527608
research-article2014
IJSXXX10.1177/1066896914527608International Journal of Surgical PathologyPatriarca et al
Original Article
Whorled Urothelial Cell Carcinoma: A Neglected Variant
International Journal of Surgical Pathology 2014, Vol. 22(5) 408–413 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914527608 ijs.sagepub.com
Carlo Patriarca, MD1, Eva Comperat, MD2, Enrico Bollito, MD3, Agazio Ussia, MD1, Giovanni Scola, MD1, Alessandra Cavallero, MD1, Lucia Ferrari, MD1, Paolo Giunta, MD4, and Giario Conti, MD1
Abstract Twelve cases of urothelial cell papillary carcinoma with a whorled pattern of growth are described. This variant is reported with clinicopathological correlations and immunohistochemical findings. All cases showed this peculiar and distinctive curlicue histological pattern, ranging from 50% to 100% of the neoplastic population. Despite the disordered/ turbulent growth pattern, the cytological grade was uniformly low. All the lesions were Ta staged and no patient experienced progression after transurethral resection, while 2 showed clinical recurrences. The immunophenotype (low p53, high p27, low Ki67, and high GATA3) of the cases contributes to define this rare variant as a low-grade tumor. Keywords urothelial carcinoma, whorled, growth pattern, variant, eddies
Introduction The criteria of grading in papillary urothelial cell neoplasms, originally described in the 1973 World Health Organization (WHO) classification,1 were revised by the 1998 International Society of Uropathology (ISUP) proposal2 and were subsequently adopted by the 2004 WHO classification system.3 The main principles of the ISUP/2004 WHO grading formulation are based on the morphological concept of architectural order. The flowchart of the differential diagnosis of noninvasive papillary urothelial tumors demands a first evaluation of the tumor pattern at no more than medium magnification and subsequently an evaluation of cytologic features of atypia, such as the chromatin pattern and alterations in the cell size. A pivotal step in the application of this grading classification is to determine whether the neoplasm shows a predominant pattern of cytoarchitectural order or rather a pattern of disorder in the histological growth, leading to a low-grade or a high-grade definition, respectively. The overall orderly appearance of low-grade tumors is based on the presence of a certain degree of nuclear polarity of the cell growth. However, a very well characterized and rare cytoarchitectural pattern might be found in daily practice that does not match the hitherto described variants of urothelial carcinoma, raising the question of an appropriate use of the usual pattern recognition approach. We gathered 12 cases of urothelial carcinoma with an undescribed whorled pattern of growth that breaks the
usual rules of urothelial carcinoma histology. Clinicopathological features of these cases are presented.
Materials and Methods Out of more than 1500 cases of transurethral resections of bladder and cold biopsies archived in the past 3 years in the Department of Pathology of 4 institutions (Azienda Ospedaliera Sant’Anna, Como, Italy; Groupe Hospitalier Pitié-Salpétrière, Paris, France; Azienda OspedalieroUniversitaria S. Luigi Gonzaga, Orbassano, Turin, Italy; Azienda Ospedaliera di Melegnano, Milan, Italy), we selected 12 cases of an unusual pattern of growth, We defined these tumors whorled for their peculiar and well characterized “turbulent” pattern of growth, present in at least 50% of the neoplastic urothelium. One case with a similar morphology coming from the upper urinary tract was dropped from the evaluation. None of the cases underwent subsequent cystectomy. Data of follow-up were recorded for each case. 1
Azienda Ospedaliera Sant’Anna, Como, Italy Groupe Hospitalier Pitié-Salpétrière, Paris, France 3 Azienda Ospedaliero-Universitaria S. Luigi Gonzaga, Orbassano, Turin, Italy 4 Azienda Ospedaliera di Melegnano, Milan, Italy 2
Corresponding Author: Carlo Patriarca, Anatomia Patologica, Azienda Ospedaliera Sant’Anna., Via Ravona 1, 22020 San Fermo della Battaglia, Como, Italy. Email: [email protected]
Downloaded from ijs.sagepub.com at UNIVERSITE DE MONTREAL on June 21, 2015
409
Patriarca et al Table 1. Demographics, Treatment, and Prognosis of the Patients.a Case No.
