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Cytogenetic analysis of six renal oncocytomas and a chromophobe cell renal carcinoma
Cytogenetic Analysis of Six Renal Oncocytomas and a Chromophobe Cell Renal Carcinoma Evidence That - Y , - 1 May Be a Characteristic Anomaly in Renal Oncocytomas Thomas B. Crotty, Kim M. Lawrence, Cheryl A. Moertel, Duane H. Bartelt, Jr., Kenneth P. Batts, Gordon W. Dewald, George M. Farrow, and Robert B. Jenkins
ABSTRACT: Renal oncocytomas are benign tumors whose morphologic features may sometimes be confused with those of certain low-grade malignant neoplasms of the kidney, e.g., chromophobe cell and granular cell variants of renal carcinoma. The presence of a specific genetic abnormality might help differentiate these tumors. Because very few cytogenetic studies of renal oncocytomas have been published, we investigated a consecutive series of six such tumors. We also performed chromosome analysis on a chromophobe cell carcinoma because cytogenetic analyses of this tumor have not been previously reported. Tumor cell metaphases were analyzed after mechanical and enzyme disaggregation, in situ culture, and robotic harvesting. Clonal abnormalities were present in five of the six oncocytomas, and loss of chromosome 1 with loss of the Y chromosome occurred in two. Review of the literature disclosed four other renal oncocytomas with the 4 4 , X , - Y , - 1 karyotype. In the chromophobe cell carcinoma, we noted an abnormal clone with a del(11)(p12p15.1); similar anomalies were not observed in the renal oncocytomas. We conclude that renal oncocytomas have clonal chromosome abnormalities and that a subgroup of these tumors may be specifically associated with loss of chromosomes 1 and Y. Because this is a small series, further investigation may help establish whether cytogenetic studies can provide diagnostic and pathogenic information about renal oncocytomas.
INTRODUCTION The term oncocytoma is applied to tumors composed of epithelial cells with round regular nuclei and abundant granular eosinophilic cytoplasm containing numerous mitochondria. Oncocytomas constitute approximately 5% of all renal neoplasms and are generally considered benign tumors [1-3]. Morphologically, renal oncocytomas may resemble malignant neoplasms of the kidney in which eosinophilic cells are present, such as the granular cell and chromophobe cell variants of renal cell carcinoma [4]. Accurate differentiation between these tumors is of considerable importance clinically because of their differing malignant potential. Only a few reports describing cytogenetic analyses of
From the Section of Surgical Pathology, the Division of Medical Oncolagy, and the Section of Laboratory Genetics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address reprint requests to: Gordon W. Dewald, Ph.D., Cytogenetics Laboratory, Mayo Clinic, 200 First St., SW, Rochester, MN 55905. Received November 18, 1991; accepted January 27, 1992.
renal oncocytomas have been published [5-12], and no specific anomaly has been described. To our knowledge, there are no reports of cytogenetic studies of chromophobe cell or granular cell variants of renal carcinoma. Thus, we performed chromosome studies on six renal oncocytomas and one chromophobe cell carcinoma. We hoped to determine whether oncocytomas have any characteristic cytogenetic abnormalities that could be used to differentiate them from morphologically similar tumors. If there are specific chromosome abnormalities, they may provide clues to the molecular pathogenesis of oncocytic renal neoplasms.
MATERIALS AND METHODS
Cytogenetic analysis was performed on a consecutive series of six oncocytomas and one chromophobe cell renal carcinoma surgically resected at our institution between March 1989 and November 1990. Clinical information for the patients was obtained by review of their medical records. Tumor cell metaphases were analyzed after mechanical and enzyme disaggregation, in situ culture, and robotic harvesting [13]. Metaphase preparations were stained for 61
© 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 61:61-66 (1992) 0165-4608/92/$05.00
62
T . B . Crotty et al.
