EURURO-5638; No. of Pages 5 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Brief Correspondence
Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastomalike Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance Rodolfo Montironi a,*, Antonio Lopez-Beltran b,c, Liang Cheng d, Andrea B. Galosi e, Francesco Montorsi f, Marina Scarpelli a a
Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy;
Pathology, Department of Surgery, Faculty of Medicine, Cordoba, Spain;
c
Fundac¸a˜o Champalimaud, Lisbon, Portugal;
d
b
Unit of Anatomic
Department of Pathology and
Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; e Urology Division, Murri Hospital, Fermo, Italy; f Department of Urology, University Vita-Salute, Scientific Institute H. San Raffaele, Milan, Italy
Article info
Abstract
Article history: Accepted April 23, 2014
The morphological features and immunohistochemical findings of two cases of clear cell renal cell carcinoma with extensive hemangioblastoma-like features are described. To the best of our knowledge, this is the first description of such a pattern, the differential diagnosis being with renal hemangioblastoma, a rare tumor that could be considered a diffuse hemangioblastoma-like change in a clear cell renal cell tumor. Even though the clinical significance and therapeutic implications are not yet known, the hemangioblastoma-like pattern could have favorable prognostic significance based on the fact that the renal hemangioblastomas described so far have benign behavior. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Clear cell renal cell carcinoma Hemangioblastoma Hemangioblastoma-like ccRCC PAX8
* Corresponding author. Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I 60126 Torrette, Ancona, Italy. E-mail address: [email protected] (R. Montironi).
1.
Introduction
Hemangioblastoma is a benign neoplasm of uncertain histogenesis that typically occurs in the central nervous system (CNS) [1,2]. Most are sporadic, although approximately 25% are associated with von Hippel-Lindau (VHL) disease, a hereditary tumor predisposition syndrome with autosomal-dominant inheritance [1,3]. Morphologically, hemangioblastoma is characterized by the presence of vacuolated tumor cells, referred to as stromal cells, closely associated with an elaborate network of capillary-sized blood vessels. Hemangioblastoma occurs most frequently in the cerebellum and less commonly at other sites in the central neuraxis such as the brain stem, spinal cord, nerve
roots, and supratentorial compartment [1,2]. Examples of hemangioblastoma developing in sites outside the CNS are exceptionally rare and have been reported in small series and as case reports including urinary bladder and kidney; many are associated with stigmata of VHL disease [4,5]. PAX8 is a cell lineage–specific transcription factor with a crucial role in the organogenesis of the kidney, thyroid gland, and Mu¨llerian duct. PAX8 is expressed in normal kidney and in many renal epithelial neoplasms, including variants of renal cell carcinoma (RCC) and renal oncocytoma. Zhao et al. [6] reported PAX8 expression in a sporadic renal hemangioblastoma occurring in 51-yr-old woman without stigmata of VHL disease. The tumor was composed of sheets of polygonal epithelioid stromal cells
http://dx.doi.org/10.1016/j.eururo.2014.04.022 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
with ample pale or eosinophilic, vacuolated cytoplasm in an arborizing capillary network. The tumor cells showed variable nuclear pleomorphism, intranuclear cytoplasmic invaginations, scattered hyaline globules, and psammoma-like calcifications. Some areas showed branching hemangiopericytoma-like vessels with tumor cells radiating from the wall, whereas other areas were edematous and hyalinized with sparse stromal cells and abundant reticular vessels. The tumor cells reacted strongly and diffusely with antibodies to PAX8, CD10, a-inhibin, S100 protein, neuron-specific enolase, and vimentin. Positive immunoreactivity for PAX8 is unexpected and contrasts with CSN hemangioblastomas, which are negative for PAX8. According to Zhao et al. [6], PAX8 expression in sporadic hemangioblastoma of the kidney supports a primary renal cell lineage. After reading recent interesting papers dealing with renal hemangioblastoma, we went back to our series of cases (from the period January 2007 to February 2014; >1000 cases) of RCC examined at the Section of Pathological Anatomy of the Polytechnic University of the Marche Region, including the consultation cases of one of our group (R.M.), whose pathology report included a description of rich capilarization. Even though our hope of finding a case of primary renal hemangioblastoma misreported as clear cell RCC (ccRCC) was not rewarded, we were able to retrieve two ccRCCs with a hemangioblastoma-like pattern. The two cases are from patients who are alive and without evidence of disease 3 yr after operation. 2.
