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Hybrid chromophobe renal cell neoplasm
ARTICLE IN PRESS
Pathology – Research and Practice 201 (2005) 385–389 www.elsevier.de/prp
ORIGINAL ARTICLE
Hybrid chromophobe renal cell neoplasm Kien T. Maia,b,, Prashant Dhamanaskarb, Eric Belangerb, William A. Stinsona,b a Division of Anatomical Pathology, Department of Laboratory Medicine, The Ottawa Hospital – Civic Campus, 1053 Carling Avenue, Ottawa, Ont., Canada, K1Y 4E9 b Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ont., Canada
Received 21 June 2004; accepted 30 March 2005
Abstract Hybrid renal cell neoplasms (HRCNs) containing areas of tumor cells displaying cytological features of chromophobe renal cell carcinoma (CHRCC) and renal oncocytoma (RO) have been recently described in patients with renal oncocytosis and Birt–Hogg–Dube (BHD) syndrome (autosomal dominant genodermatosis). In this study, we identified cases of sporadic HRCN. We reviewed 425 consecutive renal cell carcinomas (RCC), 18 CHRCC, six HRCN, and 25 RO. Five HRCN were identified, including four from the group of RCC and two from RO. Patient age ranged from 40 to 68 years (mean age: 54 years), and the male:female ratio was 4:1. Tumors measured from 1.8 to 5 cm (mean diameter: 3.0 cm). Tumoral necrosis was not seen. Vascular invasion into medium-sized veins was identified in one HRCN. Chromophobe cells accounted for 20–80% of the tumors. Hale’s colloidal stain showed weak to moderate diffuse cytoplasmic staining in scattered cells corresponding to those displaying routine staining features of chromophobe cells. Areas of oncocytic cells in studied tumors and control oncocytomas showed negative or focal cytoplasmic staining usually bordering extra- or intra-cytoplasmic lumina. Immunostaining for cytokeratin 7 and vimentin showed focal immunoreactivity in three cases and negative reactivity in all six cases, respectively. None of the study cases had microscopic RO, as commonly seen in renal oncocytosis, or were associated with BHD syndrome Sporadic HRCN accounted for 1% of RCC. They were of smaller size than RCC and were associated with a favorable prognosis. r 2005 Elsevier GmbH. All rights reserved.
Introduction Chromophobe renal cell carcinoma (CHRCC) accounts for about 5% of renal cell carcinoma (RCC) [24]. It is distinguished from clear cell RCC and papillary RCC by the characteristic chromophil cytoplasm seen Corresponding author. Anatomical Pathology, The Ottawa Hospital, Civic Campus, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. Tel.: +613 761 4344; fax: +613 761 4846. E-mail address: [email protected] (K.T. Mai).
0344-0338/$ - see front matter r 2005 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2005.03.008
with eosin or phloxin stain [23]. Cytogenetically, CHRCC is associated with various combinations of allelic loss of chromosomes 2, 6, 10, 13, and 17 [8,19]. Immunohistochemically, it shares lectin and immunological markers of the intercalated cells and oncocytoma [3,6,12,13,18,20]. Recently, hybrid renal cell neoplasm (HRCN), having an admixture of areas of CHRCC and areas consisting of oncocytes, have been described in patients presenting multiple renal oncocytomas (ROs) and Birt–Hogg–Dube (BHD) syndrome (autosomal dominant genodermatosis) [2,14,20,22]. In this study,
ARTICLE IN PRESS 386
K.T. Mai et al. / Pathology – Research and Practice 201 (2005) 385–389
Table 1. #
1 2 3 4 5
Summary of clinical and pathological features of study cases
Age
45 56 40 62 68
Gender
M M M F M
Tumor diameter
2.5 1.8 2.5 5 3.5
% of chromophobe cells
30% 20% 80% 60% 45%
Associated with CHRCC
RO
+
+
VI
Follow-up
+
1 year, ND 5 years, ND 14 years, ND 10 years, ND 5 years, ND
M: male, F: female, VI: venous invasion, ND: no disease.
we reviewed cases of renal epithelial neoplasms at our institution to identify cases of sporadic HRCN and to study the clinical behavior of this entity.
