ANATOMIC PATHOLOGY Original Article
Renal Oncocytoma and Granular Renal Cell Carcinoma A Comparative Clinicopathologic and DNA Flow Cytometric Study R. WARREN J. HARTWICK, M.D., F.R.C.P.C.,1 ADEL K. EL-NAGGAR, M.D., PH.D., 1 JAE Y. RO, M.D., PH.D., 1 JOHN R. SRIGLEY, M.D., F.R.C.P.C., 2 DONIA D. McLEMORE, HLT(ASCP),1 EDWARD C. JONES, M.D., F.R.C.P.C., 4 DAVID J. GRIGNON, M.D., F.R.C.P.C., 3 M. JANE THOMAS, M.D., F.R.C.P.C., 5 AND ALBERTO G. AY ALA, M.D. 1
1942,' the debate pertaining to its histopathologic features and clinical behavior remains unsettled.2"8 Generally RO runs a clinically benign course, 2,9 " 20 but reports disputing such a contention have been published. From the 'Department of Pathology. University of Texas, M.D. An- In these reports, D N A aneuploidy and aggressive biologic derson Cancer Center, Houston. Texas; 2Sunnybrook Medical Center, 3,6 7 21 43 Toronto, Ontario; * Victoria Hospital, London, Ontario; * Vancouverbehavior was described. ' ' " The selection criteria for 5 General Hospital, Vancouver. British Columbia; and the Canadian RefRO in most of these studies, however, were either loosely erence Center for Cancer Pathology. Ottawa, Ontario, Canada. described or lacked the gross description.6'7'40'44 Accordingly, the possibility that some of these studies may have Dr. Hartwick was supported by a McEachern Fellowship of the Caincluded renal cell carcinoma (RCC) with predominant nadian Cancer Society and a Desmond Magner Award of the National Cancer Institute of Canada. granular cytoplasmic features cannot be ruled out. Dr. Hartwick is a Staff Pathologist, Department of Pathology, Mount In the present study, we analyzed the clinicopathologic Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. Received December 23, 1991; revised manuscript accepted March 27, features and the D N A content of 23 ROs and, for com1992. parison, 18 granular renal cell carcinomas (GRCC) to deAddress reprint requests to Dr. El-Naggar: Department of Pathology, fine better parameters that may characterize and distinBox 85, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, guish between these two entities. Texas 77030. Although renal oncocytoma (RO) has been the subject of many reports since it was first described by Zippel in
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gross appearance of GRCC was variegated, yellow to tan, and punctuated with geographic areas of necrosis. Eleven patients with GRCC were stage 1,4 were stage II, 2 were stage Ilia, and 1 patient had metastases at initial examination (stage IV). Seven GRCCs were DNA diploid, one was DNA tetraploid, and 10 tumors were DNA aneuploid. Twelve patients were alive with no evidence of disease (12 to 36 months; median, 26 months). All patients with DNA diploid neoplasm pursued benign clinical courses. One patient was alive with metastatic disease and two patients developed metastases and died of their disease; all three patients had DNA aneuploid tumors. Two patients died of other causes and one patient was lost to follow-up. Our data indicate that renal oncocytoma is a distinct clinicopathologic disease with characteristic gross, histologic, DNA flow cytometric, and biologic features that are different from GRCC. (Key words: Renal neoplasms; Oncocytoma; Flow cytometry; Carcinoma; Granular renal cell carcinoma) Am J Clin Pathol 1992; 98:587-593
Twenty-three renal oncocytomas and 18 granular renal cell carcinomas (GRCC) were comparatively studied clinicopathologically and by DNA flow cytometry to delineate their differences. Of the patients with renal oncocytomas, IS were men and 8 were women, and their ages ranged from 42 to 81 years (mean, 64 years). The gross appearance of renal oncocytomas was characteristically homogeneous tan-brown, with variable scarring, without areas of large hemorrhage, and with no apparent necrosis. Twenty-two renal oncocytomas were confined within the kidney (Robson stage I) and one tumor extended into the renal vein (stage Ilia). Twenty-two renal oncocytomas, including the stage Ilia tumor, manifested diploid DNA content and only one neoplasm showed a feature suggestive of near-diploid DNA aneuploidy. Of the 17 patients with renal oncocytomas who had adequate follow-up, none developed metastasis or died of disease. Of the patients with GRCC, 13 were men and 5 were women, and their ages ranged from 30 to 73 years (mean, 53 years). The
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ANATOMIC PATHOLOGY Original Article MATERIALS AND METHODS
