The chromophobe variant of renal cell carcinoma is a recently described and frequently unrecognized tumor. Because the prognosis of the chromophobe variant appears to be intermediate between that of oncocytoma and the clear cell variant of renal cell carcinoma, accurate diagnosis may be important for appropriate clinical management.
A retrospective analysis of fine-needle aspirations of four primary and two metastatic chromophobe renal cell carcinomas (five typical and one eosinophilic variant) with histologically confirmed primary tumors was performed. Hale's colloidal iron stain was strongly positive in a diffuse cytoplasmic pattern in all resected primary tumors.
All fine-needle aspirations were characterized by cellular smears comprised of single cells and small groups of cells. The cytoplasm varied from granular to flocculent. A characteristic feature was the presence of occasional markedly enlarged, bizarre, often multinucleated cells, within a background of moderately atypical cells. Nuclear enlargement, hyperchromasia, pleomorphism, and outline irregularity were noted in all cases. These features imparted a koilocyte-like appearance to many of the cells. Intranuclear pseudoinclusions were present in four cases and were numerous in two.
Chromophobe renal cell carcinoma is a variant of renal cell carcinoma (RCC) that was first described in humans by Thoenes et al. in 19851 and is estimated to comprise 2-5% of RCCs.6, 31 Compared with other subtypes of RCC, chromophobe RCC has distinct histologic, histochemical, ultrastructural, cytogenetic, and prognostic features.1-9 Nevertheless, this variant may be misdiagnosed as either clear cell (including both clear and granular cell tumors) RCC or oncocytoma. To the authors' knowledge, to date, the cytologic features of only a few cases have been described.10, 11 Within 1 year of reporting their experience with fine-needle aspiration (FNA) of 2 cases, the authors examined an additional 6 cases, including 2 metastatic lesions. Herein, they report the cytologic features of these six cases, which serve to further define the cytologic characteristics of this tumor.
MATERIALS AND METHODS
Six FNAs were identified in patients with histologically confirmed chromophobe RCC. In all cases, the resected primary tumor showed typical histology and diffuse staining with Hale's colloidal iron stain.1, 6, 10 In one case electron microscopy was performed, which demonstrated the characteristic vesicles. An FNA was performed under radiologic guidance for a renal mass in one patient and cytologic material was obtained during intraoperative (both FNA and direct smears) consultation of a renal mass in three patients. In two cases, FNAs of metastatic liver lesions were examined. In both cases, the resected primary RCC was reviewed and the diagnosis confirmed as above. Alcohol-fixed, Papanicolaou stained direct smears, Papanicolaou stained Thinprep® (Cytyc Corp., Boxborough, MA) preparations, air-dried Diff-Quik® stained smears, and hematoxylin and eosin stained cell block and direct smear material were examined. The medical record was reviewed for clinical information.
A summary of the pertinent clinical, pathologic, and cytologic findings is presented in Table 1. Three patients were men and three were women. Their ages ranged from 41-83 years (mean, 56.8 years). A renal mass was an incidental finding in three patients during workup for unrelated disease. A renal mass was discovered in Case 4 during a workup for dyspepsia and right upper-quadrant pain. The patient in Case 5 developed a liver lesion 6 years after radical nephrectomy. The patient in Case 6 developed liver lesions 3 years after radical nephrectomy.
Table 1. Clinical and Pathologic Findings in Chromophobe RCC
Right renal mass discovered during workup for prostate carcinoma
Right renal mass
Right renal mass discovered during workup for urinary retention
Right renal mass
Left renal mass discovered during workup for cholelithiasis
Left renal mass
Renal mass discovered during workup for dyspepsia and right upper quadrant pain
Right renal mass
New liver lesion developed 6 years after radical nephrectomy
Liver lesions noted 3 years after radical nephrectomy
The primary tumors ranged in size from 3-14 cm in greatest dimension. Three tumors that were grossly examined within the study pathology department demonstrated characteristic features of chromophobe RCC. Namely, they were well circumscribed, soft, and gelatinous with a homogeneous beige or tan color, without any golden-yellow or orange areas (Fig. 1). Hemorrhage was inconspicuous and necrosis was not present. Histologically, the tumors were comprised of large cells arranged in sheets and trabeculae with hyperchromatic nuclei with irregular nuclear membranes. The cells were frequently binucleate (Fig. 2). Intranuclear pseudoinclusions were present in four cases; they were numerous in two cases and focal in two, and were often present in the largest cells. The cytoplasm was abundant and fluffy, and the cell membranes were prominent and thickened. Transparency of the cytoplasm in the perinuclear zone was a striking finding in many cells. The presence of frequent binucleation and central cytoplasmic clearing associated with a distinct cell border, together with the “rasinoid” appearance of the nuclei, imparted a strong resemblance to koilocytes (Fig. 2). In Case 1, the perinuclear cytoplasmic clearing was focal and the cytoplasm was more uniformly eosinophilic and granular; these findings were consistent with the eosinophilic variant of chromophobe RCC. The nuclear features in Case 1 were similar to Cases 2-6. Overall, the vast majority of cells had a nuclear size that was consistent with Fuhrman Grade 2 or 3. However, nucleoli were present in only occasional cells. In these cells, the nucleoli were of either Fuhrman Grade 2 or 3. In four cases, a striking feature was the presence of occasional (0-5 per high-power field) cells with large, bizarre nuclei that were often binucleate (Fig. 2). These nuclei only rarely contained prominent nucleoli.
