaplan-Meier method and overall survival was compared between patient
groups using the log-rank test. All tests were two-sided andP-values
less than .05 were considered statistically significant. Statistical analysis
was performed using SAS software (SAS Institute, Cary, NC, USA).


## 3. Results

Multifocal RCC was present in 5.4% (60/1113) of patients with a primary tumor ≤ 4 cm.
Clinical and pathologic features between patients with solitary and
multifocal RCC tumors ≤ 4.0 cm are summarized in Table2. Multifocal
disease was suspected in only 27% (16/60) of patients based on preoperative
imaging. Median age at surgery for the solitary patients was 64 years (mean
62.3; range 22–87) compared with 67.5 years (mean 64.1; range
21–82) for the multifocal patients (P = .147).
Median tumor size for the solitary patients was 3.0 cm (mean 2.8; range 0.2–4.0) compared with 2.9 cm (mean 2.8; range 0.4–4.0) for the multifocal patients (P = .631).
A comparison of histologic subtype is shown in Table 3. Note that 10/60 (17%) of
the patients with multifocal RCC had multiple tumors of different histologic subtypes.Table 2
Clinical and pathologic features.
SolitaryN = 1053MultifocalN = 60FeatureN (%)P-valueAge at Surgery (years)<65554 (52.6)23 (38.3).031≥65499 (47.4)37 (61.7)SexFemale339
(32.2)11 (18.3).025Male714 (67.8)49 (81.7)Symptoms at presentationAbsent582 (55.3)39 (65.0).140Present471 (44.7)21 (35.0)Constitutional symptoms at presentationAbsent893 (84.8)49 (81.7).512Present160 (15.2)11 (18.3)ECOG Performance status (N = 903)0749 (88.4)50 (89.3).846≥198 (11.6)6 (10.7)Type of SurgeryOpen radical nephrectomy532 (50.5)41 (68.3).007Open nephron-sparing surgery460 (43.7)16 (26.7)Laparoscopic radical nephrectomy23 (2.2)3 (5.0)Laparoscopic nephron-sparing surgery38 (3.6)02002 Primary tumor classificationpT1a1020 (96.9)59 (98.3)1.00pT3a20 (1.9)1 (1.7)pT3b11 (1.0)0pT3c2 (0.2)0RCC Nuclear grade1147 (14.0)6 (10.0).6722673 (63.9)40 (66.7)3221 (21.0)14 (23.3)412 (1.1)0Coagulative tumor necrosisAbsent921 (87.5)54 (90.0).562Present132 (12.5)6 (10.0)Sarcomatoid DifferentiationAbsent1048 (99.5)60 (100.0)1.00Present5 (0.5)0Table 3
RCC histologic subtype.
Patient GroupN (%)Solitary RCC (N = 1053)Clear cell771 (73.2)Papillary226 (21.5)Chromophobe45 (4.3)Collecting duct2 (0.2)RCC, not otherwise specified9 (0.9)Multifocal RCC (N = 60)Clear cell26 (43.3)Papillary23 (38.3)Chromophobe1 (1.7)Clear cell + papillary8 (13.3)Clear cell + chromophobe1 (1.7)Papillary + chromophobe1 (1.7)Among the 1053 patients with solitary RCC, 414 died at a median of 7.7 years
following surgery (range 1 day to 37.0 years), including 29 who died from RCC
at a median of 5.5 years following surgery (range 0.5–21.5). Among the 639 patients who were still
alive at last followup, the median duration of followup was 6.8 years (range 2
days to 35.1 years). Forty-four patients experienced distant metastases at a
median of 4.0 years following surgery (range 0.2–21.5). Sixteen patients experienced a