Table 1
Clinical and Pathologic features of six oncocytomas and one c h r o m o p h o b e cell c a r c i n o m a
Case/Age (yr)/sex 1/83/M 2/64/M 3/65/M 4/73/M 5/74/M 6/57/F 7/58/M
Follow-up (mo)
Status
Tumor (n)
Tumor size (cm)
Morphology
18 24 6 1 6 7 2
A A A D A A A
1 1 2b 2b 1 1 1
4.5 3.1 3.5; 0.2 7.5; 2.5 2.8 5.0 18.0
Oncocytoma Oncocytoma a Oncocytoma Oncocytoma Oncocytoma Oncocytoma Chromophobe
Capsular invasion Absent Absent Absent Present Absent Absent Absent
Abbreviations: A, alive with no evidence of disease; D, dead of unrelated illness. ~'Associated with multiple carcinoid tumors of small bowel. bUnilateral tumors.
c h r o m o s o m e analysis w i t h quinacrine mustard (QFQbanding) and L e i s h m a n ' s stain after trypsinization (GTLbanding). The International System for H u m a n Cytogenetic N o m e n c l a t u r e [14] was used to define the karyotypes of abnormal clones. We defined an abnormal clone as observation of two or more cells w i t h the same c h r o m o s o m e abnormality. These abnormal cells were required to occur in two or more p r i m a r y cultures [15].
RESULTS The clinical and pathologic features for each of the seven cases are s u m m a r i z e d in Table 1. Each of the oncocytomas was well-circumscribed, mahogany-brown, and located in the renal cortex. These tumors were c o m p o s e d of uniform cells with a b u n d a n t granular e o s i n o p h i l i c c y t o p l a s m and small r o u n d nuclei (Fig. 1). Focal capsular invasion was
present in one o n c o c y t o m a (patient 4). Two patients (patients 3 and 4) each had two separate unilateral tumors. In each patient, cytogenetic studies were p e r f o r m e d on only one of the tumors. The c h r o m o p h o b e cell renal c a r c i n o m a was well c i r c u m s c r i b e d and tan. It was c o m p o s e d of large cells with uniform, slightly irregular n u c l e i and reticular eosinophilic c y t o p l a s m (Fig. 2). A l t h o u g h our followup information is limited, the t u m o r d i d not recur nor d i d metastasis occur in any of the seven patients. Clonal c h r o m o s o m e abnormalities were present in five of the six renal oncocytomas (Table 2). In patient 1, each of the cells had an aberrant c h r o m o s o m e 16, w h i c h a p p e a r e d most like a b a l a n c e d paracentric inversion and could have been a constitutional a b n o r m a l i t y rather than part of the neoplastic process. Unfortunately, we d i d not have the o p p o r t u n i t y to study p e r i p h e r a l blood to investigate this possibility. Thirty of the 31 m e t a p h a s e s in this t u m o r were
Figure 1 Renal oncocytoma, characterized by uniform cells with homogeneous eosinophilic cytoplasm and regular round nuclei. (H&E; original magnification × 360.)
Cytogenetics of Renal Oncocytomas
63
Figure 2 Chromophobe cell renal carcinoma, showing moderately r e t i c u l a t e d c y t o p l a s m . (H&E; o r i g i n a l m a g n i f i c a t i o n × 360.)
also lacking a Y c h r o m o s o m e and had m o n o s o m y 1 (Fig. 3). A similar k a r y o t y p e was observed in the tumor from patient 2. The t u m o r cells from patient 3 had m o n o s o m y 22. The tumors from cases 4 and 5 each a p p e a r e d to have two different clones. Seven cells from the tumor of case 4 had m o n o s o m y 21 and an u n b a l a n c e d (15;21) translocation. Four of these cells were lacking a Y chromosome, and three had a b a l a n c e d Y;22 translocation. Eight different cells
Table 2 Case
large cells with slightly atypical nuclei and
from the tumor of patient 4 had a balanced Y;21 translocation. Two cells from the tumor of patient 5 had trisomy 7; six other cells had m o n o s o m y 9 and 20 and had an unidentified marker chromosome. No cytogenetically abnormal clone was identified in patient 6. The chromophobe cell carcinoma had an abnormal clone that involved loss of the Y chromosome and an interstitial deletion for part of a chromosome 11 p-arm (Fig. 4).