Age
Gender
Initial Treatment
Outcome (Months)
1 2 3 4 5 6 7 8 9 10 11 12
84 64 79 75 72 86 61 63 80 74 78 75
Female Male Male Male Female Male Male Male Male Male Female Female
Surveillance Surveillance Surveillance Surveillance Surveillance Surveillance/BCG MMC Surveillance Surveillance BCG/surveillance MMC/surveillance Surveillance
NED (24) NED (22) Not available NED (12) NED (20) Recurrence (24), NED (28) Recurrence (9), NED (15) NED (34) NED (120) NED (36) NED (33) NED (36)
Abbreviations: BCG, Bacillus Calmette-Guerin; MMC, intravesicle chemotherapy with mitomycin; NED, no evidence of disease. a Data of follow-up are based on CTM (malignant tumor cells) and/or cystoscopy.
The original diagnoses and grading were based on criteria set in the 2004 blue book of the WHO classification of tumors of the urinary system and male genital organ.3 Sections 4-µm thick, stained for hematoxylin and eosin, were reviewed by 3 of the authors (CP, EC, EB). In case of lack of agreement, the cases were reviewed together to reach a consensus. A cytological grading according to the 1973 WHO classification was applied1 and the 2004 WHO grading was blindly applied again to the cases. Moreover, the percentage of whorling pattern of each case was recorded. Additional sections were obtained for immunohistochemistry and stained for GATA3, and for Ki 67, p53, and p27, as put forward by the Shariat algorithm.4 GATA3 immunostaining was performed using monoclonal mouse antibody (L50-823, BioCare 1:50 diluted, Concord CA), Ki67 immunostaining was performed using monoclonal mouse antibody (30-9, Roche Ventana prediluted MoAb, Tucson, AZ). Immunostaining for p53 was accomplished with primary antibody against p53 (Bp5311, Roche Ventana prediluted MoAb) and for p27 with MoAb against p27 (clone IB4 Novocastra 1:30, Wetzlar, Germany). Sections were pretreated with appropriate heat-induced antigen retrieval protocols after deparaffinization and rehydratation of 3-µm thick sections. In automated immunostainer, endogenous peroxidase was blocked for 4 minutes and section incubated, first in primary antibodies following manufacturer’s instructions and then in secondary antibodies for 8 minutes. Localization was performed with standard immunoperoxidase methods with 3,3′-diaminobenzidine as chromogen. As cutoffs of these biomarkers, we used the criteria validated in the literature and reported by Shariat et al.4 These criteria allowed us to split the results in abnormal versus normal immunostaining. In particular, Ki 67 nuclear
immunoreactivity was considered high when reaching 20% or more. Nuclear p53 immunostaining was considered abnormal when at least 10% of cells were positive and p27 immunostaining was taken as altered when nuclear staining was less than 30%. The percentages of staining were evaluated and reported for each immunostaining. Since only the presence of the 3 altered biomarkers was independently associated with a greater risk of disease recurrence and cancer-specific mortality, we also evaluated the combination of the 3 biomarkers.
Results Of the 12 cases, 8 were males and 4 were females with age ranging from 61 to 86 years (mean age = 74 years). No cystoscopic data concerning the dimensions of the papillary lesions were available. Nevertheless, according to the information on the macroscopy of the transurethral resection specimens, the neoplasms ranged from 0.8 to 3 cm. No cold biopsies harboring whorling pattern were identified. Cytology data were available only in 4 cases of positive cytology. The data concerning demographics, treatment, and prognosis are reported in Table 1. The morphologic review of the cases, based on variations in nuclear polarity, size, shape, and chromatin pattern, are reported in Table 2. Our cases of urothelial cell carcinoma with whorling pattern were characterized by papillary growth of urothelial cell carcinoma harboring this peculiar pattern present in at least 50% of the tumor, and ranging from 50% to 100% of the neoplastic growth. As whorled we defined a pattern of growth characterized by concentrically organized cell structures, without morphological evidence of keratinization, similar to the
Downloaded from ijs.sagepub.com at UNIVERSITE DE MONTREAL on June 21, 2015
410
International Journal of Surgical Pathology 22(5)
Table 2. Morphological and Phenotypical Data of the Tumors.
