Skip to main content
Top
Published in: Diagnostic Pathology 1/2010

Open Access 01-12-2010 | Research

Confirmation of a low HER2 positivity rate of breast carcinomas - limitations of immunohistochemistry and in situ hybridization

Author: Ulrich F Vogel

Published in: Diagnostic Pathology | Issue 1/2010

Login to get access

Abstract

Background

Accurate assessment of the human epidermal growth factor receptor 2 (HER2) of invasive breast cancer is essential to treatment decisions since the advent of targeted therapy with the humanized monoclonal antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib. In the literature, the percentage of HER2-overexpressed/amplified breast carcinomas range from 3% to 30%. The routinely assigned low rate of 9% of HER2-overexpressed breast carcinomas alarmed one of our gynecologists who requested to confirm our HER2 test results.

Methods

A small study of 83 patients with breast carcinoma was designed to reexamine the routinely assessed HER2 status using immunohistochemistry and fluorescence in situ hybridization.

Results

The low rate of 9% of HER2-overexpressed/amplified breast tumors (DIN1C-3, invasive carcinoma) could be confirmed. However, FISH revealed two false positive cases and one false negative case. Moreover a case with an equivocal result in FISH was detected.

Conclusion

The HER2 positivity rate may be as low as 9%. The novel ASCO/CAP criteria for assessing immunohistochemical results in HER 2 testing reduce the false positive rate of HER2. First-line testing with immunohistochemistry may obscure false positive and false negative test results. In heterogeneous carcinomas even fluorescence in situ hybridization may not succeed in a correct evaluation of HER2.
Appendix
Available only for authorised users
Literature
1.
go back to reference Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006, 355: 2733-2743. 10.1056/NEJMoa064320.CrossRefPubMed Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006, 355: 2733-2743. 10.1056/NEJMoa064320.CrossRefPubMed
2.
go back to reference Lin A, Rugo HS: The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Curr Treat Options Oncol. 2007, 8: 47-60. 10.1007/s11864-007-0008-2.CrossRefPubMed Lin A, Rugo HS: The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Curr Treat Options Oncol. 2007, 8: 47-60. 10.1007/s11864-007-0008-2.CrossRefPubMed
3.
go back to reference Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999, 17: 2639-2648.PubMed Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999, 17: 2639-2648.PubMed
4.
go back to reference Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A: Studies of HER2/neu protooncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152.CrossRefPubMed Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A: Studies of HER2/neu protooncogene in human breast and ovarian cancer. Science. 1989, 244: 707-712. 10.1126/science.2470152.CrossRefPubMed
5.
go back to reference Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007, 25: 118-145. 10.1200/JCO.2006.09.2775.CrossRefPubMed Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007, 25: 118-145. 10.1200/JCO.2006.09.2775.CrossRefPubMed
6.
go back to reference Mass RD, Press MF, Anderson S, Cobleigh MA, Vogel CL, Dybdal N, Leiberman G, Slamon DJ: Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005, 6: 240-246. 10.3816/CBC.2005.n.026.CrossRefPubMed Mass RD, Press MF, Anderson S, Cobleigh MA, Vogel CL, Dybdal N, Leiberman G, Slamon DJ: Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer. 2005, 6: 240-246. 10.3816/CBC.2005.n.026.CrossRefPubMed
7.
go back to reference Tapia C, Schraml P, Simon R, Al-Kuraya KS, Maurer R, Mirlacher M, Novotny H, Spichtin H, Mihatsch MJ, Sauter G: HER2 analysis in breast cancer: reduced immunoreactivity in FISH non-informative cancer biopsies. Int J Oncol. 2004, 25: 1551-1557.PubMed Tapia C, Schraml P, Simon R, Al-Kuraya KS, Maurer R, Mirlacher M, Novotny H, Spichtin H, Mihatsch MJ, Sauter G: HER2 analysis in breast cancer: reduced immunoreactivity in FISH non-informative cancer biopsies. Int J Oncol. 2004, 25: 1551-1557.PubMed
8.
