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Polish Journal of Pathology
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Original paper

Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12)

Naoto Kuroda
,
Kenji Yorita
,
Naomi Sasaki
,
Akira Ishihara
,
Keiko Matsuura
,
Tsutomu Daa
,
Shintaro Mori
,
Aya Sasaki
,
Shuji Mikami
,
Kazuto Shigematsu
,
Yoji Nagashima

Pol J Pathol 2017; 68 (1): 66-72
Online publish date: 2017/05/23
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- Clinicopathological.pdf  [0.78 MB]
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Introduction

The new category of MiT/TFE family translocation renal cell carcinoma (RCC) has been recently proposed and incorporated into the recent World Health Organization classification in 2016 [1, 2, 3, 4, 5]. The MiT/TFE family RCC chiefly consists of Xp11.2 RCC and t(6;11) RCC showing the overexpression of TFE3 and TFEB protein. However, reported cases of t(6;11) RCC are still limited. We performed a clinicopathological study of 5 Japanese cases with t(6;11) RCC to elucidate the clinicopathological characteristics.

Material and methods

Among 655 cases with renal tumors consulted in the Department of Diagnostic Pathology, Kochi Red Cross Hospital during January 2010 and December 2015, 5 cases with t(6;11) RCC were selected in this study. In this study, the clinicopathologic characteristics were predominantly analyzed with the focus on symptoms, follow-up data, macroscopic and microscopic findings, immunohistochemical findings and molecular genetic findings. Histologic sections were cut from formalin-fixed paraffin-embedded tissue blocks and stained with hematoxylin and eosin. For the immunohistochemistry, tissue sections were cut and stained with Ventana Benchmark XT or Ultra autostainer (Ventana Medical Systems, Tucson, AZ). Primary antibodies against TFEB (polyclonal, V-17, 1 : 400, Santa Cruz Biotechnology, Inc., Dallas, TX), TFE3 (MRQ-37, prediluted, Ventana Medical Systems, Inc., Tucson, AZ), cathepsin-K (3F9, 1 : 6400, Abcam, Tokyo, Japan), melanosome-related antigen (MRA) (HMB45, prediluted, DAKO, Glostrup, Denmark), Melan A (A103, 1 : 100, Novocastra Laboratories Ltd, Newcastle upon Tyne NE 128EW, UK), CD10 (56C16, prediluted, Novocastra Laboratories Ltd, Newcastle upon Tyne NE 128EW, UK) and AMACR (P504S)(13H4, 1 : 100, DAKO, Glostrup, Denmark) were employed in the present study. Fluorescence in situ hybridization (FISH) was performed using the TFEB gene Break Apart Probe (Empire Genomics, New York, USA). Pretreatment using VP-2000 Processor (Abott Molecular, Tokyo, Japan) was performed according to the manufacturer’s protocol for HER2, and hybridization was carried out using ThermoBrite (Abott Molecular, Tokyo, Japan). However, the hand-driven method was adopted for the immunohistochemistry of TFEB protein. FISH signals were observed using the Axio Imager 2 Upright Microscope (Zeiss, Tokyo, Japan) and analyzed using the MetaCyte Lite (MetaSystems, Altlussheim, Germany) with Isis (Zeiss). The positive cut-off value of the separate signals between red and green in FISH results was considered as more than 10%. This study was approved by the ethical committee of Kochi Red Cross Hospital (number 143).

Results

Patient information and symptoms/reason for discovery

The results are summarized in Table I. The patients consisted of 4 males and 1 female. The age of patients ranged from 17 to 57 years with a mean age of 38.6 years. One patient presented with acute abdomen because of severe hemorrhage due to capsular rupture of the tumor, and one patient complained of right subcostal pain. One patient and two patients were incidentally found during medical check-up and further examinations of other diseases.

Imaging analyses

Ultrasound sonography and computed tomography (CT) scan showed a well-circumscribed tumor. In two cases, contrast dynamic CT scan of the abdomen revealed heterogeneous enhancement in the renal tumorous lesion. Magnetic resonance imaging showed high intensity in T1 and low intensity in T2 in one tumor (case 2). FDG-PET was not available in all tumors.

Tumor size and pathological stage

The results are summarized in Table II. The size ranged from 2.8 to 11 cm with a mean of 6.5 cm. Two patients, one patient, one patient and one patient were of stages I, II, III and IV, respectively.