Materials and methods Files at the Anatomical Pathology Laboratory of the Ottawa Hospital, from 1983 to 2002, and General Campus, from 1999 to 2002, were reviewed to identify HRCN. Oncocytic cells were defined as tubular cells having prominent abundant granular eosinophilic cytoplasm. CHRCC was diagnosed using mainly the current cytoplasmic criteria with H&E staining. The diagnosis was supported by their positive reaction with Hale’s colloidal stain. Each surgical specimen was represented by 3–12 sections, stained with hematoxylin–phloxin–saffron or H&E. HRCN was diagnosed when single or groups of chromophobe cells were identified and accounted for more than 20% of the tumor mass represented by available microscopic sections. Due to the presence of ‘‘pale’’ cells and occasional oncocytic cells showing a peri-nuclear halo that may mimic chromophobe cells in RO and the frequent weakly positive staining for Hale’s colloidal iron in chromophobe cells, we arbitrarily excluded cases having less than 20% ‘‘chromophobe-like’’ cells from the group of HCRN. The size of the lesions was taken from the gross description of the specimen after formalin fixation or by measurement of the lesion on the glass slide. One representative tissue block of each tumor was used for immunostaining. Immunostaining was done on the formalinfixed tissue sections using the avidin–biotin peroxidase complex (ABC) method with an ABC kit (Vector Laboratories, Burlingame, CA, USA) for cytokeratin cytokeratin 7
(Dako dilution 1:200) and vimentin (Dako, dilution 1:100). Clinical follow-up of up to 17 years was available for the majority of cases. A t-test was performed to analyze the statistical significance of the results.
Results There were 403 consecutive non-chromophobe RCC, 18 CHRCC, six HRCN, and 23 oncocytomas. CHRCC were characterized by chromophobe cells with conspicuous cytoplasmic membrane, ballooned, reticulated, or eosinophilic cytoplasm that had a decreased tinctorial staining as compared to the cytoplasmic membrane. Nuclear halo was frequently seen in tumor cells with eosinophilic cytoplasm. Nuclei frequently displayed varying degrees of ‘‘raisinoid’’ changes. Focal areas with features of oncocytoma were not seen. All oncocytomas were distinguished from CHRCC by the cytoplasm that was granular and eosinophilic with indiscernible cytoplasmic borders. Peri-nuclear halos were occasionally and barely seen in focal areas. Pale cells in oncocytomas were distinguished from chromophobe cells by the absence of the peri-nuclear halo and the distinct cytoplasmic borders. For five HRCN, patient age ranged from 40 to 68 years (mean age: 54 years). The male:female ratio was 4:1. The tumors measured from 1.2 to 5.0 cm (mean diameter: 3.0 cm) in greatest diameter. Two HRCN were associated with CHRCC and oncocytomas (Table 1). All associated oncocytomas measured more than 1 cm in
Fig. 1–3. 1. Case 1: HRCN with a history of CHRCC and a synchronous RO. (A) A poorly delineated nodule formed by chromophobe cells in RO. (B) A high magnification of the transitional area between RO and nodule of chromophobe cells. Note the conspicuous cell borders, translucent cytoplasm, and large raisinoid nuclei of chromophobe cells (arrowhead) as compared with indistinct cell borders, dense or occasionally light cytoplasm (arrow), and round or oval nuclei smooth nuclear contour in RO. (C) Hale’s colloidal iron stain showing positive staining in large cytoplasmic portions in the nodule of chromophobe cells and negative staining or focal cytoplasmic staining in RO cells (arrow). 2. Case 3: HRCN predominantly formed by chromophobe cells (80% of tumor cells) with vascular invasion. (A) The tumor with thick capsule and vascular invasion. (B) An area of tumor with a mass of chromophobe cells and focus of chromophobe cells intermingled with oncocytic cells (arrows). (C) Hale’s colloidal iron stain showing positive staining in chromophobe cells and negative staining in RO cells. 3. Case 5: HRCN with 50% of chromophobe cells in the upper half of the photomicrographs. (A, B) Low and high magnification showing area of chromophobe cells and area of RO. (C) Hale’s colloidal iron stain and immunostaining for cytokeratin 70 showing positive staining in the chromophobe cell component and almost negative staining in RO cells.
