Histopathology 2014, 64, 1032–1036. DOI: 10.1111/his.12359
SHORT REPORT
Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1 Xavier Leroy,1,2 Philippe Camparo,3 Viviane Gnemmi,1,2 Sebastien Aubert,1,2 Vincent Flamand,4 Morgan Roupret,5 Jean-Christophe Fantoni4 & Eva Comperat6 1
Department of Pathology, University Hospitals CHRU, 2University Lille Nord de France, Lille, 3Centre of Pathology, Amiens, 4Department of Urology, Hospital Huriez CHRU, Lille, 5Department of Urology, CHU Pitie Salpetriere, and 6 Department of Pathology, CHU Pitie-Salpetriere, Paris, France Date of submission 15 October 2013 Accepted for publication 27 December 2013 Published online Article Accepted 2 January 2014
Leroy X, Camparo P, Gnemmi V, Aubert S, Flamand V, Roupret M, Fantoni J-C, Comperat E (2014) Histopathology 64, 1032–1036
Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1 Aims: Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression. Methods and results: The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal,
with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10–72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases. Conclusion: CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour.
Keywords: clear cell papillary carcinoma, cyclin D1, immunohistochemistry, kidney
Introduction Papillary renal cell carcinoma is the second most frequent renal cell carcinoma after renal clear cell carcinoma.1 There is a large spectrum of renal neoplasms with papillary features, including several subtypes with various prognoses.2 Clear cell papillary renal cell Address for correspondence: X Leroy, Department of Pathology, Centre de Biologie Pathologie, CHRU 59037 Lille, France. e-mail: [email protected] © 2013 John Wiley & Sons Ltd.
carcinoma (CCPRCC) is a recently recognized entity: it was first described in patients with end-stage renal failure,3 but has also been described since in patients without other kidney disease.4 Because of morphological overlap with other entities, CCPRCC is probably under-recognized and frequently misdiagnosed as type 1 papillary carcinoma or conventional clear cell renal cell carcinoma. The prognosis of this entity seems to be favourable, but few relevant studies are available. We present here a large series of CCPRCC with, in particular, analysis of cyclin D1 expression.
Cyclin D1 in clear cell papillary carcinoma 1033
Material and methods CASE SELECTION
Forty-two cases were retrieved from the files of three central pathology laboratories. All cases were selected and reviewed by three experienced uropathologists (X.L., P.C., E.C.). Samples of all tumours had been fixed in 10% buffered formalin then routinely embedded in paraffin; both slides and paraffin blocks were available for all 42 cases, and were reviewed for the study. Clinical data were recorded by the referring physicians. PATHOLOGY ANALYSES
Morphological criteria, TNM stage 2009 and Fuhrman nuclear grade were determined using routine sections stained with haematoxylin, eosin and saffron by three pathologists (X.L., P.C., E.C.).
All tumours were stage pT1 N0. Macroscopically, 35 tumours were entirely or partially cystic; seven tumours were solid. All were well circumscribed and limited to the renal parenchyma, without fat invasion or renal vein thrombosis. Microscopically, a papillary architecture was found in every tumour, corresponding to 5–95% of the area of the tumour (Figure 1) with small, delicate papillae covered by cuboidal or large tumour cells with clear cytoplasm (Figure 2). Nuclei were round with a small nucleolus and frequently polarized in the middle or at the luminal part of the tumour cells (Figure 3). For four of the 42 tumours the area comprising papillary structures was minimal, with tubules and acini being major components: they were closely packed, mimicking a conventional clear cell renal cell carcinoma (Figure 4). In
IMMUNOHISTOCHEMISTRY
An automated immunostainer (Benchmark, XT; Ventana, Strasbourg, France) and antibodies against CK7 (OVTL 12/30, 1/100 dilution; Dako, Glostrup, Denmark), CD10 (1/10; Novocastra, Milton Keynes, UK), AMACR (4A4, 1/25; Clinisciences, Nanterre, France), TFE3 (1/100; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and cyclin D1 (Ventana SP4, prediluted) were used for immunhistochemistry. Appropriate positive and negative controls were included in each run. Immunohistochemical staining was scored as positive if more than 5% of tumour cells were stained, and scored as diffuse if present in more than 75% of tumour cells. Figure 1. CCPRCCs were mainly cystic, with papillae and tubules.
Results CLINICAL FINDINGS
Forty-two patients were included in the study; 25 were men and 17 were women and the mean age was 60.7 years (range 35–78 years). Thirty-five patients were treated by partial nephrectomy and seven by radical nephrectomy. Seventeen patients presented with end-stage renal disease and 10 had kidney grafts. During follow-up (range 10–72 months, median 36 months), no patient developed recurrence or metastasis. One patient died from an unrelated cause. PATHOLOGICAL FINDINGS
Tumours measured from 0.5 to 5.5 cm (mean 2.2 cm) in diameter. Six cases were multifocal, involving from two to seven tumours. © 2013 John Wiley & Sons Ltd, Histopathology, 64, 1032–1036.