Cytogenetic results for six oncocytomas and one c h r o m o p h o b e cell carcinoma Morphology
1
Oncocytoma
2
Oncocytoma
3 4
Oncocytoma Oncocytoma
5
Oncocytoma
6 7
Oncocytoma Chromophobe
Cells 1 24 4 2 1 22 2 30 15 4 3 8 6 2 6 4 30 6 1 1 2
Karyotype a 46,XY,rea(16)(p11.2p13.1) or der(16)t(16;?)(p11.2;?) 4 4 , X , - Y, - 1 , i d e m e n d 4 4 , X , - Y, - 1 , i d e m 8 8 , X X , - Y, - Y, - 1, - 1 , i d e m 46,XY 4 4 , X , - Y, - 1 8 8 , X X , - Y, - Y, - 1, - 1 4 5 , X Y , - 22 46,XY 4 5 , X , - Y , d e r ( 1 5 ) t ( 1 5 ; 2 1 ) ( p 1 1 ; q 1 1 ) , - 21, + m a r 44,X,dic(Y;22)(q11.2;p11),der(15)t(15;21)(p11;q11),45,X,dic(Y;21)(q11.2;p13) 46,XY 47,XY, + 7 4 5 , X Y , - 9, - 20, + m a r Abnormal nonclonal 46,XX 46,XY 45,X, - Y,del(11)(p12p15.1) 90,XX,-Y,Y,del(11)(p12p15.1) x 2 1 3 5 , X X X , - Y, - Y, - Y , d e l ( 1 1 ) ( p 1 2 p 1 5 . 1 ) x 3
21
° R a n d o m loss, obvious t e c h n i c a l artifacts, a n d single a b n o r m a l cells were i n c l u d e d in the clone w i t h the most similar k a r y o t y p e to derive a m o d a l or c o m p o s i t e karyotype.
64
T.B. Crotty et al.
1
2
3
4
6
11
5
1o
t X
| 16
21
17
22
18
Y
F i g u r e 3 A representative GTL-banded karyotype of a renal oncocytoma (patient 1). The karyotype is 44,X, - Y , - 1,rea(16)(p11.2p13.1) or der(16)t(16;?)(p11.2;?).
DISCUSSION The results of this study indicate that chromosomally abnormal clones are common in oncocytomas. Only a few reports dealing with the cytogenetics of renal oncocytomas exist, and none of the investigators has yet suggested any consistent chromosome anomaly (Table 3). In our series, two oncocytomas were 44,X,- Y , - 1 (Table 2). The coincident loss of a Y chromosome and chromosome 1 has been described in four other renal oncocytomas [8, 9,12]. Weaver et al. [16] reported similar abnormalities in a renal tumor of unspecified type. We are not aware that the coincident loss of a Y chromosome and chromosome 1 as the sole
abnormality has been reported in other solid tumors; thus, this cytogenetic finding may be specific for some renal oncocytomas. That many of the reported oncocytomas had different chromosome abnormalities not including - Y, - 1 suggests, however, that oncocytomas comprise a cytogenetically heterogeneous group of tumors with potential cytogenetic subsets. Although in most cases renal oncocytomas can be easily differentiated from morphologically similar tumors, such as the granular cell and chromophobe cell variants of renal carcinoma, detection of 44,X, - Y, - 1 may be diagnostically helpful in problem cases. Further studies and longer follow-up will be necessary to determine
F i g u r e 4 GTL-banded chromosomes 11 from two ceils of a chromophobe cell renal carcinoma (patient 7). Arrows: A del(11)(p12p15.1).
