Chromophobe Renal Cell CarcinomaAnalysis of 61 Cases

Michael Peyromaure, M.D.1

Vincent Misrai, M.D.1

Nicolas Thiounn, M.D., Ph.D.1

Annick Vieillefond, M.D.2

Marc Zerbib, M.D.1

Thierry A. Flam, M.D.1

Bernard Debre, M.D.1

1 Department of 1 Urology, Cochin Hospital, Paris,France.

2 Department of Pathology, Cochin Hospital, Paris,France.

Address for reprints: Michael Peyromaure, M.D.,Service d’Urologie, Hopital Cochin, 27, rue duFaubourg Saint-Jacques, 75014 Paris, France;Fax: (011) 33 1 01 58 41 27 55; E-mail:michael.peyromaure@cch.ap-hop-paris.fr

Received October 15, 2003; accepted January 12,2004.

BACKGROUND. Chromophobe renal cell carcinoma (CRCC) is often associated with

a favorable prognosis. However, to the authors’ knowledge, only few clinical data

are available regarding this variant of tumor. In the current study, the authors

report their experience with CRCC over the last 14 years.

METHODS. Since 1989, 61 patients have been treated at the study institution for

CRCC. Tumor characteristics and patient outcome were analyzed retrospectively.

Data were obtained from the patients’ medical records.

RESULTS. The mean age of the patients was 58 years. Of the 61 tumors, 68.8% were

discovered incidentally. The mean tumor size was 6.9 cm. Fifty-seven patients

(93.4%) were treated with radical nephrectomy and 4 patients (6.6%) underwent

partial nephrectomy. According to the 1997 TNM classification, the pathologic

tumor stage was T1 in 65.6% of cases, T2 in 31.1% of cases, and T3a in 3.3% of

cases. All tumors were staged as N0M0. Nuclear grade was low (1 or 2) in 88.5% of

cases. In no case of CRCC was a sarcomatoid component observed. At a mean

follow-up of 49.5 months (range, 5–135 months), no patient had experienced

tumor recurrence or disease progression, and none had died of renal carcinoma.

CONCLUSIONS. In the authors’ experience, CRCC carries an excellent prognosis,

possibly due to the high rate of low-stage and low-grade tumors. Cancer 2004;100:

1406 –10. © 2004 American Cancer Society.

KEYWORDS: renal carcinoma, chromophobe, nephrectomy, prognosis.

Chromophobe renal cell carcinoma (CRCC) is a rare variant of renalcarcinoma, with distinct histochemical, ultrastructural, and ge-

netic characteristics. CRCC accounts for approximately 4% of allkidney neoplasms.1,2 Although the pathologic features and moleculargenetic characteristics of this tumor have been described extensively,to our knowledge there is little information available regarding theclinical outcome of patients with CRCC. To analyze the clinical be-havior of CRCC further, we reviewed the data from 61 consecutivepatients treated in the study institution for this type of tumor.

MATERIALS AND METHODSBetween January 1989 and January 2003, 61 patients (34 men and 27women) were treated for CRCC at Cochin Hospital in Paris. The meanpatient age was 58 years (range, 23– 82 years). Data were obtainedfrom the patients’ medical records. Presenting symptoms, pathologicfeatures, treatment, and patient outcome were analyzed retrospec-tively.

Preoperative investigations included clinical examination, com-plete blood count, renal function test, abdominal computed tomog-raphy (CT) scan, and chest radiography. Patients with suspectedmetastatic disease underwent pulmonary CT scan and bone scintig-

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© 2004 American Cancer SocietyDOI 10.1002/cncr.20128

raphy. Renal magnetic resonance imaging (MRI) wasperformed in those patients with suspected renal an-giomyolipoma.

In all cases, CRCC was diagnosed on a nephrec-tomy specimen. Pathologic studies included light mi-croscopy and immunohistochemistry. Each tumorwas reviewed by the same pathologist and staged ac-cording to the 1997 TNM classification.

Patient outcome was assessed by clinical exami-nation and abdominal and pulmonary CT scans every3 months for the first year, then every 6 months for thenext 2 years, and annually thereafter.

RESULTSThe 61 cases of CRCC represented 4.1% of the 1488renal tumors resected in the study department duringthis period.

