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Case report
Clear cell papillary renal cell carcinoma as part of histologically discordant multifocal renal cell carcinoma: A case report and review of literature Tiffany Shao a , Peter Yousef b , Irina Shipilova b , Rola Saleeb a , Jason Y. Lee b,c , Adriana Krizova a,d,∗ a Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King’s College Cir, Toronto, ON, Canada M5S 1A8 b St. Michael’s Hospital and Li Ka Shing Knowledge Institute, 209 Victoria St, Toronto, ON, Canada M5B 1T8 c Department of Surgery, University of Toronto, Canada d St. Michael’s Hospital, 30 Bond St, Toronto, ON, Canada M5B 1W8
a r t i c l e
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Article history: Received 20 August 2015 Received in revised form 1 December 2015 Accepted 8 December 2015 Keywords: Multifocal histologically discordant renal cell carcinoma Clear cell papillary renal cell carcinoma Molecular analysis
a b s t r a c t Background: Multifocal renal cell carcinoma of different histological subtypes within a single kidney is rare. We report a recently classified clear cell (tubulo) papillary renal cell carcinoma as part of an unusual case of multifocal renal cell carcinoma of discordant histological subtypes. Results: A 57 year-old-man was found to have multiple renal tumors and cysts on imaging and underwent a laparoscopic left radical nephrectomy. Pathological review showed multifocal renal cell carcinoma (clear cell (tubulo) papillary, clear cell and papillary renal cell carcinomas and papillary adenomas). Morphology of clear cell papillary renal cell carcinoma was supported by immunohistochemical profile (CK7+, HMWK+, CAIX+, AMACR−, CD10−, TFE3−). Conclusions: This is the first report of clear cell papillary renal cell carcinoma as part of multifocal renal cell carcinoma of different histological subtypes. Related lineage of clear cell renal cell carcinoma and papillary renal cell carcinoma is supported by the highest prevalence of their combination within multifocal renal cell carcinoma of different histological subtypes along with their molecular interconnection. Clear cell papillary renal cell carcinoma may be uniquely placed between clear cell and papillary renal cell carcinomas since it shows morphological features intermediate between clear cell and papillary renal cell carcinoma along with overlapping but unique immunohistochemical profile. Clear cell papillary renal cell carcinoma may be molecularly related to clear cell and papillary renal cell carcinomas since the tumors overexpress markers of HIF pathway activation with normal/elevated VHL mRNA expression and some tumors show losses of chromosome 3. Due to the overlapping morphology, it is possible that cases of clear cell papillary renal cell carcinoma may have been misclassified as papillary or clear cell renal cell carcinoma in the literature, incorrectly increasing their reported prevalence. Identification of multifocal RCCs may be related to the extent of pathological sampling. © 2016 Elsevier GmbH. All rights reserved.
1. Introduction
Abbreviations: RCC, renal cell carcinoma; pRCC, papillary renal cell carcinoma; ccRCC, clear cell renal cell carcinoma; ccpRCC, clear cell papillary renal cell carcinoma; HIF, hypoxia inducible factors; VHL, Von Hippel–Lindau. ∗ Corresponding author at: Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King’s College Cir, Toronto, ON, Canada M5S 1A8. E-mail addresses: [email protected] (T. Shao), py [email protected] (P. Yousef), [email protected] (R. Saleeb), [email protected] (J.Y. Lee), [email protected] (A. Krizova).
The frequency of sporadic multifocal renal cell carcinoma (RCC) is reported to be between 4 and 25% in patients undergoing unilateral radical nephrectomy, with clinically occult multifocality representing the majority [1–12]. Most multifocal tumors are of the same histological subtype; however, different histological subtypes are observed in up to 30% of cases of multifocal RCC [2–4]. The majority of cases with discordant tumor subtypes are composed of clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) [5,7,13]. Clear cell (tubulo) papillary renal
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Table 1 Pathological findings and molecular analysis of tumors. Diagnosis
Tumor 1 Clear cell RCC
Tumor 2 Papillary RCC
Tumor 3 Clear cell (tubulo) papillary RCC
Macroscopic features
5 cm Solid/cystic Yellow color Hemorrhage, focal
1.2 cm Solid Tan to yellow color Hemorrhage, focal
2 cm Cystic Tan-white color Papillary/granular content
Microscopic findings
Nests and alveoli surrounded by intricate fibrovascular septations. Clear cell cytology.