Cytogenetics of Renal Oncocytomas
Table 3
65
Previously reported cytogenetic abnormalities in oncocytomas No. of cases
Reference
Normal
Abnormal
[5] [6]
0 0
1° 1
[8] [9] [10]
0 1 0
[11] [12]
0 1
1 1 1 1 1 2
Summary of clonal abnormalities 46,X,-X,+ 7,+ 7 , - 12 45,X,- X,rcp(8;19),der(13)t(X;13)(q11;p13) 46,XY,del(1)(q21),der(13)t(1;13)(q21;q34) 44,X,- Y, - 1 44,X,-Y,- 1 45,XY, - 19, - 20, + mar Various nonclonal aberrations 46,XY,t(9;11)(p23;ql 2) -Y,-1
° This patient had bilateral tumors with identical chromosomeabnormalities.
whether the 44,X, - Y, - 1 karyotype has prognostic significance. The tumor from patient 3 in our series was an oncocytoma, and its karyotype was 4 5 , X X , - 22. Monosomy 22 is c o m m o n in brain tumors, especially meningiomas [17]. Although oncocytomas may have little in c o m m o n with meningiomas, the u n d e r l y i n g molecular pathogenesis may be similar. None of the abnormalities we noted in the tumors from patients 4 and 5 were observed in previously reported renal oncocytomas. Tetraploid cells were observed in three tumors in our series. In each, the tetraploid cells appeared to be derived from an abnormal near-diploid clone. This conclusion is based on observation of two copies of the primary chromosome abnormalities in the near-tetraploid cells and only one copy of these abnormalities in the near-diploid clone. In patient 1, we suspect that the tetraploid cells may have resulted from e n d o r e d u p l i c a t i o n because we observed m a n y endoreduplicated cells with the same abnormalities as those in both the diploid and the polyploid cells. Endoreduplication has been proposed as a m e c h a n i s m for polyploidy in other tumors [18]. Tetraploid cells have been detected by flow cytometry in oncocytomas [19], and occasional bizarre cells with large nuclei are c o m m o n in m a n y of these tumors [3]. The chromophobe cell carcinoma in our series appears to be the first for which results of cytogenetic studies have been reported. The tumor had a deletion for part of the short arm of chromosome 11. Similar anomalies occur in some Wilms' tumors of the kidney [20]. Chromophobe cell carcinoma and Wilms' tumor of the kidney are markedly different neoplasms in terms of both their clinical features and their pathobiology. Observation of similar chromosome 11 abnormalities may suggest a c o m m o n molecular pathogenesis in these tumors. REFERENCES
1. Klein MJ, Valensi QJ (1976): Proximal tubular adenomas of kidney with so-called oncocytic features: A clinicopathologic study of 13 cases of a rarely reported neoplasm. Cancer 38:906-914. 2. Lieber MM, Tomera KM, Farrow GM (1981): Renal oncocytoma. J Urol 125:481-485.
3. Farrow GM (1989): Diseases of the kidney. In: Urological Pathology, WM Murphy, ed. W.B. Saunders, Philadelphia, pp. 445-451. 4. Thoenes W, St6rkel ST, Rumpelt H-J, Moll R, Baum HP, Werner S (1988): Chromophobe cell renal carcinoma and its variants--a report on 32 cases. J Pathol 155:277-287. 5. Psihramis KE, Althausen AF, Yoshida MA, Prout GR Jr, Sandberg AA (1986): Chromosome anomalies suggestive of malignant transformation in bilateral renal oncocytoma. J Urol 136:892-895. 6. Kovacs G, Sztics S, Eichner W, Maschek H-J, Wahnschaffe U, De Riese W (1987): Renal oncocytoma: A cytogenetic and morphologic study. Cancer 59:2071-2077. 7. Kovacs G, Mtiller-Brechlin R, Szt~cs S (1987): Telomeric association in two human renal tumors. Cancer Genet Cytogenet 28:363-366. 8. Psihramis KE, Dal Cin P, Dretler SP, Prout GR Jr, Sandberg AA (1988): Further evidence that renal oncocytoma has malignant potential. J Urol 139:585-587. 