Presenting SymptomsThe majority (68.9%) of the cases were discoveredincidentally. The most common presenting symptomswere flank discomfort (18%) and macroscopic hema-turia (13.1%). No patient presented with weight loss,poor general condition, or fever. At the time of pre-sentation, no patient was found to have paraneoplas-tic anemia or polycythemia; only 2 patients (3.3%) hada palpable lumbar mass.

Imaging FeaturesTumors were located in the right kidney in 54% ofpatients and in the left kidney in 46% of patients; therewere no bilateral tumors detected. The ultrasono-graphic and tomodensitometric appearance of CRCCwas similar to that of other renal solid tumors; en-hancement was observed in 93.4% of patients, necro-sis was present in 31% of patients, calcification waspresent in 21.3% of patients, and cystic foci werepresent in 6.5% of patients. Two tumors (3.3%) weresuspected to be oncocytomas because of the presenceof a central scar. The renal vein was involved in onlyone case and the caval vein was normal in all cases.MRI was performed in five patients with suspectedrenal angiomyolipoma; the tumor was considered tobe an usual solid carcinoma in four patients and anoncocytoma in one patient.

TreatmentOf the 61 patients, 57 (93.4%) underwent radical ne-phrectomy and 4 (6.6%) underwent partial nephrec-tomy for small (� 3 cm) and peripheral tumors. Nopatient received adjuvant treatment. Although frozensections were subjected to pathologic examinationduring surgery for 13 patients, a diagnosis of CRCCwas established in only 2 patients.

Pathologic FeaturesThe mean tumor dimension was 6.9 cm (range, 1.5–25cm). Sixty tumors were solitary. One patient had 2CRCC foci measuring 5 cm and 2.5 cm, respectively.Macroscopically, all tumors had a homogeneous, lightbrown (54.1%) or white (45.9%) surface (Fig. 1). Lightmicroscopy showed that the tumors were comprisedof sheets or trabeculae with variable proportions ofclear cells and eosinophilic cells; 21 (34.4%) were clas-sified as predominantly eosinophilic, 9 (14.8%) wereclassified as predominantly clear cell, and 31 (50.8%)tumors were found to be comprised of equal numbersof clear and eosinophilic cells (Fig. 2). In no case didthe tumor have a sarcomatoid component. Some ar-eas of necrosis were present in 36% of tumors. Halecolloidal iron stain was found to be positive in all cases(Fig. 3). At the start of the current series, ultrastruc-tural investigation of seven tumors showed the pres-

FIGURE 1. Macroscopic appearance of chromophobe renal cell carcinoma.

Note that it is a homogeneous, well delineated, light-brown tumor.

FIGURE 2. Chromophobe renal cell carcinoma showing sheets of chromo-

phobe cells with large cytoplasm and indented nuclei (H & E, �200).

Chromophobe Renal Cell Carcinoma/Peyromaure et al. 1407

ence of intracytoplasmic vesicles in all cases, therebyconfirming the diagnosis of CRCC. Of the 61 patients,3 had undergone renal biopsy before undergoing ne-phrectomy; however, in no patient had this led to asuspected diagnosis of CRCC.

The TNM stage and nuclear grade of all the tu-mors are summarized in Table 1. Tumors were con-fined to the kidney in 96.7% of patients and were oflow grade (Fuhrman grade of 1 or 2) in 88.5% ofpatients.

Patient OutcomeThe mean follow-up after surgery was 49.5 months(range, 5–135 months). Nine patients were lost to fol-low-up, with a mean interval after nephrectomy of 13months. During the follow-up period, no patient ex-perienced tumor recurrence or metastases, and nonedied of renal carcinoma; 2 patients died of unrelatedcauses at 54 months and 82 months, respectively.

DISCUSSIONThe first cases of CRCC in humans were described byThoenes et al.3 in 1985. This variant of renal tumor isshown to be comprised of variable proportions ofclear (“chromophobe”) cells and eosinophilic cellswhen stained with hematoxylin and eosin. The chro-mophobe cells contain opaque or finely reticular cy-toplasm, and demonstrate deep staining with Halecolloidal iron. Electronmicroscopically, the cytoplasmcontains microvesicular structures (150 –300 nanome-ters), possibly derived from the endoplasmic reticu-lum or mitochondria.