Fibrovascular cores lined by cells with eosinophilic cytoplasm and nuclear pseudostratification.
Well circumscribed, cystic with focal tubular/acinar features. Cells with clear cytoplasm. Nuclei in linear arrangement away from basal aspect of cells.
Stage Fuhrman nuclear grade Immunohistochemistry
pT1b 2 Positive for CD10, HMWK and focally for CK7. Negative for racemase and TFE3.
pT1a 3 Positive for CK7 and racemase.
pT1a 1 Positive for CK7 (diffuse, strong), CAIX and HMWK (patchy). Negative for CD10, racemase and TFE3.
VHL mutation sequencing 3x (3 fold coverage)
c.585 586delGAinsAT (p.Lys196Ter) 18% mutant allele
Normal
Normal
LOH VHL methylation status (PCR)
LOH present Normal
LOH present Normal
No LOH Normal
Molecular analysis of the background non-tumor kidney tissue showed no molecular changes (normal VHL sequencing, LOH N/A, and normal methylation status). Molecular analysis was performed by Impact Genetics (http://impactgenetics.com). Abbreviations: RCC – renal cell carcinoma; VHL – von-Hippel–Lindau; PCR – polymerase chain reaction; LOH – loss of heterozygosity.
cell carcinoma (ccpRCC) is a new entity that has recently been recognized as a distinct epithelial tumor by the International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia [14]. Here we report this novel entity as part of an unusual case of multifocal histologically discordant RCC. 2. Case report 2.1. Clinical history This 57-year-old man with past medical history of diabetes mellitus, hypercholesterolemia, hypertension, asthma, obstructive sleep apnea, ankylosing spondylitis and morbid obesity was found to have incidental proteinuria. Initial CT scan of the abdomen showed a heterogeneous 6 cm enhancing mass, multiple complex cysts and a staghorn stone within the left kidney. At repeat staging, biphasic CT scan 2 months later showed three masses: a multiseptated exophytic mixed solid and cystic left upper pole mass with minimal eccentric calcification measuring 6.4 cm in maximum diameter; a second solid cortical mass measuring 1.5 cm in maximum diameter and a third ill-defined heterogeneous mass straddling the corticomedullary junction measuring 2.9 cm in maximum diameter. Multiple additional bilateral renal lesions were identified, favored to represent cysts. There was no evidence of extra-renal extension, contralateral renal mass or distal metastasis and the left staghorn stone was still in situ. There was no family or personal history suggestive of a von Hippel–Lindau (VHL) disease or syndrome, specifically, there was no history of hemangioblastomas, pheochromocytomas, multiple cysts in pancreas or kidneys, other than the kidney cysts reported in the imaging studies. The patient underwent a laparoscopic radical nephrectomy. 2.2. Pathological and molecular findings The resected left kidney had four well circumscribed tumors, multiple simple cysts and a large staghorn and multiple small
calculi occupying renal pelvis and calyces. Pathological and molecular findings of the three tumors are presented in Table 1 and Fig. 1. All tumors were confined to the renal parenchyma, none invaded the renal vasculature, ureters or renal sinus fat. None of the tumors had tumor necrosis (gross or microscopic) or sarcomatoid growth. Additional (fourth) tumor described on radiology was a papillary adenoma. On microscopic examination, multiple additional papillary adenomas were found. VHL functional status was assessed by mutational DNA sequencing, loss of heterozygosity (LOH) and VHL promoter methylation. A novel deletion/insertion mutation c.585 586delGAinsAT was identified in 18% of the malignant cells of ccRCC. The mosaic pattern of the mutation and its absence in the normal kidney suggests it is of somatic origin and that it arose later in the tumor progression sequence. There was also detectable LOH by microsatellite analysis in ccRCC. pRCC, despite showing LOH, had no accompanying detectable sequencing abnormalities or VHL promoter methylation. ccpRCC and the background non-tumor kidney parenchyma showed no VHL abnormalities.