go back to reference Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF: Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009, 27: 1323-1333. 10.1200/JCO.2007.14.8197.CrossRefPubMed Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF: Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009, 27: 1323-1333. 10.1200/JCO.2007.14.8197.CrossRefPubMed
9.
go back to reference Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, Gralow JR, Livingston RB, Gown AM: HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004, 291: 1972-1977. 10.1001/jama.291.16.1972.CrossRefPubMed Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, Gralow JR, Livingston RB, Gown AM: HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004, 291: 1972-1977. 10.1001/jama.291.16.1972.CrossRefPubMed
10.
go back to reference Owens MA, Horten BC, Da Silva MM: HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004, 5: 63-69. 10.3816/CBC.2004.n.011.CrossRefPubMed Owens MA, Horten BC, Da Silva MM: HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004, 5: 63-69. 10.3816/CBC.2004.n.011.CrossRefPubMed
11.
go back to reference Vogel UF, Bueltmann B: Application of a novel and low cost technique to construct paraffin tissue microarrays out of paraffinized needle biopsy specimens from patients with breast cancer. J Clin Pathol. 2010, 63: 640-643. 10.1136/jcp.2010.076356.CrossRefPubMed Vogel UF, Bueltmann B: Application of a novel and low cost technique to construct paraffin tissue microarrays out of paraffinized needle biopsy specimens from patients with breast cancer. J Clin Pathol. 2010, 63: 640-643. 10.1136/jcp.2010.076356.CrossRefPubMed
12.
go back to reference Vogel UF, Bueltmann B: Simple, inexpensive, and precise paraffin tissue microarrays constructed with a conventional microcompound table and a drill grinder. Am J Clin Pathol. 2006, 126: 342-348. 10.1309/F2Q38DXN1V1V4GQM.CrossRefPubMed Vogel UF, Bueltmann B: Simple, inexpensive, and precise paraffin tissue microarrays constructed with a conventional microcompound table and a drill grinder. Am J Clin Pathol. 2006, 126: 342-348. 10.1309/F2Q38DXN1V1V4GQM.CrossRefPubMed
13.
go back to reference Chen N, Zhou Q: Constructing tissue microarrays without prefabricating recipient blocks. A novel approach. Am J Clin Pathol. 2005, 124: 103-107. 10.1309/LHCJRFBUH8Q6QD3N.CrossRefPubMed Chen N, Zhou Q: Constructing tissue microarrays without prefabricating recipient blocks. A novel approach. Am J Clin Pathol. 2005, 124: 103-107. 10.1309/LHCJRFBUH8Q6QD3N.CrossRefPubMed
14.
go back to reference Vogel UF: Combining different techniques to construct paraffin tissue microarrays of superior quality. Histopathology. 2009, 54: 624-626. 10.1111/j.1365-2559.2009.03249.x.CrossRefPubMed Vogel UF: Combining different techniques to construct paraffin tissue microarrays of superior quality. Histopathology. 2009, 54: 624-626. 10.1111/j.1365-2559.2009.03249.x.CrossRefPubMed
15.
go back to reference Wasielewski R, Hasselmann S, Rüschoff J, Fisseler-Eckhoff A, Kreipe H: Proficiency testing of immunohistochemical biomarker assays in breast cancer. Virchows Arch. 2008, 453: 537-543. 10.1007/s00428-008-0688-4.CrossRefPubMed Wasielewski R, Hasselmann S, Rüschoff J, Fisseler-Eckhoff A, Kreipe H: Proficiency testing of immunohistochemical biomarker assays in breast cancer. Virchows Arch. 2008, 453: 537-543. 10.1007/s00428-008-0688-4.CrossRefPubMed
16.
go back to reference Bilous M, Ades C, Armes J, Bishop J, Brown R, Cooke B, Cummings M, Farshid G, Field A, Morey A, McKenzie P, Raymond W, Robbins P, Tan L: Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study. Breast. 2003, 12: 92-98. 10.1016/S0960-9776(02)00273-4.CrossRefPubMed Bilous M, Ades C, Armes J, Bishop J, Brown R, Cooke B, Cummings M, Farshid G, Field A, Morey A, McKenzie P, Raymond W, Robbins P, Tan L: Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study. Breast. 2003, 12: 92-98. 10.1016/S0960-9776(02)00273-4.CrossRefPubMed
17.
go back to reference Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K: Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008, 26: 5697-5704. 10.1200/JCO.2007.15.8659.CrossRefPubMed Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K: Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008, 26: 5697-5704. 10.1200/JCO.2007.15.8659.CrossRefPubMed