The diffuse positivity for Hale colloidal iron stainin relation to the presence of cytoplasmic vesicles isone characteristic and distinguishing feature of CRCC;however, the differential diagnosis with renal oncocy-toma can be challenging because this variant of tumorclosely resembles CRCC. Moreover, renal oncocytomaoccasionally is positive for Hale colloidal iron stainand in some cases contains cytoplasmic mi-crovesicles.4,5 Some authors therefore have investi-gated other methods with which to distinguish bothtumors. Leroy et al.4 reported that immunohistochem-ical staining for cytokeratin 7 may be useful; in theirstudy, all CRCC specimens showed strong cytoplasmicstaining for cytokeratin 7, whereas the majority ofoncocytomas were negative.

It is now acknowledged that CRCC and renal on-cocytoma arise from the intercalated cells of the col-lecting duct system. Some cases of coexistent CRCCand oncocytoma (so-called renal oncocytosis) havebeen reported.5 These findings give strong support toa common origin. Conversely, chromosomal analysesof both tumors show different features. A low chro-mosome number (due to the loss of chromosomes 1,2, 6, 10, 13, 17, and 21) is characteristic of CRCC.6

Recently, an oncogene (KIT) has been shown to beinvolved specifically in the development of CRCC.7

Renal oncocytoma shows different genetic character-istics, including combined loss of chromosomes Y and1, rearrangements affecting band 11q12–13, involve-ment of 12q12–13, and loss of 14q.8 To our knowledge,the relation between both tumors has yet to be clari-fied, because some cases of hybrid tumors demon-strating CRCC features with components of oncocy-toma have been reported.8

To our knowledge, only a few authors to date havestudied outcome in patients with CRCC. In 1995,Crotty et al.1 reported a series of 50 patients treated forCRCC. With a mean follow-up of 6 years, the rates ofspecific mortality and recurrence were found to beonly 2% and 6%, respectively. In this series, 2 patientsdeveloped early recurrence at 6 months and 12

FIGURE 3. Hale colloidal iron staining showing diffuse blue cytoplasmic

vacuoles.

TABLE 1Pathologic Stage and Nuclear Grade of the 61 Cases of CRCC in theCurrent Series

Pathologic stagea No. (%)

T1N0M0 40 (65.6)T2N0M0 19 (31.1)T3aN0M0 2 (3.3)Nuclear Fuhrman grade1 12 (19.7)2 42 (68.9)3 7 (11.4)

CRCC: chromophobe renal cell carcinoma.a According to the 1997 TNM classification.

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months, respectively; another patient developed me-tastases 7 years after undergoing nephrectomy anddied rapidly.

Recently, all patients who had undergone radicalnephrectomy between 1970 and 2000 at the MayoClinic were reviewed retrospectively.2 In this series of2385 patients, 102 (4.3%) originally were diagnosedwith CRCC. The 5-year disease-specific survival rate inthis group was 86.7%. Patients with clear cell renalcarcinoma were found to have a poorer prognosis,with a 5-year disease-specific survival rate of 68.9% (P� 0.001). The authors found no difference with regardto specific survival between CRCC and papillary renalcarcinoma. In this study, the TNM stage, tumor size,nuclear grade, presence of a sarcomatoid component,and tumor necrosis were reported to be associatedsignificantly with a poor prognosis. The disease-spe-cific survival rates with and without necrosis were60.7% and 94%, respectively. In the current series,necrosis was found to be present in 36% of cases.However, this feature did not appear to have anyprognostic impact.