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diameter. The studied tumors were either encapsulated (three cases) or circumscribed with focal infiltrating borders. The proportion of chromophobe cells ranged from 20% to 80% of the total neoplastic cells. Case 3 (Table 1) displayed an admixture of single and small groups of oncocytic cells and chromophobe cells. Chromophobe and oncocytic cells were either disposed
387
in small or large areas or were intermingled into each other. All oncocytic cells did not have peri-nuclear halos or discernible cytoplasmic membranes. Vascular invasion into medium-sized veins was identified in one HRCN. None of the patients in this study developed recurrent or metastatic diseases for a clinical follow-up from 1 to 14 years (Table 1, Figs. 1–3).
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Hale’s colloidal stain showed a weak to moderate, diffuse staining in scattered cells corresponding to those displaying routine staining features of chromophobe cells. Areas typical for oncocytoma in studied tumors and control oncocytomas showed negative staining or focal cytoplasmic staining usually bordering extra- or intra-cytoplasmic lumina. The control CHRCC showed moderate to strong diffuse staining. Immunostaining for CK7 and VIM showed focal immunoreactivity in three cases and negative reactivity in all six cases, respectively.
Discussion In the setting of this study, five cases displayed features intermediate between RO and CHRCC due to: (a) an admixture of areas typical of RO and CHRCC or (b) the presence of scattered chromophobe cells varying from 20% to 80% of neoplastic cells in the background of RO and (c) immunostaining features intermediate between RO and CHRCC [9,21,25]. Tumors with similar histopathological features have been recently described in patients having oncocytosis and BHD syndrome [14,22]. Oncocytosis is characterized by multiple microscopic, small and large-sized oncocytomas, CHRCC, and HRCN [10,22]. Furthermore, BHD is frequently associated with oncocytosis. Cytogenetically, there is a subset of oncocytoma sharing the same loss of chromosomes 1 and Y, as seen in CHRCC [1,4,5,7,15,17]. This subset of RO may represent a precursor of CHRCC, with HRCN representing an intermediate stage. Review of medical literature on sporadic renal cell neoplasms reveals one report describing a similar neoplasm [11]. All the tumors, including those in our five cases, as well as cases previously reported, were relatively small, circumscribed, or encapsulated [5,22]. Clinical outcome was not available for previously reported cases; however, none of our cases was associated with lymph node or distant metastasis for a follow-up period from 1 to 14 years despite the presence of tumoral invasion into a small vessel associated with one of the tumors. We believe it is appropriate to designate the studied tumor as HRCN instead of RCC. Recognition of HRCN as an entity that may occur in patients with or without BHD or renal oncocytosis is important, since it may have a biological behavior different from RO and CHRCC. RO usually is a benign tumor with exceptionally rare distant metastasis. High-grade HRCC, a subtype of CHRCC, has an aggressive behavior [16], whereas the five cases of HRCN in this study are associated with innocuous clinical outcome.