Case 1
This case refers to a partial right nephrectomy specimen (5.5 5 4 cm) from a 49-yr-old man without stigmata of VHL disease. The cut surface shows a well demarcated nodule, 3.5 cm in greatest diameter, reddish in color at the periphery, with scattered yellow spots and a white central area. Figure 1A shows the whole-mount section of the specimen with the tumor nodule. The reddish component seen macroscopically, representing approximately 70% of the neoplasm, shows a rich capillary network of singlelayered flat endothelial cells enclosing stromal cells (Fig. 1B). The latter cell type shows a pale or eosinophilic cytoplasm exhibiting occasional lipid droplets and hyaline globules, oval nuclei, delicate chromatin, and inconspicuous nucleoli. Rare cell nuclei are enlarged, pleomorphic, or bizarre (Fig. 1C). Histologically, the yellow spots seen macroscopically, representing approximately 5% of the neoplasm, show the features of ccRCC, Fuhrman and International Society of Urological Pathology grade 1 (Fig. 1D). The white central area, approximately 15% of the neoplasm, shows an edematous background, devoid of cells, with a rich mesh of capillaries (Fig. 1E). There is a gradual transition between the hemangioblastoma-like component and the areas of ccRCC. In part of the tumor, the endothelial lining and capilarization become less prominent in association with the expansion of the clear cell component. There is also transition with edematous
background and rich capillary mesh of the central part of the neoplasm (Fig. 1F). 2.1.
Immunohistochemistry
The cells in the hemangioblastoma-like component express a-inhibin (Fig. 2A and 2B), PAX8 (Fig. 2C), RCC marker (Fig. 2D), CD10 (Fig. 2E), and S100. The immunohistochemical findings in the ccRCC component are those typically seen in ccRCC. The cells are negative for a-inhibin (Fig. 2B) and S100 and are positive for PAX8 (Fig. 2C), RCC marker (Fig. 2D), CD10 (Fig. 2E), and vimentin. CD34 underscores the rich and delicate vascular channels in the hemangioblastoma-like component (Fig. 2F). 3.
Case 2
This case refers to a right total nephrectomy specimen with a tumor 3.2 cm in greatest diameter from a woman aged 32 yr, without stigmata of VHL disease. The morphologic features and the immunohistochemical findings are identical to those of case 1, with the ccRCC component representing approximately 20% of the tumor, the hemangioblastoma-like pattern representing 60%, and the central area with regressive changes representing 20%. 4.
Additional clinicopathologic studies
For comparison, we investigated three groups of patients. The first included 20 patients with ccRCC without the hemangioblastoma-like pattern (mean age: 61.4 yr [range: 37–79 yr]; 11 men, 9 women). One of the patients had VHL disease. PAX8 was positive in all cases in the neoplastic clear cells. Expression of a-inhibin was negative in all cases. The second group included nine patients with metastatic ccRCC in various body locations: six in the adrenal gland, two in the brain, and one in the bone (mean age: 61.9 yr [range: 37–77 yr]; three men, six women). None showed the hemangioblastoma-like pattern when the slides were reviewed. PAX8 was positive in all cases in the neoplastic clear cells, whereas a-inhibin was negative in all cases. The third group was composed of 12 patients with hemangioblastoma of the cerebellum (mean age: 50.7 yr [range: 24–77 yr]; 9 men, 3 women). One of patients had VHL disease. PAX8 was negative, whereas a-inhibin was positive in all cases. 5.