3. Discussion ccpRCC is a relatively recently recognized renal epithelial tumor. Its morphological features are intermediate between ccRCC and pRCC, with an overlapping but unique immunohistochemical profile. The tumor is characterized by variable papillary, tubular/acinar and cystic architecture with clear cells of low nuclear grade and linear arrangement of nuclei away from the basal aspect of cells. Its clinical behavior is that of a low stage, indolent tumor (limited data to date) [14]. It has also been suggested that renal angiomyoadenomatous tumor (RAT) may be related to ccpRCC and some consider these two tumors as a spectrum of a distinct tumor entity [15,16]. VHL alterations are the hallmark of ccRCC. Our findings of a VHL mutation and LOH in the ccRCC are consistent with the literature. Although VHL mutations have been recently described in ccpRCC at frequencies ranging from 15% to 30%, mutational analysis of ccpRCC in our case did not mimic these findings [15,16].
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lymphovascular invasion, bilateral disease, nodal status and histologic subtype. Two series that performed multivariate analysis to demonstrate the relationship between clinicopathological features and multifocal RCC showed that primary tumor size [5], bilateral disease, lymph node metastasis and papillary subtype are predictors of multifocality [4]. The current literature suggests that cancer specific outcomes in non-syndromic RCC are similar between patients with solitary and multifocal RCCs when treated with radical nephrectomy [2–4,19–21]. 3.2. Are ccRCC, pRCC and ccpRCC related?
Fig. 1. Photomicrographs of clear cell papillary RCC. (A) Hematoxylin & eosin stained tumor tissue shows papillary proliferation in a portion of a cyst with clear cell cytology. The nuclei are aligned away from the basal aspect of cells. Tumor cells are positive for CK7 (B) and CAIX (C).
pRCC showed LOH; however this was not accompanied by a mutation or a promoter methylation. This finding is also consistent with the literature, where instead of VHL alterations pRCC are known to have trisomies of chromosomes 7, 17 and loss of Y. Chromosomal number changes were not tested in this study, however the distinct morphology and immunohistochemical profile of the tumors distinguishes between these entities. Previous studies that looked into chromosomal number anomalies in ccpRCC did not find any of the characteristic 7, 17 and Y changes common to pRCC [15,17]. 3.1. This is the second report of ccpRCC as part of multifocal histologically discordant RCC The presence of ccpRCC as part of multifocal RCC has been reported in a single report in which ccpRCC was seen along with ccRCC in acquired cystic kidney disease [18]. Several clinicopathological features have been suggested to be associated with multifocal renal cell carcinomas including primary tumor size,
Even though the most prevalent form of RCC is ccRCC, the most common tumor subtype found in most series of multifocal RCC is pRCC [3,4,13]. Discordant histopathology between the primary and satellite tumor(s) occurs in 11–30% of multifocal tumors, with ccRCC and pRCC being the most common combination (Table 2). It is possible that separate events are responsible for multifocal RCC of discordant histological subtypes; however, it is also plausible that these tumors may be of a related lineage given the highest prevalence of their combination within multifocal RCC of discordant histopathology along with their molecular inter-connection [22–26]. ccpRCC may be uniquely placed between ccRCC and pRCC – it shows morphological features intermediate between ccRCC and pRCC along with overlapping but unique immunohistochemical profile. An miRNA signature study showed that ccRCC and pRCC subtypes are more closely related when compared with chromophobe RCC and oncocytoma, further confirming the related lineage of ccRCC and pRCC [25]. Although ccpRCC has not been shown to have consistent molecular changes thus far, literature suggests that these tumors overexpress markers of HIF pathway activation with