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Histological features of skin and subcutaneous tissue in patients with breast cancer who have received neoadjuvant chemotherapy and their relationship to post-treatment edema

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Abstract

Background

Lymphedema is a major complication of treatment for breast cancer. Although chemotherapy can cause lymphedema, there have been few reports about histological changes in skin and subcutaneous tissue after chemotherapy. The aim of our study was to determine whether chemotherapy affects blood and lymphatic vessels in the skin and subcutaneous fat and to investigate the relationship between these changes and extent of post-chemotherapy edema.

Methods

We compared histological findings in skin and subcutaneous fat of mastectomy specimens from 38 patients who had received NAC (neoadjuvant chemotherapy) and 56 who had not (non-NAC) attending our institution from 2007 to 2016. Patients whose tumor may have affected the area examined were excluded. Blood and lymphatic vessels were identified by CD31 and D2-40, respectively. We assessed microvessel density (MVD), lymphatic microvessel density (MLVD), lumen cross-sectional area (LA), and amount of endothelium (AE) in blood and lymphatic vessels. To minimize surgical effects, we measured edema, defined as ≥ 15% thicker dorsal subcutaneous tissue than baseline, on the contralateral side.

Results

MVD, LA, and AE of blood vessels were greater and MLVD not significantly different in the skin of NAC patients than in that of non-NAC patients. MVD was greater and AE of blood vessels less in subcutaneous fat of NAC patients than in that of non-NAC patients. Patients with edema had significantly less AE of blood vessels in skin than did those without it.

Conclusions

These pathological findings can help to identify patients who will develop edema and improve their treatment.

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References

  1. Ridner SH. Quality of life and a symptom cluster associated with breast cancer treatment-related lymphedema. Support Care Cancer. 2005;13:904–11.

    Article  Google Scholar 

  2. Taghian NR, Miller CL, Jammallo LS, O’Toole J, Skolny MN. Lymphedema following breast cancer treatment and impact on quality of life: a review. Crit Rev Oncol Hematol. 2014;92:227–34.

    Article  Google Scholar 

  3. Nguyen TT, Hoskin TL, Habermann EB, Cheville AL, Boughey JC. Breast cancer-related lymphedema risk is related to multidisciplinary treatment and not surgery alone: results from a large cohort study. Ann Surg Oncol. 2017;24:2972–80.

    Article  Google Scholar 

  4. Cariati M, Bains SK, Grootendorst MR, Suyoi A, Peters AM, Mortimer P, et al. Adjuvant taxanes and the development of breast cancer-related arm lymphoedema. Br J Surg. 2015;102:1071–8.

    Article  CAS  Google Scholar 

  5. Kim M, Shin KH, Jung SY, Lee S, Kang HS, Lee ES, et al. Identification of prognostic risk factors for transient and persistent lymphedema after multimodal treatment for breast cancer. Cancer Res Treat. 2016;48:1330–7.

    Article  CAS  Google Scholar 

  6. Early Breast Cancer Trialists’ Collaborative G, Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432–44.

    Article  Google Scholar 

  7. Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23:5542–51.

    Article  CAS  Google Scholar 

  8. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–9.

    Article  CAS  Google Scholar 

  9. Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, et al. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016;17:90–8.

    Article  CAS  Google Scholar 

  10. Kim M, Park IH, Lee KS, Ro J, Jung SY, Lee S, et al. Breast cancer-related lymphedema after neoadjuvant chemotherapy. Cancer Res Treat. 2015;47:416–23.

    Article  Google Scholar 

  11. Ohsumi S, Shimozuma K, Ohashi Y, Takeuchi A, Suemasu K, Kuranami M, et al. Subjective and objective assessment of edema during adjuvant chemotherapy for breast cancer using taxane-containing regimens in a randomized controlled trial: The National Surgical Adjuvant Study of Breast Cancer 02. Oncology. 2012;82:131–8.

    Article  CAS  Google Scholar 

  12. Torrisi JS, Joseph WJ, Ghanta S, Cuzzone DA, Albano NJ, Savetsky IL, et al. Lymphaticovenous bypass decreases pathologic skin changes in upper extremity breast cancer-related lymphedema. Lymphat Res Biol. 2015;13:46–53.

    Article  CAS  Google Scholar 

  13. Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS ONE. 2009;4:e8380.

    Article  Google Scholar 

  14. Cheung L, Han J, Beilhack A, Joshi S, Wilburn P, Dua A, et al. An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis. BioDrugs. 2006;20:363–70.