The following selection criteria were used for oncocytomas. (1) With gross examination, the tumor was well circumscribed, with homogeneously brown or tan surface color, and lacked evidence of necrosis or hemorrhage. (2) With microscopic examination, the tumor consisted of a uniform population of oncocytic cells with some cellular pleomorphism and nuclear hyperchromatism and eosinophilic cytoplasm. (3) There was no evidence of mitosis or clear cells in any of the histologic slides examined. Eighteen GRCCs were selected for comparison; at least 75% of the neoplastic cells comprised granular cells and none contained more than 25% clear cell RCC component. All tumors were staged using the system of Robson and associates.45 The neoplasms were graded histologically using Fuhrman and colleagues'46 nuclear grading criteria. Nuclear grade was assigned based on the highest grade in each neoplasm. Clinical information was obtained from the hospital medical records. Flow Cytometric Analysis DNA flow cytometric analysis was performed on one to three blocks per neoplasm (mean, 1.3). Tissue was fixed in 4% formaldehyde for 2 to 8 hours and embedded in paraffin (Paraplast Monoject Scientific, St. Louis, MO) with a melting point of 56 °C. Nuclear suspensions of the neoplasms were prepared using a modified version of the method of Hedley and others.47'48 Briefly, three 50-^mthick sections cut from the tissue blocks were deparaffinized in Histo-Solv (Biochemical Sciences Inc., Bridgeport, NJ) and rehydrated in a series of graded alcohols. Disaggregation was accomplished by treatment with 0.5% pepsin (Sigma Chemical Co., St. Louis, MO), pH 1.5, at 37 °C. After 20 minutes the samples were drawn into 3mL syringes through 20-gauge needles and forcefully ex-
FIG. 1. Gross picture of a renal oncocytoma showing a well-circumscribed homogeneous mass with a centralfibrousscar.
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Twenty-three ROs and 18 GRCCs were retrieved from the surgical pathology archives of the M.D. Anderson Cancer Center, Houston, Texas; Victoria Hospital, London, Ontario; Mount Sinai Hospital, Toronto, Ontario; Vancouver General Hospital, Vancouver, British Columbia; and the Canadian Reference Center for Cancer Pathology, Ottawa, Ontario, Canada. These neoplasms were selected during review of approximately 500 renal tumors. All cases from 1985 to 1989, originally diagnosed as RCC or RO with available tissue blocks for flow cytometric analysis, complete gross description of the neoplasms, and extensive sampling of the tumors (at least one block for each centimeter of the tumor), were selected for this study. Gross pathologic appearance of the tumors was obtained from the surgical pathology report. An average of nine (range, 4 to 15) hematoxylin-and-eosin-stained histologic sections per neoplasm were reviewed.
pelled three to four times into disposable culture tubes. Digestion was then terminated by adding 1 mL 0.005% pepstatin solution (Sigma Chemical Co.) and placing the solution on ice. The samples were then centrifuged, washed twice with Dulbecco's phosphate-buffered saline (Gibco Laboratories, Grand Island, NY), and incubated with 0.3 mL freshly prepared RNAse (Worthington Biochemical, Freehold, NJ) at 37 °C for 20 minutes. After the samples were stained with propidium iodide (Sigma Chemical Co.) and filtered through a 37-jtm nylon mesh filter (Small Parts Inc., Miami, FL). In each block selected for analysis, at least 75% of the tissue was neoplastic. In renal cell carcinomas, if possible, tissue blocks with more than 10% necrosis were avoided. Otherwise, the necrotic areas were mapped and non-necrotic tissue was reembedded for flow cytometric analysis. Specimens were analyzed on an EPICS Profile I Flow Cytometer (EPICS Division, Coulter Electronics, Hialeah, FL) equipped with an argon ion laser operating at 488 nm, with a 610-nm-long pass filter and 488 band pass. Flow rates were adjusted to count approximately 75 nuclei per second. Peak versus integral signals were used to gate out doublets. Cytospin slides were prepared from a 106 nuclei/mL concentration (unexposed to RNAse) and stained with Wright's-Giemsa. The slides were reviewed to confirm the presence of tumor nuclei as well as to monitor the quality of processing. In each sample, at least 10,000 nuclei were evaluated. The DNA histograms were analyzed using the "boxogram" gating procedure of Johnston and associates.49 Coulter Cytologic Software, version 2.2, was used only in cases exhibiting excessive debris using the builtin debris substraction model. Non-neoplastic renal tissue in the same tumor block and normal kidney tissue from separate blocks were used as the biologic diploid standard, and the first Gn/G] population was used to denote the diploid stemline.
HARTWICK ET AL.
