- Email: [email protected]
Met
ARTICLE IN PRESS
Pathology – Research and Practice 205 (2009) 57–61 www.elsevier.de/prp
TEACHING CASES
TFE3-renal carcinoma in an adult patient: A case with strong expression of phosphorylated hepatocyte growth factor (HGFR)/Met Yuji Sagaraa, Yasuyoshi Miyataa,, Koichiro Nomataa, Kuniko Abeb, Jiro Eguchia, Tomayoshi Hayashib, Hideki Sakaia, Shigeru Kandac, Hiroshi Kanetakea a
Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan Department of Pathology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan c National Hospital Organization, Nagasaki Hospital, 6-41 Sakuragi-cho, Nagasaki 850-8523, Japan b
Received 7 June 2008; accepted 19 August 2008
Abstract TFE3-renal carcinoma is rare in adults. Patients with this disease often have a poor prognosis, because it has reached an advanced stage at presentation, and there is lack of an effective therapy. The exact mechanism of its malignant behavior is still unclear. In recent years, a significant relationship between TFE3 fusion protein and hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase activity was reported in several malignancies. We previously reported that phosphorylation of HGFR/Met was associated with malignant aggressiveness and survival in patients with conventional RCC. Here, using immunohistochemical techniques, we examined two types of phosphorylated HGFR/Met (pY1234/1235 and pY1349) in a specimen of a 29-year-old man with TFE3-renal carcinoma. Strong expression of both proteins was detected in carcinoma cells, but not in normal kidney tissues. In addition, they were expressed more strongly in TFE3-renal carcinoma than in conventional RCC. Although tumor was diagnosed at T1N0M0 and the patient received radical nephrectomy, the tumor metastasized to multiple organs, and he died 2 years after surgery. We speculate that upregulated phosphorylation of HGFR/Met could be partly associated with the malignant aggressiveness and poor survival of this patient. r 2008 Elsevier GmbH. All rights reserved. Keywords: TFE-3 renal carcinoma; Hepatocyte growth factor receptor/Met; Phosphorylation; Immunohistochemistry
Introduction Renal cell carcinoma (RCC) is a common urological malignancy in the developed countries. The peak incidence of RCC is between 60 and 70 years of age [7]. Regarding the histological type, the clear cell (conventional) type is the most common one, followed by chromophobe and papillary RCC. The 2004 WHO Corresponding author. Tel.: +81 95 849 7340; fax: +81 95 849 7343. E-mail address: [email protected] (Y. Miyata).
0344-0338/$ - see front matter r 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2008.08.001
classification of kidney tumors includes the entity of RCC associated with Xp11.2 translocations/TFE3 gene fusion (TFE3-renal carcinoma) [1]. This tumor is reported to account for approximately 5–20% of RCC in the pediatric and adolescent age groups, although it is much less common in adults [2–4]. One of the representative clinical features is the advanced stage at presentation of the patients, associated with poor prognosis due to the lack of effective therapy apart from surgery [3,6]. Therefore, many investigators have investigated the pathogenetic mechanisms of this tumor. In an infantile TFE-3 renal carcinoma, several factors
ARTICLE IN PRESS 58
Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
are known to be associated with malignant aggressiveness [9]. On the other hand, information about such mechanisms and factors in adult patients is scarce. In recent years, TFE3 was reported to mediate upregulation of the hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase signaling pathway in malignant cells [10]. Phosphorylation of HGFR/Met has also been reported to be associated with malignant aggressiveness and poor survival in conventional RCC [8]. However, there is no report on its pathological significance in TFE3-renal carcinoma. Based on these facts, we describe the use of two types of antiphosphorylated HGFR/Met antibodies to examine TFE3-renal carcinoma from an adult patient.