Postoperative therapy and follow-up data

The results are summarized in Table III. Regarding postoperative therapy, three patients received no additional therapies. Case 2 received interferon- (IFN-), vascular endothelial growth factor receptor/platelet-derived growth factor receptor (VEGFR/PDGFR) inhibitor (sunitinib) and mammalian target of rapamycin (mTOR) inhibitor (temsirolimus), case 3 underwent IFN- therapy. Regarding outcome, case 5 was very recent and the follow-up data of case 1 was not available. In the remaining three cases, the follow-up duration ranged from 19 to 84 months with a mean of 43.7 months. Although the case 2 patient received IFN-, VEGFR/PDGFR inhibitor and mTOR inhibitor, he died of the disease after 28 months of follow-up. The case 3 patient who received IFN- therapy is alive without disease with 84 months of follow-up. The case 4 patient received hemodialysis postoperatively and died of another unrelated disease with 19 months follow-up.

Macroscopic findings

The results are summarized in Table IV. The cut surface of the tumor showed gray color in three tumors, grayish white to yellow color in one tumor, and brown to grayish-white color in one tumor (Fig. 1). Hemorrhage was identified in two tumors, while no necrosis was seen in any tumors. Daughter nodules and cystic formation were observed in three tumors and two tumors, respectively.

Microscopic findings

The results are summarized in Table V. Histologically, the tumor predominantly showed solid to alveolar growth pattern of neoplastic cells with eosinophilic and clear cytoplasm (Fig. 2A). Additionally, the tumor consisted of the two components of large cells and small cells in all tumors (Fig. 2B). However, small cells were considerably scant in case 4. Basement membrane-like materials were observed in the small cell area with a round pattern, resulting in rosette-like structures (Fig. 2B). In one tumor (case 4), rosette-like structures were indistinct, because the number of small cells were very limited. Papillary architectures were present in four tumors (Fig. 2C). A proliferating area of tubules with eosinophilic to oncocytic cytoplasm was observed in one tumor (Fig. 2D). Mitotic figures and angiolymphatic invasion were observed in one tumor (case 2). Psammoma bodies were observed in the stroma of three tumors (Fig. 2E). Additionally, entrapped tubules in the tumor-center stroma were identified in three tumors (Fig. 2F). No infiltrating lymphocytes were identified in the tumorous stroma.

Immunohistochemical findings

The results are summarized in Table VI. All the tumors showed positivity for TFEB (Fig. 3A). Four tumors showed diffuse positivity with more than 2+ intensity, whereas one tumor showed focal positivity with 1+ intensity. At contrast, all tumors showed negative results for TFE3. Cathepsin-K was positive in all tumors with diffuse distribution in three tumors and focal distribution in two tumors (Fig. 3B). Melanosome-related antigen (MRA) (HMB45) was focally positive in two tumors. The remaining three tumors were completely negative for MRA. Melan A was positive in all tumors with diffuse distribution in three and focal localization in the remaining two tumors. CD10 was focally positive in two tumors and AMACR was focally positive in three tumors.

Molecular genetic findings

In TFEB gene break-apart FISH analyses of two tumors, TFEB gene splitting was observed (Fig. 4). In case 4, 212 tumor cells were counted and showed positive signals in 42%. In case 5, 108 tumor cells were counted and showed positive signals in 62.5%.