contralateral recurrence at a median of 2.9 years following surgery (range 0.3–13.8).Among the 60 patients with multifocal RCC, 23 died at a median of 6.1 years following
surgery (range 0.7–14.1), including 4 who died from RCC at 1.0,
3.4, 5.7, and 9.5 years following surgery, respectively. Among the 37 patients
who were still alive at last followup, the median duration of followup was 7.6
years (range 0.7–29.3). Three patients experienced distant
metastases at 0.8, 0.9 and 6.8 years following surgery, respectively. Eight
patients experienced a contralateral recurrence at a median of 5.5 years
following surgery (range 0.6–8.1).Overall survival rates (SE, number still at risk) at 5 and 10 years following surgery
were 84.8% (1.2%, 691) and 68.4% (1.7%, 373), respectively, for patients with
solitary RCC compared with 84.0% (4.9%, 40) and 63.3% (7.5%, 17), respectively,
for patients with multifocal RCC (P = .531; Figure 1). Median overall survival
for the two groups was 15.2 and 12.3 years, respectively.Figure 1
Overall survival in patients with multifocal versus solitary RCC.Cancer-specific survival rates (SE, number still at risk) at 5 and 10 years following surgery
were 98.7% (0.4%, 691) and 96.7% (0.7%, 373), respectively, for patients with
solitary RCC compared with 96.2% (2.6%, 40) and 89.0% (5.7%, 17), respectively,
for patients with multifocal RCC (Figure2). Median cancer-specific survival
was not attained for either group during the observed duration of followup.  Because so few patients with multifocal RCC
died from RCC, no statistical comparison of outcome between the two patient
groups was performed.Figure 2
Cancer-specific survival in patients with multifocal versus solitary RCC.Distant metastases-free survival rates (SE, number still at risk) at 5 and 10 years
following surgery were 97.6% (0.5%, 687) and 95.1% (0.9%, 368), respectively,
for patients with solitary RCC compared with 96.5% (2.1%, 39) and 93.7% (3.7%,
17), respectively, for patients with multifocal RCC (Figure3). Median distant
metastases-free survival was not attained for either group during the observed
duration of followup.  Because so few patients with multifocal RCC experienced distant metastases, no statistical
comparison of outcome between the two patient groups was performed.Figure 3
Distant
metastasis-free survival in patients with multifocal versus solitary RCC.Contralateral recurrence-free survival rates (SE, number still at risk) at 5 and 10 years
following surgery were 99.1% (0.3%, 684) and 98.3% (0.5%, 366), respectively,
for patients with solitary RCC compared with 94.4% (3.2%, 38) and 79.2% (6.9%,
16), respectively, for patients with multifocal RCC (P < .001; Figure 4).
Median contralateral recurrence-free survival was not attained for either group
during the observed duration of followup.Figure 4
Contralateral recurrence-free survival in patients with multifocal versus solitary RCC.