Case report A 29-year-old man was admitted to our hospital because of gross hematuria. Computerized tomography (CT) revealed a well-defined 2.5-cm cystic homogenous mass lesion of the right kidney, and it was not enhanced by contrast. There was no evidence of lymphadenopathy or metastatic disease by imagining examination. The patient was followed up for hemorrhage cyst. A further CT carried out 6 months later showed that tumor size and density had not changed. Although we planned periodic examinations every 6 months, the patient refused to undergo these investigations. After 20 months, he presented with gross hematuria and abdominal pain. CT revealed that the tumor mass had reached a size of 4.5 cm. Enlarged lymph node or metastatic mass was not detected by CT of the abdomen and chest and bone scintigraphy. The patient underwent laparoscopic right radical nephrectomy under the tentative diagnosis of renal cancer (T1N0M0), and the tumor was removed completely. Six months after surgery, chest X-ray revealed multiple lung metastases. Despite various treatment modalities, including immunotherapy (interferon and interleukin-2), the tumor metastasized to other multiple organs, including lymph node and liver, and the patient died 2 years after surgery.
Antigen retrieval was performed at 95 1C for 40 min in 0.01 M sodium citrate buffer (pH 6.0). All sections were then immersed in 3% hydrogen peroxide for 30 min. Sections were incubated overnight with the primary antibody (Cell Signaling Technology, Beverly, MA) at 4 1C. The sections were then incubated with peroxidase using the labeled polymer method with Dako EnVision+TM Peroxidase (Dako Corporation, Carpinteria, CA) for 60 min. The peroxidase reaction was visualized with the liquid 3,3-diaminobenzidine tetrahydrochloride (DAB) substrate kit (Zymed Laboratories Inc.). Sections were counterstained in hematoxylin. Conventional RCC tissue was used as a positive control for phosphorylated HGFR/c-Met, and a consecutive section from each sample processed without the primary antibody was used as a negative control. TFE3 expression was also examined using a similar method (primary antibody was purchased from Santa Cruz Biotechnology, Inc., CA). Evaluation of this expression was assessed semiquantitatively, taking into account the percentage of positively stained cancer cells (at least 800 carcinoma cells were examined).
Results Macroscopic and microscopic findings of routine examination The right kidney showed a 6.5-cm yellow-tan mass with areas of hemorrhage and necrosis. Invasion of the renal capsule, calyx, ureter, or renal vein was not detected. Microscopic examination revealed that the tumor consisted of a single population of neoplastic epithelial cells, some having voluminous clear cytoplasm and solid and partially papillary architecture (Fig. 1).
Materials and methods The histological diagnosis was reached by routine examination (hematoxylin and eosin), and immunohistochemical examination was performed using formalinfixed, paraffin-embedded sections. The expression of pY1234/1235 and pY1349, two types of phosphorylated HGFR/Met, was analyzed as described previously [8]. Briefly, 5-mm-thick sections were deparaffinized in xylene and re-hydrated in graded solutions of ethanol.
Fig. 1. The tumor has a solid and papillary architecture, with carcinoma cells containing clear cytoplasm ( 200).
ARTICLE IN PRESS Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
Carcinoma cells were not detected in renal capsule or calyx by microscopic examination. The hematoxylin and eosin staining pattern is not that typically seen in either conventional or papillary RCC. There was no obvious psammomatous calcification. Therefore, we carried out immunohistochemical examination using several available antibodies. The carcinoma cells were positive for vimentin and CD10. Concerning the cytokeratin
59
markers, staining was negative for cytokeratin 7 and 34bE12, and positive for cytokeratin 19 and AE1/AE3. Strong nuclear labeling of TFE3 protein was shown in approximately 70% of carcinoma cells (Fig. 2). Finally, this tumor was diagnosed as a TFE3-renal carcinoma, because the immunohistological detection of TFE3 protein is highly specific and highly sensitive for this disease [2].
Immunohistochemistry of phosphorylated HGFR/Met pY1234/1234 and pY1349 HGFR/Met were also expressed in carcinoma cells (Fig. 3a and b). The proportions of pY1234/1235 and pY1349 HGFR/Metpositive cancer cells were 48.7% and 71.3%, respectively. In contrast, their expression was rare in normal kidney areas (Fig. 3c and d).
Discussion
Fig. 2. Expression of TFE3 protein: Note the strong and widespread nuclear positivity in malignant cells ( 400).