Discussion
In the kidney, only 11 cases of sporadic hemangioblastoma have been published in the English literature [4–11], typically posing a challenging differential diagnosis. The list of differential diagnoses of this rare renal tumor includes ccRCC, translocation-associated RCC, and epithelioid angiomyolipoma. Other differential diagnoses include paraganglioma, capillary hemangioma, and epithelioid peripheral nerve tumor, which very rarely affects the kidney but may show similarity to hemangioblastoma either histologically or
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 EUROPEAN UROLOGY XXX (2014) XXX–XXX
3
Fig. 1 – (A) Whole-mount section of the specimen with the tumor nodule. (B) Rich capillary network of single-layered flat endothelial cells; (C) rare cell nuclei are enlarged, pleomorphic, or bizarre. (D) Clear cell renal cell carcinoma, Fuhrman and International Society of Urological Pathology grade 1. (E) Edematous background, devoid of cells, with a rich mesh of capillaries. (F) Transition with edematous background and rich capillary mesh of the central part of the neoplasm.
immunohistochemically. Attention to the characteristic morphologic and immunophenotypic features of renal hemangioblastoma will help distinguish this rare tumor from such lesions. The hemangioblastoma-like component seen in our cases is identical morphologically and immunohistochemically to
that of the renal hemangioblastoma described recently by Zhao and coworkers [6] and by others [4,5,7–11]. The difference from the cases already reported is that ours show an unequivocal ccRCC component with a central regressive area and gradual transition with the hemangioblastoma-like part, highlighting the fact that all components belong to
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 4
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Fig. 2 – The cells in the hemangioblastoma-like component express (A,B) a-inhibin, (C) PAX8, (D) renal cell carcinoma marker (RCCm), and (E) CD10. The cells in the clear cell RCC component are negative for a-inhibin (b, asterisks) and are positive for PAX8 (c, arrow), RCC marker (d, arrow), and CD10 (e, arrow). (F) CD34 immunohistochemistry underscores the rich and delicate vascular channels in the hemangioblastoma-like component.
the same tumor and not to a composite neoplasm. It is the same tumor in which the capillary network is richer in the hemangioblastoma-like part compared with that of the typical ccRCC, whereas the clear cells of the typical ccRCC are replaced with the so-called stromal cells. These cells,
while maintaining the immunohistochemical features of the neoplastic clear cells in terms of PAX8, RCC marker, and CD10 expression, acquire the expression of a-inhibin and S100. This is more typical of hemangioblastoma, even though in rare cases a-inhibin has been reported to be expressed by
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 EUROPEAN UROLOGY XXX (2014) XXX–XXX
ccRCC as well [12]. Our interpretation is that this is a ccRCC with regressive changes in the central part identical to those usually seen in most ccRCCs. The hemangioblastoma-like part might represent a component in which the tumor cells have disappeared, as in the central part, and have been replaced by the stromal cells. This brings us to two considerations. The first consideration is the origin of the stromal cells. We agree with the hypothesis put forward by Zhao et al. [6] that the immunoprofile of extraneural hemangioblastoma can vary with the site of origin, perhaps as a result of tumor cell lineage and retention of organ-specific markers or acquisition of site-specific antigens due to local factors. In fact, the nuclear positivity for PAX8 in the current cases, along with the expression of RCC marker and CD10, also lends support to the idea that these tumors are capable of expressing site-specific antigens, perhaps as a result of derivation from organ-specific pluripotent cells or due to local or microenvironmental factors influencing antigen expression [4,13,14]. Related to this phenomenon, the endothelial cells of CNS hemangioblastomas typically express glucose transporter 1 (GLUT1), similar to normal CNS endothelium, whereas the endothelial cells of renal hemangioblastomas appear not to express GLUT1, similar to the endothelium of the normal peripheral vasculature [5]. The second consideration is whether the hemangioblastoma cases reported in the literature should be considered as true renal hemangioblastomas, as claimed by the authors, or—as seen in our cases—as a diffuse hemangioblastoma-like change in a clear cell renal cell tumor. We do not have an answer, although our findings lend strong support to the latter hypothesis.
