eISSN: 2084-9869
ISSN: 1233-9687
Polish Journal of Pathology
Current issue Archive Manuscripts accepted About the journal Supplements Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
4/2018
vol. 69
 
Share:
Share:
more
 
 
Original paper

The incidence of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in Saudi adult patients with renal cancer: a retrospective tissue microarray analysis

Jaudah Al-Maghrabi
,
Shagufta Mufti
,
Wafaey Gomaa

Pol J Pathol 2018; 69 (4): 376-383
Online publish date: 2019/01/31
Article file
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
 

Introduction

Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney. It constitutes about 2-3% of all cancers worldwide. In 30% of tumours, patients present with metastasis. The prognosis of patients with RCC varies according to the stage and histological grade [1]. In Saudi Arabia, renal tumours constitute 3.6% of all tumours in males and 2.2% in females. RCC is the most common renal tumour both in males and females [2]. RCC associated with Xp11.2 translocation/TFE3 (transcription factor E3) gene fusions (Xp11.2 RCC) was first reported by de Jong et al. [3]. It is uncommon and characterised by several different translocations involving the TFE3 gene. This tumour may have been previously diagnosed as other types of renal tumours. However, in the 2004 WHO classification of kidney tumours, it was recognised as a distinct entity [4, 5]. In 2016, a World Health Organisation classification of tumours of the kidney was issued. A new entity was introduced named microphthalmia-associated transcription factor family (MiT) RCC. This group has two varieties: RCCs associated with Xp1 1 translocations with gene fusions involving TF3; and RCCs with t(6;11) translocation with a MALA T1-TFEB gene fusion [6]. Xp11.2 RCC is thought to be more common in children and less frequent in adults [7, 8]. However, Xp11.2 RCC is increasingly reported in adults, and these patients have a clinicopathologically poor prognosis [9, 10, 11].
The overexpressed TFE3 protein is now detectable using a sensitive and specific polyclonal immunohistochemical marker, which reflects nuclear over- expression of the TFE3 protein [7, 8]. The detection of TFE3 protein overexpression by immunohistochemistry is commonly used in diagnostic practice. Nuclear immunohistochemical labelling for TFE3 is used as a marker of Xp11.2 RCC. Strong nuclear TFE3 immunostaining represents its overexpression as a fusion of proteins relative to native TFE3 [7]. TFE3 immuno-labelling is absent in conventional clear-cell and papillary RCC [12].
The scientific value of the available evidence for using TFE3 immunohistochemical expression in screening for Xp11.2 RCC needs to be evaluated. The aim of this retrospective study is to determine the prevalence of nuclear immunoreactivity for TFE3 in a subset of Saudi adult patients diagnosed with RCC. Additionally, we aimed to evaluate the usefulness of TFE3 immunostain screening for Xp11.2 RCC.

Material and methods

Patients

The study was retrospective and included paraffin wax blocks of tumours from 112 adult patients with RCC from 1995 to 2016. Blocks were retrieved from the archives of the Department of Pathology at King Abdulaziz University, Jeddah, Saudi Arabia and King Faisal Specialist Hospital and Research Centre. Clinical and pathological data were collected from patients’ record. Data are presented in Table I. Pathological staging of tumours was performed according to the seventh edition of the American Joint Committee on Cancer [13]. The study was approved by the Research Committee of the Biomedical Ethics Unit, Faculty of Medicine, King Abdulaziz University.

Tissue microarray construction

Tissue microarrays were constructed from formalin-fixed and paraffin-embedded blocks, as previously described [14]. New sections were prepared from the donor blocks and stained with haematoxylin-eosin (HE). These slides were used to guide the sampling from morphologically representative regions. A tissue array instrument (TMA Master 3D Histech, EU Ltd., Budapest, Hungary) was used to make holes in the recipient paraffin block and to retrieve 1.5-mm tumour tissue cores from the donor paraffin block. After construction of the array blocks, 4-µm thick sections were cut.

Immunohistochemistry

TMA paraffin blocks were cut at 4 µm and mounted on positively charged slides (Leica Microsystems plus slides, Menzel, Braunschweig, Germany). Immunostaining was performed in an automated immunostainer (BenchMark XT, Ventana® Medical Systems Inc., Tucson, AZ, USA). Sections were deparaffinised in xylene and rehydrated. Pre-treatment was done using a prediluted cell conditioning solution (CC1) for 60 min. TFE3-MRQ-37 (Cell Marque, Sierra College Blvd, Rocklin, CA 95677, USA) primary antibody was incubated at 37◦C for 16 minutes with TMA sections. The Ventana® I-view DAB detection kit was used according to the manufacturer’s instructions. Subsequently, slides were washed, counterstained with Mayer’s haematoxylin, and mounted. Negative control tissue (by substitution of primary antibody with Tris-buffered saline) and positive control tissue were included.