References [1] P. Bugert, C. Gaul, K. Weber, J. Herbers, M. Akhtar, B. Ljungberg, G. Kovacs, Specific genetic changes of diagnostic importance in chromophobe renal cell carcinomas, Lab. Invest. 76 (2) (1997) 203–208. [2] T.S. Chen, M. McNally, W. Hulbert, P.A. Di Sant’Agnese, J. Huang, Renal oncocytosis presenting in childhood: a case report, Int. J. Surg. Pathol. 11 (4) (2003) 325–329. [3] B. Cochand-Priollet, V. Molinie, J. Bougaran, R. Bouvier, M.C. Dauge-Geffroy, S. Deslignieres, J.C. Fournet, P. Gros, A. Lesourd, J.P. Saint-Andre, M. Toublanc, A. Vieillefond, M. Wassef, A. Fontaine, L. Groleau, Renal chromophobe cell carcinoma and oncocytoma. A comparative morphologic, histochemical, and immunohistochemical study of 124 cases, Arch. Pathol. Lab. Med. 121 (10) (1997) 1081–1086. [4] T.B. Crotty, K.M. Lawrence, C.A. Moertel, D.H. Bartelt Jr., K.P. Batts, G.W. Dewald, G.M. Farrow, R.B. Jenkins, Cytogenetic analysis of six renal oncocytomas and a chromophobe cell renal carcinoma. Evidence that –Y, –1 may be a characteristic anomaly in renal oncocytomas, Cancer Genet. Cytogenet. 61 (1) (1992) 61–66. [5] T. Dijkhuizen, E. van den Berg, S. Storkel, B. de Vries, A.Y. van der Veen, M. Wilbrink, A. Geurts van Kessel, B. de Jong, Renal oncocytoma with t(5;12;11), der(1)1;8) and add(19): ‘‘true’’ oncocytoma or chromophobe adenoma?, Int. J. Cancer. 73 (1997) 521–524. [6] C.D. Gerharz, R. Moll, S. Storkel, U. Ramp, W. Thoenes, H.E. Gabbert, Ultrastructural appearance and cytoskeletal architecture of the clear, chromophilic, and chromophobe types of human renal cell carcinoma in vitro, Am. J. Pathol. 142 (3) (1993) 851–859. [7] A. Kovacs, G. Kovacs, Low chromosome number in chromophobe renal cell carcinomas, Genes Chromosomes Cancer 4 (3) (1992) 267–268. [8] G. Kovacs, Molecular cytogenetics of renal cell tumors, Adv. Cancer Res. 62 (1993) 89–124. [9] X. Leroy, D. Moukassa, M.C. Copin, F. Saint, E. Mazeman, B. Gosselin, Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from renal oncocytoma, Eur. Urol. 37 (4) (2000) 484–487. [10] X. Leroy, L. Lemaitre, A. De La Taille, M. Hazzan, B. Delepaul, J. Couturier, B. Gosselin, Bilateral renal oncocytosis with renal failure, Arch. Pathol. Lab. Med. 125 (5) (2001) 683–685. [11] S. Noguchi, Y. Nagashima, T. Shuin, Y. Kubota, H. Kitamura, M. Yao, M. Hosaka, Renal oncocytoma containing ‘‘chromophobe’’ cells, Int. J. Urol. 2 (4) (1995) 279–280. [12] M. Ortmann, M. Vierbuchen, Lectin histochemistry in the kidney and renal tumors, Verh. Dtsch. Ges. Pathol. 73 (1989) 339–349. [13] M. Ortmann, M. Vierbuchen, R. Fischer, Sialylated glycoconjugates in chromophobe cell renal carcinoma compared with other renal cell tumors. Indication of its development from the collecting duct epithelium, Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 61 (2) (1991) 123–132.
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[14] C.P. Pavlovich, M.M. Walther, R.A. Eyler, S.M. Hewitt, B. Zbar, W.M. Linehan, M.J. Merino, Renal tumors in the Birt–Hogg–Dube syndrome, Am. J. Surg. Pathol. 26 (12) (2002) 1542–1552. [15] J.C. Presti Jr., H. Moch, V.E. Reuter, D. Huynh, F.M. Waldman, Comparative genomic hybridization for genetic analysis of renal oncocytomas, Genes Chromosomes Cancer 17 (4) (1996) 199–204. [16] A.A. Renshaw, E.P. Henske, K.R. Loughlin, C. Shapiro, D.S. Weinberg, Aggressive variants of chromophobe renal cell carcinoma, Cancer 78 (8) (1996) 1756–1761. [17] R.F. Schwerdtle, S. Storkel, C. Neuhaus, H. Brauch, E. Weidt, W. Brenner, R. Hohenfellner, C. Huber, H.J. Decker, Allelic losses at chromosomes 1p, 2p, 6p, 10p, 13q, 17p, and 21q significantly correlate with the chromophobe subtype of renal cell carcinoma. Cancer Res. 56(13) (1996) 2927–2930. Retraction, In: R.F. Schwerdtle, C. Neuhaus, E. Weidt, C. Huber, W. Brenner, R. Hohenfellner, A. Winterpacht, B. Zabel, H.J. Decker, S. Storkel, H. Brauch. Cancer Res. 59(8) (1999) 2021. [18] S. Storkel, P.V. Steart, D. Drenckhahn, W. Thoenes, The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct, Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 56 (4) (1989) 237–245. [19] S. Storkel, J.N. Eble, K. Adlakha, M. Amin, M.L. Blute, D.G. Bostwick, M. Darson, B. Delahunt, K. Iczkowski, Classification of renal cell carcinoma: Workgroup No. 1.
