Breast Cancer Research and Treatment

, Volume 174, Issue 1, pp 103–111 | Cite as

Prognostic impact and possible pathogenesis of lymph node metastasis in ductal carcinoma in situ of the breast

  • Rika Yonekura
  • Tomo OsakoEmail author
  • Takuji Iwase
  • Akiko Ogiya
  • Takayuki Ueno
  • Masanobu Kitagawa
  • Shinji Ohno
  • Futoshi Akiyama
Preclinical study



Ductal carcinoma in situ (DCIS)—preinvasive breast cancer—with lymph node metastasis can clinically be treated as different stages: occult invasive cancer with true metastasis (T1N1) or pure DCIS with iatrogenic dissemination (TisN0). In this retrospective cohort study, we aimed to elucidate the prognostic impact and possible pathogenesis of nodal metastasis in DCIS to improve clinical management.


Subjects were comprised of 427 patients with routine postoperative diagnosis of DCIS who underwent sentinel node (SN) biopsy using molecular whole-lymph-node analysis. Clinicopathological characteristics and prognosis were compared between SN-positive and -negative patients. Primary tumour tissues of SN-positive patients were exhaustively step-sectioned to detect occult invasions, and predictive factors for occult invasion were investigated. Median follow-up time was 73.6 months.


Of the 427 patients, 19 (4.4%) were SN-positive and 408 (95.6%) were SN-negative. More SN-positive patients received adjuvant systemic therapy than SN-negative patients (84.2% vs. 5.4%). Seven-year distant disease-free survivals were favourable for both cohorts (SN-positive, 100%; SN-negative, 99.7%). By examining 1421 slides, occult invasion was identified in 9 (47.4%) of the 19 SN-positive patients. Tumour burdens in SN and incidence of non-SN metastasis were similar between patients with and without occult invasion, and no predictive factor for occult invasion was found.


Node-positive DCIS has favourable prognosis with adjuvant systemic therapy. Half of the cases may be occult invasive cancer with true metastasis. In practical settings, clinicians may have to treat these tumours as node-positive small invasive cancers because it is difficult to predict the pathogenesis without exhaustive primary tumour sectioning.


Breast cancer DCIS Lymph node metastasis OSNA Survival Parallel progression model 



We thank Drs. Masujiro Makita, Seiichiro Nishimura, Yumi Miyagi, Kotaro Iijima, Hidetomo Morizono, Kiyomi Kimura, and Takehiko Sakai (Breast Oncology Center, the Cancer Institute Hospital) for providing clinical samples, and Mr. Motoyoshi Iwakoshi (Division of Pathology, the Cancer Institute) for sectioning primary tumour tissues.


This work was supported in part by a Grant-in-Aid for Young Scientists (B) (No. 21791264) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology and a Research Grant from the Foundation for the Promotion of Cancer Research in Japan (to Tomo Osako).

Compliance with ethical standards

Conflict of interest

Futoshi Akiyama received consulting fee from Sysmex Corporation paid to the Japanese Foundation for Cancer Research. The other authors declare no conflicts of interest.

Ethical approval

This study was approved by the Institutional Review Board of the Cancer Institute Hospital (Reference Nos. 2011-1015 and 2012-1061), and performed in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The written general consent was obtained from each of the patients.