## 4. Discussion

In the current series of tumors ≤ 4 cm, the rate of multifocal RCC was similar
to prior reports. In a review of series published between 1988 to 1999, multifocal
disease was noted in 15.2% (179/1,180) of patients, with 9–100% of the primary
tumors being ≤ 4 cm in individual reports [13]. Contemporary series have shown
a similar rate of multifocal RCC, ranging from 4.3% to 21.4% [4–9, 17, 18]. With the known incidence of
multifocal disease, the ability to identify multifocal renal tumors preoperatively
is extremely important and has been evaluated by several series. Kletscher et
al. noted that preoperative imaging suggested multifocality in only 44% (7/16) of
patients prior to nephrectomy [19]. While in the series by
Richstone etal. only 33% of multifocal tumors were identified on preoperative
imaging, resulting in the discovery of occult multifocal disease in 3.5% of all
patients overall at the time of nephrectomy [7]. Another series by Schlichter
etal. investigated the ability of ultrasound and computed tomography to identify
multifocality. Upon pathologic evaluation 17.1% (48/281) of radical nephrectomy
specimens contained multifocal RCC. However, preoperative imaging was only able
to identify 23% (11/48) of multifocal tumors. Collectively, these and the
current series demonstrate that preoperative imaging is not a sensitive means
of identifying multifocal disease preoperatively. Thus complete mobilization
and inspection on the entire kidney is warranted when performing NSS to
properly evaluate the presence of multifocal disease.Several associations have been suggested between clinicopathologic features and the
presence of multifocal RCC including primary tumor size, histologic subtype,
bilateral disease, nodal status, and tumor stage. However, only two series have
performed multivariate analysis when evaluating the associations between
multifocality and clinicopathologic features. Baltaci etal. evaluated 103
cases of RCC and noted the incidence of multifocal RCC to be 21.4% [18]. Univariate and multiple
logistic regression analysis demonstrated that primary tumor stage was the only
independent predictor of multifocality. In the series by Richstone etal. of
1071 radical nephrectomy specimens, 5.3% of patients were noted to have
multifocal RCC [7]. Multivariate analysis of this
population revealed significant associations between multifocality with
papillary subtype, lymph node metastasis, advanced tumor stage (pT4), and
bilateral disease. Interestingly, neither series noted a significant association with tumor size and multifocal
RCC. This is important to consider when treating small renal tumors, as size
alone has not been shown to predict the presence of multifocal disease.Discordant pathology between the primary and satellite tumors occurs in up to 6–30% of
multifocal tumors [4, 7, 19]. A similar rate of
discordant histology between the primary and satellite tumors was noted in the
current series at 17%. Although it is obvious that separate events are likely responsible
for multifocal RCC with discordant histology, the origin of multifocal RCC with
concordant histology is not as apparent. However, the evaluation of genetic markers has provided insight into the
origin of multifocal RCC. An initial report by Miyake etal. evaluated the loss
of heterozygosity (LOH) using 18 satellite markers in 10 patients with
multifocal clear cell RCC (ccRCC) [20]. Identical LOH patterns were
noted in 80% (8/10) cases, suggesting that multifocal ccRCC represent
intrarenal metastasis. In a second report examining the genetic clonality of multifocal
ccRCC by Junker etal. 89% (17/19) cases demonstrated identical LOH patterns [17]. In contrast to ccRCC, multifocal
papillary RCC appears to represent independent primary tumors. In a report by
Jones etal. LOH was examined in 21 patients with multifocal papillary RCC [21]. The majority, 95% (20/21),
of cases demonstrated distinct LOH patterns between tumors suggesting that
multifocal papillary tumors do not represent intrarenal metastasis, unlike
ccRCC.Survival outcomes following the treatment of multifocal RCC have been evaluated in several series
(Table4). Dimarco etal. reviewed 2373 patients treated for RCC over 30 years.
Multifocal disease was present in 4.3% (101/2373) of all patients. Of the
patients with multifocal disease 70% (71/101) had multifocal lesions of the
same histologic subtype; these patients were utilized to evaluate survival outcomes.
Ipsilateral recurrence rates were similar between multifocal and solitary RCC
following radical nephrectomy. Contralateral recurrence was more common in patients
with multifocal ccRCC with an increased risk ratio of 2.91; however, this
increase did not reach statistical significance (P = 1.42). However, in a
separate report by Bani-Hani etal. a significant association between the risk
of contralateral recurrence and multifocality was demonstrated [22]. The association between
contralateral recurrence and multifocality was again noticed in current series
which only includes RCC ≤4 cm. Cancer-specific survival was similar
between patients with multifocal RCC at 1, 5, and 10 years following nephrectomy
in patients with clear cell and papillary RCC [23]. Similar findings were noted
by Lang etal. in the review of 255 patients undergoing radical nephrectomy [5]. In this series
multifocality was present in 14.5% (37/255) of patients undergoing radical
nephrectomy for RCC. Multifocality was not associated with metastatic