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Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC), Cancer 80 (5) (1997) 987–989. A. Taki, Y. Nakatani, K. Misugi, M. Yao, Y. Nagashima, Chromophobe renal cell carcinoma: an immunohistochemical study of 21 Japanese cases, Mod. Pathol. 12 (3) (1999) 310–317. S.K. Tickoo, M.B. Amin, R.J. Zarbo, Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining, Am. J. Surg. Pathol. 22 (4) (1998) 419–424. S.K. Tickoo, V.E. Reuter, M.B. Amin, J.R. Srigley, J.I. Epstein, K.W. Min, M.A. Rubin, J.Y. Ro, Renal oncocytosis: a morphologic study of fourteen cases, Am. J. Surg. Pathol. 23 (9) (1999) 1094–1101. W. Thoenes, S. Storkel, H.J. Rumpelt, Human chromophobe cell renal carcinoma, Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 48 (3) (1985) 207–217. W. Thoenes, S. Storkel, H.J. Rumpelt, R. Moll, H.P. Baum, S. Werner, Chromophobe cell renal carcinoma and its variants – a report on 32 cases, J. Pathol. 155 (4) (1988) 277–287. S.L. Wu, P. Kothari, T.M. Wheeler, T. Reese, J.H. Connelly, Cytokeratins 7 and 20 immunoreactivity in chromophobe renal cell carcinomas and renal oncocytomas, Mod. Pathol. 15 (7) (2002) 712–717.
Pathology – Research and Practice 201 (2005) 385–389 www.elsevier.de/prp
ORIGINAL ARTICLE
Hybrid chromophobe renal cell neoplasm Kien T. Maia,b,, Prashant Dhamanaskarb, Eric Belangerb, William A. Stinsona,b a Division of Anatomical Pathology, Department of Laboratory Medicine, The Ottawa Hospital – Civic Campus, 1053 Carling Avenue, Ottawa, Ont., Canada, K1Y 4E9 b Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ont., Canada
Received 21 June 2004; accepted 30 March 2005
Abstract Hybrid renal cell neoplasms (HRCNs) containing areas of tumor cells displaying cytological features of chromophobe renal cell carcinoma (CHRCC) and renal oncocytoma (RO) have been recently described in patients with renal oncocytosis and Birt–Hogg–Dube (BHD) syndrome (autosomal dominant genodermatosis). In this study, we identified cases of sporadic HRCN. We reviewed 425 consecutive renal cell carcinomas (RCC), 18 CHRCC, six HRCN, and 25 RO. Five HRCN were identified, including four from the group of RCC and two from RO. Patient age ranged from 40 to 68 years (mean age: 54 years), and the male:female ratio was 4:1. Tumors measured from 1.8 to 5 cm (mean diameter: 3.0 cm). Tumoral necrosis was not seen. Vascular invasion into medium-sized veins was identified in one HRCN. Chromophobe cells accounted for 20–80% of the tumors. Hale’s colloidal stain showed weak to moderate diffuse cytoplasmic staining in scattered cells corresponding to those displaying routine staining features of chromophobe cells. Areas of oncocytic cells in studied tumors and control oncocytomas showed negative or focal cytoplasmic staining usually bordering extra- or intra-cytoplasmic lumina. Immunostaining for cytokeratin 7 and vimentin showed focal immunoreactivity in three cases and negative reactivity in all six cases, respectively. None of the study cases had microscopic RO, as commonly seen in renal oncocytosis, or were associated with BHD syndrome Sporadic HRCN accounted for 1% of RCC. They were of smaller size than RCC and were associated with a favorable prognosis. r 2005 Elsevier GmbH. All rights reserved.
Introduction Chromophobe renal cell carcinoma (CHRCC) accounts for about 5% of renal cell carcinoma (RCC) [24]. It is distinguished from clear cell RCC and papillary RCC by the characteristic chromophil cytoplasm seen Corresponding author. Anatomical Pathology, The Ottawa Hospital, Civic Campus, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. Tel.: +613 761 4344; fax: +613 761 4846. E-mail address: [email protected] (K.T. Mai).