5
Critical revision of the manuscript for important intellectual content: LopezBeltran, Galosi. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: Cheng. Supervision: Montironi, Montorsi. Other (specify): None. Financial disclosures: Rodolfo Montironi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
References [1] Hussein MR. Central nervous system capillary haemangioblastoma: the pathologist’s viewpoint. Int J Exp Pathol 2007;88:311–24. [2] Aldape KD, Plate KH, Vortmeyer AO, Zagzag D, Neumann HPH. Haemangioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. Lyon, France: IARC Press; 2007. p. 184–6. [3] Plate KH, Vortmeyer AO, Zagzag D, Neumann HPH. von Hippel-Lindau disease and haemangioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, CaveneeWK, editors. WHO classification of tumours of the central nervous system. Lyon, France: IARC Press; 2007. p. 215–7. [4] Nonaka D, Rodriguez J, Rosai J. Extraneural hemangioblastoma: a report of 5 cases. Am J Surg Pathol 2007;31:1545–51. [5] Ip YT, Yuan JQ, Cheung H, Chan JK. Sporadic hemangioblastoma of the kidney: an underrecognized pseudomalignant tumor? Am J Surg Pathol 2010;34:1695–700. [6] Zhao M, Williamson SR, Yu J, et al. PAX8 expression in sporadic hemangioblastoma of the kidney supports a primary renal cell lineage: implications for differential diagnosis. Hum Pathol 2013;44: 2247–55.
6.
Conclusions
[7] Verine J, Sandid W, Miquel C, Vignaud JM, Mongiat-Artus P. Sporadic hemangioblastoma of the kidney: an underrecognized pseu-
We reported two cases of ccRCC with an extensive hemangioblastoma-like pattern. To the best of our knowledge, this is the first description of such a pattern, the clinical significance and therapeutic implications of which are not yet known and the differential diagnosis being with renal hemangioblastoma, a rare tumor considered to have benign behavior. We believe that the hemangioblastomalike pattern could have a favorable prognostic significance based on the fact that the renal hemangioblastomas described so far have benign behavior.
domalignant tumor? Am J Surg Pathol 2011;35:623–4. [8] Wang CC, Wang SM, Liau JY. Sporadic hemangioblastoma of the kidney in a 29-year-old man. Int J Surg Pathol 2012;20:519–22. [9] Yin WH, Li J, Chan JK. Sporadic haemangioblastoma of the kidney with rhabdoid features and focal CD10 expression: report of a case and literature review. Diagn Pathol 2012;7:39. [10] Liu Y, Qiu XS, Wang EH. Sporadic hemangioblastoma of the kidney: a rare renal tumor. Diagn Pathol 2012;7:49. [11] Doyle LA, Fletcher CD. Peripheral hemangioblastoma: clinicopathologic characterization in a series of 22 cases. Am J Surg Pathol 2014;38:119–27. [12] Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from
Author contributions: Rodolfo Montironi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Montironi, Scarpelli. Acquisition of data: Montironi. Analysis and interpretation of data: Montironi, Scarpelli. Drafting of the manuscript: Cheng.
metastatic clear cell renal cell carcinoma. Mod Pathol 2005;18: 788–94. [13] Frank TS, Trojanowski JQ, Roberts SA, Brooks JJ. A detailed immunohistochemical analysis of cerebellar hemangioblastoma: an undifferentiated mesenchymal tumor. Mod Pathol 1989;2:638–51. [14] Fanburg-Smith JC, Gyure KA, Michal M, Katz D, Thompson LD. Retroperitoneal peripheral hemangioblastoma: a case report and review of the literature. Ann Diagn Pathol 2000;4:81–7.
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Brief Correspondence
Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastomalike Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance Rodolfo Montironi a,*, Antonio Lopez-Beltran b,c, Liang Cheng d, Andrea B. Galosi e, Francesco Montorsi f, Marina Scarpelli a a
Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy;
Pathology, Department of Surgery, Faculty of Medicine, Cordoba, Spain;
c
Fundac¸a˜o Champalimaud, Lisbon, Portugal;
d
b
Unit of Anatomic
Department of Pathology and
Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; e Urology Division, Murri Hospital, Fermo, Italy; f Department of Urology, University Vita-Salute, Scientific Institute H. San Raffaele, Milan, Italy
Article info
Abstract
Article history: Accepted April 23, 2014
The morphological features and immunohistochemical findings of two cases of clear cell renal cell carcinoma with extensive hemangioblastoma-like features are described. To the best of our knowledge, this is the first description of such a pattern, the differential diagnosis being with renal hemangioblastoma, a rare tumor that could be considered a diffuse hemangioblastoma-like change in a clear cell renal cell tumor. Even though the clinical significance and therapeutic implications are not yet known, the hemangioblastoma-like pattern could have favorable prognostic significance based on the fact that the renal hemangioblastomas described so far have benign behavior. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Clear cell renal cell carcinoma Hemangioblastoma Hemangioblastoma-like ccRCC PAX8
* Corresponding author. Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Via Conca 71, I 60126 Torrette, Ancona, Italy. E-mail address: [email protected] (R. Montironi).
1.
Introduction
Hemangioblastoma is a benign neoplasm of uncertain histogenesis that typically occurs in the central nervous system (CNS) [1,2]. Most are sporadic, although approximately 25% are associated with von Hippel-Lindau (VHL) disease, a hereditary tumor predisposition syndrome with autosomal-dominant inheritance [1,3]. Morphologically, hemangioblastoma is characterized by the presence of vacuolated tumor cells, referred to as stromal cells, closely associated with an elaborate network of capillary-sized blood vessels. Hemangioblastoma occurs most frequently in the cerebellum and less commonly at other sites in the central neuraxis such as the brain stem, spinal cord, nerve
roots, and supratentorial compartment [1,2]. Examples of hemangioblastoma developing in sites outside the CNS are exceptionally rare and have been reported in small series and as case reports including urinary bladder and kidney; many are associated with stigmata of VHL disease [4,5]. PAX8 is a cell lineage–specific transcription factor with a crucial role in the organogenesis of the kidney, thyroid gland, and Mu¨llerian duct. PAX8 is expressed in normal kidney and in many renal epithelial neoplasms, including variants of renal cell carcinoma (RCC) and renal oncocytoma. Zhao et al. [6] reported PAX8 expression in a sporadic renal hemangioblastoma occurring in 51-yr-old woman without stigmata of VHL disease. The tumor was composed of sheets of polygonal epithelioid stromal cells
http://dx.doi.org/10.1016/j.eururo.2014.04.022 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
with ample pale or eosinophilic, vacuolated cytoplasm in an arborizing capillary network. The tumor cells showed variable nuclear pleomorphism, intranuclear cytoplasmic invaginations, scattered hyaline globules, and psammoma-like calcifications. Some areas showed branching hemangiopericytoma-like vessels with tumor cells radiating from the wall, whereas other areas were edematous and hyalinized with sparse stromal cells and abundant reticular vessels. The tumor cells reacted strongly and diffusely with antibodies to PAX8, CD10, a-inhibin, S100 protein, neuron-specific enolase, and vimentin. Positive immunoreactivity for PAX8 is unexpected and contrasts with CSN hemangioblastomas, which are negative for PAX8. According to Zhao et al. [6], PAX8 expression in sporadic hemangioblastoma of the kidney supports a primary renal cell lineage. After reading recent interesting papers dealing with renal hemangioblastoma, we went back to our series of cases (from the period January 2007 to February 2014; >1000 cases) of RCC examined at the Section of Pathological Anatomy of the Polytechnic University of the Marche Region, including the consultation cases of one of our group (R.M.), whose pathology report included a description of rich capilarization. Even though our hope of finding a case of primary renal hemangioblastoma misreported as clear cell RCC (ccRCC) was not rewarded, we were able to retrieve two ccRCCs with a hemangioblastoma-like pattern. The two cases are from patients who are alive and without evidence of disease 3 yr after operation. 2.