Scoring of immunohistochemistry

The interpretation of immunoreactivity for TFE3 was evaluated as previously described using the intensity of nuclear immunostaining. Tumours were scored as negative (0), weak positive (1+), moderate positive (2+), and strongly positive (3+) [8, 15, 16]. A tumour was considered positive for TFE3 when diffuse strong TFE3 immunopositivity was reported.

Fluorescent in situ hybridization

A dual-colour, break-apart fluorescent in situ hybridisation (FISH) assay was performed to detect rearrangement of the TFE3 locus with probes for the 5’ and 3’ regions of the TFE3 gene at Xp11.2. DXZ1 used as a probe. FISH was performed at the Mayo Clinic Cytogenetics Laboratory.

Statistical analysis

Descriptive statistics of patients and the frequency of TFE3 immunostaining in RCC were performed. To test the difference between two variables, the Wilcoxon signed-rank test was used. A two-sided p-value of ≤ 0.05 was used to determine the statistical significance. SPSS® Version 16.0 (SPSS, Chicago, Ill) was used.

Results

Immunostaining of TFE3

We determined the incidence of Xp11.2 RCC by immunostaining for TFE3. Among all tumours (112), five showed diffuse strong-positive TFE3 immunostaining (Xp11.2 RCC; 4.5%). Figure 1 shows tumours that demonstrate diffuse and strong nuclear immunoreactivity for TFE3. Weak immunostaining was reported in eight tumours (7.1%). The clinical and pathological TFE3-positive characteristics are shown in Table II. There was significantly more positivity in males (p = 0.046), middle-aged population (p = 0.025), and in higher tumour grades (p = 0.035). Positivity was exclusively associated with all large sized-tumours (p = 0.025) and tumours with the presence of necrosis (p = 0.025). Most positive tumours show a clear and papillary morphology.

Histopathological features

The HE slide whole tissue sections of TFE3-positive tumours were retrieved to re-examine the histological pattern. Tumours showed a heterogeneous morphology including a papillary configuration, a nested pattern, and/or a mixed pattern. The mixed pattern is a clear-cell or papillary RCC papillary structures lined by clear-to-eosinophilic cells. The cells show voluminous cytoplasm that is clear-to-eosinophilic. Nuclear features were also variable, ranging from small, uniform nuclei to larger nuclei with prominent nucleoli (Fig. 1).

Fluorescence in situ hybridisation

FISH analysis was positive for TFE3 gene rearrangements in only two tumours (two out of five TFE3 immunopositive tumours = 40%), while 60% were negative. According to FISH positivity, 1.7% of the overall tumour population are positive. Results are shown in Table III.