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Renal Cell Carcinoma
The DNA index is defined as the ratio of the peak channel number of the test sample to the peak channel number of the normal diploid control. By definition, the DNA index of a diploid population is equal to 1.0. A tumor is considered aneuploid when a distinct second G 0 /Gi peak, accounting for at least 10% of the cells analyzed, is present (or any number of such separate peaks). The coefficient of variation for all cases was less than 5%. Statistics The association between the categories was examined using Student's Mest. RESULTS
Clinical. The patient population consisted of 15 men and 8 women whose ages at diagnosis ranged from 42 to 81 years (mean, 64 years). Twenty-two tumors were stage 1 and one tumor was stage Ilia. Twenty-one patients were treated by radical nephrectomy. In two cases the tumors were incidental postmortem findings, submitted to the Canadian Reference Center for Cancer Pathology in pathologic consultation. Twelve patients were alive and disease free from 12 months to 12 years (median, 50 months; mean, 54 months) after operation. Three patients were dead of other causes at 7 months, 34 months, and 17 years after operation. There were no instances of local recurrence or regional lymph nodal or distant metastasis by the tumors. Six patients were lost to follow-up. Gross Pathologic Findings. Tumors were typically described as well-circumscribed, rounded masses with lightbrown to light-tan homogeneous appearance and with or without fibrous bands (Fig. 1). Unlike classical RCCs, there was no mention of variegated appearance, necrosis, or large hemorrhage. Small foci of hemorrhage, however, were described in four neoplasms. Tumors measured from 2 to 12 cm in greatest dimension (mean, 6.4 cm). Microscopic Pathologic Findings. In all neoplasms, polygonal-shaped cells with abundant granular eosinophilic cytoplasm were uniformly present (Fig. 2A). Cells were arranged in clusters, cords, or tubules and contained round nuclei with dense chromatin and some pleomorphism. Eighteen tumors were nuclear grade 2, three tumors were nuclear grade 3, and two tumors were nuclear grade 4. Sixteen tumors contained foci of large oncocytic cells with enlarged pleomorphic nuclei (Fig. 3,4). DNA Flow Cytometric Findings. DNA flow cytometric analysis showed DNA-diploidy (DNA index, 1.0) in 22 tumors (96%), including 21 stage I tumors and one stage Ilia tumor (Fig. 3B). Both intrarenal and intravenous Vol.
B
2n DNA
4-n 6n CONTENT
FIGS. 1A and B. A. Oncocytoma displaying clusters of uniform cells with granular cytoplasm and occasional nuclear enlargement, divided by thin sinusoidal vasculatures. B. Histogram of this oncocytoma showing a diploid peak and an additional shoulder on the down slope, suggesting a near-diploid aneuploid DNA content.
samples of the stage Ilia tumor were DNA-diploid. Neoplasms with enlarged pleomorphic nuclei were also DNAdiploid. In 1 of the 23 cases (4.3%), DNA flow cytometric analysis suggested a near-diploid DNA-aneuploidy (Fig. 2B). There were no histologic features that distinguished this case from DNA-diploid neoplasms. All neoplasms with multiple tissue blocks that were analyzed exhibited homogenous intratumoral DNA content. Granular Cell Renal Carcinoma Clinical. The patient population was composed of 13 men and 5 women whose ages ranged at diagnosis from 30 to 73 years (mean, 53 years). Eleven tumors were stage •No. 6
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Renal Oncocytomas
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ANATOMIC PATHOLOGY Original Article Microscopic Pathologic Findings. All tumors were composed of two tumor cell populations. The predominant population (more than 75%) consisted of polygonalshaped cells with variably granular eosinophilic cytoplasm (Fig. 4A). The smaller population (fewer than 25%) consisted of polygonal-shaped cells with clear cytoplasm. Both cell types displayed prominent cell borders and were arranged in solid sheets or tubules. The cells contained round to irregularly shaped nuclei that varied in nuclear grade. Six tumors were nuclear grade 2, 10 tumors were nuclear grade 3, and 2 tumors were nuclear grade 4. DNA Flow Cytometric Findings. DNAflowcytometric analysis showed DNA-diploidy in 7 tumors (38.9%). One tumor (5.6%) was DNA-tetraploid (DNA index = 2.0) and 10 tumors (55.6%) were DNA-aneuploid (Fig. 4B). Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
c o u N T .dW"^
B
4-n 6n CONTENT
FIGS 3A and B. A. An oncocytoma showing nuclear pleomorphism. B. DNA histogram of the same tumor displaying a diploid DNA content (CV, 2.2).
I, four tumors were stage II, two tumors were stage Ilia, and one tumor was stage IV. Seventeen patients were treated with radical nephrectomy and in one case the tumor was an incidental postmortem finding. Twelve patients (70%) were alive and disease free from 12 to 36 months (mean, 26 months; median, 24 months). One patient (6%) was alive with metastatic disease at 14 months. Two patients (12%) died of their disease at 11 and 18 months, respectively; two patients (12%) died of other causes; and one patient was lost to follow-up. Gross Pathologic Findings. The gross appearance of the tumors was that of a well-circumscribed solid mass. Tumors measured from 2.3 to 15 cm in greatest dimension (mean, 7.8 cm). Tumors were typically variegated in color with yellow, tan, and white areas admixed with foci of necrosis and/or hemorrhage.