The FNA specimens were cellular and comprised predominantly of single cells and small cell clusters. The cells were frequently binucleate, and showed striking nuclear size variation. The cytoplasm was abundant and ranged from dense and granular to fluffy or flocculent (Fig. 3). Occasional cells showed perinuclear clearing, creating a halo around the nucleus. A conspicuously thickened cytoplasmic membrane was appreciated in the cell block preparations in cases with sufficient material for this technique. A notable feature in four cases was the presence of a minor population of cells with markedly enlarged, hyperchromatic, bizarre nuclei that were frequently binucleate (Fig. 4). The presence of frequent binucleation and hyperchromasia associated with cytoplasmic clearing and distinct cell borders (especially well observed in cell block material) gave a koilocyte-like appearance to many of these cells. However, the perinuclear clearing was only observed in occasional cells and was less conspicuous in the direct smears and Thinprep® material. Intranuclear pseudoinclusions were noted in four cases (numerous in two cases) and were often present within the large bizarre nuclei (Fig. 5). Marked irregularity of nuclear membranes, including nuclear grooves, was common in two cases and focal in a third (Fig. 5). Despite the large size of the nuclei, nucleoli were only present in occasional cells; these cells were either Fuhrman Grade 2 or 3. Case 1, the only case that was consistent histologically with an eosinophilic variant of chromophobe RCC, was similar to the other cases with only minor differences. This case showed less nuclear pleomorphism and had more uniform eosinophilic granularity of the cytoplasm compared with the other cases (Fig. 6). However, some cells contained heterogeneous granular cytoplasm with some degree of vacuolization. In addition, focal perinuclear cytoplasmic clearing was noted.
In Cases 5 and 6, air-dried, Diff-Quik stained material showed small cell clusters and individual cells with abundant bluish-gray cytoplasm. Many cells showed rare to numerous small cytoplasmic vacuoles (Fig. 7). In a minority of cells, the extent of vacuolization was sufficient to impart a clear cell appearance to these cells. The vacuoles were randomly distributed in most cells; however, in some cells the vacuoles tended to be concentrated in the perinuclear zone.
It is estimated that chromophobe RCC comprises between 2-5% of all RCCs.6, 31 Histologically, the tumor cells are large, arranged in trabeculae, and have abundant granular to fluffy cytoplasm with thick cytoplasmic borders. Multinucleation is common. Typical, eosinophilic, and mixed variants have been described. The eosinophilic variant tends to have more uniformly granular cytoplasm; however, cells with flocculent cytoplasm are invariably present. In difficult cases, a positive reaction to Hale's colloidal iron or ultrastructural demonstration of numerous distinctive oval cytoplasmic vesicles establishes the correct diagnosis.12-14 Chromophobe RCC has been shown to be immunoreactive for keratins 18 (uniformly), 7, and 19 (variably), and to be negative for vimentin.8 Cytogenetic analysis of chromophobe RCC has demonstrated loss of numerous chromosomes, including 1, 2, 3, 6, 7, 9, 10, 11, 12, 13, 17, 18, and 21.15, 16 These findings have been confirmed by both restriction fragment length polymorphism analysis,17 and comparative genomic hybridization.18 The characteristic chromosomal abnormalities demonstrated in clear cell RCC (including both clear cell and clear and granular cell tumors) (loss of 3p) and papillary RCC (trisomy 7 and 17) have not been demonstrated in chromophobe RCC; this is perhaps the most compelling evidence that chromophobe RCC is a distinct entity. Although the overall prognosis is excellent, metastases may rarely develop, especially in large and multifocal tumors.19 The high incidence of metastatic lesions (two of six) in this series is not representative of the overall prognosis of patients with this tumor.