  1. 1.
    Burstein HJ, Polyak K, Wong JS, Lester SC, Kaelin CM (2004) Ductal carcinoma in situ of the breast. N Engl J Med 350:1430–1441. CrossRefGoogle Scholar
  2. 2.
    Ansari B, Ogston SA, Purdie CA, Adamson DJ, Brown DC, Thompson AM (2008) Meta-analysis of sentinel node biopsy in ductal carcinoma in situ of the breast. Br J Surg 95:547–554. CrossRefGoogle Scholar
  3. 3.
    El Hage Chehade H, Headon H, Wazir U, Abtar H, Kasem A, Mokbel K (2017) Is sentinel lymph node biopsy indicated in patients with a diagnosis of ductal carcinoma in situ? A systematic literature review and meta-analysis. Am J Surg 213:171–180. CrossRefGoogle Scholar
  4. 4.
    Osako T, Iwase T, Kimura K, Horii R, Akiyama F (2013) Detection of occult invasion in ductal carcinoma in situ of the breast with sentinel node metastasis. Cancer Sci 104:453–457. CrossRefGoogle Scholar
  5. 5.
    Osako T, Iwase T, Kimura K, Masumura K, Horii R, Akiyama F (2012) Incidence and possible pathogenesis of sentinel node micrometastases in ductal carcinoma in situ of the breast detected using molecular whole lymph node assay. Br J Cancer 106:1675–1681. CrossRefGoogle Scholar
  6. 6.
    NCCN (2018) National comprehensive cancer network clinical practice guidelines in oncology. Breast Cancer ver. 1, 2018Google Scholar
  7. 7.
    Zetterlund L, Stemme S, Arnrup H, de Boniface J (2014) Incidence of and risk factors for sentinel lymph node metastasis in patients with a postoperative diagnosis of ductal carcinoma in situ. Br J Surg 101:488–494. CrossRefGoogle Scholar
  8. 8.
    Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T, Iwase T, Akiyama F, Kato Y, Tsuda H, Ueda S, Sato K, Tamaki Y, Noguchi S, Kataoka TR, Nakajima H, Komoike Y, Inaji H, Tsugawa K, Suzuki K, Nakamura S, Daitoh M, Otomo Y, Matsuura N (2007) One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients. Clin Cancer Res 13:4807–4816. CrossRefGoogle Scholar
  9. 9.
    Tamaki Y, Akiyama F, Iwase T, Kaneko T, Tsuda H, Sato K, Ueda S, Mano M, Masuda N, Takeda M, Tsujimoto M, Yoshidome K, Inaji H, Nakajima H, Komoike Y, Kataoka TR, Nakamura S, Suzuki K, Tsugawa K, Wakasa K, Okino T, Kato Y, Noguchi S, Matsuura N (2009) Molecular detection of lymph node metastases in breast cancer patients: results of a multicenter trial using the one-step nucleic acid amplification assay. Clin Cancer Res 15:2879–2884. CrossRefGoogle Scholar
  10. 10.
    Osako T, Iwase T, Kimura K, Yamashita K, Horii R, Akiyama F (2011) Accurate staging of axillary lymph nodes from breast cancer patients using a novel molecular method. Br J Cancer 105:1197–1202. CrossRefGoogle Scholar
  11. 11.
    Osako T, Iwase T, Kimura K, Yamashita K, Horii R, Yanagisawa A, Akiyama F (2011) Intraoperative molecular assay for sentinel lymph node metastases in early stage breast cancer: a comparative analysis between one-step nucleic acid amplification whole node assay and routine frozen section histology. Cancer 117:4365–4374. CrossRefGoogle Scholar
  12. 12.
    Amin MB (2018) American Joint Committee on cancer cancer staging manual, 8th edn. Springer, New YorkGoogle Scholar
  13. 13.
    Osako T, Iwase T, Ushijima M, Horii R, Fukami Y, Kimura K, Matsuura M, Akiyama F (2014) Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ. Cancer Sci 105:576–582. CrossRefGoogle Scholar
  14. 14.
    Brennan ME, Turner RM, Ciatto S, Marinovich ML, French JR, Macaskill P, Houssami N (2011) Ductal carcinoma in situ at core-needle biopsy: meta-analysis of underestimation and predictors of invasive breast cancer. Radiology 260:119–128. CrossRefGoogle Scholar
  15. 15.
    Bleiweiss IJ, Nagi CS, Jaffer S (2006) Axillary sentinel lymph nodes can be falsely positive due to iatrogenic displacement and transport of benign epithelial cells in patients with breast carcinoma. J Clin Oncol 24:2013–2018. CrossRefGoogle Scholar
  16. 16.
    Moore KH, Thaler HT, Tan LK, Borgen PI, Cody HS 3rd (2004) Immunohistochemically detected tumor cells in the sentinel lymph nodes of patients with breast carcinoma: biologic metastasis or procedural artifact? Cancer 100:929–934. CrossRefGoogle Scholar
  17. 17.
    Tvedskov TF, Jensen MB, Kroman N, Balslev E (2012) Iatrogenic displacement of tumor cells to the sentinel node after surgical excision in primary breast cancer. Breast Cancer Res Treat 131:223–229. CrossRefGoogle Scholar
  18. 18.
    Diaz LK, Wiley EL, Venta LA (1999) Are malignant cells displaced by large-gauge needle core biopsy of the breast? AJR Am J Roentgenol 173:1303–1313CrossRefGoogle Scholar
  19. 19.
    Fisher B, Bauer M, Wickerham DL, Redmond CK, Fisher ER, Cruz AB, Foster R, Gardner B, Lerner H, Margolese R, Poisson R, Shibata H, Volk H, (1983) Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer 52:1551–1557CrossRefGoogle Scholar
  20. 20.
    Iqbal J, Ginsburg O, Giannakeas V, Rochon PA, Semple JL, Narod SA (2017) The impact of nodal micrometastasis on mortality among women with early-stage breast cancer. Breast Cancer Res Treat 161:103–115. CrossRefGoogle Scholar
  21. 21.
    Osako T, Iwase T, Ushijima M, Yonekura R, Ohno S, Akiyama F (2017) A new molecular-based lymph node staging classification determines the prognosis of breast cancer patients. Br J Cancer 117:1470–1477. CrossRefGoogle Scholar
  22. 22.
    Newman EL, Kahn A, Diehl KM, Cimmino VM, Kleer CA, Chang AE, Newman LA, Sabel MS (2006) Does the method of biopsy affect the incidence of sentinel lymph node metastases? Breast J 12:53–57. CrossRefGoogle Scholar
  23. 23.
    Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9:302–312. CrossRefGoogle Scholar
  24. 24.
    Narod SA, Sopik V (2018) Is invasion a necessary step for metastases in breast cancer? Breast Cancer Res Treat 169:9–23. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of PathologyThe Cancer Institute of the Japanese Foundation for Cancer ResearchTokyoJapan
  2. 2.Breast Oncology CenterThe Cancer Institute Hospital of the Japanese Foundation for Cancer ResearchTokyoJapan
  3. 3.Department of Comprehensive Pathology, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  4. 4.Department of PathologyThe Cancer Institute Hospital of the Japanese Foundation for Cancer ResearchTokyoJapan

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