B
2n DNA
4-n CONTENT
FIGS 44 and B. A. Granular renal cell carcinoma showing tumor cells with the increased nuclear cytoplasmic ratio, the variability in the nuclear chromatin, and the nucleolar prominence. B. A single parameter histogram of this neoplasm showing aneuploid DNA stemline diploid index of 1.36.
A.J.C.P. • December 1992
HARTWICK ET AL. Renal Oncocytoma and Granular Renal Cell Carcinoma All patients with DNA-diploid tumors, the 1 patient with DN A-tetraploid tumor, and 5 ofthe 10 patients with DN Aaneuploid neoplasms pursued benign clinical courses. The three patients with aggressive clinical outcome had DNAaneuploid tumors. All but two neoplasms with multiple tissue blocks analyzed manifested intratumoral DNA homogeneity. In these two instances, DNA-diploidy and aneuploidy were noted in different neoplastic blocks. The difference between the percentages of DNA-nondiploidy of RO (4.3%) and GRCC (55.5%) was statistically significant (P < 0.001).
DISCUSSION
but rather the extent of such aberration that affects the biologic course of a given neoplasm. Our results concur with those of Eble and Sledge59 and Psihramis and Goldberg,60 but differ from those of Rainwater and associates.61 In the latter study,61 however, only 15% of the neoplasms manifested DNA-aneuploidy and the remaining 85% of the neoplasms displayed diploid or tetraploid DNA content. The major difference between our study and that of Rainwater and associates61 is the high incidence of tetraploid DNA in their neoplasms. Given the current lack of standardized criteria for defining tetraploidy, as well as its biologic significance and whether it reflects a significant cytogenetic event in tumors, it may be beneficial to combine them with DNA-diploid neoplasms. Tetraploidy aside, the low incidence of aneuploidy in their study corresponds, in general, with our findings. Our findings and those of others59,60 in RO differ significantly from those in RCC. Our data also indicate a significant clinical and DNA content difference between strictly defined ROs and GRCCs. None of the patients with RO in our series displayed recurrence, metastasis, or death, whereas 18% of GRCCs manifested aggressive behavior and DNA aneuploidy despite the relatively short follow-up period. It must be realized, however, that approximately 25% of our patients were lost to follow-up. The DNA content analysis and the biologic course of the GRCCs in our study, however, are comparable to those in previous studies of RCCs.62"72 Our study indicates that strictly defined ROs manifest significantly different clinical behavior and DNA content from typical GRCCs. Therefore it supports the recognition of ROs as a distinct clinicopathologic entity in the spectrum of renal cortical tumors. Acknowledgments. The authors thank Anna Litvan for administrative assistance, Diane Jeans for technical assistance, Elsa Ramos for photographic assistance, and Sulema M. Martinez for typing the manuscript.
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Renal oncocytoma is an uncommon renal cortical neoplasm with controversial clinicopathologic features.2"19,39'44 Earlier reports have distinctly separated ROs from conventional RCCs based on histopathologic as well as biologic differences.1315 Subsequent studies, however, contradicted these findings and argued against the merit of separating these neoplasms.' 729,3 '" 35,37,39,4 '" 43 Several studies of small numbers of ROs have documented a malignant outcome.39,42,43 In these studies, the extent of histologic sampling and the gross appearance of the tumors were either absent or not sufficiently described. Furthermore, hybrid tumors with both RO and RCC features, called "congeners of RO," have been described.17 Central to this dispute is the strictness of the criteria by which RO is clearly distinguished from predominantly GRCC. 7,40,44 The implication of this, therefore, is that some of the later studies may have included GRCC in their population and consequently led to the purported aggressive behavior of RO. We contend that a comparative study of strictly defined groups of these neoplasms may be useful in settling this controversy. Our data support that RO is a distinct renal neoplasm with morphologic, DNA flow cytometric, and biologic characteristics that set it apart from predominantly granular RCC and other forms of RCC. In ROs with and without nuclear atypia, a benign clinical course ensued. Similarly, none of these neoplasms manifested abnormal DNA content, except for one neoplasm that displayed a DNA pattern suggestive of near-diploid aneuploidy. Although such a feature may not be considered conclusive evidence of aneuploid DNA content, it did represent a deviation from the other neoplasms. The mere presence of DNA-aneuploidy may not necessarily connote a malignant condition. There has been previous documentation of aneuploid DNA patterns in several benign neoplastic diseases,50"58 and in these neoplasms, near-diploid stemlines were expressed. In that context, it may not be the presence of DNA-aneuploidy