In the opinion of most authors, CRCC has a favor-able prognosis. In the current series, no patient expe-rienced tumor recurrence or disease progression, andnone died of renal carcinoma after a mean follow-upof 49.5 months. It is interesting to note that the tumorsfor the most part were staged as T1/T2 (96.7% ofcases), and were of low grade (88.5% of cases). Nopatient was found to have lymph node involvement ormetastases at the time of presentation; moreover, inno case did the CRCC contain a sarcomatoid compo-nent. The patient outcome in the current study mostlikely can be explained in terms of these favorablefeatures; indeed, it has been widely accepted thatTNM stage and nuclear grade are the most importantprognostic factors in patients with renal carcino-ma.9,10

However, in some series, aggressive variants ofCRCC have been reported. Grabowski et al.11 evalu-ated the survival of 42 patients with rare subtypes ofrenal carcinoma; of their 9 patients with CRCC, 2(22.2%) died during follow-up. Renshaw et al.12 re-ported a series of 25 cases of CRCC, comprised of 23cases of solitary tumors and 2 cases of coexistentpapillary carcinoma. In that report, 7 patients (28%)developed metastases. Of these patients, 5 had a sol-itary CRCC measuring � 8 cm in dimension and de-veloped liver metastases; the other 2 patients (thosewith coexistent papillary carcinoma) developed me-tastases in the lung but it was not known which tumor(CRCC or papillary carcinoma) metastasized.

Onishi et al.13 have suggested that the eosino-philic subtype of CRCC has a better prognosis than the

typical (chromophobe) subtype. In a long-term seriesof 35 patients, comprised of 26 with the typical sub-type and 9 patients with the eosinophilic subtype,these authors noted a different outcome for each vari-ant; there were no disease-related deaths reported inpatients with eosinophilic CRCC whereas, of thosepatients with the typical subtype, 5 (19.2%) diedwithin 2 years of surgery. Of these 5 patients, 3 withhigh-stage disease were found to have varying degreesof sarcomatoid change. Conversely, the other 2 pa-tients developed disease recurrence � 10 years aftersurgery (late recurrence). No sarcomatoid changeswere noted in either of these patients, nor in any of thepatients who later died from carcinoma. To ourknowledge, the hypothesis that the eosinophilic sub-type of CRCC has a better prognosis than the typicalsubtype has not been confirmed to date. In the currentseries, 34.4% of the tumors were classified as predom-inantly eosinophilic. These tumors were not found tobe associated with a better prognosis.

Finally, a radical nephrectomy was performed in� 93% of cases. However, a partial nephrectomywould have been more appropriate in a large propor-tion of patients because most of them had small, low-grade tumors.

The results of the current study provide clear ev-idence that CRCC carries a favorable prognosis. How-ever, other authors have reported that this variant oftumor may sometimes have an aggressive course.Larger studies are needed to elucidate the clinicalbehavior of CRCC further.

ConclusionsIn our experience, CRCC carries an excellent progno-sis, which may be explained in terms of the high rateof low-stage and low-grade tumors. However, largerseries with a longer follow-up period are required toimprove our understanding of this type of tumor.

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carcinoma: clinicopathological features of 50 cases. J Urol.1995;154:964 –967.

2. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML.Comparisons of outcome and prognostic features amonghistologic subtypes of renal cell carcinoma. Am J SurgPathol. 2003;27:612– 624.

3. Thoenes W, Storkel S, Rumpelt HJ. Human chromophobecell renal carcinoma. Virchows Arch B Cell Pathol Incl MolPathol. 1985;48:207–217.

4. Leroy X, Moukassa D, Copin MC, Saint F, Mazeman E,Gosselin B. Utility of cytokeratin 7 for distinguishing chro-mophobe renal cell carcinoma from renal oncocytoma. EurUrol. 2000;37:484 – 487.

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5. Tickoo SK, Lee MW, Eble JN, et al. Ultrastructural observa-tions on mitochondria and microvesicles in renal oncocy-toma, chromophobe renal carcinoma, and eosinophilicvariant of conventional (clear cell) renal cell carcinoma.Am J Surg Pathol. 2000;24:1247–1256.

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10. Di Silverio F, Casale P, Colella D, Andrea L, Seccareccia F,Sciarra A. Independent value of tumor size and DNA ploidyfor the prediction of disease progression in patients withorgan-confined renal cell carcinoma. Cancer. 2000;88:835–843.

11. Grabowski M, Huzarski T, Lubinski J, Sikorski A. Survival inpatients with rare subtypes of renal cell carcinoma. BJU Int.2002;89:599 – 600.

12. Renshaw AA, Henske EP, Loughlin KR, Shapiro C, WeinbergDS. Aggressive variants of chromophobe renal cell carci-noma. Cancer. 1996;78:1756 –1761.

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