TFE3-renal carcinoma belongs to a new subgroup of renal carcinoma and is rare in adults. In most cases, adult patients with this disease have a poor prognosis for life [3,6]. One reason for such an aggressive course is that many patients already have local invasion and/or
Fig. 3. Expression of pY1234/1235 HGFR/Met (a: 200) and pY1349 (b: 200) in cancer cells. Expression of pY1234/1235 HGFR/Met (c: 200) and pY1349 (d: 200) in normal kidney tissues. Note the strong expressions of both proteins in cancer cells, but not in the normal kidney.
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metastasis at diagnosis. Argani et al. [3] reported that 16 of 28 patients (57.1%) were in stage 3 or 4. In addition, Meyer et al. [6] reported that all of five adult patients were in an advanced stage. On the other hand, although our patient did not have metastatic tumor and primary tumor did not invade into the renal capsule, this tumor metastasized to multiple organs, and he died 2 years after surgery. For patients with metastatic or recurrent tumor, there is no effective and optimal therapy. Immunotherapy was often performed as in conventional RCC. However, its anti-tumoral effect was disappointing as in our patient [3]. From these facts, many investigators are searching for useful information to discuss treatment strategies and the therapeutic target. Tsuda et al. [10] reported that TFE3 increased Met protein expression in several cancer cell lines, including renal carcinoma. They also found that this induction was associated with Met phosphorylation at tyrosine residues 1234/1235. In our case, strong expression of pY1234/1235 HGFR/Met was detected. We were surprised by this finding, because such a strong expression of pY1234/1235 was not found in 114 cases of conventional RCC in our previous report [8]. The result of this study cannot explain the reason for this disparity. Using kinetic analysis, we showed that the period of pY1234/1235 phosphorylation in RCC cells was short [8]. Because pY1234/1235 expression was detected despite a short period of phosphorylation, pY1234/1235 phosphorylation might be extremely strong in TFE3-renal carcinoma. On the other hand, of the above-mentioned 114 patients, we examined 20 specimens with pY1234/1235 immunostaining for TFE3 expression but found no expression in all these specimens (data not shown). From these results, we speculate that the relationship between TFE3 protein and phosphorylation of pY1234/1235 is characteristic of TFE3-renal carcinoma, but not of conventional RCC. Concerning pY1349 HGFR/Met, we also found that it was strongly expressed in this case. We reported that increased expression of pY1349 HGFR/Met was detected in conventional RCC and was associated with malignant aggressiveness and poor survival [8]. Likewise, we believe that the phosphorylation of pY1349 plays important roles in the malignant behavior of TFE3-renal carcinoma. Interestingly, the pY1349 expression rate (71.3%) in this specimen was higher than that in the conventional RCC of our previous report (0–64.3%) [8]. HGFR/Met signaling pathway is known to stimulate cell proliferation and migration (for review, see Refs. [5,11]). On the other hand, inhibition of Met activation resulted in reduced cell growth in cancer cell lines containing endogenous TFE3 fusion protein [10]. Based on this background and the present case, it is conceivable that upregulated phosphorylation of HGFR/Met could be partly associated with the
malignant aggressiveness of TFE3-renal carcinoma and poor survival of such patients, and that the HGFR/Met system is a potentially suitable therapeutic target not only in RCC but also in TFE3-renal carcinoma. In conclusion, we reported TFE3-renal carcinoma with strong expression of phosphorylated HGFR/Met in an adult patient. pY1234/1235 and pY1349 HGFR/Met were expressed more strongly than in conventional RCC. We presume that upregulation of HGFR/Met is partly associated with malignant behavior of TFE3-renal carcinoma and propose further studies on the pathological significance of the HGFR/Met system in TFE3-renal carcinoma patients, including child cases.