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Renal Oncocytoma and Granular Renal Cell Carcinoma A Comparative Clinicopathologic and DNA Flow Cytometric Study R. WARREN J. HARTWICK, M.D., F.R.C.P.C.,1 ADEL K. EL-NAGGAR, M.D., PH.D., 1 JAE Y. RO, M.D., PH.D., 1 JOHN R. SRIGLEY, M.D., F.R.C.P.C., 2 DONIA D. McLEMORE, HLT(ASCP),1 EDWARD C. JONES, M.D., F.R.C.P.C., 4 DAVID J. GRIGNON, M.D., F.R.C.P.C., 3 M. JANE THOMAS, M.D., F.R.C.P.C., 5 AND ALBERTO G. AY ALA, M.D. 1
1942,' the debate pertaining to its histopathologic features and clinical behavior remains unsettled.2"8 Generally RO runs a clinically benign course, 2,9 " 20 but reports disputing such a contention have been published. From the 'Department of Pathology. University of Texas, M.D. An- In these reports, D N A aneuploidy and aggressive biologic derson Cancer Center, Houston. Texas; 2Sunnybrook Medical Center, 3,6 7 21 43 Toronto, Ontario; * Victoria Hospital, London, Ontario; * Vancouverbehavior was described. ' ' " The selection criteria for 5 General Hospital, Vancouver. British Columbia; and the Canadian RefRO in most of these studies, however, were either loosely erence Center for Cancer Pathology. Ottawa, Ontario, Canada. described or lacked the gross description.6'7'40'44 Accordingly, the possibility that some of these studies may have Dr. Hartwick was supported by a McEachern Fellowship of the Caincluded renal cell carcinoma (RCC) with predominant nadian Cancer Society and a Desmond Magner Award of the National Cancer Institute of Canada. granular cytoplasmic features cannot be ruled out. Dr. Hartwick is a Staff Pathologist, Department of Pathology, Mount In the present study, we analyzed the clinicopathologic Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. Received December 23, 1991; revised manuscript accepted March 27, features and the D N A content of 23 ROs and, for com1992. parison, 18 granular renal cell carcinomas (GRCC) to deAddress reprint requests to Dr. El-Naggar: Department of Pathology, fine better parameters that may characterize and distinBox 85, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, guish between these two entities. Texas 77030. Although renal oncocytoma (RO) has been the subject of many reports since it was first described by Zippel in
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gross appearance of GRCC was variegated, yellow to tan, and punctuated with geographic areas of necrosis. Eleven patients with GRCC were stage 1,4 were stage II, 2 were stage Ilia, and 1 patient had metastases at initial examination (stage IV). Seven GRCCs were DNA diploid, one was DNA tetraploid, and 10 tumors were DNA aneuploid. Twelve patients were alive with no evidence of disease (12 to 36 months; median, 26 months). All patients with DNA diploid neoplasm pursued benign clinical courses. One patient was alive with metastatic disease and two patients developed metastases and died of their disease; all three patients had DNA aneuploid tumors. Two patients died of other causes and one patient was lost to follow-up. Our data indicate that renal oncocytoma is a distinct clinicopathologic disease with characteristic gross, histologic, DNA flow cytometric, and biologic features that are different from GRCC. (Key words: Renal neoplasms; Oncocytoma; Flow cytometry; Carcinoma; Granular renal cell carcinoma) Am J Clin Pathol 1992; 98:587-593
Twenty-three renal oncocytomas and 18 granular renal cell carcinomas (GRCC) were comparatively studied clinicopathologically and by DNA flow cytometry to delineate their differences. Of the patients with renal oncocytomas, IS were men and 8 were women, and their ages ranged from 42 to 81 years (mean, 64 years). The gross appearance of renal oncocytomas was characteristically homogeneous tan-brown, with variable scarring, without areas of large hemorrhage, and with no apparent necrosis. Twenty-two renal oncocytomas were confined within the kidney (Robson stage I) and one tumor extended into the renal vein (stage Ilia). Twenty-two renal oncocytomas, including the stage Ilia tumor, manifested diploid DNA content and only one neoplasm showed a feature suggestive of near-diploid DNA aneuploidy. Of the 17 patients with renal oncocytomas who had adequate follow-up, none developed metastasis or died of disease. Of the patients with GRCC, 13 were men and 5 were women, and their ages ranged from 30 to 73 years (mean, 53 years). The
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ANATOMIC PATHOLOGY Original Article MATERIALS AND METHODS