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Stage
Nuclear Grade
WHO 2004 Grade
% WP
GATA3 (%)
Ki67 (%)
p27 (%)
p53 (%)
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
I-II I-II II II I-II I II-III I I I-II I-II I-II
PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade PUC low gradeb PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade
100 80 70 50 70 80a 80a 50 50 70 90 70
100 100 100 100 100 100 90 100 NA 100 100 100
research-article2014
IJSXXX10.1177/1066896914527608International Journal of Surgical PathologyPatriarca et al
Original Article
Whorled Urothelial Cell Carcinoma: A Neglected Variant
International Journal of Surgical Pathology 2014, Vol. 22(5) 408–413 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914527608 ijs.sagepub.com
Carlo Patriarca, MD1, Eva Comperat, MD2, Enrico Bollito, MD3, Agazio Ussia, MD1, Giovanni Scola, MD1, Alessandra Cavallero, MD1, Lucia Ferrari, MD1, Paolo Giunta, MD4, and Giario Conti, MD1
Abstract Twelve cases of urothelial cell papillary carcinoma with a whorled pattern of growth are described. This variant is reported with clinicopathological correlations and immunohistochemical findings. All cases showed this peculiar and distinctive curlicue histological pattern, ranging from 50% to 100% of the neoplastic population. Despite the disordered/ turbulent growth pattern, the cytological grade was uniformly low. All the lesions were Ta staged and no patient experienced progression after transurethral resection, while 2 showed clinical recurrences. The immunophenotype (low p53, high p27, low Ki67, and high GATA3) of the cases contributes to define this rare variant as a low-grade tumor. Keywords urothelial carcinoma, whorled, growth pattern, variant, eddies
Introduction The criteria of grading in papillary urothelial cell neoplasms, originally described in the 1973 World Health Organization (WHO) classification,1 were revised by the 1998 International Society of Uropathology (ISUP) proposal2 and were subsequently adopted by the 2004 WHO classification system.3 The main principles of the ISUP/2004 WHO grading formulation are based on the morphological concept of architectural order. The flowchart of the differential diagnosis of noninvasive papillary urothelial tumors demands a first evaluation of the tumor pattern at no more than medium magnification and subsequently an evaluation of cytologic features of atypia, such as the chromatin pattern and alterations in the cell size. A pivotal step in the application of this grading classification is to determine whether the neoplasm shows a predominant pattern of cytoarchitectural order or rather a pattern of disorder in the histological growth, leading to a low-grade or a high-grade definition, respectively. The overall orderly appearance of low-grade tumors is based on the presence of a certain degree of nuclear polarity of the cell growth. However, a very well characterized and rare cytoarchitectural pattern might be found in daily practice that does not match the hitherto described variants of urothelial carcinoma, raising the question of an appropriate use of the usual pattern recognition approach. We gathered 12 cases of urothelial carcinoma with an undescribed whorled pattern of growth that breaks the
usual rules of urothelial carcinoma histology. Clinicopathological features of these cases are presented.
Materials and Methods Out of more than 1500 cases of transurethral resections of bladder and cold biopsies archived in the past 3 years in the Department of Pathology of 4 institutions (Azienda Ospedaliera Sant’Anna, Como, Italy; Groupe Hospitalier Pitié-Salpétrière, Paris, France; Azienda OspedalieroUniversitaria S. Luigi Gonzaga, Orbassano, Turin, Italy; Azienda Ospedaliera di Melegnano, Milan, Italy), we selected 12 cases of an unusual pattern of growth, We defined these tumors whorled for their peculiar and well characterized “turbulent” pattern of growth, present in at least 50% of the neoplastic urothelium. One case with a similar morphology coming from the upper urinary tract was dropped from the evaluation. None of the cases underwent subsequent cystectomy. Data of follow-up were recorded for each case. 1
Azienda Ospedaliera Sant’Anna, Como, Italy Groupe Hospitalier Pitié-Salpétrière, Paris, France 3 Azienda Ospedaliero-Universitaria S. Luigi Gonzaga, Orbassano, Turin, Italy 4 Azienda Ospedaliera di Melegnano, Milan, Italy 2
Corresponding Author: Carlo Patriarca, Anatomia Patologica, Azienda Ospedaliera Sant’Anna., Via Ravona 1, 22020 San Fermo della Battaglia, Como, Italy. Email: [email protected]
Downloaded from ijs.sagepub.com at UNIVERSITE DE MONTREAL on June 21, 2015
409
Patriarca et al Table 1. Demographics, Treatment, and Prognosis of the Patients.a Case No.