Discussion

Before the current study, we thought that some tumours that were diagnosed as RCC (clear-cell, papillary, or chromophobe) were originally Xp11.2 RCC. Thus, we re-evaluated a subset of renal tumours that were diagnosed as other RCC types by immunostaining for TFE3. To the best of our knowledge, this is the first report to evaluate the incidence Xp11.2 RCC in Saudi adult patients with RCC.
Xp11.2 RCC is a rare subtype of RCC [16]. The results from our study show that 4.5% of our subset was positive for TFE3 immunostaining in tumours that were previously diagnosed as other types of RCC. Two were confirmed by FISH (1.7% of the tumour population). This finding is comparable to previous studies [17, 18]. The age incidence of this tumour was originally thought to be specific to paediatric and adolescent age groups [19]. However, Xp11.2 RCC is increasingly reported in middle-aged people [11, 17, 20]. The age incidence in our study was 24-81 years, which is similar to previous reports [21, 22]. Pathologists should take into account the possibility that Xp11.2 RCC may occur in adults. Xp11.2 RCC should be suspected in any RCC with an unusual histology, regardless of the patient’s age. Many studies revealed a female predominance of Xp11.2 RCC [1, 18, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30]. However, in the present study most patients were males, as reported in previous studies [21, 31, 32, 33]. A difference in the incidence of Xp11.2 RCC related to gender remains controversial [1]. We reported a small percentage of Xp11.2 RCC with nodal metastasis. Positive nodal metastasis was associated with Xp11.2 RCC in many studies [1, 15, 25, 26]. However, there was no difference in incidence of tumour stages [1, 15, 25, 26]. Some case reports showed low stage I incidence [34, 35], while in another report it was associated tumour stage III [36].
Microscopically, the most characteristic histological feature of Xp11.2 RCC is a mixture of papillary and nested/alveolar architecture with extensive psammoma bodies. Cytological features include clear and/or eosinophilic, voluminous, granular cytoplasm; discrete cell borders; vesicular chromatin; and prominent nucleoli. However, the Xp11.2 RCC is morphologically heterogeneous [9, 12, 21, 28, 37]. Whenever this tumour as well as RCC with t(6;11)(p21;q12) are grossly suspected, extensive sections should be taken [38]. In the current study, tumours shown to be positive for TFE3 immunostaining showed similar histological features without reporting psammoma bodies. A histological clue for this type of RCC should be suspected during microscopic examination. The presence of the above-mentioned histological features should guarantee the use of TFE3 immunostaining to diagnose Xp11.2 RCC.
Translocation of Xp11.2 RCC is accompanied by TFE3 protein overexpression. Thus, immunostaining for TFE3 is a commonly used diagnostic technique in diagnostic practice [8, 12, 16, 25, 39, 40, 41]. We used a score of 3+ in staining intensity as the cut-off point for TFE3 positivity, which is similar to previous reports [21, 42]. Other studies used a staining intensity of 2+ or 3+ to represent a positive result [8, 19]. In the present study, five tumours showed the criteria for positive TFE3 immunostaining (strong diffuse nuclear immunostaining). For these tumours, a TFE3 break-apart FISH assay was performed to confirm the diagnosis of Xp11.2 RCC. FISH was confirmatory in only 40% of the tumours. The results of our study are comparable with previous reports [31]. There was an increase in reporting of TFE3 immunostaining false-positive results [12, 23, 31, 41, 43, 44]. This may be because break-apart FISH probes cannot detect each translocation partner, which leaves significant room for FISH-negative cases to still be harbouring a particular gene translocation [45]. Although there are false-positive results, nuclear TFE3 immunostaining in Xp11.2 RCC is a useful tool to screen for this type of tumour. However, FISH is a helpful tool and should be used alongside immunostaining to diagnose patients with Xp11.2 RCC [25, 31, 40, 41, 46].
Another issue in TFE3 immunostaining is false- negative results. False-negative TFE3 immunostaining results were previously reported [12, 21, 31, 44]. False-negative and -positive immunostaining can be explained by technical problems, including tissue fixation issues, antigen retrieval, scoring method, and the anti-TFE3 antibody [12, 23, 31, 41, 43]. Anti-TFE3 antibody binds to the C-terminus, which is retained in TFE3 fusion proteins. Xp11.2/TFE3 gene fusion consistently leads to TFE3 over-immunostaining [8]. The sensitivity and specificity in TFE3 immunostaining differs between overnight manual incubation and automated incubation (30 minutes). TFE3 immunostaining using overnight manual incubation may provide more accurate results than the short automated incubation. The shorter incubation time and enhanced automated detection system creates a more sensitive but less specific method to detect the TFE3 protein [47]. However, in daily diagnostic practice, it is impractical to use manual immunostaining only for TFE3. TFE3 automated immunostaining showed false-positive staining without any false-negative tumours. TFE3 automated immunostaining is considered to be a sensitive method to diagnose Xp11.2 translocation RCC, but it is less specific [31]. In our study, we used the automated immunostaining method and applied a strict cut-off for positive results, which are diffuse and strong immunoreactivity. Limitations of the current study include the small number of tumours diagnosed as Xp11.2 RCC. This may be attributable to the rare incidence of this RCC subtype.

Conclusions

In summary, we reported the incidence of Xp11.2 RCC in a subset of adult Saudi patients diagnosed with RCC. Clinicians and pathologists should be aware of this tumour entity, not only in children but also among the adult population. These tumours classically have papillary pattern. Distinguishing Xp11.2 RCC from papillary RCC subtype is important because they tend to have worse prognosis. Immunostaining for TFE3 can be used as a screening method, and TFE3 break-apart FISH might be used as a confirmatory method for specific translocation. The results from our study and other reports suggest that we cannot determine whether the gold standard for detection of the Xp11.2 RCC is immunostaining or FISH. The issue remains controversial, and a combination of morphological, TFE3 immunostaining, and FISH should be applied for tumours that are expected to be Xp11.2 RCC based on the morphological features. The molecular pathogenesis of Xp11.2 RCC remains unclear, and thus, further larger cohort studies are required to validate the gold standard for pathological diagnosis.