Although the cytologic features of clear cell RCC,20, 21 papillary RCC,22-24 oncocytoma,25-28 collecting duct carcinoma,29 and sarcomatoid RCC20, 30 have been previously described, there have been only a few reported cases of chromophobe RCC diagnosed on FNA material.10, 11, 32 The results of these previously reported cases taken together with the data presented here suggest that chromophobe RCC has sufficiently distinctive cytologic features to permit a specific diagnosis of this subtype of RCC in many instances. Although the authors believe the cytologic features of chromophobe RCC are unique, several tumors must be considered in the differential diagnosis. Perhaps most difficult is discriminating between chromophobe RCC and oncocytoma. In a study of the accuracy of FNA in distinguishing subtypes of RCC, the authors were able to correctly classify all 4 oncocytomas and both chromophobe RCCs in a group of 38 FNA specimens without knowledge of the resection diagnosis.33 Although the abundance of granular cytoplasm in some cells of chromophobe RCC and the predominance of single cells rather than large groups is similar to oncocytoma, other cytoplasmic and nuclear features are different. First, chromophobe RCC lacks uniformly granular cytoplasm, but instead has a heterogeneous cytoplasmic texture ranging from granular to fluffy or flocculent. Even the eosinophilic variant lacks uniformly granular cytoplasm. Second, the presence of perinuclear clearing in at least some cells is characteristic. Third, the presence of occasional to frequent cells with bizarre nuclei in a background of less pleomorphic cells is characteristic of chromophobe RCC. By definition, oncocytoma generally has Fuhrman Grade 1 or at most focal Grade 2 nuclei. However, some authors believe that oncocytoma may focally show bizarre nuclei and these cases may be difficult to distinguish on cytologic grounds alone.31 Clearly, further study is needed before accepting such changes in oncocytoma. Nevertheless, a Hale's colloidal iron stain should distinguish these tumors.
Clear cell RCC may also be difficult to distinguish from chromophobe RCC. Although the degree of nuclear atypia observed focally in chromophobe RCC can be present in clear cell RCC, the pattern of cells with mostly moderately atypical nuclei punctuated by a minor population of markedly bizarre cells with frequent multinucleation is unusual in clear cell RCC. Marked nuclear atypia and pleomorphism unassociated with conspicuous or prominent nucleoli are characteristic of chromophobe RCC and highly unusual in clear cell RCC. Intranuclear pseudoinclusions also favor a diagnosis of chromophobe RCC. In the authors' experience, intranuclear inclusions are only rarely observed in clear cell RCC; however, there are reports of rare clear cell RCCs with intranuclear inclusions.34, 35 A predominance of single cells and small clusters rather than large groups also favors a diagnosis of chromophobe RCC. Finally, in difficult cases a Hale's colloidal iron stain may be useful.
Other renal neoplasms may also be included in the different diagnosis, although in most cases distinction should not be as difficult as in oncocytoma and clear cell RCC. The presence of markedly atypical isolated nuclei may suggest a sarcomatoid RCC. However, spindled cells are not observed in chromophobe RCC. Similarly, angiomyolipoma may have scattered markedly atypical cells in a background of less pleomorphic cells. Although these cells are often spindled, they can be epithelioid. Identification of adipocytes or immunoreactivity for HMB-45 is helpful.
Despite the excellent prognosis associated with chromophobe RCC, some tumors may metastasize, as demonstrated in this series. Metastatic chromophobe RCC appears most commonly in the liver,19 and must be distinguished from tumors of nonrenal origin such as hepatocellular carcinoma. The presence of abundant granular cytoplasm in chromophobe RCC imparts a superficial resemblance to hepatocellular carcinoma. Chromophobe RCC can be distinguished from hepatocellular carcinoma by the presence of only occasional prominent nucleoli, few naked nuclei, and absence of tissue fragments lined by endothelial cells. It should be noted that both tumors often show intranuclear pseudoinclusions; therefore, this feature does not allow for distinction between these tumors. The presence of fluffy cytoplasm with perinuclear cytoplasmic clearing and large bizarre hyperchromatic nuclei without prominent nucleoli favors a diagnosis of chromophobe RCC.
Distinction of chromophobe RCC from other types of RCC on FNA material is no longer of only theoretic value but may have important therapeutic implications. In selected patients, a diagnosis of chromophobe RCC on FNA may lead to consideration of partial rather than radical nephrectomy. Several large series have shown that the prognosis of chromophobe RCC is excellent,8, 36, 37 and is especially good in small tumors, which may be most amenable to partial resection.19 Thus, the distinction of chromophobe RCC from other tumors is most important in cases in which partial nephrectomy may not be the treatment of choice. Although oncocytomas are benign and theoretically do not need to be removed, a definitive diagnosis of oncocytoma on FNA is treacherous, due to inherent sampling issues.21 In the study hospital, most urologists would consider partial nephrectomy in selected patients for presumed oncocytoma. Because the therapeutic options are the same, the distinction of oncocytoma from chromophobe RCC in this setting is less important. Conversely, whether partial nephrectomy is the best treatment for clear cell RCC is less certain. Thus, the distinction between chromophobe and clear cell RCC may be more therapeutically important than the distinction between chromophobe RCC and oncocytoma.
In conclusion, chromophobe RCC has distinctive cytologic features that facilitate a specific diagnosis on FNA. Correct diagnosis is important, because this tumor appears to have a better prognosis than clear cell RCC and the possibility of a partial rather than radical nephrectomy may be considered in selected patients. In difficult cases, a Hale's colloidal iron stain can be used to distinguish this tumor from other types of RCC and oncocytoma.