Skip to main content

Advertisement

SpringerLink
Log in

Histopathological characterization of ductal carcinoma in situ (DCIS) of the breast according to HER2 amplification status and molecular subtype

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

This study aimed to characterize ductal carcinoma in situ (DCIS) according to human epidermal growth factor receptor 2 (HER2) amplification status and molecular subtype. In addition, we performed a detailed HER2 and CEP17 copy number analysis and we assessed the impact of recent changes in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 immunohistochemical (IHC) scores in DCIS. Nuclear grade, extensive comedonecrosis, stromal architecture, stromal inflammation, and progesterone receptor (PR) expression were significantly associated with HER2 amplification status. In multivariate analysis, stromal inflammation and extensive comedonecrosis were the only two features that remained significantly related to HER2 amplification status. The recent changes in ASCO/CAP guidelines resulted in significant upgrading of HER2 IHC score. Remarkably, about one in five non-amplified DCIS presented a 3+ IHC score, regardless of the scoring method. The biological significance of this phenomenon is presently unknown. After categorization according to molecular subtype, luminal A DCIS mainly presented histopathological features associated with good prognosis, whereas luminal B/HER2+ and HER2+ categories displayed a more aggressive phenotype. Overall, our results demonstrate that HER2-amplified DCIS constitute a clearly distinct subgroup which is characterized by histopathological features associated with poor prognosis. Further studies are required to elucidate the biological significance of a 3+ IHC score in non-amplified DCIS, as well as its mechanism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BCS:

Breast-conserving surgery

CEP:

Chromosome enumeration probe

CI:

Confidence interval

DCIS:

Ductal carcinoma in situ

ER:

Estrogen receptor

FFPE:

Formalin-fixed paraffin-embedded

H&E:

Hematoxylin and eosin

HER2:

Human epidermal growth factor receptor 2

IDC:

Invasive ductal carcinoma

IHC:

Immunohistochemistry

PR:

Progesterone receptor

References

  1. Allred DC, Clark GM, Molina R, Tandon AK, Schnitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL (1992) Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 23:974–979

    Article  CAS  PubMed  Google Scholar 

  2. Altintas S, Lambein K, Huizing MT, Braems G, Tjin Asjoe F, Hellemans H, Van Marck E, Weyler J, Praet M, Van den Broecke R, Vermorken JB, Tjalma WA (2009) Prognostic significance of oncogenic markers in ductal carcinoma in situ of the breast: a clinicopathologic study. Breast J 15:120–132

    Article  CAS  PubMed  Google Scholar 

  3. Barnes DM, Bartkova J, Camplejohn RS, Gullick WJ, Smith PJ, Millis RR (1992) Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance? Eur J Cancer 28:644–648

    Article  CAS  PubMed  Google Scholar 

  4. Bijker N, Donker M, Wesseling J, den Heeten GJ, Rutgers EJ (2013) Is DCIS breast cancer, and how do I treat it? Curr Treat Options Oncol 14:75–87. doi:10.1007/s11864-012-0217-1

    Article  CAS  PubMed  Google Scholar 

  5. Burkhardt L, Grob TJ, Hermann I, Burandt E, Choschzick M, Janicke F, Muller V, Bokemeyer C, Simon R, Sauter G, Wilczak W, Lebeau A (2010) Gene amplification in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 123:757–765. doi:10.1007/s10549-009-0675-8

    Article  CAS  PubMed  Google Scholar 

  6. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750. doi:10.1093/jnci/djp082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Clark SE, Warwick J, Carpenter R, Bowen RL, Duffy SW, Jones JL (2011) Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease. Br J Cancer 104:120–127. doi:10.1038/sj.bjc.6606021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Claus EB, Chu P, Howe CL, Davison TL, Stern DF, Carter D, DiGiovanna MP (2001) Pathobiologic findings in DCIS of the breast: morphologic features, angiogenesis, HER-2/neu and hormone receptors. Exp Mol Pathol 70:303–316. doi:10.1006/exmp.2001.2366

    Article  CAS  PubMed  Google Scholar 

  9. Cuzick J, Sestak I, Pinder SE, Ellis IO, Forsyth S, Bundred NJ, Forbes JF, Bishop H, Fentiman IS, George WD (2011) Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12:21–29. doi:10.1016/s1470-2045(10)70266-7

    Article  CAS  PubMed  Google Scholar 

  10. Ferretti G, Felici A, Papaldo P, Fabi A, Cognetti F (2007) HER2/neu role in breast cancer: from a prognostic foe to a predictive friend. Curr Opin Obstet Gynecol 19:56–62

    Article  PubMed  Google Scholar 

  11. Giordano C, Vizza D, Panza S, Barone I, Bonofiglio D, Lanzino M, Sisci D, De Amicis F, Fuqua SA, Catalano S, Ando S (2013) Leptin increases HER2 protein levels through a STAT3-mediated up-regulation of Hsp90 in breast cancer cells. Mol Oncol 7:379–391. doi:10.1016/j.molonc.2012.11.002

    Article  CAS  PubMed  Google Scholar 

  12. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223. doi:10.1093/annonc/mdt303

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC, American Society of Clinical O, College of American P (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134:e48–e72. doi:10.1043/1543-2165-134.7.e48

    CAS  PubMed  Google Scholar 

  14. Han K, Nofech-Mozes S, Narod S, Hanna W, Vesprini D, Saskin R, Taylor C, Kong I, Paszat L, Rakovitch E (2012) Expression of HER2neu in ductal carcinoma in situ is associated with local recurrence. Clin Oncol 24:183–189. doi:10.1016/j.clon.2011.09.008

    Article  CAS  Google Scholar 

  15. Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481

    CAS  PubMed  Google Scholar 

  16. Holmes P, Lloyd J, Chervoneva I, Pequinot E, Cornfield DB, Schwartz GF, Allen KG, Palazzo JP (2011) Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone. Cancer 117:3650–3657. doi:10.1002/cncr.25942

    Article  CAS  PubMed  Google Scholar 

  17. Hoorntje LE, Schipper MEI, Peeters PHM, Bellot F, Storm RK, Borel Rinkes IHM (2003) The finding of invasive cancer after a preoperative diagnosis of ductal carcinoma-in-situ: causes of ductal carcinoma-in-situ underestimates with stereotactic 14-gauge needle biopsy. Ann Surg Oncol 10:748–753. doi:10.1245/aso.2003.11.011

    Article  PubMed  Google Scholar 

  18. Horimoto Y, Tokuda E, Arakawa A, Kosaka T, Saito M, Kasumi F (2011) Significance of HER2 protein examination in ductal carcinoma in situ. J Surg Res 167:e205–e210. doi:10.1016/j.jss.2009.07.030

    Article  CAS  PubMed  Google Scholar 

  19. Jang MH, Kim EJ, Choi Y, Lee HE, Kim YJ, Kim JH, Kang E, Kim SW, Kim IA, Park SY (2012) FGFR1 is amplified during the progression of in situ to invasive breast carcinoma. Breast Cancer Res 14:R115. doi:10.1186/bcr3239

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Kepple J, Henry-Tillman RS, Klimberg VS, Layeeque R, Siegel E, Westbrook K, Korourian S (2006) The receptor expression pattern in ductal carcinoma in situ predicts recurrence. Am J Surg 192:68–71. doi:10.1016/j.amjsurg.2006.04.002

    Article  PubMed  Google Scholar 

  21. Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Waldman F, Bennington J, Sanchez H, Jimenez C, Stewart K, Chew K, Ljung BM, Tlsty TD (2010) Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst 102:627–637. doi:10.1093/jnci/djq101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Knudsen ES, Pajak TF, Qeenan M, McClendon AK, Armon BD, Schwartz GF, Witkiewicz AK (2012) Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression. J Natl Cancer Inst 104:1825–1836. doi:10.1093/jnci/djs446

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kulkarni S, Patil DB, Diaz LK, Wiley EL, Morrow M, Khan SA (2008) COX-2 and PPARgamma expression are potential markers of recurrence risk in mammary duct carcinoma in-situ. BMC Cancer 8:36. doi:10.1186/1471-2407-8-36

    Article  PubMed Central  PubMed  Google Scholar 

  24. Lambein K, Praet M, Forsyth R, Van den Broecke R, Braems G, Matthys B, Cocquyt V, Denys H, Pauwels P, Libbrecht L (2011) Relationship between pathological features, HER2 protein expression and HER2 and CEP17 copy number in breast cancer: biological and methodological considerations. J Clin Pathol 64:200–207. doi:10.1136/jcp.2010.084863

    Article  CAS  PubMed  Google Scholar 

  25. Lambein K, Van Bockstal M, Denys H, Libbrecht L (2014) 2013 Update of the American Society of Clinical Oncology/College of American Pathologists guideline for human epidermal growth factor receptor 2 testing: impact on immunohistochemistry-negative breast cancers. J Clin Oncol. doi:10.1200/JCO.2013.54.2530

    PubMed  Google Scholar 

  26. Lambein K, Van Bockstal M, Vandemaele L, Geenen S, Rottiers I, Nuyts A, Matthys B, Praet M, Denys H, Libbrecht L (2013) Distinguishing score 0 from score 1+ in HER2 immunohistochemistry-negative breast cancer: clinical and pathobiological relevance. Am J Clin Pathol 140:561–566. doi:10.1309/AJCP4A7KTAYHZSOE

    Article  PubMed  Google Scholar 

  27. Latta EK, Tjan S, Parkes RK, O’Malley FP (2002) The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol 15:1318–1325. doi:10.1097/01.MP.0000038462.62634.B1

    Article  CAS  PubMed  Google Scholar 

  28. Liao N, Zhang GC, Liu YH, Li XR, Yao M, Xu FP, Li L, Wu YL (2011) HER2-positive status is an independent predictor for coexisting invasion of ductal carcinoma in situ of the breast presenting extensive DCIS component. Pathol Res Pract 207:1–7. doi:10.1016/j.prp.2010.08.005

    Article  CAS  PubMed  Google Scholar 

  29. Nofech-Mozes S, Spayne J, Rakovitch E, Kahn HJ, Seth A, Pignol JP, Lickley L, Paszat L, Hanna W (2008) Biological markers predictive of invasive recurrence in DCIS. Clin Med Oncol 2:7–18

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Noh JM, Lee J, Choi DH, Cho EY, Huh SJ, Park W, Nam SJ, Lee JE, Kil WH (2013) HER-2 overexpression is not associated with increased ipsilateral breast tumor recurrence in DCIS treated with breast-conserving surgery followed by radiotherapy. Breast 22:894–897. doi:10.1016/j.breast.2013.04.001

    Article  PubMed  Google Scholar 

  31. Park K, Han S, Kim HJ, Kim J, Shin E (2006) HER2 status in pure ductal carcinoma in situ and in the intraductal and invasive components of invasive ductal carcinoma determined by fluorescence in situ hybridization and immunohistochemistry. Histopathology 48:702–707. doi:10.1111/j.1365-2559.2006.02403.x

    Article  CAS  PubMed  Google Scholar 

  32. Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE, Martino S, Sledge GW, Harris LN, Gralow JR, Dueck AC, Ketterling RP, Ingle JN, Lingle WL, Kaufman PA, Visscher DW, Jenkins RB (2010) HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol 28:4307–4315. doi:10.1200/JCO.2009.26.2154

    Article  PubMed Central  PubMed  Google Scholar 

  33. Pinder SE, Duggan C, Ellis IO, Cuzick J, Forbes JF, Bishop H, Fentiman IS, George WD, Party UKCCoCRDCISW (2010) A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial. Br J Cancer 103:94–100. doi:10.1038/sj.bjc.6605718

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Pinder SE, Ellis IO, Schnitt SJ, Tan PH, Rutgers E, Morrow M (2012) Microinvasive carcinoma. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (eds) World Health Organization classification of tumours. WHO Press, Geneva, pp 95–97

    Google Scholar 

  35. Punglia RS, Schnitt SJ, Weeks JC (2013) Treatment of ductal carcinoma in situ after excision: would a prophylactic paradigm be more appropriate? J Natl Cancer Inst 105:1527–1533. doi:10.1093/jnci/djt256

    Article  CAS  PubMed  Google Scholar 

  36. Qian L, Chen L, Shi M, Yu M, Jin B, Hu M, Xia Q, Zhang X, Shen B, Guo N (2006) A novel cis-acting element in Her2 promoter regulated by Stat3 in mammary cancer cells. Biochem Biophys Res Commun 345:660–668. doi:10.1016/j.bbrc.2006.04.153

    Article  CAS  PubMed  Google Scholar 

  37. Rakovitch E, Nofech-Mozes S, Hanna W, Narod S, Thiruchelvam D, Saskin R, Spayne J, Taylor C, Paszat L (2012) HER2/neu and Ki-67 expression predict non-invasive recurrence following breast-conserving therapy for ductal carcinoma in situ. Br J Cancer 106:1160–1165. doi:10.1038/bjc.2012.41

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rauch GM, Kuerer HM, Scoggins ME, Fox PS, Benveniste AP, Park YM, Lari SA, Hobbs BP, Adrada BE, Krishnamurthy S, Yang WT (2013) Clinicopathologic, mammographic, and sonographic features in 1,187 patients with pure ductal carcinoma in situ of the breast by estrogen receptor status. Breast Cancer Res Treat 139:639–647. doi:10.1007/s10549-013-2598-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Roses RE, Paulson EC, Sharma A, Schueller JE, Nisenbaum H, Weinstein S, Fox KR, Zhang PJ, Czerniecki BJ (2009) HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiol Biomarkers Prev 18:1386–1389. doi:10.1158/1055-9965.EPI-08-1101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF (2009) Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol 27:1323–1333. doi:10.1200/JCO.2007.14.8197

    Article  CAS  PubMed  Google Scholar 

  41. Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, Lewinsky B, Gamagami P, Slamon DJ (1995) Prognostic classification of breast ductal carcinoma-in-situ. Lancet 345:1154–1157

    Article  CAS  PubMed  Google Scholar 

  42. Siziopikou KP, Anderson SJ, Cobleigh MA, Julian TB, Arthur DW, Zheng P, Mamounas EP, Pajon ER, Behrens RJ, Eakle JF, Leasure NC, Atkins JN, Polikoff JA, Seay TE, McCaskill-Stevens WJ, Rabinovitch R, Costantino JP, Wolmark N (2013) Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43. Breast Cancer Res Treat 142:415–421. doi:10.1007/s10549-013-2755-z

    Article  CAS  PubMed  Google Scholar 

  43. Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, Deitz AC, Connolly JL, Schnitt SJ, Colditz GA, Collins LC (2008) Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res 10:R67. doi:10.1186/bcr2128

    Article  PubMed Central  PubMed  Google Scholar 

  44. Van Bockstal M, Lambein K, Gevaert O, De Wever O, Praet M, Cocquyt V, Van den Broecke R, Braems G, Denys H, Libbrecht L (2013) Stromal architecture and periductal decorin are potential prognostic markers for ipsilateral locoregional recurrence in ductal carcinoma in situ of the breast. Histopathology 63:520–533. doi:10.1111/his.12188

  45. Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, Land SR, Margolese RG, Swain SM, Costantino JP, Wolmark N (2011) Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478–488. doi:10.1093/jnci/djr027

    Article  PubMed Central  PubMed  Google Scholar 

  46. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, College of American P (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. doi:10.1200/JCO.2013.50.9984

    Article  PubMed  Google Scholar 

  47. 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 O, College of American P (2007) 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 25:118–145. doi:10.1200/JCO.2006.09.2775

    Article  CAS  PubMed  Google Scholar 

  48. Yang M, Moriya T, Oguma M, De La Cruz C, Endoh M, Ishida T, Hirakawa H, Orita Y, Ohuchi N, Sasano H (2003) Microinvasive ductal carcinoma (T1mic) of the breast. The clinicopathological profile and immunohistochemical features of 28 cases. Pathol Int 53:422–428

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all lab technicians of the Department of Pathology of Ghent University Hospital for their excellent technical assistance. This study was funded by the ‘Klinisch onderzoeksfonds’ (clinical research fund) and the ‘Speerpunt Oncologie’ (spearhead oncology) from Ghent University Hospital, Ghent, Belgium, and by the Cancer Plan of the Federal Public Service (FPS) Health, Food Chain Safety and Environment (project number KPC-29-2012), Belgium.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, Ghent University, Ghent, Belgium

    Mieke Van Bockstal, Kathleen Lambein & Louis Libbrecht

  2. Department of Pathology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Mieke Van Bockstal, Kathleen Lambein, Ann Nuyts & Louis Libbrecht

  3. Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium

    Hannelore Denys & Veronique Cocquyt

  4. Department of Gynecology, Ghent University Hospital, Ghent, Belgium

    Geert Braems & Rudy Van den Broecke

  5. Laboratory of Experimental Cancer Research, Department of Radiotherapy and Nuclear Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium

    Olivier De Wever

Authors
  1. Mieke Van Bockstal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathleen Lambein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hannelore Denys
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geert Braems
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann Nuyts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rudy Van den Broecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Veronique Cocquyt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olivier De Wever
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Louis Libbrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mieke Van Bockstal.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Bockstal, M., Lambein, K., Denys, H. et al. Histopathological characterization of ductal carcinoma in situ (DCIS) of the breast according to HER2 amplification status and molecular subtype. Virchows Arch 465, 275–289 (2014). https://doi.org/10.1007/s00428-014-1609-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1609-3

Keywords

Search

Navigation