    Article  Google Scholar 

  15. Ogata F, Fujiu K, Matsumoto S, Nakayama Y, Shibata M, Oike Y, et al. Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T cells drives the pathogenesis of lymphedema. J Invest Dermatol. 2016;136:706–14.

    Article  CAS  Google Scholar 

  16. Moon A, Smith GH, Kong J, Rogers TE, Ellis CL, Farris ABB 3rd. Development of CD3 cell quantitation algorithms for renal allograft biopsy rejection assessment utilizing open source image analysis software. Virchows Arch. 2018;472:259–69.

    Article  CAS  Google Scholar 

  17. Brazdziute E, Laurinavicius A. Digital pathology evaluation of complement C4d component deposition in the kidney allograft biopsies is a useful tool to improve reproducibility of the scoring. Diagn Pathol. 2011;6(Supp1):S5.

    Article  Google Scholar 

  18. Akita S, Ogata F, Manabe I, Mitsuhashi A, Nakamura R, Yamaji Y, et al. Noninvasive screening test for detecting early stage lymphedema using follow-up computed tomography imaging after cancer treatment and results of treatment with lymphaticovenular anastomosis. Microsurgery. 2017;37:910–6.

    Article  Google Scholar 

  19. Luengo-Gil G, Gonzalez-Billalabeitia E, Chaves-Benito A, Garcia Martinez E, Garcia Garre E, Vicente V, et al. Effects of conventional neoadjuvant chemotherapy for breast cancer on tumor angiogenesis. Breast Cancer Res Treat. 2015;151:577–87.

    Article  CAS  Google Scholar 

  20. Polcher M, Rudlowski C, Friedrichs N, Mielich M, Holler T, Wolfgarten M, et al. In vivo intratumor angiogenic treatment effects during taxane-based neoadjuvant chemotherapy of ovarian cancer. BMC Cancer. 2010;10:137.

    Article  Google Scholar 

  21. Mitrofanova I, Zavyalova M, Riabov V, Cherdyntseva N, Kzhyshkowska J. The effect of neoadjuvant chemotherapy on the correlation of tumor-associated macrophages with CD31 and LYVE-1. Immunobiology. 2018;223:449–59.

    Article  CAS  Google Scholar 

  22. Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, et al. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 2016;17:1344–56.

    Article  CAS  Google Scholar 

  23. Hung CH, Chan SH, Chu PM, Tsai KL. Docetaxel facilitates endothelial dysfunction through oxidative stress via modulation of protein kinase c beta: the protective effects of sotrastaurin. Toxicol Sci. 2015;145:59–67.

    Article  CAS  Google Scholar 

  24. Semb KA, Aamdal S, Oian P. Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol. 1998;16:3426–32.

    Article  CAS  Google Scholar 

  25. Béhar A, Pujade-Lauraine E, Maurel A, Brun MD, Chauvin FF, Feuilhade de Chauvin F, et al. The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication. Br J Clin Pharmacol. 1997;43:653–8.

    Article  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the generous contributions of the staff of the Department of Pathology and Ms. Hiroko Kawamura for their slide preparation and wish to thank Dr. Rikiya Nakamura, Department of Breast Surgery, Chiba Cancer Center for advice on experimental design. We also thank Dr. Trish Reynolds, MBBS, FRACP, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Ayako Nakagawa, Hiroshi Fujimoto, Takeshi Nagashima, Takafumi Sangai, Mamoru Takada, Takahito Masuda, Ryotaro Teranaka & Masayuki Ohtsuka

  2. Department of Pathology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan

    Satoshi Ota

  3. Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Jun Matsushima

  4. Department of Plastic, Reconstructive, and Aesthetic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Shinsuke Akita

Authors
  1. Ayako Nakagawa
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  2. Hiroshi Fujimoto
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  3. Takeshi Nagashima
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  6. Takahito Masuda
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  9. Jun Matsushima
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  10. Shinsuke Akita
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  11. Masayuki Ohtsuka
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Corresponding author

Correspondence to Hiroshi Fujimoto.

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Conflict of interest

This work was supported by Grants from Chiba Foundation for Health Promotion & Disease Prevention. There are no other potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all study participants.

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Nakagawa, A., Fujimoto, H., Nagashima, T. et al. Histological features of skin and subcutaneous tissue in patients with breast cancer who have received neoadjuvant chemotherapy and their relationship to post-treatment edema. Breast Cancer 27, 77–84 (2020). https://doi.org/10.1007/s12282-019-00996-x

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  • DOI: https://doi.org/10.1007/s12282-019-00996-x

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