Discussion

RCC with t(6;11)(p21;q12) has been incorporated into the MiT translocation carcinoma of the recent WHO classification [1, 2, 3, 4, 5]. As this tumor generally occurs in children and young adults, urologists and pathologists should take the differential diagnosis of renal tumor arising in children and young adults into consideration [6, 7, 8, 9, 10, 11, 12, 13]. As observed in the present study, this tumor may occur even at the age over 40 years [14, 15, 16, 17, 18, 19, 20]. In some cases, previous cytotoxic chemotherapy may be involved in the pathogenesis of this tumor [8]. Therefore, the presence of a past history is very important for urologists. Regarding the reason for discovery, this tumor seems to be often found during the medical check-up or further examination of other diseases. Macroscopically, this tumor is often found at a large size, because this tumor often occurs in young adults and these patients have no chance receiving a medical check-up until the renal tumor is discovered. Based on the results of gross findings, grayish-white color and presence of hemorrhage, cyst and daughter nodules seem to be characteristic of this tumor. A tubulocystic pattern was also reported previously, but this phenomenon seems to be very rare [20]. Histologically, this tumor is chiefly composed of two kinds of neoplastic cells of both large cells resembling usual clear cell RCC cells and small cells simulating lymphocytes [21, 22, 23, 24]. This finding seems to be a most important diagnostic clue. However, small cells may be indistinct or absent in some cases, as observed in one tumor of the present study [12, 25]. For this reason, pathologists should try extensive tumor sampling at the gross examination or seek the small cell area deliberately at the histological examination whenever RCC with t(6;11)(p21;q12) is clinically and histologically suspected. Psammoma bodies in the stroma seem to be often observed in RCC with t(6;11)(p21;q12) as well as Xp11.2 RCC [26]. This tumor shows overexpression of TFEB protein because of the formation of the Alpha-TFEB chimeric transcript caused by chromosomal translocation between 6p21 and 11q12, and nuclear expression of TFEB is a highly sensitive and specific diagnostic marker [7]. The combined immunohistochemical stainings for cathepsin K, melanosome-related antigen (clone HMB45) and melan A seem to be an adjunctive diagnostic tool in identification of RCC with t(6;11)(p21;q12) [4, 6, 7, 11, 13, 15, 16, 18, 19, 20, 21, 22, 23, 24, 27, 28]. The break-apart FISH study for the TFEB gene seems to be an excellent measure for the definite diagnosis because the fusion partner for the TFEB gene is limited to the Alpha (MALAT) gene [17, 20, 23, 28, 29]. This fact essentially seems to differ from that of Xp11.2/TFE3 translocation-associated RCC having several fusion partners [1, 2, 3, 4, 5, 21, 30]. Cytogenetics and RT-PCR analyses are also available for the detection of this tumor [6, 7, 14, 16, 18, 31]. The prognosis seems to be generally excellent [10, 11, 18, 27, 30] with several exceptions. Some tumors did cause recurrence, metastasis or a dismal outcome, particularly in adult cases [15, 16, 25]. In metastatic tumors, mTOR inhibitor may be effective because this tumor is nowadays considered to be related to the mTOR pathway [29]. Immune therapy such as interferon and a VEGF/PDGF inhibitor such as sunitinib may be valuable in some cases [15]. In this viewpoint, evaluation of the vascular pattern in RCC with t(6;11)(p21;q12) may be important, as some histological subtypes including clear cell, papillary, chromophobe and unclassified RCCs were analyzed [31]. Anti-immune check point agents could be hopeful. As downregulation of miR-630 can inhibit the tumor progression in RCC, miR-630 may be a potential therapeutic target also in RCC with t(6;11)(p21;q12) [32, 33].
In conclusion, urologists and pathologists need to consider RCC with t(6;11)(p21;q12) when the patients are children and young adults, and the tumor shows a grayish-white color with hemorrhage, cyst and daughter nodules. In such a situation, the immunohistochemistry of TFEB protein and break-apart FISH for the TFEB gene may be available for an accurate diagnosis.

The authors declare no conflicts of interest.