normal/elevated VHL mRNA expression [9] and some tumors show losses of chromosome 3 [10]. The miRNA expression profile of ccpRCC has a unique pattern of expression with some overlapping characteristics with expression profiles of ccRCC and pRCC [23]. ccpRCC is more similar to ccRCC than to pRCC in regards to the pattern of up-regulated miRNAs [17]. Shared up-regulation of miRNAs, such as miR-210 (central player in the hypoxia pathway), between ccpRCC and ccRCC may be responsible for an overlap in oncogenic mechanism in these two tumor subtypes via the hypoxia pathway. This pathway is activated by loss of VHL function in ccRCC and via other genetic or epigenetic factors independent of VHL loss in ccpRCC [17,23,27]. As Munari hypothesized, miR-210 upregulation in ccpRCC could be responsible for miR-210 activation of the hypoxia pathway in the absence of VHL. These findings support the notion that ccpRCC is a novel entity and may be uniquely placed between ccRCC and pRCC. Furthermore, the overlapping characteristics of ccpRCC with ccRCC and pRCC shed light to the occurrence of ccRCC, ccpRCC, and pRCC in our reported multifocal RCC case. Since some histological subtypes of RCC can have papillary architecture and/or clear cell morphology, it is possible that cases of ccpRCC may have been misclassified as pRCC or ccRCC in the literature, incorrectly increasing their reported incidence. Our finding emphasizes the importance of revisiting reported subtypes, as ccpRCC can be missed or misdiagnosed as Type 2 pRCC or as ccRCC. Morphology along with judicious use of immunohistochemistry can be of value in making the diagnosis in permanent histopathology sections. 3.3. Identification of multifocal RCCs may be related to the extent of pathological sampling Due to the high prevalence of clinically occult multifocality, proper specimen sectioning is crucial in order to identify tumors that may have been missed during preoperative investigations
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Table 2 Incidence of multifocal histologically discordant RCC in prior series. Authors
Gohji et al. [7]
Total number of cases
Number of multifocal RCCs (%)
Number of histologically discordant multifocal RCCs (Number of histologically discordant RCCs/number of multifocal RCCs (%))
64
10 (16%)
3/10 (30%) - clear cell and granular subtype x2 - clear cell and mixed subtype
103
22 (21%)
3/22 (14%) - cell subtypes not specified
Richstone et al. [4]
1071
57 (5%)
15/57 (26%) - cell subtypes not specified
Crispen et al. [2]
1113
60 (5%)
10/60 (17%) - ccRCC + pRCC x8 - ccRCC + chRCC x1 - pRCC + chRCC x1
Simhan et al. [29]
2569
76 (3%)
8/76 (11%) - ccRCC and pRCC
960
34 (4%)
4/34 (12%) - ccRCC + chRCC x2 - ccRCC + pRCC x1 - ccRCC + pRCC + chRCC x1
Baltaci et al. [5]
Minervini et al. [30]
Abbreviations: renal cell carcinoma (RCC); clear cell renal cell carcinoma (ccRCC); papillary renal cell carcinoma (pRCC); chromophobe renal cell carcinoma (chRCC).
[5,7,28]. Even though prognosis of multifocal RCCs is similar to solitary RCC, judicious sampling of each tumor as per ISUP recommendations – 1 block per cm with a minimum of 3 blocks; in cases with multiple tumors, sampling should include at a minimum the 5 largest tumors [14] is warranted since RCC prognostication is linked to microscopic features such as Fuhrman nuclear grade, presence of necrosis, microvascular invasion and sarcomatoid differentiation. Our findings are in agreement with ISUP’s recommendations, emphasizing the importance of sectioning multiple tumors and the need for multiple sections. In conclusion, this is the second report of ccpRCC as part of multifocal RCC. Multifocal RCCs of different histological subtypes are rare. However, the most frequent combination of subtypes may be tumors that are of related lineage. As per ISUP’s recommendations, more comprehensive sampling may be warranted to identify occult disease, tumors of differing subtypes and prognostic variables such as differing nuclear grade. In addition, our findings emphasize the importance of revisiting reported frequency of RCC subtypes in the literature.