9. Miles J, Michalski K, Kouba M, Weaver DJ (1988): Genomic defects in nonfamilial renal cell carcinoma: Possible specific chromosome change. Cancer Genet Cytogenet 34:135-142. 10. Kovacs G, Welter C, Wilkens L, Blin N, Deriese W (1989): Renal oncocytoma: A phenotypic and genotypic entity of renal parenchymal tumors. Am J Pathol 134:967-971. 11. Walter TA, Pennington RD, Decker H-JH, Sandberg AA (1989): Translocation t(9;11)(p23;q12): A primary chromosomal change in renal oncocytoma. J Urol 142:117-119. 12. Jordan D, Sheffield V, Divelbiss J, Waziri M, Duyk G, Patil S (1991): Cytogenetic abnormalities and absence of p53 mutations in renal tumors, pheochromocytomas, and hemangioblastomas. Am J Hum Genet 49(suppl):242. 13. Spurbeck JL, Carlson RO, Allen JE, Dewald GW (1988): Culturing and robotic harvesting of bone marrow, lymph nodes, peripheral blood, fibroblasts, and solid tumors with in situ techniques. Cancer Genet Cytogenet 32:59-66. 14. ISCN (1985): An International System for Human Cytogenetic Nomenclature, Harnden DG, Klinger HP (eds); published in collaboration with Cytogenet Cell Genet (Karger, Basel 1985); also in Birth Defects: Original Article Series, Vol. 21, No. 1 (March of Dimes Birth Defects Foundation, New York 1985). 15. Jenkins RB, Kimmel DW, Moertel CA, Schultz CG, Scheithauer BW, Kelly PJ, Dewald GW (1989): A cytogenetic study of 53 human gliomas. Cancer Genet Cytogenet 39:253-279. 16. Weaver DJ, Michalski K, Miles J (1988): Cytogenetic analysis in renal cell carcinoma: Correlation with tumor aggressiveness. Cancer Res 48:2887-2889.
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17. Zang KD (1982): Cytological and cytogenetical studies on human meningioma. Cancer Genet Cytogenet 6:249-274. 18. Muleris M, Delattre O, Olschwang S, Dutrillaux A-M, Remvikos Y, Salmon R-J, Thomas G, Dutrillaux B (1990): Cytogenetic and molecular approaches of polyploidization in colorectal adenocarcinomas. Cancer Genet Cytogenet 44:107-118.
T . B . Crotty et al.
19. Rainwater LM, Farrow GM, Lieber MM (1986): Flow cytometry of renal oncocytoma: Common occurrence of deoxyribonucleic acid polyploidy and aneuploidy. J Urol 135:11671171. 20. Slater RM (1986): The cytogenetics of Wilms' tumor. Cancer Genet Cytogenet 19:37-41.
ABSTRACT: Renal oncocytomas are benign tumors whose morphologic features may sometimes be confused with those of certain low-grade malignant neoplasms of the kidney, e.g., chromophobe cell and granular cell variants of renal carcinoma. The presence of a specific genetic abnormality might help differentiate these tumors. Because very few cytogenetic studies of renal oncocytomas have been published, we investigated a consecutive series of six such tumors. We also performed chromosome analysis on a chromophobe cell carcinoma because cytogenetic analyses of this tumor have not been previously reported. Tumor cell metaphases were analyzed after mechanical and enzyme disaggregation, in situ culture, and robotic harvesting. Clonal abnormalities were present in five of the six oncocytomas, and loss of chromosome 1 with loss of the Y chromosome occurred in two. Review of the literature disclosed four other renal oncocytomas with the 4 4 , X , - Y , - 1 karyotype. In the chromophobe cell carcinoma, we noted an abnormal clone with a del(11)(p12p15.1); similar anomalies were not observed in the renal oncocytomas. We conclude that renal oncocytomas have clonal chromosome abnormalities and that a subgroup of these tumors may be specifically associated with loss of chromosomes 1 and Y. Because this is a small series, further investigation may help establish whether cytogenetic studies can provide diagnostic and pathogenic information about renal oncocytomas.