Case 1
This case refers to a partial right nephrectomy specimen (5.5 5 4 cm) from a 49-yr-old man without stigmata of VHL disease. The cut surface shows a well demarcated nodule, 3.5 cm in greatest diameter, reddish in color at the periphery, with scattered yellow spots and a white central area. Figure 1A shows the whole-mount section of the specimen with the tumor nodule. The reddish component seen macroscopically, representing approximately 70% of the neoplasm, shows a rich capillary network of singlelayered flat endothelial cells enclosing stromal cells (Fig. 1B). The latter cell type shows a pale or eosinophilic cytoplasm exhibiting occasional lipid droplets and hyaline globules, oval nuclei, delicate chromatin, and inconspicuous nucleoli. Rare cell nuclei are enlarged, pleomorphic, or bizarre (Fig. 1C). Histologically, the yellow spots seen macroscopically, representing approximately 5% of the neoplasm, show the features of ccRCC, Fuhrman and International Society of Urological Pathology grade 1 (Fig. 1D). The white central area, approximately 15% of the neoplasm, shows an edematous background, devoid of cells, with a rich mesh of capillaries (Fig. 1E). There is a gradual transition between the hemangioblastoma-like component and the areas of ccRCC. In part of the tumor, the endothelial lining and capilarization become less prominent in association with the expansion of the clear cell component. There is also transition with edematous
background and rich capillary mesh of the central part of the neoplasm (Fig. 1F). 2.1.
Immunohistochemistry
The cells in the hemangioblastoma-like component express a-inhibin (Fig. 2A and 2B), PAX8 (Fig. 2C), RCC marker (Fig. 2D), CD10 (Fig. 2E), and S100. The immunohistochemical findings in the ccRCC component are those typically seen in ccRCC. The cells are negative for a-inhibin (Fig. 2B) and S100 and are positive for PAX8 (Fig. 2C), RCC marker (Fig. 2D), CD10 (Fig. 2E), and vimentin. CD34 underscores the rich and delicate vascular channels in the hemangioblastoma-like component (Fig. 2F). 3.
Case 2
This case refers to a right total nephrectomy specimen with a tumor 3.2 cm in greatest diameter from a woman aged 32 yr, without stigmata of VHL disease. The morphologic features and the immunohistochemical findings are identical to those of case 1, with the ccRCC component representing approximately 20% of the tumor, the hemangioblastoma-like pattern representing 60%, and the central area with regressive changes representing 20%. 4.
Additional clinicopathologic studies
For comparison, we investigated three groups of patients. The first included 20 patients with ccRCC without the hemangioblastoma-like pattern (mean age: 61.4 yr [range: 37–79 yr]; 11 men, 9 women). One of the patients had VHL disease. PAX8 was positive in all cases in the neoplastic clear cells. Expression of a-inhibin was negative in all cases. The second group included nine patients with metastatic ccRCC in various body locations: six in the adrenal gland, two in the brain, and one in the bone (mean age: 61.9 yr [range: 37–77 yr]; three men, six women). None showed the hemangioblastoma-like pattern when the slides were reviewed. PAX8 was positive in all cases in the neoplastic clear cells, whereas a-inhibin was negative in all cases. The third group was composed of 12 patients with hemangioblastoma of the cerebellum (mean age: 50.7 yr [range: 24–77 yr]; 9 men, 3 women). One of patients had VHL disease. PAX8 was negative, whereas a-inhibin was positive in all cases. 5.
Discussion
In the kidney, only 11 cases of sporadic hemangioblastoma have been published in the English literature [4–11], typically posing a challenging differential diagnosis. The list of differential diagnoses of this rare renal tumor includes ccRCC, translocation-associated RCC, and epithelioid angiomyolipoma. Other differential diagnoses include paraganglioma, capillary hemangioma, and epithelioid peripheral nerve tumor, which very rarely affects the kidney but may show similarity to hemangioblastoma either histologically or
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 EUROPEAN UROLOGY XXX (2014) XXX–XXX
3
Fig. 1 – (A) Whole-mount section of the specimen with the tumor nodule. (B) Rich capillary network of single-layered flat endothelial cells; (C) rare cell nuclei are enlarged, pleomorphic, or bizarre. (D) Clear cell renal cell carcinoma, Fuhrman and International Society of Urological Pathology grade 1. (E) Edematous background, devoid of cells, with a rich mesh of capillaries. (F) Transition with edematous background and rich capillary mesh of the central part of the neoplasm.