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Case report
Clear cell papillary renal cell carcinoma as part of histologically discordant multifocal renal cell carcinoma: A case report and review of literature Tiffany Shao a , Peter Yousef b , Irina Shipilova b , Rola Saleeb a , Jason Y. Lee b,c , Adriana Krizova a,d,∗ a Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King’s College Cir, Toronto, ON, Canada M5S 1A8 b St. Michael’s Hospital and Li Ka Shing Knowledge Institute, 209 Victoria St, Toronto, ON, Canada M5B 1T8 c Department of Surgery, University of Toronto, Canada d St. Michael’s Hospital, 30 Bond St, Toronto, ON, Canada M5B 1W8
a r t i c l e
i n f o
Article history: Received 20 August 2015 Received in revised form 1 December 2015 Accepted 8 December 2015 Keywords: Multifocal histologically discordant renal cell carcinoma Clear cell papillary renal cell carcinoma Molecular analysis
a b s t r a c t Background: Multifocal renal cell carcinoma of different histological subtypes within a single kidney is rare. We report a recently classified clear cell (tubulo) papillary renal cell carcinoma as part of an unusual case of multifocal renal cell carcinoma of discordant histological subtypes. Results: A 57 year-old-man was found to have multiple renal tumors and cysts on imaging and underwent a laparoscopic left radical nephrectomy. Pathological review showed multifocal renal cell carcinoma (clear cell (tubulo) papillary, clear cell and papillary renal cell carcinomas and papillary adenomas). Morphology of clear cell papillary renal cell carcinoma was supported by immunohistochemical profile (CK7+, HMWK+, CAIX+, AMACR−, CD10−, TFE3−). Conclusions: This is the first report of clear cell papillary renal cell carcinoma as part of multifocal renal cell carcinoma of different histological subtypes. Related lineage of clear cell renal cell carcinoma and papillary renal cell carcinoma is supported by the highest prevalence of their combination within multifocal renal cell carcinoma of different histological subtypes along with their molecular interconnection. Clear cell papillary renal cell carcinoma may be uniquely placed between clear cell and papillary renal cell carcinomas since it shows morphological features intermediate between clear cell and papillary renal cell carcinoma along with overlapping but unique immunohistochemical profile. Clear cell papillary renal cell carcinoma may be molecularly related to clear cell and papillary renal cell carcinomas since the tumors overexpress markers of HIF pathway activation with normal/elevated VHL mRNA expression and some tumors show losses of chromosome 3. Due to the overlapping morphology, it is possible that cases of clear cell papillary renal cell carcinoma may have been misclassified as papillary or clear cell renal cell carcinoma in the literature, incorrectly increasing their reported prevalence. Identification of multifocal RCCs may be related to the extent of pathological sampling. © 2016 Elsevier GmbH. All rights reserved.
1. Introduction
Abbreviations: RCC, renal cell carcinoma; pRCC, papillary renal cell carcinoma; ccRCC, clear cell renal cell carcinoma; ccpRCC, clear cell papillary renal cell carcinoma; HIF, hypoxia inducible factors; VHL, Von Hippel–Lindau. ∗ Corresponding author at: Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King’s College Cir, Toronto, ON, Canada M5S 1A8. E-mail addresses: [email protected] (T. Shao), py [email protected] (P. Yousef), [email protected] (R. Saleeb), [email protected] (J.Y. Lee), [email protected] (A. Krizova).
The frequency of sporadic multifocal renal cell carcinoma (RCC) is reported to be between 4 and 25% in patients undergoing unilateral radical nephrectomy, with clinically occult multifocality representing the majority [1–12]. Most multifocal tumors are of the same histological subtype; however, different histological subtypes are observed in up to 30% of cases of multifocal RCC [2–4]. The majority of cases with discordant tumor subtypes are composed of clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) [5,7,13]. Clear cell (tubulo) papillary renal
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Table 1 Pathological findings and molecular analysis of tumors. Diagnosis
Tumor 1 Clear cell RCC
Tumor 2 Papillary RCC
Tumor 3 Clear cell (tubulo) papillary RCC
Macroscopic features
5 cm Solid/cystic Yellow color Hemorrhage, focal
1.2 cm Solid Tan to yellow color Hemorrhage, focal
2 cm Cystic Tan-white color Papillary/granular content
Microscopic findings
Nests and alveoli surrounded by intricate fibrovascular septations. Clear cell cytology.