List of abbreviations

FISH, fluorescence in situ hybridisation; RCC, renal cell carcinoma; TFE3, transcription factor E3; Xp11.2 RCC, RCC with Xp11.2 translocation

This project was funded by the National Plan for Science, Technology, and Innovation (MAARIFAH) – King Abdulaziz City for Science and Technology – the Kingdom of Saudi Arabia – award number (11-BIO1524-03). The authors also acknowledge with thanks the Science and Technology Unit, King Abdulaziz University for technical support.
The authors declare no conflict of interest.

References

1. Ahluwalia P, Nair B, Kumar G. Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusion: A Rare Case Report with Review of the Literature. Case Rep Urol 2013; 2013: 810590.
2. Al-Eid H, Bazarbashi S. Cancer Incidence Report Saudi Arabia 2010.
3. de Jong B, Molenaar I, Leeuw J, et al. Cytogenetics of a renal adenocarcinoma in a 2-year-old child. Cancer Genet Cytogenet 1986; 21: 165-169.
4. Argani P, Ladanyi M. Renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press, Lyon 2004;37-38.
5. Lopez-Beltran A, Scarpelli M, Montironi R, et al. 2004 WHO classification of the renal tumors of the adults. Eur Urol 2006; 49: 798-805.
6. Argani P, Cheville JC, Ladanyi M. MiT family translocation renal cell carcinomas. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: International Agency for Research on Cancer (IARC). 2016; 33-34.
7. Argani P, Ladanyi M. The evolving story of renal translocation carcinomas. Am J Clin Pathol 2006; 126: 332-334.
8. Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003; 27: 750-761.
9. Argani P, Ladanyi M. Translocation carcinomas of the kidney. Clin Lab Med 2005;25:363-378.
10. Sudour-Bonnange H, Leroy X, Chauvet MP, et al. Cutaneous metastases during an aggressive course of Xp11.2 translocation renal cell carcinoma in a teenager. Pediatr Blood Cancer 2014; 61: 1698-1700.
11. Qu Y, Gu C, Wang H, et al. Diagnosis of adults Xp11.2 translocation renal cell carcinoma by immunohistochemistry and FISH assays: clinicopathological data from ethnic Chinese population. Sci Rep 2015; 6: 21677.
12. 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; 32: 656-670.
13. Edge S, Byrd D, Compton C. AJCC Cancer Staging Handbook 2010.
14. Kallioniemi OP, Wagner U, Kononen J, Sauter G. Tissue microarray technology for high-throughput molecular profiling of cancer. Hum Mol Genet 2001; 10: 657-662.
15. 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.
16. Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001; 159: 179-192.
17. Zhong 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.
18. Sukov WR, Hodge JC, Lohse CM, et al. TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. Am J Surg Pathol 2012; 36: 663-670.
19. Kuroda N, Kawada C, Tamura K, et al. Re-evaluation of histological type by immunohistochemical and genetic study of transcription factors (TFE3 and TFEB) of VHL gene mutation-negative clear cell renal cell carcinoma and other special types of renal tumor. Med Mol Morphol 2011; 44: 46-51.
20. Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007; 31: 1149-1160.
21. Rao Q, Williamson SR, Zhang S, et al. TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum. Am J Surg Pathol 2013; 37: 804-815.
22. Hung CC, Pan CC, Lin CC, et al. XP11.2 translocation renal cell carcinoma: clinical experience of Taipei Veterans General Hospital. J Chin Med Assoc 2011; 74: 500-504.
23. Klatte T, Streubel B, Wrba F, et al. Renal cell carcinoma associated with transcription factor E3 expression and Xp11.2 translocation: incidence, characteristics, and prognosis. Am J Clin Pathol 2012; 137: 761-768.
24. Zhong M, De Angelo P, Osborne L, et al. Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. Am J Surg Pathol 2010; 34: 757-766.
25. Green WM, Yonescu R, Morsberger L, et al. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol 2013; 37: 1150-1163.
26. Pflueger D, Sboner A, Storz M, et al. Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing. Neoplasia 2013; 15: 1231-1240.