18.
go back to reference Layfield LJ, Willmore-Payne C, Isom G, Holden JA: Monoplex LightCycler Polymerase Chain Reaction Quantitation of the HER2 Gene for Quality Assurance of HER2/neu Testing by Immunohistochemistry and Fluorescence In Situ Hybridization. Appl Immunohistochem Mol Morphol. 2008, 16: 562-567. 10.1097/PAI.0b013e318171923a.CrossRefPubMed Layfield LJ, Willmore-Payne C, Isom G, Holden JA: Monoplex LightCycler Polymerase Chain Reaction Quantitation of the HER2 Gene for Quality Assurance of HER2/neu Testing by Immunohistochemistry and Fluorescence In Situ Hybridization. Appl Immunohistochem Mol Morphol. 2008, 16: 562-567. 10.1097/PAI.0b013e318171923a.CrossRefPubMed
19.
go back to reference Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, Oliva C, Stein S, Gagnon R, Arbushites M, Koehler MT: HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008, 14: 7861-7870. 10.1158/1078-0432.CCR-08-1056.CrossRefPubMed Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, Oliva C, Stein S, Gagnon R, Arbushites M, Koehler MT: HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008, 14: 7861-7870. 10.1158/1078-0432.CCR-08-1056.CrossRefPubMed
20.
go back to reference Pertschuk LP, Axiotis CA, Feldman JG, Kim YD, Karavattayhayyil SJ, Braithwaite L: Marked intratumoral heterogeneity of the proto-oncogene HER-2/neu determined by three different detection systems. Breast J. 1999, 5: 369-374. 10.1046/j.1524-4741.1999.97088.x.CrossRefPubMed Pertschuk LP, Axiotis CA, Feldman JG, Kim YD, Karavattayhayyil SJ, Braithwaite L: Marked intratumoral heterogeneity of the proto-oncogene HER-2/neu determined by three different detection systems. Breast J. 1999, 5: 369-374. 10.1046/j.1524-4741.1999.97088.x.CrossRefPubMed
21.
go back to reference Brunelli M, Manfrin E, Martignoni G, Miller K, Remo A, Reghellin D, Bersani S, Gobbo S, Eccher A, Chilosi M, Bonetti F: Genotypic intratumoral heterogeneity in breast carcinoma with HER2/neu amplification: evaluation according to ASCO/CAP criteria. Am J Clin Pathol. 2009, 131: 678-682. 10.1309/AJCP09VUTZWZXBMJ.CrossRefPubMed Brunelli M, Manfrin E, Martignoni G, Miller K, Remo A, Reghellin D, Bersani S, Gobbo S, Eccher A, Chilosi M, Bonetti F: Genotypic intratumoral heterogeneity in breast carcinoma with HER2/neu amplification: evaluation according to ASCO/CAP criteria. Am J Clin Pathol. 2009, 131: 678-682. 10.1309/AJCP09VUTZWZXBMJ.CrossRefPubMed
22.
go back to reference Tubbs RR, Hicks DG, Cook J, Downs-Kelly E, Pettay J, Hartke MB, Hood L, Neelon R, Myles J, Budd GT, Moore HC, Andresen S, Crowe JP: Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 status in adenocarcinoma of the breast. Diagn Mol Pathol. 2007, 16: 207-210. 10.1097/PDM.0b013e318064c72a.CrossRefPubMed Tubbs RR, Hicks DG, Cook J, Downs-Kelly E, Pettay J, Hartke MB, Hood L, Neelon R, Myles J, Budd GT, Moore HC, Andresen S, Crowe JP: Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 status in adenocarcinoma of the breast. Diagn Mol Pathol. 2007, 16: 207-210. 10.1097/PDM.0b013e318064c72a.CrossRefPubMed
23.
go back to reference Shah SS, Wang Y, Tull J, Zhang S: Effect of high copy number of HER2 associated with polysomy 17 on HER2 protein expression in invasive breast carcinoma. Diagn Mol Pathol. 2009, 18: 30-33. 10.1097/PDM.0b013e31817c1af8.CrossRefPubMed Shah SS, Wang Y, Tull J, Zhang S: Effect of high copy number of HER2 associated with polysomy 17 on HER2 protein expression in invasive breast carcinoma. Diagn Mol Pathol. 2009, 18: 30-33. 10.1097/PDM.0b013e31817c1af8.CrossRefPubMed
24.
go back to reference Bartlett J, Going J, Mallon E, Watters AD, Reeves JR, Stanton P, Richmond J, Donald B, Ferrier R, Cooke TG: Evaluating HER2 amplification and overexpression in breast cancer. J Pathol. 2001, 195: 422-428. 10.1002/path.971.CrossRefPubMed Bartlett J, Going J, Mallon E, Watters AD, Reeves JR, Stanton P, Richmond J, Donald B, Ferrier R, Cooke TG: Evaluating HER2 amplification and overexpression in breast cancer. J Pathol. 2001, 195: 422-428. 10.1002/path.971.CrossRefPubMed