References [1] P. Argani, M. Ladanyi, Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions, in: J.M. Eble, G. Sauter, J. Epstein, I. Sesterhenn (Eds.), Pathology and Genetics of Tumors of the Urinary System & Male Genital Organs, IARC Press, Lyon, 2004, pp. 37–38. [2] P. Argani, P. Lai, B. Huchinson, M.Y. Lui, V.E. Reuter, M. Ladanyi, Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay, Am. J. Surg. Pathol. 27 (2003) 750–761. [3] P. Argani, S. Olgac, S.K. Tickoo, M. Goldfischer, H. Moch, D.Y. Chan, J.N. Eble, S.M. Bonsib, M. Jimero, J. Lloreta, A. Billis, J. Hicks, A.M. De Marzo, V.E. Leuter, M. Ladanyi, Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum, Am. J. Surg. Pathol. 31 (2007) 1149–1160. [4] E. Bruder, O. Passera, D. Harms, I. Leuschner, M. Ladanyi, P. Argagni, J.N. Eble, K. Struckmann, P. Schraml, H. Mock, Morphologic and molecular characterization of renal cell carcinoma in children and young adults, Am. J. Surg. Pathol. 28 (2004) 1117–1132. [5] A. Gentile, L. Trusolino, P.M. Comoglio, The Met tyrosine kinase receptor in development and cancer, Cancer Metastasis Rev. 27 (2008) 85–94. [6] P.N. Meyer, J.J. Clark, R.C. Flanigan, M.M. Picken, Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults, Am. J. Clin. Pathol. 128 (2007) 70–79. [7] D. Mitropoulos, A. Petrolekas, I. Anastasiou, I. Adamakis, A. Kyroudi-Voulgari, E. Serafetinides, A. Zervas, Difference of presentation characteristics of renal cell carcinoma in the last 25 years: a single center experience, J. Cancer Res. Clin. Oncol. in press. [8] Y. Miyata, S. Kanda, H. Kanetake, Presence of phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor progression and survival in patients with conventional renal cell carcinoma, Clin. Cancer Res. 15 (2006) 4876–4881.
ARTICLE IN PRESS Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
[9] J. Mu¨ller-Ho¨cker, G. Babaryka, I. Scmid, A. Jung, Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion, Pathol. Res. Pract. 204 (2008) 589–597. [10] M. Tsuda, I.J. Davis, P. Argani, N. Shukla, G.G. McGill, M. Nagai, T. Saito, M. Lae´, M.L. Fisher, M. Ladanyi,
61
TFE3 fusion activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition, Cancer Res. 67 (2007) 919–929. [11] Wernert, Multiple roles of tumour stroma, Virchows Arch. 430 (1997) 433–443.
Pathology – Research and Practice 205 (2009) 57–61 www.elsevier.de/prp
TEACHING CASES
TFE3-renal carcinoma in an adult patient: A case with strong expression of phosphorylated hepatocyte growth factor (HGFR)/Met Yuji Sagaraa, Yasuyoshi Miyataa,, Koichiro Nomataa, Kuniko Abeb, Jiro Eguchia, Tomayoshi Hayashib, Hideki Sakaia, Shigeru Kandac, Hiroshi Kanetakea a
Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan Department of Pathology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan c National Hospital Organization, Nagasaki Hospital, 6-41 Sakuragi-cho, Nagasaki 850-8523, Japan b
Received 7 June 2008; accepted 19 August 2008
Abstract TFE3-renal carcinoma is rare in adults. Patients with this disease often have a poor prognosis, because it has reached an advanced stage at presentation, and there is lack of an effective therapy. The exact mechanism of its malignant behavior is still unclear. In recent years, a significant relationship between TFE3 fusion protein and hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase activity was reported in several malignancies. We previously reported that phosphorylation of HGFR/Met was associated with malignant aggressiveness and survival in patients with conventional RCC. Here, using immunohistochemical techniques, we examined two types of phosphorylated HGFR/Met (pY1234/1235 and pY1349) in a specimen of a 29-year-old man with TFE3-renal carcinoma. Strong expression of both proteins was detected in carcinoma cells, but not in normal kidney tissues. In addition, they were expressed more strongly in TFE3-renal carcinoma than in conventional RCC. Although tumor was diagnosed at T1N0M0 and the patient received radical nephrectomy, the tumor metastasized to multiple organs, and he died 2 years after surgery. We speculate that upregulated phosphorylation of HGFR/Met could be partly associated with the malignant aggressiveness and poor survival of this patient. r 2008 Elsevier GmbH. All rights reserved. Keywords: TFE-3 renal carcinoma; Hepatocyte growth factor receptor/Met; Phosphorylation; Immunohistochemistry
Introduction Renal cell carcinoma (RCC) is a common urological malignancy in the developed countries. The peak incidence of RCC is between 60 and 70 years of age [7]. Regarding the histological type, the clear cell (conventional) type is the most common one, followed by chromophobe and papillary RCC. The 2004 WHO Corresponding author. Tel.: +81 95 849 7340; fax: +81 95 849 7343. E-mail address: [email protected] (Y. Miyata).
