Hematogenous and lymphatic tumor cell dissemination may be detected in patients diagnosed with ductal carcinoma in situ of the breast

Abstract

Tumor cell dissemination in bone marrow (BM) and lymph nodes is considered an important step in systemic disease progression and is associated with poor prognosis. Only invasive cancers are assumed to shed isolated tumor cells (ITC) into the bloodstream and infiltrate lymph nodes. However, latest studies indicate that tumor cell dissemination may occur before stroma invasion, i.e., in ductal carcinoma in situ (DCIS). Therefore, the purpose of this study was to examine the incidence of ITC in bone marrow and sentinel lymph nodes (SN) in patients diagnosed with DCIS and its correlation with clinicopathological factors. 266 patients who were treated at the Department of Gynecology and Obstetrics (University Hospital Tuebingen, Germany) between 2003 and 2009 with DCIS were included into this study. BM aspirates were analyzed by immunocytochemistry (pancytokeratin antibody A45-B/B3) using ACIS system (Chromavision) according to the ISHAGE evaluation criteria. SN were analyzed in 221 of these patients by extensive step sectioning and hematoxylin-eosin staining. In 34 of 266 patients (13%), ITC in BM could be detected. There was no correlation found between tumor size, grading, histology, or Van Nuys Prognostic Index and tumor cell dissemination. In two cases, metastatic spread into lymph nodes was observed (pN1mi), whereas in one case, ITC in lymph nodes were detected; however, additional sectioning and immunohistochemical staining of the primary lesion in the cases with positive SN did not reveal invasive cancer. Interestingly, all the three patients were BM negative. Tumor cell dissemination may be detected in patients diagnosed with DCIS. Either these cells have started already to disseminate from preinvasive mammary lesions or from occult invasive tumors or represent the earliest step of microinvasion in a preinvasive lesion. The clinical relevance of these cells has to be further evaluated.

Molecular Markers as Prognostic Factors in DCIS and Small Invasive Breast Cancers

“…Interestingly, the frequency of DCIS with disseminated tumor cells (25.0%) did not significantly differ from that of invasive breast cancer (19.6 %; p = 0.57). Despite caution should be taken because of the very small sample size in our study, this observation supports previous results of early dissemination and systemic spread already in pre-invasive disease [18][19][20][21].…”

“…This result seems counterintuitive and sample size is again an issue here. But beside potential technical and statistical issues similar data have been obtained before [18][19][20][21]28] suggesting that profound but undetectable dissemination may occur very early. Our results also hint towards a better prognosis of luminal type tumors both in DCIS and invasive breast cancer.…”

The Utility of Sentinel Lymph Node Biopsy in Patients with Ductal Carcinoma In Situ Suspicious for Microinvasion on Core Biopsy

“…However, the incidence of a positive SLN in patients with DCIS has been reported to be 1.1-8.5 % (0-2.8 % for macroscopic nodal disease), which is most likely due to unrecognized underlying invasive carcinoma. 1,8,9,13,25,29 A positive SLN in DCIS has been associated with the presence of a mass and a larger volume of DCIS. 9,13,28 Klauber-DeMore et al 1 examined patients who underwent SLNB for high-risk DCIS, defined as patients with a palpable mass (21 %), mammographic mass (34 %), histology suspicious but not diagnostic for microinvasion (24 %), multicentric disease requiring mastectomy 12 (53 %), or high nuclear grade or non-high nuclear grade with necrosis 12 (72 %).…”

The Biology of Bone Metastasis

“…While metastasis is typically characterized as the final step of primary tumor growth, this study demonstrates that primary tumors and metastatic lesions can develop in parallel rather than in sequence; a hypothesis that is further supported by the fact that DTC status is not correlated to tumor size (Hüsemann et al 2008). This finding was clinically validated by the detection of DTCs in the bone marrow of patients diagnosed only with breast ductal carcinoma in situ (DCIS) (Sänger et al 2011; Banys et al 2012) or localized Prostate cancer (Melchior et al 1997). …”