Fibrovascular cores lined by cells with eosinophilic cytoplasm and nuclear pseudostratification.
Well circumscribed, cystic with focal tubular/acinar features. Cells with clear cytoplasm. Nuclei in linear arrangement away from basal aspect of cells.
Stage Fuhrman nuclear grade Immunohistochemistry
pT1b 2 Positive for CD10, HMWK and focally for CK7. Negative for racemase and TFE3.
pT1a 3 Positive for CK7 and racemase.
pT1a 1 Positive for CK7 (diffuse, strong), CAIX and HMWK (patchy). Negative for CD10, racemase and TFE3.
VHL mutation sequencing 3x (3 fold coverage)
c.585 586delGAinsAT (p.Lys196Ter) 18% mutant allele
Normal
Normal
LOH VHL methylation status (PCR)
LOH present Normal
LOH present Normal
No LOH Normal
Molecular analysis of the background non-tumor kidney tissue showed no molecular changes (normal VHL sequencing, LOH N/A, and normal methylation status). Molecular analysis was performed by Impact Genetics (http://impactgenetics.com). Abbreviations: RCC – renal cell carcinoma; VHL – von-Hippel–Lindau; PCR – polymerase chain reaction; LOH – loss of heterozygosity.
cell carcinoma (ccpRCC) is a new entity that has recently been recognized as a distinct epithelial tumor by the International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia [14]. Here we report this novel entity as part of an unusual case of multifocal histologically discordant RCC. 2. Case report 2.1. Clinical history This 57-year-old man with past medical history of diabetes mellitus, hypercholesterolemia, hypertension, asthma, obstructive sleep apnea, ankylosing spondylitis and morbid obesity was found to have incidental proteinuria. Initial CT scan of the abdomen showed a heterogeneous 6 cm enhancing mass, multiple complex cysts and a staghorn stone within the left kidney. At repeat staging, biphasic CT scan 2 months later showed three masses: a multiseptated exophytic mixed solid and cystic left upper pole mass with minimal eccentric calcification measuring 6.4 cm in maximum diameter; a second solid cortical mass measuring 1.5 cm in maximum diameter and a third ill-defined heterogeneous mass straddling the corticomedullary junction measuring 2.9 cm in maximum diameter. Multiple additional bilateral renal lesions were identified, favored to represent cysts. There was no evidence of extra-renal extension, contralateral renal mass or distal metastasis and the left staghorn stone was still in situ. There was no family or personal history suggestive of a von Hippel–Lindau (VHL) disease or syndrome, specifically, there was no history of hemangioblastomas, pheochromocytomas, multiple cysts in pancreas or kidneys, other than the kidney cysts reported in the imaging studies. The patient underwent a laparoscopic radical nephrectomy. 2.2. Pathological and molecular findings The resected left kidney had four well circumscribed tumors, multiple simple cysts and a large staghorn and multiple small
calculi occupying renal pelvis and calyces. Pathological and molecular findings of the three tumors are presented in Table 1 and Fig. 1. All tumors were confined to the renal parenchyma, none invaded the renal vasculature, ureters or renal sinus fat. None of the tumors had tumor necrosis (gross or microscopic) or sarcomatoid growth. Additional (fourth) tumor described on radiology was a papillary adenoma. On microscopic examination, multiple additional papillary adenomas were found. VHL functional status was assessed by mutational DNA sequencing, loss of heterozygosity (LOH) and VHL promoter methylation. A novel deletion/insertion mutation c.585 586delGAinsAT was identified in 18% of the malignant cells of ccRCC. The mosaic pattern of the mutation and its absence in the normal kidney suggests it is of somatic origin and that it arose later in the tumor progression sequence. There was also detectable LOH by microsatellite analysis in ccRCC. pRCC, despite showing LOH, had no accompanying detectable sequencing abnormalities or VHL promoter methylation. ccpRCC and the background non-tumor kidney parenchyma showed no VHL abnormalities.