progression, cancer-specific or overall survival in patients treated with
radical nephrectomy during median followup of 183 months compared to patients
treated for solitary tumors. Additionally, in the report by Richstone etal. no
significant difference was noted in 5 year disease-free (71.5% versus 73.2%)
and overall (75.2% versus 79.3%) survival when comparing patients with
multifocal and solitary RCC [7]. In another study by Méjean
etal. focusing on papillary RCC, the presence of multifocal disease was not a
significant predictor of overall survival compared to solitary tumors [16]. Collectively these results,
with the inclusion of the results from the current series, suggest that cancer
specific outcomes are equivalent between patients with multifocal and solitary
RCC when treated with radical nephrectomy.Table 4
Cancer-specific survival in patients with multifocal versus solitary RCC. ccRCC = clear cell
renal cell carcinoma; pRCC = papillary renal cell carcinoma; NS = not significant.
AuthorN multifocal5 year survivalN solitary5 year survivalP-valueDimarco etal. [4]40 (ccRCC)74.6%1934
(ccRCC)69.0%.4729 (pRCC)100%237(pRCC)86.6%.62Lang etal. [5]3774.0%21879.9%.26Richstone etal. [7]5171.5%*93873.2%*NSMéjean etal. [16]28
(pRCC)96%30 (pRCC)100%.53*Disease-free survival.NSS in the management of solitary RCC provides equivalent oncologic efficacy while
improving overall survival compared to radical nephrectomy [13, 24, 25].  Although there are limited data on the efficacy of NSS when treating sporadic multifocal
RCC, available data suggest that NSS has equivalent oncologic efficacy when
treating multifocal disease. An initial report from the Mayo Clinic by Blute et
al. reviewed 16 cases of multifocal tumors treated with NSS [23]. 6/16 (38%) of these
patients had a solitary kidney at the time of presentation. Local recurrence
was noted in 2/16 patients at 1.7 and 2.8 years following NSS. Recurrent
disease was treated with repeat NSS in one patient and systemic therapy in the
other. Cancer specific survival was 100% at 5 years, however 2/16 patients died
of RCC at 6 and 11 years postoperatively. Because of the small number of
patients treated, survival outcome comparisons were not made between patients
treated with NSS and radical nephrectomy.Additionally, when considering disease recurrence in patients undergoing NSS for multifocal
disease, it can be difficult discriminating recurrent and persistent disease.  Local treatment failures in patients
previously treated for multifocal RCC does not automatically indicate radical
nephrectomy of the renal remnant. Two recent series have reported the
feasibility and outcomes of salvage partial nephrectomy in patients with local
recurrence following a previous partial nephrectomy [26, 27]. Bratslavsky etal. reported
on 11 patients undergoing salvage partial nephrectomies for von Hippel-Lindau
disease [27]. Three renal remnants were
lost while attempting to preserve renal function, and 46% of cases were
associated with major postoperative complications. It should be noted that
salvage partial nephrectomy in this series was defined as at least the third
partial nephrectomy on the renal remnant. A second series by Magera etal.
reported outcomes following salvage partial nephrectomy in 18 patients (8
solitary kidneys, 7 patients with von Hippel-Lindau disease) [26]. Postoperative complications
were noted in 28% of patients. Although there was no reported loss of a renal
remnant in this series, chronic renal insufficiency (serum creatinine > 2.0 mg/dl) was noted in one patient and chronic renal failure (serum creatine
> 2.5 mg/dl) in two others. Obviously, salvage partial nephrectomy was
performed for absolute indications in all cases in an attempt to preserve renal
function and avoid long-term hemodialysis.Additional data from series evaluating the efficacy of NSS for multifocal RCC in patients with
von Hippel-Lindau disease have demonstrated the significant impact of tumor
size on future disease progression. In the series by Duffey etal., NSS was
utilized in 97% of patients with tumors ≤3 cm compared to 69% in
patients with tumors >3 cm [14]. Progression to metastatic
disease was noted in 27% of patients treated for tumors >3 cm (mean followup
73 months); however, no patients treated for tumors ≤3 cm demonstrated
disease progression (mean followup 58 months). Although these data suggest that
small multifocal RCCs can be treated with NSS, with a low rate of progression
to metastatic disease, direct comparisons between the natural history of
sporadic and hereditary multifocal RCC should be made with caution.


## 5. Conclusions

In the current series multifocal RCC was present in 5.4% of patients with tumors ≤4 cm. Multifocal
RCC presents several challenges in terms of diagnosis and treatment.  Although multifocal disease is
present in only a small proportion of patients with RCC, recognition of
multifocality is important to ensure appropriate treatment. As preoperative
imaging is an imperfect means of establishing the presence of multifocal
disease, careful intraoperative inspection of the entire renal unit should be
performed routinely during NSS. Based on the current and other available
series, the presence of multifocal disease does not portend a worse prognosis
compared to solitary RCC. Additional evaluation of the role of NSS in patients
with multifocal sporadic RCC, especially among those with tumors ≤4 cm, is warranted.



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