The following selection criteria were used for oncocytomas. (1) With gross examination, the tumor was well circumscribed, with homogeneously brown or tan surface color, and lacked evidence of necrosis or hemorrhage. (2) With microscopic examination, the tumor consisted of a uniform population of oncocytic cells with some cellular pleomorphism and nuclear hyperchromatism and eosinophilic cytoplasm. (3) There was no evidence of mitosis or clear cells in any of the histologic slides examined. Eighteen GRCCs were selected for comparison; at least 75% of the neoplastic cells comprised granular cells and none contained more than 25% clear cell RCC component. All tumors were staged using the system of Robson and associates.45 The neoplasms were graded histologically using Fuhrman and colleagues'46 nuclear grading criteria. Nuclear grade was assigned based on the highest grade in each neoplasm. Clinical information was obtained from the hospital medical records. Flow Cytometric Analysis DNA flow cytometric analysis was performed on one to three blocks per neoplasm (mean, 1.3). Tissue was fixed in 4% formaldehyde for 2 to 8 hours and embedded in paraffin (Paraplast Monoject Scientific, St. Louis, MO) with a melting point of 56 °C. Nuclear suspensions of the neoplasms were prepared using a modified version of the method of Hedley and others.47'48 Briefly, three 50-^mthick sections cut from the tissue blocks were deparaffinized in Histo-Solv (Biochemical Sciences Inc., Bridgeport, NJ) and rehydrated in a series of graded alcohols. Disaggregation was accomplished by treatment with 0.5% pepsin (Sigma Chemical Co., St. Louis, MO), pH 1.5, at 37 °C. After 20 minutes the samples were drawn into 3mL syringes through 20-gauge needles and forcefully ex-
FIG. 1. Gross picture of a renal oncocytoma showing a well-circumscribed homogeneous mass with a centralfibrousscar.
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Twenty-three ROs and 18 GRCCs were retrieved from the surgical pathology archives of the M.D. Anderson Cancer Center, Houston, Texas; Victoria Hospital, London, Ontario; Mount Sinai Hospital, Toronto, Ontario; Vancouver General Hospital, Vancouver, British Columbia; and the Canadian Reference Center for Cancer Pathology, Ottawa, Ontario, Canada. These neoplasms were selected during review of approximately 500 renal tumors. All cases from 1985 to 1989, originally diagnosed as RCC or RO with available tissue blocks for flow cytometric analysis, complete gross description of the neoplasms, and extensive sampling of the tumors (at least one block for each centimeter of the tumor), were selected for this study. Gross pathologic appearance of the tumors was obtained from the surgical pathology report. An average of nine (range, 4 to 15) hematoxylin-and-eosin-stained histologic sections per neoplasm were reviewed.
pelled three to four times into disposable culture tubes. Digestion was then terminated by adding 1 mL 0.005% pepstatin solution (Sigma Chemical Co.) and placing the solution on ice. The samples were then centrifuged, washed twice with Dulbecco's phosphate-buffered saline (Gibco Laboratories, Grand Island, NY), and incubated with 0.3 mL freshly prepared RNAse (Worthington Biochemical, Freehold, NJ) at 37 °C for 20 minutes. After the samples were stained with propidium iodide (Sigma Chemical Co.) and filtered through a 37-jtm nylon mesh filter (Small Parts Inc., Miami, FL). In each block selected for analysis, at least 75% of the tissue was neoplastic. In renal cell carcinomas, if possible, tissue blocks with more than 10% necrosis were avoided. Otherwise, the necrotic areas were mapped and non-necrotic tissue was reembedded for flow cytometric analysis. Specimens were analyzed on an EPICS Profile I Flow Cytometer (EPICS Division, Coulter Electronics, Hialeah, FL) equipped with an argon ion laser operating at 488 nm, with a 610-nm-long pass filter and 488 band pass. Flow rates were adjusted to count approximately 75 nuclei per second. Peak versus integral signals were used to gate out doublets. Cytospin slides were prepared from a 106 nuclei/mL concentration (unexposed to RNAse) and stained with Wright's-Giemsa. The slides were reviewed to confirm the presence of tumor nuclei as well as to monitor the quality of processing. In each sample, at least 10,000 nuclei were evaluated. The DNA histograms were analyzed using the "boxogram" gating procedure of Johnston and associates.49 Coulter Cytologic Software, version 2.2, was used only in cases exhibiting excessive debris using the builtin debris substraction model. Non-neoplastic renal tissue in the same tumor block and normal kidney tissue from separate blocks were used as the biologic diploid standard, and the first Gn/G] population was used to denote the diploid stemline.