3. Discussion ccpRCC is a relatively recently recognized renal epithelial tumor. Its morphological features are intermediate between ccRCC and pRCC, with an overlapping but unique immunohistochemical profile. The tumor is characterized by variable papillary, tubular/acinar and cystic architecture with clear cells of low nuclear grade and linear arrangement of nuclei away from the basal aspect of cells. Its clinical behavior is that of a low stage, indolent tumor (limited data to date) [14]. It has also been suggested that renal angiomyoadenomatous tumor (RAT) may be related to ccpRCC and some consider these two tumors as a spectrum of a distinct tumor entity [15,16]. VHL alterations are the hallmark of ccRCC. Our findings of a VHL mutation and LOH in the ccRCC are consistent with the literature. Although VHL mutations have been recently described in ccpRCC at frequencies ranging from 15% to 30%, mutational analysis of ccpRCC in our case did not mimic these findings [15,16].
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lymphovascular invasion, bilateral disease, nodal status and histologic subtype. Two series that performed multivariate analysis to demonstrate the relationship between clinicopathological features and multifocal RCC showed that primary tumor size [5], bilateral disease, lymph node metastasis and papillary subtype are predictors of multifocality [4]. The current literature suggests that cancer specific outcomes in non-syndromic RCC are similar between patients with solitary and multifocal RCCs when treated with radical nephrectomy [2–4,19–21]. 3.2. Are ccRCC, pRCC and ccpRCC related?
Fig. 1. Photomicrographs of clear cell papillary RCC. (A) Hematoxylin & eosin stained tumor tissue shows papillary proliferation in a portion of a cyst with clear cell cytology. The nuclei are aligned away from the basal aspect of cells. Tumor cells are positive for CK7 (B) and CAIX (C).
pRCC showed LOH; however this was not accompanied by a mutation or a promoter methylation. This finding is also consistent with the literature, where instead of VHL alterations pRCC are known to have trisomies of chromosomes 7, 17 and loss of Y. Chromosomal number changes were not tested in this study, however the distinct morphology and immunohistochemical profile of the tumors distinguishes between these entities. Previous studies that looked into chromosomal number anomalies in ccpRCC did not find any of the characteristic 7, 17 and Y changes common to pRCC [15,17]. 3.1. This is the second report of ccpRCC as part of multifocal histologically discordant RCC The presence of ccpRCC as part of multifocal RCC has been reported in a single report in which ccpRCC was seen along with ccRCC in acquired cystic kidney disease [18]. Several clinicopathological features have been suggested to be associated with multifocal renal cell carcinomas including primary tumor size,
Even though the most prevalent form of RCC is ccRCC, the most common tumor subtype found in most series of multifocal RCC is pRCC [3,4,13]. Discordant histopathology between the primary and satellite tumor(s) occurs in 11–30% of multifocal tumors, with ccRCC and pRCC being the most common combination (Table 2). It is possible that separate events are responsible for multifocal RCC of discordant histological subtypes; however, it is also plausible that these tumors may be of a related lineage given the highest prevalence of their combination within multifocal RCC of discordant histopathology along with their molecular inter-connection [22–26]. ccpRCC may be uniquely placed between ccRCC and pRCC – it shows morphological features intermediate between ccRCC and pRCC along with overlapping but unique immunohistochemical profile. An miRNA signature study showed that ccRCC and pRCC subtypes are more closely related when compared with chromophobe RCC and oncocytoma, further confirming the related lineage of ccRCC and pRCC [25]. Although ccpRCC has not been shown to have consistent molecular changes thus far, literature suggests that these tumors overexpress markers of HIF pathway activation with normal/elevated VHL mRNA expression [9] and some tumors show losses of chromosome 3 [10]. The miRNA expression profile of ccpRCC has a unique pattern of expression with some overlapping characteristics with expression profiles of ccRCC and pRCC [23]. ccpRCC is more similar to ccRCC than to pRCC in regards to the pattern of up-regulated miRNAs [17]. Shared up-regulation of miRNAs, such as miR-210 (central player in the hypoxia pathway), between ccpRCC and ccRCC may be responsible for an overlap in oncogenic mechanism in these two tumor subtypes via the hypoxia pathway. This pathway is activated by loss of VHL function in ccRCC and via other genetic or epigenetic factors independent of VHL loss in ccpRCC [17,23,27]. As Munari hypothesized, miR-210 upregulation in ccpRCC could be responsible for miR-210 activation of the hypoxia pathway in the absence of VHL. These findings support the notion that ccpRCC is a novel entity and may be uniquely placed between ccRCC and pRCC. Furthermore, the overlapping characteristics of ccpRCC with ccRCC and pRCC shed light to the occurrence of ccRCC, ccpRCC, and pRCC in our reported multifocal RCC case. Since some histological subtypes of RCC can have papillary architecture and/or clear cell morphology, it is possible that cases of ccpRCC may have been misclassified as pRCC or ccRCC in the literature, incorrectly increasing their reported incidence. Our finding emphasizes the importance of revisiting reported subtypes, as ccpRCC can be missed or misdiagnosed as Type 2 pRCC or as ccRCC. Morphology along with judicious use of immunohistochemistry can be of value in making the diagnosis in permanent histopathology sections. 3.3. Identification of multifocal RCCs may be related to the extent of pathological sampling Due to the high prevalence of clinically occult multifocality, proper specimen sectioning is crucial in order to identify tumors that may have been missed during preoperative investigations
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Table 2 Incidence of multifocal histologically discordant RCC in prior series. Authors
Gohji et al. [7]
Total number of cases
Number of multifocal RCCs (%)
Number of histologically discordant multifocal RCCs (Number of histologically discordant RCCs/number of multifocal RCCs (%))
64
10 (16%)
3/10 (30%) - clear cell and granular subtype x2 - clear cell and mixed subtype
103
22 (21%)
3/22 (14%) - cell subtypes not specified
Richstone et al. [4]
1071
57 (5%)
15/57 (26%) - cell subtypes not specified
Crispen et al. [2]
1113
60 (5%)
10/60 (17%) - ccRCC + pRCC x8 - ccRCC + chRCC x1 - pRCC + chRCC x1
Simhan et al. [29]
2569
76 (3%)
8/76 (11%) - ccRCC and pRCC
960
34 (4%)
4/34 (12%) - ccRCC + chRCC x2 - ccRCC + pRCC x1 - ccRCC + pRCC + chRCC x1
Baltaci et al. [5]
Minervini et al. [30]
Abbreviations: renal cell carcinoma (RCC); clear cell renal cell carcinoma (ccRCC); papillary renal cell carcinoma (pRCC); chromophobe renal cell carcinoma (chRCC).
[5,7,28]. Even though prognosis of multifocal RCCs is similar to solitary RCC, judicious sampling of each tumor as per ISUP recommendations – 1 block per cm with a minimum of 3 blocks; in cases with multiple tumors, sampling should include at a minimum the 5 largest tumors [14] is warranted since RCC prognostication is linked to microscopic features such as Fuhrman nuclear grade, presence of necrosis, microvascular invasion and sarcomatoid differentiation. Our findings are in agreement with ISUP’s recommendations, emphasizing the importance of sectioning multiple tumors and the need for multiple sections. In conclusion, this is the second report of ccpRCC as part of multifocal RCC. Multifocal RCCs of different histological subtypes are rare. However, the most frequent combination of subtypes may be tumors that are of related lineage. As per ISUP’s recommendations, more comprehensive sampling may be warranted to identify occult disease, tumors of differing subtypes and prognostic variables such as differing nuclear grade. In addition, our findings emphasize the importance of revisiting reported frequency of RCC subtypes in the literature.
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