Figure 2. The tumour papillae are small and aborted, without infiltration of foamy histiocytes.
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Figure 3. Tumour cells are cuboidal with an abundant clear cytoplasm. The nuclei are located at the apical part of the tumour cells.
Figure 5. In solid areas, a mixture of clear and eosinophilic tumour cells can be observed.
Figure 4. Some areas of closely packed tubules mimicked clear cell renal cell carcinoma.
Figure 6. An abundant angioleiomyomatous stroma was observed in four cases.
these solid areas, cells were frequently granular and eosinophilic (Figure 5). The mitotic index was very low (less than one mitotic figure per 10 high-power fields). The stroma contained delicate small capillaries. An abundant angioleiomyomatous stroma was observed in four cases (Figure 6). Neither necrosis nor microvascular invasion nor any sarcomatoid area was observed. Fuhrman nuclear grade was grade 2 for 37 tumours and grade 1 for five tumours.
staining in five of 42 cases and in 5% of the tumour cells in these cases. Tumour cells were all negative for TFE3 immunoreactivity. The antibody against cyclin D1 diffusely immunostained all the tumours, with strong and diffuse nuclear staining in 35 tumours and focal staining in seven cases (Figure 8).
Discussion IMMUNOHISTOCHEMISTRY
The antibody against CK7 labelled all the tumours diffusely with cytoplasmic and membranous staining (Figure 7). All cases were negative with the antibody against AMACR. The CD10 antibody gave positive
Since the publication of the 2004 WHO classification, several new entities have emerged from within the papillary renal carcinoma family.1,2,5,6 Described initially in patients with end-stage kidney disease, CCPRCC has also been diagnosed since in patients © 2013 John Wiley & Sons Ltd, Histopathology, 64, 1032–1036.
Cyclin D1 in clear cell papillary carcinoma 1035
Figure 7. Diffuse cytoplasmic and membranous staining with antibody to cytokeratin 7.
Figure 8. Diffuse nuclear staining with antibody to cyclin D1.
with normal renal function.3,4,7–9 This tumour is probably under-recognized by generalist pathologists, because it is frequently confused with conventional clear cell renal cell carcinoma or type 1 papillary renal carcinoma. Our study confirms that CCPRCC is a tumour with a slight male predominance; patients are mainly in their late 60 s and the tumour is associated with chronic renal failure in 40% of cases.4,8 The clinical presentation is non-specific, and in most cases the tumour is discovered incidentally. Macroscopically, most of these tumours were cystic and well-delimited, with a median size
SHORT REPORT
Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1 Xavier Leroy,1,2 Philippe Camparo,3 Viviane Gnemmi,1,2 Sebastien Aubert,1,2 Vincent Flamand,4 Morgan Roupret,5 Jean-Christophe Fantoni4 & Eva Comperat6 1
Department of Pathology, University Hospitals CHRU, 2University Lille Nord de France, Lille, 3Centre of Pathology, Amiens, 4Department of Urology, Hospital Huriez CHRU, Lille, 5Department of Urology, CHU Pitie Salpetriere, and 6 Department of Pathology, CHU Pitie-Salpetriere, Paris, France Date of submission 15 October 2013 Accepted for publication 27 December 2013 Published online Article Accepted 2 January 2014
Leroy X, Camparo P, Gnemmi V, Aubert S, Flamand V, Roupret M, Fantoni J-C, Comperat E (2014) Histopathology 64, 1032–1036
Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1 Aims: Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression. Methods and results: The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal,
with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10–72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases. Conclusion: CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour.
Keywords: clear cell papillary carcinoma, cyclin D1, immunohistochemistry, kidney
Introduction Papillary renal cell carcinoma is the second most frequent renal cell carcinoma after renal clear cell carcinoma.1 There is a large spectrum of renal neoplasms with papillary features, including several subtypes with various prognoses.2 Clear cell papillary renal cell Address for correspondence: X Leroy, Department of Pathology, Centre de Biologie Pathologie, CHRU 59037 Lille, France. e-mail: [email protected] © 2013 John Wiley & Sons Ltd.
carcinoma (CCPRCC) is a recently recognized entity: it was first described in patients with end-stage renal failure,3 but has also been described since in patients without other kidney disease.4 Because of morphological overlap with other entities, CCPRCC is probably under-recognized and frequently misdiagnosed as type 1 papillary carcinoma or conventional clear cell renal cell carcinoma. The prognosis of this entity seems to be favourable, but few relevant studies are available. We present here a large series of CCPRCC with, in particular, analysis of cyclin D1 expression.
Cyclin D1 in clear cell papillary carcinoma 1033
Material and methods CASE SELECTION
Forty-two cases were retrieved from the files of three central pathology laboratories. All cases were selected and reviewed by three experienced uropathologists (X.L., P.C., E.C.). Samples of all tumours had been fixed in 10% buffered formalin then routinely embedded in paraffin; both slides and paraffin blocks were available for all 42 cases, and were reviewed for the study. Clinical data were recorded by the referring physicians. PATHOLOGY ANALYSES
Morphological criteria, TNM stage 2009 and Fuhrman nuclear grade were determined using routine sections stained with haematoxylin, eosin and saffron by three pathologists (X.L., P.C., E.C.).