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Renal Cell Carcinoma
The DNA index is defined as the ratio of the peak channel number of the test sample to the peak channel number of the normal diploid control. By definition, the DNA index of a diploid population is equal to 1.0. A tumor is considered aneuploid when a distinct second G 0 /Gi peak, accounting for at least 10% of the cells analyzed, is present (or any number of such separate peaks). The coefficient of variation for all cases was less than 5%. Statistics The association between the categories was examined using Student's Mest. RESULTS
Clinical. The patient population consisted of 15 men and 8 women whose ages at diagnosis ranged from 42 to 81 years (mean, 64 years). Twenty-two tumors were stage 1 and one tumor was stage Ilia. Twenty-one patients were treated by radical nephrectomy. In two cases the tumors were incidental postmortem findings, submitted to the Canadian Reference Center for Cancer Pathology in pathologic consultation. Twelve patients were alive and disease free from 12 months to 12 years (median, 50 months; mean, 54 months) after operation. Three patients were dead of other causes at 7 months, 34 months, and 17 years after operation. There were no instances of local recurrence or regional lymph nodal or distant metastasis by the tumors. Six patients were lost to follow-up. Gross Pathologic Findings. Tumors were typically described as well-circumscribed, rounded masses with lightbrown to light-tan homogeneous appearance and with or without fibrous bands (Fig. 1). Unlike classical RCCs, there was no mention of variegated appearance, necrosis, or large hemorrhage. Small foci of hemorrhage, however, were described in four neoplasms. Tumors measured from 2 to 12 cm in greatest dimension (mean, 6.4 cm). Microscopic Pathologic Findings. In all neoplasms, polygonal-shaped cells with abundant granular eosinophilic cytoplasm were uniformly present (Fig. 2A). Cells were arranged in clusters, cords, or tubules and contained round nuclei with dense chromatin and some pleomorphism. Eighteen tumors were nuclear grade 2, three tumors were nuclear grade 3, and two tumors were nuclear grade 4. Sixteen tumors contained foci of large oncocytic cells with enlarged pleomorphic nuclei (Fig. 3,4). DNA Flow Cytometric Findings. DNA flow cytometric analysis showed DNA-diploidy (DNA index, 1.0) in 22 tumors (96%), including 21 stage I tumors and one stage Ilia tumor (Fig. 3B). Both intrarenal and intravenous Vol.
B
2n DNA
4-n 6n CONTENT
FIGS. 1A and B. A. Oncocytoma displaying clusters of uniform cells with granular cytoplasm and occasional nuclear enlargement, divided by thin sinusoidal vasculatures. B. Histogram of this oncocytoma showing a diploid peak and an additional shoulder on the down slope, suggesting a near-diploid aneuploid DNA content.
samples of the stage Ilia tumor were DNA-diploid. Neoplasms with enlarged pleomorphic nuclei were also DNAdiploid. In 1 of the 23 cases (4.3%), DNA flow cytometric analysis suggested a near-diploid DNA-aneuploidy (Fig. 2B). There were no histologic features that distinguished this case from DNA-diploid neoplasms. All neoplasms with multiple tissue blocks that were analyzed exhibited homogenous intratumoral DNA content. Granular Cell Renal Carcinoma Clinical. The patient population was composed of 13 men and 5 women whose ages ranged at diagnosis from 30 to 73 years (mean, 53 years). Eleven tumors were stage •No. 6
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Renal Oncocytomas
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ANATOMIC PATHOLOGY Original Article Microscopic Pathologic Findings. All tumors were composed of two tumor cell populations. The predominant population (more than 75%) consisted of polygonalshaped cells with variably granular eosinophilic cytoplasm (Fig. 4A). The smaller population (fewer than 25%) consisted of polygonal-shaped cells with clear cytoplasm. Both cell types displayed prominent cell borders and were arranged in solid sheets or tubules. The cells contained round to irregularly shaped nuclei that varied in nuclear grade. Six tumors were nuclear grade 2, 10 tumors were nuclear grade 3, and 2 tumors were nuclear grade 4. DNA Flow Cytometric Findings. DNAflowcytometric analysis showed DNA-diploidy in 7 tumors (38.9%). One tumor (5.6%) was DNA-tetraploid (DNA index = 2.0) and 10 tumors (55.6%) were DNA-aneuploid (Fig. 4B). Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 5, 2016
c o u N T .dW"^
B
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FIGS 3A and B. A. An oncocytoma showing nuclear pleomorphism. B. DNA histogram of the same tumor displaying a diploid DNA content (CV, 2.2).
I, four tumors were stage II, two tumors were stage Ilia, and one tumor was stage IV. Seventeen patients were treated with radical nephrectomy and in one case the tumor was an incidental postmortem finding. Twelve patients (70%) were alive and disease free from 12 to 36 months (mean, 26 months; median, 24 months). One patient (6%) was alive with metastatic disease at 14 months. Two patients (12%) died of their disease at 11 and 18 months, respectively; two patients (12%) died of other causes; and one patient was lost to follow-up. Gross Pathologic Findings. The gross appearance of the tumors was that of a well-circumscribed solid mass. Tumors measured from 2.3 to 15 cm in greatest dimension (mean, 7.8 cm). Tumors were typically variegated in color with yellow, tan, and white areas admixed with foci of necrosis and/or hemorrhage.