Age
Gender
Initial Treatment
Outcome (Months)
1 2 3 4 5 6 7 8 9 10 11 12
84 64 79 75 72 86 61 63 80 74 78 75
Female Male Male Male Female Male Male Male Male Male Female Female
Surveillance Surveillance Surveillance Surveillance Surveillance Surveillance/BCG MMC Surveillance Surveillance BCG/surveillance MMC/surveillance Surveillance
NED (24) NED (22) Not available NED (12) NED (20) Recurrence (24), NED (28) Recurrence (9), NED (15) NED (34) NED (120) NED (36) NED (33) NED (36)
Abbreviations: BCG, Bacillus Calmette-Guerin; MMC, intravesicle chemotherapy with mitomycin; NED, no evidence of disease. a Data of follow-up are based on CTM (malignant tumor cells) and/or cystoscopy.
The original diagnoses and grading were based on criteria set in the 2004 blue book of the WHO classification of tumors of the urinary system and male genital organ.3 Sections 4-µm thick, stained for hematoxylin and eosin, were reviewed by 3 of the authors (CP, EC, EB). In case of lack of agreement, the cases were reviewed together to reach a consensus. A cytological grading according to the 1973 WHO classification was applied1 and the 2004 WHO grading was blindly applied again to the cases. Moreover, the percentage of whorling pattern of each case was recorded. Additional sections were obtained for immunohistochemistry and stained for GATA3, and for Ki 67, p53, and p27, as put forward by the Shariat algorithm.4 GATA3 immunostaining was performed using monoclonal mouse antibody (L50-823, BioCare 1:50 diluted, Concord CA), Ki67 immunostaining was performed using monoclonal mouse antibody (30-9, Roche Ventana prediluted MoAb, Tucson, AZ). Immunostaining for p53 was accomplished with primary antibody against p53 (Bp5311, Roche Ventana prediluted MoAb) and for p27 with MoAb against p27 (clone IB4 Novocastra 1:30, Wetzlar, Germany). Sections were pretreated with appropriate heat-induced antigen retrieval protocols after deparaffinization and rehydratation of 3-µm thick sections. In automated immunostainer, endogenous peroxidase was blocked for 4 minutes and section incubated, first in primary antibodies following manufacturer’s instructions and then in secondary antibodies for 8 minutes. Localization was performed with standard immunoperoxidase methods with 3,3′-diaminobenzidine as chromogen. As cutoffs of these biomarkers, we used the criteria validated in the literature and reported by Shariat et al.4 These criteria allowed us to split the results in abnormal versus normal immunostaining. In particular, Ki 67 nuclear
immunoreactivity was considered high when reaching 20% or more. Nuclear p53 immunostaining was considered abnormal when at least 10% of cells were positive and p27 immunostaining was taken as altered when nuclear staining was less than 30%. The percentages of staining were evaluated and reported for each immunostaining. Since only the presence of the 3 altered biomarkers was independently associated with a greater risk of disease recurrence and cancer-specific mortality, we also evaluated the combination of the 3 biomarkers.
Results Of the 12 cases, 8 were males and 4 were females with age ranging from 61 to 86 years (mean age = 74 years). No cystoscopic data concerning the dimensions of the papillary lesions were available. Nevertheless, according to the information on the macroscopy of the transurethral resection specimens, the neoplasms ranged from 0.8 to 3 cm. No cold biopsies harboring whorling pattern were identified. Cytology data were available only in 4 cases of positive cytology. The data concerning demographics, treatment, and prognosis are reported in Table 1. The morphologic review of the cases, based on variations in nuclear polarity, size, shape, and chromatin pattern, are reported in Table 2. Our cases of urothelial cell carcinoma with whorling pattern were characterized by papillary growth of urothelial cell carcinoma harboring this peculiar pattern present in at least 50% of the tumor, and ranging from 50% to 100% of the neoplastic growth. As whorled we defined a pattern of growth characterized by concentrically organized cell structures, without morphological evidence of keratinization, similar to the
Downloaded from ijs.sagepub.com at UNIVERSITE DE MONTREAL on June 21, 2015
410
International Journal of Surgical Pathology 22(5)
Table 2. Morphological and Phenotypical Data of the Tumors.
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Stage
Nuclear Grade
WHO 2004 Grade
% WP
GATA3 (%)
Ki67 (%)
p27 (%)
p53 (%)
Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta Ta
I-II I-II II II I-II I II-III I I I-II I-II I-II
PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade PUC low gradeb PUC low grade PUC low grade PUC low grade PUC low grade PUC low grade
100 80 70 50 70 80a 80a 50 50 70 90 70
100 100 100 100 100 100 90 100 NA 100 100 100