25.
go back to reference Watters AD, Going JJ, Cooke TG, Bartlett JM: Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat. 2003, 77: 109-114. 10.1023/A:1021399923825.CrossRefPubMed Watters AD, Going JJ, Cooke TG, Bartlett JM: Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat. 2003, 77: 109-114. 10.1023/A:1021399923825.CrossRefPubMed
26.
go back to reference Egervari K, Szollosi Z, Nemes Z: Tissue microarray technology in breast cancer HER2 diagnostics. Pathol Res Pract. 2007, 203: 169-177. 10.1016/j.prp.2006.12.004.CrossRefPubMed Egervari K, Szollosi Z, Nemes Z: Tissue microarray technology in breast cancer HER2 diagnostics. Pathol Res Pract. 2007, 203: 169-177. 10.1016/j.prp.2006.12.004.CrossRefPubMed
27.
go back to reference Neyt MJ, Albrecht JA, Clarysse B, Cocquyt VF: Cost-effectiveness of Herceptin: a standard cost model for breast-cancer treatment in a Belgian university hospital. Int J Technol Assess Health Care. 2005, 21: 132-137. 10.1017/S0266462305050178.CrossRefPubMed Neyt MJ, Albrecht JA, Clarysse B, Cocquyt VF: Cost-effectiveness of Herceptin: a standard cost model for breast-cancer treatment in a Belgian university hospital. Int J Technol Assess Health Care. 2005, 21: 132-137. 10.1017/S0266462305050178.CrossRefPubMed
28.
go back to reference Pakkiri P, Lakhani SR, Smart CE: Current and future approach to the pathologist's assessment for targeted therapy in breast cancer. Pathology. 2009, 41: 89-99. 10.1080/00313020802563551.CrossRefPubMed Pakkiri P, Lakhani SR, Smart CE: Current and future approach to the pathologist's assessment for targeted therapy in breast cancer. Pathology. 2009, 41: 89-99. 10.1080/00313020802563551.CrossRefPubMed
29.
go back to reference Dendukuri N, Khetani K, McIsaac M, Brophy J: Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ. 2007, 176: 1429-1434.PubMedCentralCrossRefPubMed Dendukuri N, Khetani K, McIsaac M, Brophy J: Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ. 2007, 176: 1429-1434.PubMedCentralCrossRefPubMed
30.
go back to reference Cuadros M, Villegas R: Systematic review of HER2 breast cancer testing. Appl Immunohistochem Mol Morphol. 2009, 17: 1-7. 10.1097/PAI.0b013e318169fc1c.CrossRefPubMed Cuadros M, Villegas R: Systematic review of HER2 breast cancer testing. Appl Immunohistochem Mol Morphol. 2009, 17: 1-7. 10.1097/PAI.0b013e318169fc1c.CrossRefPubMed
31.
go back to reference Elkin EB, Weinstein MC, Winer EP, Kuntz KM, Schnitt SJ, Weeks JC: HER-2 testing and trastuzumab therapy for metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol. 2004, 22: 854-863. 10.1200/JCO.2004.04.158.CrossRefPubMed Elkin EB, Weinstein MC, Winer EP, Kuntz KM, Schnitt SJ, Weeks JC: HER-2 testing and trastuzumab therapy for metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol. 2004, 22: 854-863. 10.1200/JCO.2004.04.158.CrossRefPubMed
32.
go back to reference Vogel UF: Paraffin Tissue Microarrays Constructed With a Cutting Board and Cutting Board Arrayer. Appl Immunohistochem Mol Morphol. 2010, 18: 283-287. 10.1097/PAI.0b013e3181c8092b.CrossRefPubMed Vogel UF: Paraffin Tissue Microarrays Constructed With a Cutting Board and Cutting Board Arrayer. Appl Immunohistochem Mol Morphol. 2010, 18: 283-287. 10.1097/PAI.0b013e3181c8092b.CrossRefPubMed
33.
go back to reference Dietel M, Ellis IO, Höfler H, Kreipe H, Moch H, Dankof A, Kölble K, Kristiansen G: Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Virchows Arch. 2007, 451: 19-25. 10.1007/s00428-007-0424-5.CrossRefPubMed Dietel M, Ellis IO, Höfler H, Kreipe H, Moch H, Dankof A, Kölble K, Kristiansen G: Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Virchows Arch. 2007, 451: 19-25. 10.1007/s00428-007-0424-5.CrossRefPubMed
Metadata
Title
Confirmation of a low HER2 positivity rate of breast carcinomas - limitations of immunohistochemistry and in situ hybridization
Author
Ulrich F Vogel
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2010
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-5-50

Other articles of this Issue 1/2010

Diagnostic Pathology 1/2010 Go to the issue