B
2n DNA
4-n CONTENT
FIGS 44 and B. A. Granular renal cell carcinoma showing tumor cells with the increased nuclear cytoplasmic ratio, the variability in the nuclear chromatin, and the nucleolar prominence. B. A single parameter histogram of this neoplasm showing aneuploid DNA stemline diploid index of 1.36.
A.J.C.P. • December 1992
HARTWICK ET AL. Renal Oncocytoma and Granular Renal Cell Carcinoma All patients with DNA-diploid tumors, the 1 patient with DN A-tetraploid tumor, and 5 ofthe 10 patients with DN Aaneuploid neoplasms pursued benign clinical courses. The three patients with aggressive clinical outcome had DNAaneuploid tumors. All but two neoplasms with multiple tissue blocks analyzed manifested intratumoral DNA homogeneity. In these two instances, DNA-diploidy and aneuploidy were noted in different neoplastic blocks. The difference between the percentages of DNA-nondiploidy of RO (4.3%) and GRCC (55.5%) was statistically significant (P < 0.001).
DISCUSSION
but rather the extent of such aberration that affects the biologic course of a given neoplasm. Our results concur with those of Eble and Sledge59 and Psihramis and Goldberg,60 but differ from those of Rainwater and associates.61 In the latter study,61 however, only 15% of the neoplasms manifested DNA-aneuploidy and the remaining 85% of the neoplasms displayed diploid or tetraploid DNA content. The major difference between our study and that of Rainwater and associates61 is the high incidence of tetraploid DNA in their neoplasms. Given the current lack of standardized criteria for defining tetraploidy, as well as its biologic significance and whether it reflects a significant cytogenetic event in tumors, it may be beneficial to combine them with DNA-diploid neoplasms. Tetraploidy aside, the low incidence of aneuploidy in their study corresponds, in general, with our findings. Our findings and those of others59,60 in RO differ significantly from those in RCC. Our data also indicate a significant clinical and DNA content difference between strictly defined ROs and GRCCs. None of the patients with RO in our series displayed recurrence, metastasis, or death, whereas 18% of GRCCs manifested aggressive behavior and DNA aneuploidy despite the relatively short follow-up period. It must be realized, however, that approximately 25% of our patients were lost to follow-up. The DNA content analysis and the biologic course of the GRCCs in our study, however, are comparable to those in previous studies of RCCs.62"72 Our study indicates that strictly defined ROs manifest significantly different clinical behavior and DNA content from typical GRCCs. Therefore it supports the recognition of ROs as a distinct clinicopathologic entity in the spectrum of renal cortical tumors. Acknowledgments. The authors thank Anna Litvan for administrative assistance, Diane Jeans for technical assistance, Elsa Ramos for photographic assistance, and Sulema M. Martinez for typing the manuscript.
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Renal oncocytoma is an uncommon renal cortical neoplasm with controversial clinicopathologic features.2"19,39'44 Earlier reports have distinctly separated ROs from conventional RCCs based on histopathologic as well as biologic differences.1315 Subsequent studies, however, contradicted these findings and argued against the merit of separating these neoplasms.' 729,3 '" 35,37,39,4 '" 43 Several studies of small numbers of ROs have documented a malignant outcome.39,42,43 In these studies, the extent of histologic sampling and the gross appearance of the tumors were either absent or not sufficiently described. Furthermore, hybrid tumors with both RO and RCC features, called "congeners of RO," have been described.17 Central to this dispute is the strictness of the criteria by which RO is clearly distinguished from predominantly GRCC. 7,40,44 The implication of this, therefore, is that some of the later studies may have included GRCC in their population and consequently led to the purported aggressive behavior of RO. We contend that a comparative study of strictly defined groups of these neoplasms may be useful in settling this controversy. Our data support that RO is a distinct renal neoplasm with morphologic, DNA flow cytometric, and biologic characteristics that set it apart from predominantly granular RCC and other forms of RCC. In ROs with and without nuclear atypia, a benign clinical course ensued. Similarly, none of these neoplasms manifested abnormal DNA content, except for one neoplasm that displayed a DNA pattern suggestive of near-diploid aneuploidy. Although such a feature may not be considered conclusive evidence of aneuploid DNA content, it did represent a deviation from the other neoplasms. The mere presence of DNA-aneuploidy may not necessarily connote a malignant condition. There has been previous documentation of aneuploid DNA patterns in several benign neoplastic diseases,50"58 and in these neoplasms, near-diploid stemlines were expressed. In that context, it may not be the presence of DNA-aneuploidy
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