References

1. Argani P, Ladanyi M. Distinctive neoplasms characterized by specific chromosomal translocations comprise a significant proportion of paediatric renal cell carcinomas. Pathology 2003; 35:492-498.
2. Argani P, Ladanyi M. Translocation carcinomas of the kidney. Clin Lab Med 2005; 25: 363-378.
3. Argani P, Ladanyi M. The evolving story of renal translocation carcinomas. Am J Clin Pathol 2006; 126: 332-334.
4. Argani P. MiT family translocation renal cell carcinoma. Semin Diagn Pathol 2015; 32: 103-113.
5. Argani P, Cheville J, Ladanyi M. MiT family translocation renal cell carcinomas. In: Moch H, Humphrey PA, Ulbright TM, et al. World Health Organization of Tumours of the Urinary System and Male Genital Organs. IRAC press, Lyon 2016; 33-34.
6. Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21,1;q12) chromosome translocation. Am J Pathol 2001; 158: 2089-2096.
7. Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation of t(6;11)(p21;q12) renal cell carcinoma inn archival paraffin-embedded material using a break-apart TFEB FISH assay expands its clinicopathologic spectrum. Am J Surg Pathol 2012; 36: 1516-1526.
8. Argani P, Laé M, Bellard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006; 24: 1529-1534.
9. Medendrop K, van Groningen JJM, Schepend M, et al. Molecular mechanisms underlying the MiT translocation subgroup of renal cell carcinomas. Cytogenet Genome Res 2007; 118: 157-165.
10. Hora M, Hes O, Ürge T, et al. A distinctive translocation carcinoma of the kidney [“rosette-like forming,” t(6;11), HMB-positive renal tumor]. Int Urol Nephrol 2009; 41: 553-557.
11. Zhan HQ, Wang CF, Zhu XZ, et al. Renal cell carcinoma with t(6;11) translocation: A patient case with a novel Alpha-TFEB fusion point. J Clin Oncol 2010; 28: e709-e713.
12. Zhoung M, De Angelo P, Osborne L, et al. Translocation renal cell carcinomas in adults: A single-institution experience. Am J Surg Pathol 2012; 36: 654-662.
13. Arneja SK, Gujar N. Renal cell carcinoma with t(6;11)(p21;q12). A case report highlighting distinctive immunohistologic features of this rare tumor. Int J Surg Case Rep 2015; 7: 16-19.
14. Pecciarini L, Cangi MG, Lo Cunsolo C, et al. Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma in an adult patient. Genes Chromosom Cancer 2007; 46: 419-426.
15. Ishihara A, Yamashita Y, Takamori H, et al. Renal carcinoma with t(6;11)(p21;q12) translocation: report of an adult case. Pathol Int 2011; 61: 539-545.
16. Inamura K, Fujisawa M, Togashi Y, et al. Diverse fusion patterns and heterogenous clinicopathologic features of renal cell carcinoma with t(6;11) translocation. Am J Surg Pathol 2012; 36: 35-42.
17. Argani P, Laé M, Hutchinson B, Reuter VE, et al. Renal carcinomas with the t(6;11)(p21;q12). Clinicopathologic features and demonstration of the specific Alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 2005; 29: 230-240.
18. Petersson F, Vaneˇcˇek T, Michal M, et al. A distinctive translocation carcinoma of the kidney: “rosette forming,” t(6;11), HMB45-positive renal tumor: a histomorhologic, immunohistochemical, ultrastructural, and molecular genetic study of 4 cases. Hum Pathol 2012; 43: 726-736.
19. Matsuura K, Inoue T, Kai T, et al. Molecular analysis of a case of renal cell carcinoma with t(6;11)(p21;q12) reveals a link to a lysosome-like structure. Histopathology 2014; 64: 306-309.
20. Rao Q, Zhang XM, Tu P, et al. Renal cell carcinomas with t(6;11)(p21;q12) presenting with tubulocystic renal cell carcinoma-like features. Int J Clin Exp Pathol 2013; 6: 1452-1457.
21. Kuroda N, Tanaka A, Sasaki N, et al. Review of renal carcinoma with t(6;11)(p21;q12) with focus on clinical and pathobiological aspects. Histol Histopathol 2013; 28: 685-690.
22. Kuroda N, Tanaka A, Ohe C, et al. Recent advances of immunohistochemistry of diagnosis of renal tumors. Pathol Int 2013; 63: 381-390.
23. Kryvenko ON, Jorda M, Argani P, et al. Diagnostic approach to eosinophilic renal neoplasms. Arch Pathol Lab Med 2014; 138: 1531-1541.
24. Kuroda N, Tanaka A. Recent classification of renal epithelial tumors. Med Mol Morphol 2014; 47: 68-75.
25. Camparo P, Vasiliu V, Molinie V, et al. Renal translocation carcinomas. Clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 2008; 35: 656-670.
26. Kuroda N, Mikami S, Pan CC, et al. Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on clinical and pathobiological aspects. Histol Histopathol 2012; 27: 133-140.
27. Martignoni G, Pea M, Gobbo S, et al. Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Mod Pathol 2009; 22: 1016-1022.
28. Rao Q, Liu B, Cheng L, et al. Renal cell carcinomas with t(6;11)(p21;q12). A clinicopathologic study emphasizing unusual morphology, novel Alpha-TFEB gene fusion point, immunobiomarkers, and ultrastructural features, as well as detection of the gene fusion by fluorescence in situ hybridization. Am J Surg Pathol 2012; 36: 1327-1338.
29. Smith NE, Illei PB, Allaf M, et al. t(6;11) renal cell carcinoma (RCC) expanded immunohistochemical profile emphasizing novel RCC markers and report of 10 new genetically confirmed cases. Am J Surg Pathol 2014; 38: 604-614.
30. Geller JL, Argani P, Adeniran A, et al. Translocation renal cell carcinoma. lack of negative impact due to lymph node spread. Cancer 2008; 112: 1607-1616.
31. Malouf GG, Camparo P, Molinié V, et al. Translocation factor E3 and translocation factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors. J Urol 2011; 185: 24-29.
32. Ferician O, Cimpean AM, Ceausu AR, et al. Heterogenous vascular patterns in renal cell carcinoma. Pol J Pathol 2016; 67: 46-53.
33. Zhao JJ, Chen PJ, Duan RQ, et al. miR-630 as a tumor oncogene in renal cell carcinoma. Arch Med Sci 2016; 12: 473-478.

Address for correspondence

Naoto Kuroda
Department of Diagnostic Pathology
Kochi Red Cross Hospital
Shin-honmachi 2-13-51, Kochi City,
Kochi 780-8562, Japan.
e-mail: kurochankochi@yahoo.co.jp
Copyright: © 2017 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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