INTRODUCTION The term oncocytoma is applied to tumors composed of epithelial cells with round regular nuclei and abundant granular eosinophilic cytoplasm containing numerous mitochondria. Oncocytomas constitute approximately 5% of all renal neoplasms and are generally considered benign tumors [1-3]. Morphologically, renal oncocytomas may resemble malignant neoplasms of the kidney in which eosinophilic cells are present, such as the granular cell and chromophobe cell variants of renal cell carcinoma [4]. Accurate differentiation between these tumors is of considerable importance clinically because of their differing malignant potential. Only a few reports describing cytogenetic analyses of
From the Section of Surgical Pathology, the Division of Medical Oncolagy, and the Section of Laboratory Genetics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address reprint requests to: Gordon W. Dewald, Ph.D., Cytogenetics Laboratory, Mayo Clinic, 200 First St., SW, Rochester, MN 55905. Received November 18, 1991; accepted January 27, 1992.
renal oncocytomas have been published [5-12], and no specific anomaly has been described. To our knowledge, there are no reports of cytogenetic studies of chromophobe cell or granular cell variants of renal carcinoma. Thus, we performed chromosome studies on six renal oncocytomas and one chromophobe cell carcinoma. We hoped to determine whether oncocytomas have any characteristic cytogenetic abnormalities that could be used to differentiate them from morphologically similar tumors. If there are specific chromosome abnormalities, they may provide clues to the molecular pathogenesis of oncocytic renal neoplasms.
MATERIALS AND METHODS
Cytogenetic analysis was performed on a consecutive series of six oncocytomas and one chromophobe cell renal carcinoma surgically resected at our institution between March 1989 and November 1990. Clinical information for the patients was obtained by review of their medical records. Tumor cell metaphases were analyzed after mechanical and enzyme disaggregation, in situ culture, and robotic harvesting [13]. Metaphase preparations were stained for 61
© 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 61:61-66 (1992) 0165-4608/92/$05.00
62
T . B . Crotty et al.
Table 1
Clinical and Pathologic features of six oncocytomas and one c h r o m o p h o b e cell c a r c i n o m a
Case/Age (yr)/sex 1/83/M 2/64/M 3/65/M 4/73/M 5/74/M 6/57/F 7/58/M
Follow-up (mo)
Status
Tumor (n)
Tumor size (cm)
Morphology
18 24 6 1 6 7 2
A A A D A A A
1 1 2b 2b 1 1 1
4.5 3.1 3.5; 0.2 7.5; 2.5 2.8 5.0 18.0
Oncocytoma Oncocytoma a Oncocytoma Oncocytoma Oncocytoma Oncocytoma Chromophobe
Capsular invasion Absent Absent Absent Present Absent Absent Absent
Abbreviations: A, alive with no evidence of disease; D, dead of unrelated illness. ~'Associated with multiple carcinoid tumors of small bowel. bUnilateral tumors.
c h r o m o s o m e analysis w i t h quinacrine mustard (QFQbanding) and L e i s h m a n ' s stain after trypsinization (GTLbanding). The International System for H u m a n Cytogenetic N o m e n c l a t u r e [14] was used to define the karyotypes of abnormal clones. We defined an abnormal clone as observation of two or more cells w i t h the same c h r o m o s o m e abnormality. These abnormal cells were required to occur in two or more p r i m a r y cultures [15].
RESULTS The clinical and pathologic features for each of the seven cases are s u m m a r i z e d in Table 1. Each of the oncocytomas was well-circumscribed, mahogany-brown, and located in the renal cortex. These tumors were c o m p o s e d of uniform cells with a b u n d a n t granular e o s i n o p h i l i c c y t o p l a s m and small r o u n d nuclei (Fig. 1). Focal capsular invasion was
present in one o n c o c y t o m a (patient 4). Two patients (patients 3 and 4) each had two separate unilateral tumors. In each patient, cytogenetic studies were p e r f o r m e d on only one of the tumors. The c h r o m o p h o b e cell renal c a r c i n o m a was well c i r c u m s c r i b e d and tan. It was c o m p o s e d of large cells with uniform, slightly irregular n u c l e i and reticular eosinophilic c y t o p l a s m (Fig. 2). A l t h o u g h our followup information is limited, the t u m o r d i d not recur nor d i d metastasis occur in any of the seven patients. Clonal c h r o m o s o m e abnormalities were present in five of the six renal oncocytomas (Table 2). In patient 1, each of the cells had an aberrant c h r o m o s o m e 16, w h i c h a p p e a r e d most like a b a l a n c e d paracentric inversion and could have been a constitutional a b n o r m a l i t y rather than part of the neoplastic process. Unfortunately, we d i d not have the o p p o r t u n i t y to study p e r i p h e r a l blood to investigate this possibility. Thirty of the 31 m e t a p h a s e s in this t u m o r were
Figure 1 Renal oncocytoma, characterized by uniform cells with homogeneous eosinophilic cytoplasm and regular round nuclei. (H&E; original magnification × 360.)