0344-0338/$ - see front matter r 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2008.08.001
classification of kidney tumors includes the entity of RCC associated with Xp11.2 translocations/TFE3 gene fusion (TFE3-renal carcinoma) [1]. This tumor is reported to account for approximately 5–20% of RCC in the pediatric and adolescent age groups, although it is much less common in adults [2–4]. One of the representative clinical features is the advanced stage at presentation of the patients, associated with poor prognosis due to the lack of effective therapy apart from surgery [3,6]. Therefore, many investigators have investigated the pathogenetic mechanisms of this tumor. In an infantile TFE-3 renal carcinoma, several factors
ARTICLE IN PRESS 58
Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
are known to be associated with malignant aggressiveness [9]. On the other hand, information about such mechanisms and factors in adult patients is scarce. In recent years, TFE3 was reported to mediate upregulation of the hepatocyte growth factor receptor (HGFR)/Met tyrosine kinase signaling pathway in malignant cells [10]. Phosphorylation of HGFR/Met has also been reported to be associated with malignant aggressiveness and poor survival in conventional RCC [8]. However, there is no report on its pathological significance in TFE3-renal carcinoma. Based on these facts, we describe the use of two types of antiphosphorylated HGFR/Met antibodies to examine TFE3-renal carcinoma from an adult patient.
Case report A 29-year-old man was admitted to our hospital because of gross hematuria. Computerized tomography (CT) revealed a well-defined 2.5-cm cystic homogenous mass lesion of the right kidney, and it was not enhanced by contrast. There was no evidence of lymphadenopathy or metastatic disease by imagining examination. The patient was followed up for hemorrhage cyst. A further CT carried out 6 months later showed that tumor size and density had not changed. Although we planned periodic examinations every 6 months, the patient refused to undergo these investigations. After 20 months, he presented with gross hematuria and abdominal pain. CT revealed that the tumor mass had reached a size of 4.5 cm. Enlarged lymph node or metastatic mass was not detected by CT of the abdomen and chest and bone scintigraphy. The patient underwent laparoscopic right radical nephrectomy under the tentative diagnosis of renal cancer (T1N0M0), and the tumor was removed completely. Six months after surgery, chest X-ray revealed multiple lung metastases. Despite various treatment modalities, including immunotherapy (interferon and interleukin-2), the tumor metastasized to other multiple organs, including lymph node and liver, and the patient died 2 years after surgery.
Antigen retrieval was performed at 95 1C for 40 min in 0.01 M sodium citrate buffer (pH 6.0). All sections were then immersed in 3% hydrogen peroxide for 30 min. Sections were incubated overnight with the primary antibody (Cell Signaling Technology, Beverly, MA) at 4 1C. The sections were then incubated with peroxidase using the labeled polymer method with Dako EnVision+TM Peroxidase (Dako Corporation, Carpinteria, CA) for 60 min. The peroxidase reaction was visualized with the liquid 3,3-diaminobenzidine tetrahydrochloride (DAB) substrate kit (Zymed Laboratories Inc.). Sections were counterstained in hematoxylin. Conventional RCC tissue was used as a positive control for phosphorylated HGFR/c-Met, and a consecutive section from each sample processed without the primary antibody was used as a negative control. TFE3 expression was also examined using a similar method (primary antibody was purchased from Santa Cruz Biotechnology, Inc., CA). Evaluation of this expression was assessed semiquantitatively, taking into account the percentage of positively stained cancer cells (at least 800 carcinoma cells were examined).
Results Macroscopic and microscopic findings of routine examination The right kidney showed a 6.5-cm yellow-tan mass with areas of hemorrhage and necrosis. Invasion of the renal capsule, calyx, ureter, or renal vein was not detected. Microscopic examination revealed that the tumor consisted of a single population of neoplastic epithelial cells, some having voluminous clear cytoplasm and solid and partially papillary architecture (Fig. 1).