0344-0338/$ - see front matter r 2005 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2005.03.008
with eosin or phloxin stain [23]. Cytogenetically, CHRCC is associated with various combinations of allelic loss of chromosomes 2, 6, 10, 13, and 17 [8,19]. Immunohistochemically, it shares lectin and immunological markers of the intercalated cells and oncocytoma [3,6,12,13,18,20]. Recently, hybrid renal cell neoplasm (HRCN), having an admixture of areas of CHRCC and areas consisting of oncocytes, have been described in patients presenting multiple renal oncocytomas (ROs) and Birt–Hogg–Dube (BHD) syndrome (autosomal dominant genodermatosis) [2,14,20,22]. In this study,
ARTICLE IN PRESS 386
K.T. Mai et al. / Pathology – Research and Practice 201 (2005) 385–389
Table 1. #
1 2 3 4 5
Summary of clinical and pathological features of study cases
Age
45 56 40 62 68
Gender
M M M F M
Tumor diameter
2.5 1.8 2.5 5 3.5
% of chromophobe cells
30% 20% 80% 60% 45%
Associated with CHRCC
RO
+
+
VI
Follow-up
+
1 year, ND 5 years, ND 14 years, ND 10 years, ND 5 years, ND
M: male, F: female, VI: venous invasion, ND: no disease.
we reviewed cases of renal epithelial neoplasms at our institution to identify cases of sporadic HRCN and to study the clinical behavior of this entity.
Materials and methods Files at the Anatomical Pathology Laboratory of the Ottawa Hospital, from 1983 to 2002, and General Campus, from 1999 to 2002, were reviewed to identify HRCN. Oncocytic cells were defined as tubular cells having prominent abundant granular eosinophilic cytoplasm. CHRCC was diagnosed using mainly the current cytoplasmic criteria with H&E staining. The diagnosis was supported by their positive reaction with Hale’s colloidal stain. Each surgical specimen was represented by 3–12 sections, stained with hematoxylin–phloxin–saffron or H&E. HRCN was diagnosed when single or groups of chromophobe cells were identified and accounted for more than 20% of the tumor mass represented by available microscopic sections. Due to the presence of ‘‘pale’’ cells and occasional oncocytic cells showing a peri-nuclear halo that may mimic chromophobe cells in RO and the frequent weakly positive staining for Hale’s colloidal iron in chromophobe cells, we arbitrarily excluded cases having less than 20% ‘‘chromophobe-like’’ cells from the group of HCRN. The size of the lesions was taken from the gross description of the specimen after formalin fixation or by measurement of the lesion on the glass slide. One representative tissue block of each tumor was used for immunostaining. Immunostaining was done on the formalinfixed tissue sections using the avidin–biotin peroxidase complex (ABC) method with an ABC kit (Vector Laboratories, Burlingame, CA, USA) for cytokeratin cytokeratin 7
(Dako dilution 1:200) and vimentin (Dako, dilution 1:100). Clinical follow-up of up to 17 years was available for the majority of cases. A t-test was performed to analyze the statistical significance of the results.
Results There were 403 consecutive non-chromophobe RCC, 18 CHRCC, six HRCN, and 23 oncocytomas. CHRCC were characterized by chromophobe cells with conspicuous cytoplasmic membrane, ballooned, reticulated, or eosinophilic cytoplasm that had a decreased tinctorial staining as compared to the cytoplasmic membrane. Nuclear halo was frequently seen in tumor cells with eosinophilic cytoplasm. Nuclei frequently displayed varying degrees of ‘‘raisinoid’’ changes. Focal areas with features of oncocytoma were not seen. All oncocytomas were distinguished from CHRCC by the cytoplasm that was granular and eosinophilic with indiscernible cytoplasmic borders. Peri-nuclear halos were occasionally and barely seen in focal areas. Pale cells in oncocytomas were distinguished from chromophobe cells by the absence of the peri-nuclear halo and the distinct cytoplasmic borders. For five HRCN, patient age ranged from 40 to 68 years (mean age: 54 years). The male:female ratio was 4:1. The tumors measured from 1.2 to 5.0 cm (mean diameter: 3.0 cm) in greatest diameter. Two HRCN were associated with CHRCC and oncocytomas (Table 1). All associated oncocytomas measured more than 1 cm in
Fig. 1–3. 1. Case 1: HRCN with a history of CHRCC and a synchronous RO. (A) A poorly delineated nodule formed by chromophobe cells in RO. (B) A high magnification of the transitional area between RO and nodule of chromophobe cells. Note the conspicuous cell borders, translucent cytoplasm, and large raisinoid nuclei of chromophobe cells (arrowhead) as compared with indistinct cell borders, dense or occasionally light cytoplasm (arrow), and round or oval nuclei smooth nuclear contour in RO. (C) Hale’s colloidal iron stain showing positive staining in large cytoplasmic portions in the nodule of chromophobe cells and negative staining or focal cytoplasmic staining in RO cells (arrow). 2. Case 3: HRCN predominantly formed by chromophobe cells (80% of tumor cells) with vascular invasion. (A) The tumor with thick capsule and vascular invasion. (B) An area of tumor with a mass of chromophobe cells and focus of chromophobe cells intermingled with oncocytic cells (arrows). (C) Hale’s colloidal iron stain showing positive staining in chromophobe cells and negative staining in RO cells. 3. Case 5: HRCN with 50% of chromophobe cells in the upper half of the photomicrographs. (A, B) Low and high magnification showing area of chromophobe cells and area of RO. (C) Hale’s colloidal iron stain and immunostaining for cytokeratin 70 showing positive staining in the chromophobe cell component and almost negative staining in RO cells.