Cytogenetics of Renal Oncocytomas
63
Figure 2 Chromophobe cell renal carcinoma, showing moderately r e t i c u l a t e d c y t o p l a s m . (H&E; o r i g i n a l m a g n i f i c a t i o n × 360.)
also lacking a Y c h r o m o s o m e and had m o n o s o m y 1 (Fig. 3). A similar k a r y o t y p e was observed in the tumor from patient 2. The t u m o r cells from patient 3 had m o n o s o m y 22. The tumors from cases 4 and 5 each a p p e a r e d to have two different clones. Seven cells from the tumor of case 4 had m o n o s o m y 21 and an u n b a l a n c e d (15;21) translocation. Four of these cells were lacking a Y chromosome, and three had a b a l a n c e d Y;22 translocation. Eight different cells
Table 2 Case
large cells with slightly atypical nuclei and
from the tumor of patient 4 had a balanced Y;21 translocation. Two cells from the tumor of patient 5 had trisomy 7; six other cells had m o n o s o m y 9 and 20 and had an unidentified marker chromosome. No cytogenetically abnormal clone was identified in patient 6. The chromophobe cell carcinoma had an abnormal clone that involved loss of the Y chromosome and an interstitial deletion for part of a chromosome 11 p-arm (Fig. 4).
Cytogenetic results for six oncocytomas and one c h r o m o p h o b e cell carcinoma Morphology
1
Oncocytoma
2
Oncocytoma
3 4
Oncocytoma Oncocytoma
5
Oncocytoma
6 7
Oncocytoma Chromophobe
Cells 1 24 4 2 1 22 2 30 15 4 3 8 6 2 6 4 30 6 1 1 2
Karyotype a 46,XY,rea(16)(p11.2p13.1) or der(16)t(16;?)(p11.2;?) 4 4 , X , - Y, - 1 , i d e m e n d 4 4 , X , - Y, - 1 , i d e m 8 8 , X X , - Y, - Y, - 1, - 1 , i d e m 46,XY 4 4 , X , - Y, - 1 8 8 , X X , - Y, - Y, - 1, - 1 4 5 , X Y , - 22 46,XY 4 5 , X , - Y , d e r ( 1 5 ) t ( 1 5 ; 2 1 ) ( p 1 1 ; q 1 1 ) , - 21, + m a r 44,X,dic(Y;22)(q11.2;p11),der(15)t(15;21)(p11;q11),45,X,dic(Y;21)(q11.2;p13) 46,XY 47,XY, + 7 4 5 , X Y , - 9, - 20, + m a r Abnormal nonclonal 46,XX 46,XY 45,X, - Y,del(11)(p12p15.1) 90,XX,-Y,Y,del(11)(p12p15.1) x 2 1 3 5 , X X X , - Y, - Y, - Y , d e l ( 1 1 ) ( p 1 2 p 1 5 . 1 ) x 3
21
° R a n d o m loss, obvious t e c h n i c a l artifacts, a n d single a b n o r m a l cells were i n c l u d e d in the clone w i t h the most similar k a r y o t y p e to derive a m o d a l or c o m p o s i t e karyotype.
64
T.B. Crotty et al.
1
2
3
4
6
11
5
1o
t X
| 16
21
17
22
18
Y
F i g u r e 3 A representative GTL-banded karyotype of a renal oncocytoma (patient 1). The karyotype is 44,X, - Y , - 1,rea(16)(p11.2p13.1) or der(16)t(16;?)(p11.2;?).