Materials and methods The histological diagnosis was reached by routine examination (hematoxylin and eosin), and immunohistochemical examination was performed using formalinfixed, paraffin-embedded sections. The expression of pY1234/1235 and pY1349, two types of phosphorylated HGFR/Met, was analyzed as described previously [8]. Briefly, 5-mm-thick sections were deparaffinized in xylene and re-hydrated in graded solutions of ethanol.
Fig. 1. The tumor has a solid and papillary architecture, with carcinoma cells containing clear cytoplasm ( 200).
ARTICLE IN PRESS Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
Carcinoma cells were not detected in renal capsule or calyx by microscopic examination. The hematoxylin and eosin staining pattern is not that typically seen in either conventional or papillary RCC. There was no obvious psammomatous calcification. Therefore, we carried out immunohistochemical examination using several available antibodies. The carcinoma cells were positive for vimentin and CD10. Concerning the cytokeratin
59
markers, staining was negative for cytokeratin 7 and 34bE12, and positive for cytokeratin 19 and AE1/AE3. Strong nuclear labeling of TFE3 protein was shown in approximately 70% of carcinoma cells (Fig. 2). Finally, this tumor was diagnosed as a TFE3-renal carcinoma, because the immunohistological detection of TFE3 protein is highly specific and highly sensitive for this disease [2].
Immunohistochemistry of phosphorylated HGFR/Met pY1234/1234 and pY1349 HGFR/Met were also expressed in carcinoma cells (Fig. 3a and b). The proportions of pY1234/1235 and pY1349 HGFR/Metpositive cancer cells were 48.7% and 71.3%, respectively. In contrast, their expression was rare in normal kidney areas (Fig. 3c and d).
Discussion
Fig. 2. Expression of TFE3 protein: Note the strong and widespread nuclear positivity in malignant cells ( 400).
TFE3-renal carcinoma belongs to a new subgroup of renal carcinoma and is rare in adults. In most cases, adult patients with this disease have a poor prognosis for life [3,6]. One reason for such an aggressive course is that many patients already have local invasion and/or
Fig. 3. Expression of pY1234/1235 HGFR/Met (a: 200) and pY1349 (b: 200) in cancer cells. Expression of pY1234/1235 HGFR/Met (c: 200) and pY1349 (d: 200) in normal kidney tissues. Note the strong expressions of both proteins in cancer cells, but not in the normal kidney.
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metastasis at diagnosis. Argani et al. [3] reported that 16 of 28 patients (57.1%) were in stage 3 or 4. In addition, Meyer et al. [6] reported that all of five adult patients were in an advanced stage. On the other hand, although our patient did not have metastatic tumor and primary tumor did not invade into the renal capsule, this tumor metastasized to multiple organs, and he died 2 years after surgery. For patients with metastatic or recurrent tumor, there is no effective and optimal therapy. Immunotherapy was often performed as in conventional RCC. However, its anti-tumoral effect was disappointing as in our patient [3]. From these facts, many investigators are searching for useful information to discuss treatment strategies and the therapeutic target. Tsuda et al. [10] reported that TFE3 increased Met protein expression in several cancer cell lines, including renal carcinoma. They also found that this induction was associated with Met phosphorylation at tyrosine residues 1234/1235. In our case, strong expression of pY1234/1235 HGFR/Met was detected. We were surprised by this finding, because such a strong expression of pY1234/1235 was not found in 114 cases of conventional RCC in our previous report [8]. The result of this study cannot explain the reason for this disparity. Using kinetic analysis, we showed that the period of pY1234/1235 phosphorylation in RCC cells was short [8]. Because pY1234/1235 expression was detected despite a short period of phosphorylation, pY1234/1235 phosphorylation might be extremely strong in TFE3-renal carcinoma. On the other hand, of the above-mentioned 114 patients, we examined 20 specimens with pY1234/1235 immunostaining for TFE3 