A case of bilateral methotrexate-associated diffuse large B-cell lymphomas of the breasts with unique clinical presentation and outcome


A 54-year-old woman on methotrexate (MTX) treatment developed reddish skin change in her right breast. Mammography and ultrasound showed no masses in the breasts but bilateral mammary glands presented diffuse lower-level echoes. Only 19 days later, the patient developed bilateral breast masses. Histological examination showed that diffuse large B-cell lymphoma cells spread widely and sparsely in the bilateral breasts in addition to the tumor cell conglomerate, leading to the diagnosis of MTX-associated lympho-proliferative disorders (MTX-LPDs). Withdrawal of MTX resulted in complete disappearance of the left MTX-LPD in 2 months but no regression of the right MTX-LPD. Chemotherapy led to a partial response followed by re-growth of the right MTX-LPD. Re-biopsy of the right MTX-LPD revealed double/triple hit lymphoma. Second-line and later-line chemotherapies caused no regression of the right MTX-LPD. The patient died in a year after the diagnosis of MTX-LPDs. Breast oncologists should note the presence, biology, and diagnostic images of MTX-LPD.

This is a preview of subscription content, access via your institution.

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


  1. 1.

    Rosen PP. Lymphoid and hematopoietic tumors. Fosen’s breast pathology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 863–873.

    Google Scholar 

  2. 2.

    Ellman MH, Hurwitz H, Thomas C, Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol. 1991;18:1741–3.

    CAS  PubMed  Google Scholar 

  3. 3.

    Niitsu N, Okamoto M, Nakamine H, Hirano M. Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate. Cancer Sci. 2010;101:1309–13.

    CAS  Article  Google Scholar 

  4. 4.

    Roka N, Matsubayashi H, Iwasaki N, Iwakuma S, Momosaki S. Methotrexate (MTX)-associated malignant lymphoma of the bilateral breast: imaging features in comparison to other nipple-areolar tumors. Clin Imaging. 2019;53:120–5.

    Article  Google Scholar 

  5. 5.

    Ichikawa A, Arakawa F, Kiyasu J, Sato K, Miyoshi H, Niino D, et al. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein–Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 2013;91:20–8.

    CAS  Article  Google Scholar 

  6. 6.

    Tokuhira M, Watanabe R, Nemoto T, Sagawa M, Tomikawa T, Tamaru J, et al. Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis. Leuk Lymphoma. 2012;53:616–23.

    CAS  Article  Google Scholar 

  7. 7.

    Satou A, Tabata T, Miyoshi H, Kohno K, Suzuki Y, Yamashita D, et al. Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases. Modern Pathology. 2019;32:1135–46.

    CAS  Article  Google Scholar 

  8. 8.

    Rosenthal A, Younes A. High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6: Double hit and triple hit lymphomas and double expressing lymphoma. Blood Rev. 2017;31:37–42.

    CAS  Article  Google Scholar 

  9. 9.

    Fouad TTM, Barrera AMG, Reuben JM, Lucci A, Woodward WA, Stauder MC, et al. Inflammatory breast cancer: a proposed conceptual shift in the UICC–AJCC TNM staging system. Lancet Oncol. 2017;18:e228–32.

    Article  Google Scholar 

  10. 10.

    Chen Y, Zhou J, Fan H, Luo Y, Peng Y, Ma B. Ultrasound diagnosis of breast lymphoma and the identification of breast infiltrating ductal carcinoma. J Ultrasound Med. 2019. https://doi.org/10.1002/jum.15209.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer. 2016;4:59.

    Article  Google Scholar 

  12. 12.

    Pereira MA, de Magalhães AV, da Motta LD, Santos AM, Segura ME, Pereira CF, et al. Fibrous mastopathy: clinical, imaging, and histopathologic findings of 31 cases. J Obstet Gynaecol Res. 2010;36:326–35.

    Article  Google Scholar 

  13. 13.

    Freeman CM, Xia BT, Wilson GC, Lewis JD, Khan S, Lee SJ, et al. Idiopathic granulomatous mastitis: a diagnostic and therapeutic challenge. Am J Surg. 2017;214:701–6.

    CAS  Article  Google Scholar 

  14. 14.

    Abdou Y, Elkhanany A, Attwood K, Ji W, Takabe K, Opyrchal M. Primary and secondary breast angiosarcoma: single center report and a meta-analysis. Breast Cancer Res Treat. 2019;178:523–33.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Shoji Oura.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Research involving human participants and/or animals

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Informed consent was obtained from the family of the deceased patient.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tomita, M., Oura, S., Nishiguchi, H. et al. A case of bilateral methotrexate-associated diffuse large B-cell lymphomas of the breasts with unique clinical presentation and outcome. Breast Cancer 27, 1038–1043 (2020). https://doi.org/10.1007/s12282-020-01102-2

Download citation


  • Breast malignant lymphoma
  • Diffuse large B-cell lymphoma
  • Methotrexate-associated lympho-proliferative disorder