DISCUSSION The results of this study indicate that chromosomally abnormal clones are common in oncocytomas. Only a few reports dealing with the cytogenetics of renal oncocytomas exist, and none of the investigators has yet suggested any consistent chromosome anomaly (Table 3). In our series, two oncocytomas were 44,X,- Y , - 1 (Table 2). The coincident loss of a Y chromosome and chromosome 1 has been described in four other renal oncocytomas [8, 9,12]. Weaver et al. [16] reported similar abnormalities in a renal tumor of unspecified type. We are not aware that the coincident loss of a Y chromosome and chromosome 1 as the sole
abnormality has been reported in other solid tumors; thus, this cytogenetic finding may be specific for some renal oncocytomas. That many of the reported oncocytomas had different chromosome abnormalities not including - Y, - 1 suggests, however, that oncocytomas comprise a cytogenetically heterogeneous group of tumors with potential cytogenetic subsets. Although in most cases renal oncocytomas can be easily differentiated from morphologically similar tumors, such as the granular cell and chromophobe cell variants of renal carcinoma, detection of 44,X, - Y, - 1 may be diagnostically helpful in problem cases. Further studies and longer follow-up will be necessary to determine
F i g u r e 4 GTL-banded chromosomes 11 from two ceils of a chromophobe cell renal carcinoma (patient 7). Arrows: A del(11)(p12p15.1).
Cytogenetics of Renal Oncocytomas
Table 3
65
Previously reported cytogenetic abnormalities in oncocytomas No. of cases
Reference
Normal
Abnormal
[5] [6]
0 0
1° 1
[8] [9] [10]
0 1 0
[11] [12]
0 1
1 1 1 1 1 2
Summary of clonal abnormalities 46,X,-X,+ 7,+ 7 , - 12 45,X,- X,rcp(8;19),der(13)t(X;13)(q11;p13) 46,XY,del(1)(q21),der(13)t(1;13)(q21;q34) 44,X,- Y, - 1 44,X,-Y,- 1 45,XY, - 19, - 20, + mar Various nonclonal aberrations 46,XY,t(9;11)(p23;ql 2) -Y,-1
° This patient had bilateral tumors with identical chromosomeabnormalities.
whether the 44,X, - Y, - 1 karyotype has prognostic significance. The tumor from patient 3 in our series was an oncocytoma, and its karyotype was 4 5 , X X , - 22. Monosomy 22 is c o m m o n in brain tumors, especially meningiomas [17]. Although oncocytomas may have little in c o m m o n with meningiomas, the u n d e r l y i n g molecular pathogenesis may be similar. None of the abnormalities we noted in the tumors from patients 4 and 5 were observed in previously reported renal oncocytomas. Tetraploid cells were observed in three tumors in our series. In each, the tetraploid cells appeared to be derived from an abnormal near-diploid clone. This conclusion is based on observation of two copies of the primary chromosome abnormalities in the near-tetraploid cells and only one copy of these abnormalities in the near-diploid clone. In patient 1, we suspect that the tetraploid cells may have resulted from e n d o r e d u p l i c a t i o n because we observed m a n y endoreduplicated cells with the same abnormalities as those in both the diploid and the polyploid cells. Endoreduplication has been proposed as a m e c h a n i s m for polyploidy in other tumors [18]. Tetraploid cells have been detected by flow cytometry in oncocytomas [19], and occasional bizarre cells with large nuclei are c o m m o n in m a n y of these tumors [3]. The chromophobe cell carcinoma in our series appears to be the first for which results of cytogenetic studies have been reported. The tumor had a deletion for part of the short arm of chromosome 11. Similar anomalies occur in some Wilms' tumors of the kidney [20]. Chromophobe cell carcinoma and Wilms' tumor of the kidney are markedly different neoplasms in terms of both their clinical features and their pathobiology. Observation of similar chromosome 11 abnormalities may suggest a c o m m o n molecular pathogenesis in these tumors. REFERENCES
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