All tumours were stage pT1 N0. Macroscopically, 35 tumours were entirely or partially cystic; seven tumours were solid. All were well circumscribed and limited to the renal parenchyma, without fat invasion or renal vein thrombosis. Microscopically, a papillary architecture was found in every tumour, corresponding to 5–95% of the area of the tumour (Figure 1) with small, delicate papillae covered by cuboidal or large tumour cells with clear cytoplasm (Figure 2). Nuclei were round with a small nucleolus and frequently polarized in the middle or at the luminal part of the tumour cells (Figure 3). For four of the 42 tumours the area comprising papillary structures was minimal, with tubules and acini being major components: they were closely packed, mimicking a conventional clear cell renal cell carcinoma (Figure 4). In
IMMUNOHISTOCHEMISTRY
An automated immunostainer (Benchmark, XT; Ventana, Strasbourg, France) and antibodies against CK7 (OVTL 12/30, 1/100 dilution; Dako, Glostrup, Denmark), CD10 (1/10; Novocastra, Milton Keynes, UK), AMACR (4A4, 1/25; Clinisciences, Nanterre, France), TFE3 (1/100; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and cyclin D1 (Ventana SP4, prediluted) were used for immunhistochemistry. Appropriate positive and negative controls were included in each run. Immunohistochemical staining was scored as positive if more than 5% of tumour cells were stained, and scored as diffuse if present in more than 75% of tumour cells. Figure 1. CCPRCCs were mainly cystic, with papillae and tubules.
Results CLINICAL FINDINGS
Forty-two patients were included in the study; 25 were men and 17 were women and the mean age was 60.7 years (range 35–78 years). Thirty-five patients were treated by partial nephrectomy and seven by radical nephrectomy. Seventeen patients presented with end-stage renal disease and 10 had kidney grafts. During follow-up (range 10–72 months, median 36 months), no patient developed recurrence or metastasis. One patient died from an unrelated cause. PATHOLOGICAL FINDINGS
Tumours measured from 0.5 to 5.5 cm (mean 2.2 cm) in diameter. Six cases were multifocal, involving from two to seven tumours. © 2013 John Wiley & Sons Ltd, Histopathology, 64, 1032–1036.
Figure 2. The tumour papillae are small and aborted, without infiltration of foamy histiocytes.
1034
X Leroy et al.
Figure 3. Tumour cells are cuboidal with an abundant clear cytoplasm. The nuclei are located at the apical part of the tumour cells.
Figure 5. In solid areas, a mixture of clear and eosinophilic tumour cells can be observed.
Figure 4. Some areas of closely packed tubules mimicked clear cell renal cell carcinoma.
Figure 6. An abundant angioleiomyomatous stroma was observed in four cases.
these solid areas, cells were frequently granular and eosinophilic (Figure 5). The mitotic index was very low (less than one mitotic figure per 10 high-power fields). The stroma contained delicate small capillaries. An abundant angioleiomyomatous stroma was observed in four cases (Figure 6). Neither necrosis nor microvascular invasion nor any sarcomatoid area was observed. Fuhrman nuclear grade was grade 2 for 37 tumours and grade 1 for five tumours.
staining in five of 42 cases and in 5% of the tumour cells in these cases. Tumour cells were all negative for TFE3 immunoreactivity. The antibody against cyclin D1 diffusely immunostained all the tumours, with strong and diffuse nuclear staining in 35 tumours and focal staining in seven cases (Figure 8).
Discussion IMMUNOHISTOCHEMISTRY
The antibody against CK7 labelled all the tumours diffusely with cytoplasmic and membranous staining (Figure 7). All cases were negative with the antibody against AMACR. The CD10 antibody gave positive
Since the publication of the 2004 WHO classification, several new entities have emerged from within the papillary renal carcinoma family.1,2,5,6 Described initially in patients with end-stage kidney disease, CCPRCC has also been diagnosed since in patients © 2013 John Wiley & Sons Ltd, Histopathology, 64, 1032–1036.
Cyclin D1 in clear cell papillary carcinoma 1035
Figure 7. Diffuse cytoplasmic and membranous staining with antibody to cytokeratin 7.
Figure 8. Diffuse nuclear staining with antibody to cyclin D1.
with normal renal function.3,4,7–9 This tumour is probably under-recognized by generalist pathologists, because it is frequently confused with conventional clear cell renal cell carcinoma or type 1 papillary renal carcinoma. Our study confirms that CCPRCC is a tumour with a slight male predominance; patients are mainly in their late 60 s and the tumour is associated with chronic renal failure in 40% of cases.4,8 The clinical presentation is non-specific, and in most cases the tumour is discovered incidentally. Macroscopically, most of these tumours were cystic and well-delimited, with a median size