immunohistochemically. Attention to the characteristic morphologic and immunophenotypic features of renal hemangioblastoma will help distinguish this rare tumor from such lesions. The hemangioblastoma-like component seen in our cases is identical morphologically and immunohistochemically to
that of the renal hemangioblastoma described recently by Zhao and coworkers [6] and by others [4,5,7–11]. The difference from the cases already reported is that ours show an unequivocal ccRCC component with a central regressive area and gradual transition with the hemangioblastoma-like part, highlighting the fact that all components belong to
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 4
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Fig. 2 – The cells in the hemangioblastoma-like component express (A,B) a-inhibin, (C) PAX8, (D) renal cell carcinoma marker (RCCm), and (E) CD10. The cells in the clear cell RCC component are negative for a-inhibin (b, asterisks) and are positive for PAX8 (c, arrow), RCC marker (d, arrow), and CD10 (e, arrow). (F) CD34 immunohistochemistry underscores the rich and delicate vascular channels in the hemangioblastoma-like component.
the same tumor and not to a composite neoplasm. It is the same tumor in which the capillary network is richer in the hemangioblastoma-like part compared with that of the typical ccRCC, whereas the clear cells of the typical ccRCC are replaced with the so-called stromal cells. These cells,
while maintaining the immunohistochemical features of the neoplastic clear cells in terms of PAX8, RCC marker, and CD10 expression, acquire the expression of a-inhibin and S100. This is more typical of hemangioblastoma, even though in rare cases a-inhibin has been reported to be expressed by
Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
EURURO-5638; No. of Pages 5 EUROPEAN UROLOGY XXX (2014) XXX–XXX
ccRCC as well [12]. Our interpretation is that this is a ccRCC with regressive changes in the central part identical to those usually seen in most ccRCCs. The hemangioblastoma-like part might represent a component in which the tumor cells have disappeared, as in the central part, and have been replaced by the stromal cells. This brings us to two considerations. The first consideration is the origin of the stromal cells. We agree with the hypothesis put forward by Zhao et al. [6] that the immunoprofile of extraneural hemangioblastoma can vary with the site of origin, perhaps as a result of tumor cell lineage and retention of organ-specific markers or acquisition of site-specific antigens due to local factors. In fact, the nuclear positivity for PAX8 in the current cases, along with the expression of RCC marker and CD10, also lends support to the idea that these tumors are capable of expressing site-specific antigens, perhaps as a result of derivation from organ-specific pluripotent cells or due to local or microenvironmental factors influencing antigen expression [4,13,14]. Related to this phenomenon, the endothelial cells of CNS hemangioblastomas typically express glucose transporter 1 (GLUT1), similar to normal CNS endothelium, whereas the endothelial cells of renal hemangioblastomas appear not to express GLUT1, similar to the endothelium of the normal peripheral vasculature [5]. The second consideration is whether the hemangioblastoma cases reported in the literature should be considered as true renal hemangioblastomas, as claimed by the authors, or—as seen in our cases—as a diffuse hemangioblastoma-like change in a clear cell renal cell tumor. We do not have an answer, although our findings lend strong support to the latter hypothesis.
5
Critical revision of the manuscript for important intellectual content: LopezBeltran, Galosi. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: Cheng. Supervision: Montironi, Montorsi. Other (specify): None. Financial disclosures: Rodolfo Montironi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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6.
Conclusions
[7] Verine J, Sandid W, Miquel C, Vignaud JM, Mongiat-Artus P. Sporadic hemangioblastoma of the kidney: an underrecognized pseu-
We reported two cases of ccRCC with an extensive hemangioblastoma-like pattern. To the best of our knowledge, this is the first description of such a pattern, the clinical significance and therapeutic implications of which are not yet known and the differential diagnosis being with renal hemangioblastoma, a rare tumor considered to have benign behavior. We believe that the hemangioblastomalike pattern could have a favorable prognostic significance based on the fact that the renal hemangioblastomas described so far have benign behavior.
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Author contributions: Rodolfo Montironi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Montironi, Scarpelli. Acquisition of data: Montironi. Analysis and interpretation of data: Montironi, Scarpelli. Drafting of the manuscript: Cheng.
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Please cite this article in press as: Montironi R, et al. Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance. Eur Urol (2014), http://dx.doi.org/ 10.1016/j.eururo.2014.04.022