ARTICLE IN PRESS K.T. Mai et al. / Pathology – Research and Practice 201 (2005) 385–389
diameter. The studied tumors were either encapsulated (three cases) or circumscribed with focal infiltrating borders. The proportion of chromophobe cells ranged from 20% to 80% of the total neoplastic cells. Case 3 (Table 1) displayed an admixture of single and small groups of oncocytic cells and chromophobe cells. Chromophobe and oncocytic cells were either disposed
387
in small or large areas or were intermingled into each other. All oncocytic cells did not have peri-nuclear halos or discernible cytoplasmic membranes. Vascular invasion into medium-sized veins was identified in one HRCN. None of the patients in this study developed recurrent or metastatic diseases for a clinical follow-up from 1 to 14 years (Table 1, Figs. 1–3).
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Hale’s colloidal stain showed a weak to moderate, diffuse staining in scattered cells corresponding to those displaying routine staining features of chromophobe cells. Areas typical for oncocytoma in studied tumors and control oncocytomas showed negative staining or focal cytoplasmic staining usually bordering extra- or intra-cytoplasmic lumina. The control CHRCC showed moderate to strong diffuse staining. Immunostaining for CK7 and VIM showed focal immunoreactivity in three cases and negative reactivity in all six cases, respectively.
Discussion In the setting of this study, five cases displayed features intermediate between RO and CHRCC due to: (a) an admixture of areas typical of RO and CHRCC or (b) the presence of scattered chromophobe cells varying from 20% to 80% of neoplastic cells in the background of RO and (c) immunostaining features intermediate between RO and CHRCC [9,21,25]. Tumors with similar histopathological features have been recently described in patients having oncocytosis and BHD syndrome [14,22]. Oncocytosis is characterized by multiple microscopic, small and large-sized oncocytomas, CHRCC, and HRCN [10,22]. Furthermore, BHD is frequently associated with oncocytosis. Cytogenetically, there is a subset of oncocytoma sharing the same loss of chromosomes 1 and Y, as seen in CHRCC [1,4,5,7,15,17]. This subset of RO may represent a precursor of CHRCC, with HRCN representing an intermediate stage. Review of medical literature on sporadic renal cell neoplasms reveals one report describing a similar neoplasm [11]. All the tumors, including those in our five cases, as well as cases previously reported, were relatively small, circumscribed, or encapsulated [5,22]. Clinical outcome was not available for previously reported cases; however, none of our cases was associated with lymph node or distant metastasis for a follow-up period from 1 to 14 years despite the presence of tumoral invasion into a small vessel associated with one of the tumors. We believe it is appropriate to designate the studied tumor as HRCN instead of RCC. Recognition of HRCN as an entity that may occur in patients with or without BHD or renal oncocytosis is important, since it may have a biological behavior different from RO and CHRCC. RO usually is a benign tumor with exceptionally rare distant metastasis. High-grade HRCC, a subtype of CHRCC, has an aggressive behavior [16], whereas the five cases of HRCN in this study are associated with innocuous clinical outcome.
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