27. Hodge JC, Pearce KE, Wang X, et al. Molecular cytogenetic analysis for TFE3 rearrangement in Xp11.2 renal cell carcinoma and alveolar soft part sarcoma: validation and clinical experience with 75 cases. Mod Pathol 2014; 27: 113-127.
28. Kuroda N, Katto K, Tanaka Y, et al. Diagnostic pitfall on the histological spectrum of adult-onset renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions. Med Mol Morphol 2010; 43: 86-90.
29. Su HH, Sung MT, Chiang PH, et al. The preliminary experiences of translocation renal cell carcinoma and literature review. Kaohsiung J Med Sci 2014; 30: 402-408.
30. Wang W, Ding J, Li Y, et al. Magnetic resonance imaging and computed tomography characteristics of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion. PLoS One 2014; 9: e99990.
31. Kim SH, Choi Y, Jeong HY, et al. Usefulness of a break-apart FISH assay in the diagnosis of Xp11.2 translocation renal cell carcinoma. Virchows Arch 2011; 459: 299-306.
32. Zou H, Kang X, Pang LJ, et al. Xp11 translocation renal cell carcinoma in adults: a clinicopathological and comparative genomic hybridization study. Int J Clin Exp Pathol 2014; 7: 236-245.
33. Wu A, Kunju LP, Cheng L, et al. Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical and molecular characteristics with an emphasis on the spectrum of Xp11.2 translocation-associated and unusual clear cell subtypes. Histopathology 2008; 53: 533-544.
34. Haudebourg J, Hoch B, Fabas T, et al. A novel case of t(X;1)(p11.2;p34) in a renal cell carcinoma with TFE3 rearrangement and favorable outcome in a 57-year-old patient. Cancer Genet Cytogenet 2010; 200: 75-78.
35. Salles PG, Soto M, Jr. Kidney carcinoma associated with Xp11.2 translocation / TFE3 (ASPL-TFE3) gene fusion. Int Braz J Urol 2005; 31: 251-254.
36. Franzini A, Picozzi SC, Politi PL, et al. A case of renal cancer with TFE3 gene fusion in an elderly man. Clinical, radiological and surgical findings. Urol Int 2007; 78: 179-181.
37. Ellis CL, Eble JN, Subhawong AP, et al. Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage. Mod Pathol 2014; 27: 875-886.
38. Kuroda N, Yorita K, Sasaki N, et al. Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12). Pol J Pathol 2017; 68: 66-72.
39. Meyer PN, Clark JI, Flanigan RC, et al. Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol 2007; 128: 70-79.
40. Pradhan D, Roy S, Quiroga-Garza G, et al. Validation and utilization of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinoma and alveolar soft part sarcoma. Diagn Pathol 2015; 10: 179.
41. Mosquera JM, Dal Cin P, Mertz KD, et al. Validation of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinomas. Diagn Mol Pathol 2011; 20: 129-137.
42. Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med 2011; 135: 92-109.
43. Macher-Goeppinger S, Roth W, Wagener N, et al. Molecular heterogeneity of TFE3 activation in renal cell carcinomas. Mod Pathol 2012; 25: 308-315.
44. Chen X, Yang Y, Gan W, et al. Newly designed break-apart and ASPL-TFE3 dual-fusion FISH assay are useful in diagnosing Xp11.2 translocation renal cell carcinoma and ASPL-TFE3 renal cell carcinoma: a STARD-compliant article. Medicine (Baltimore) 2015; 94: e873.
45. Armah HB, Parwani AV. Xp11.2 translocation renal cell carcinoma. Arch Pathol Lab Med 2010; 134: 124-129.
46. Akhavein A, Han J, Carter C, et al. Xp11 Translocation Renal Cell Carcinoma: Unusual Variant Masquerading as Upper Tract Urothelial Cell Carcinoma. Urol Case Rep 2014; 2: 75-77.
47. Argani P, Aulmann S, Illei PB, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010; 34: 1395-1406.

Address for correspondence

Prof. Jaudah Al-Maghrabi
Department of Pathology
Faculty of Medicine
King Abdulaziz University
P.O. BOX 80205
Jeddah 21589, Kingdom of Saudi Arabia
tel.: 012-966-2-6401000 ext. 17069
mobile: 0504680456
fax: 012-966-2-6408433
Copyright: © 2019 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.
FEATURED PRODUCTS
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe