Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance

Škrtić, Anita; Korać, Petra; Krišto, Delfa Radić; Ajduković Stojisavljević, Radmila; Ivanković, Davor; Dominis, Mara

doi:10.1016/j.humpath.2010.05.002

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Volume 41, Issue 12 , Pages 1702-1710, December 2010

Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance

Anita Škrtić, MD
- Department of Pathology and Cytology, University of Zagreb, School of Medicine, University Hospital Merkur, 10000 Zagreb, Croatia
- Corresponding author.
Petra Korać, PhD
- Department of Pathology and Cytology, University of Zagreb, School of Medicine, University Hospital Merkur, 10000 Zagreb, Croatia
Delfa Radić Krišto, MD
- Department of Medicine, University Hospital Merkur, 10000 Zagreb, Croatia
Radmila Ajduković Stojisavljević, MD
- Department of Medicine, University Hospital Dubrava, 10000 Zagreb, Croatia
Davor Ivanković, MD, PhD
- Department of Medical Statistics, Epidemiology and Medical Informatics, Andrija Stampar School of Public Health, University of Zagreb, School of Medicine, 10000 Zagreb, Croatia
Mara Dominis, MD, PhD
- Department of Pathology and Cytology, University of Zagreb, School of Medicine, University Hospital Merkur, 10000 Zagreb, Croatia

Received 7 December 2009; received in revised form 27 April 2010; accepted 7 May 2010. published online 30 August 2010.

Summary

Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration (P = .002) and an immature morphologic type of plasma cells (P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 (P = .484) and JAGGED1 (P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.

Keywords: Multiple myeloma, NOTCH1, JAGGED1, IGH translocations, Immunohistochemistry