expression but found no expression in all these specimens (data not shown). From these results, we speculate that the relationship between TFE3 protein and phosphorylation of pY1234/1235 is characteristic of TFE3-renal carcinoma, but not of conventional RCC. Concerning pY1349 HGFR/Met, we also found that it was strongly expressed in this case. We reported that increased expression of pY1349 HGFR/Met was detected in conventional RCC and was associated with malignant aggressiveness and poor survival [8]. Likewise, we believe that the phosphorylation of pY1349 plays important roles in the malignant behavior of TFE3-renal carcinoma. Interestingly, the pY1349 expression rate (71.3%) in this specimen was higher than that in the conventional RCC of our previous report (0–64.3%) [8]. HGFR/Met signaling pathway is known to stimulate cell proliferation and migration (for review, see Refs. [5,11]). On the other hand, inhibition of Met activation resulted in reduced cell growth in cancer cell lines containing endogenous TFE3 fusion protein [10]. Based on this background and the present case, it is conceivable that upregulated phosphorylation of HGFR/Met could be partly associated with the
malignant aggressiveness of TFE3-renal carcinoma and poor survival of such patients, and that the HGFR/Met system is a potentially suitable therapeutic target not only in RCC but also in TFE3-renal carcinoma. In conclusion, we reported TFE3-renal carcinoma with strong expression of phosphorylated HGFR/Met in an adult patient. pY1234/1235 and pY1349 HGFR/Met were expressed more strongly than in conventional RCC. We presume that upregulation of HGFR/Met is partly associated with malignant behavior of TFE3-renal carcinoma and propose further studies on the pathological significance of the HGFR/Met system in TFE3-renal carcinoma patients, including child cases.
References [1] P. Argani, M. Ladanyi, Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions, in: J.M. Eble, G. Sauter, J. Epstein, I. Sesterhenn (Eds.), Pathology and Genetics of Tumors of the Urinary System & Male Genital Organs, IARC Press, Lyon, 2004, pp. 37–38. [2] P. Argani, P. Lai, B. Huchinson, M.Y. Lui, V.E. Reuter, M. Ladanyi, Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay, Am. J. Surg. Pathol. 27 (2003) 750–761. [3] P. Argani, S. Olgac, S.K. Tickoo, M. Goldfischer, H. Moch, D.Y. Chan, J.N. Eble, S.M. Bonsib, M. Jimero, J. Lloreta, A. Billis, J. Hicks, A.M. De Marzo, V.E. Leuter, M. Ladanyi, Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum, Am. J. Surg. Pathol. 31 (2007) 1149–1160. [4] E. Bruder, O. Passera, D. Harms, I. Leuschner, M. Ladanyi, P. Argagni, J.N. Eble, K. Struckmann, P. Schraml, H. Mock, Morphologic and molecular characterization of renal cell carcinoma in children and young adults, Am. J. Surg. Pathol. 28 (2004) 1117–1132. [5] A. Gentile, L. Trusolino, P.M. Comoglio, The Met tyrosine kinase receptor in development and cancer, Cancer Metastasis Rev. 27 (2008) 85–94. [6] P.N. Meyer, J.J. Clark, R.C. Flanigan, M.M. Picken, Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults, Am. J. Clin. Pathol. 128 (2007) 70–79. [7] D. Mitropoulos, A. Petrolekas, I. Anastasiou, I. Adamakis, A. Kyroudi-Voulgari, E. Serafetinides, A. Zervas, Difference of presentation characteristics of renal cell carcinoma in the last 25 years: a single center experience, J. Cancer Res. Clin. Oncol. in press. [8] Y. Miyata, S. Kanda, H. Kanetake, Presence of phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor progression and survival in patients with conventional renal cell carcinoma, Clin. Cancer Res. 15 (2006) 4876–4881.
ARTICLE IN PRESS Y. Sagara et al. / Pathology – Research and Practice 205 (2009) 57–61
[9] J. Mu¨ller-Ho¨cker, G. Babaryka, I. Scmid, A. Jung, Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion, Pathol. Res. Pract. 204 (2008) 589–597. [10] M. Tsuda, I.J. Davis, P. Argani, N. Shukla, G.G. McGill, M. Nagai, T. Saito, M. Lae´, M.L. Fisher, M. Ladanyi,
61
TFE3 fusion activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition, Cancer Res. 67 (2007) 919–929. [11] Wernert, Multiple roles of tumour stroma, Virchows Arch. 430 (1997) 433–443.