Breast cancer close to the nipple: Does this carry a higher risk ofaxillary node metastasesupon diagnosis?

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1 Breast cancer close to the nipple: Does this carry a higher risk ofaxillary node metastasesupon diagnosis? Erin I. Lewis, BUSM 2010 Cheri Nguyen, BUSM 2008 Priscilla Slanetz, M.D., MPH Al Ozonoff, Ph.d.

2 Introduction Breast cancer is the most common cancer among women, and is the second leading cause of cancer death. Axillary lymph node metastasis is currently the single most reliable predictor for recurrence risk and survival in patients with invasive breast carcinoma. In clinical practice, the size of breast cancers is positively correlated with the presence of axillary nodal metastases; the larger the tumor, the more likely it has spread to the regional lymph nodes. Breast cancer is thought to primarily metastasize through the lymphatic system. It is now well known that lymphatic drainage of all tumors passes first through h the subareolar lymphatic plexus prior to draining into the axilla. Recently the proximity of the tumor to the skin has been shown to be positively correlated with axillary a metastasis s due to the rich lymphatic network in the dermis of the skin. Based upon clinical impression, and the knowledge that lymphatic drainage of all tumors pass through the subareolar lymphatic plexus prior to the axilla, we hypothesize that small breast cancers more proximal to the nipple are more likely to be positive for axillary lymph node metastasis.

3 Lymphatic Drainage of the Breast Lymphatic drainage travels first to the subareolar lymphatic plexus Then to axillary lymph nodes (95%) or to parasternal lymph nodes and contralateral breast (5%) Netter

4 Study Participants This study was a retrospective review of medical records and imaging of 285 women with invasive breast cancer diagnosed d at BUMC between January 2001 and April During the study period, 682 women with invasive breast carcinoma were treated at Boston University Medical Center with conservative surgery, chemotherapy, and/or radiation therapy. Throughout the study period dedicated breast mammography and ultrasound were routinely used for diagnostic evaluation. Eligibility criteria were: female of any age or ethnicity; histologically confirmed invasive stage T1-T4 breast cancer, surgical axillary staging data available, breast mammography and ultrasound prior to cancer treatment, no chemotherapy or radiation therapy between ultrasound and axillary staging; and mammogram and ultrasound films available for review.

5 Clinical Data Medical records provided medical history and family history of breast cancer in 1 st -degree relatives. Pathologic reports provided information on the tumor characteristics (size of invasive component, histologic type, histologic grade, hormone receptor expression status, axillary stage and lymphovascular invasion). Mammographic density was abstracted from mammogram reports.

6 Measurements Breast mammogram examinations were performed with dedicated breast mammography equipment. Utilizing the cranial-caudal view of the breast, the lesion was demarcated by a radiologist. The distance of the lesion from the nipple was measured in its relation to the posterior nipple line (from surface of nipple, to the edge of the pectoralis muscle). Two relationships to the posterior nipple line were calculated, utilizing a triangle drawn on the breast. One relationship was the ratio of the lesion parallel to the posterior nipple line. The other relationship was the ratio radially oriented to the posterior nipple line. This measurement allows us to standardize for difference in breast size among patients. On the available ultrasound images a measurement was taken from the skin to the most superficial aspect of the tumor.

7 Mammography Measurements Measurements taken using Cranial Caudal View 1) a/pnl 2) c/pnl Cranial Caudal c c Breast Cancer b a a posterior nipple line (pnl) Posterior Nipple Line (pnl)

8 Ultrasound Measurements measurement Proximity to the skin was defined as the distance from the skin surface to the closest leading edge of the tumor as imaged on ultrasound film Leading edge of hypoechoic mass

9 Data During the study period, January 2001 to June 2007, the clinic diagnosed 682 female patients with invasive T1-T4 breast cancer. 398 patients were excluded due to no axillary surgical staging g data available, chemotherapy prior to staging or surgery, mammography film unavailable, Paget s disease, or multifocal cancer. The final analytic dataset was comprised of all 285 eligible patients. Initially, bivariate i associations between outcome (metastasis) and each clinical variable of interest was assessed using logistic regression. Candidate variables were then selected on the basis of strength of bivariate association, in order to construct an intermediate multivariable model. The final model selected removed predictors that demonstrated no independent association with outcome in the intermediate model. Associations are presented as odds ratios with 95% confidence intervals. All hypothesis tests were performed using a significance level of 0.05, and all analyses were done with the R Statistical Package version 2.4 (2007, R Foundation, Vienna Austria).

10 Bivariate Associations ocp-hrt palpable calcifications lvs grade location - relative to UIQ UOQ LOQ LIQ retro/peri type** type**** size***** < er pr her density*** family-hx prior-benign prior-hx dist-skin a.pnl c.pnl curage < agedx < Mulivariate Associations palpable lvs agedx **Type collapsed to: 1 (invasive ductal) versus 2,3,4 (all others) ***Density collapsed to: 1,2 (fatty-normal density) versus 3,4 (dense-very dense) ****Type collapsed to: 1,4 (ductal) versus 2,3 (lobular) *****Size collapsed to: 1,2 (less than or equal to 1.0cm) versus 3,4 (greater than 1.0cm) (Abbreviations: Ocp/hrt- hormones, lvs - lymphovascular invasion, UIQ - upper inner quandrant, UOQ - upper outer quadrant, LOQ - lower outer quadrant, LIQ - lower inner quadrant, curage - current age, age dx- age at diagnosis)

11 Analysis of Data As expected, tumors with a larger size (p= <.0001), higher histologic grade (p =.004) and lymphovascular invasion (p =.0001) were associated with axillary nodal metastasis. In addition, palpable tumors were significantly more likely to be associated with positive axillary nodal metastasis (p =.0003). Increased density of the breast was also associated with nodal metastasis (p =.02). Interestingly, the younger the age of diagnosis was also correlated with positive nodal metastasis (p = <.0001). In the multivariable model palpable breast cancer (p =.06), lymphovascular invasion (p=.002), and age of diagnosis (p=.03) were all associated with positive nodal metastasis.

12 Conclusion In this retrospective review of women with invasive breast cancer, we tested the hypothesis that breast cancers closer to the nipple are more likely to have metastasized to axillary lymph nodes. From our data we concluded that location of the primary tumor doesn t predict presence or absence of axillary metastasis. We also found that a positive family history, previous benign biopsy, and a prior diagnosis of breast cancer, and tumor type (ductal vs. lobular) are not linked to the presence of axillary lymph node disease at diagnosis. On the other hand, other variables can help predict the presence or absence or axillary metastasis: Denser breast tissue is associated with a greater probability of axillary metastasis The younger the age of diagnosis, the more likely there are positive lymph nodes The higher the grade of the tumor and the presence of lymphovascular invasion are associated with positive lymph nodes at diagnosis The larger the tumor size (> 1cm) and the palpability of the tumor are associated with a greater probability of axillary metastasis

13 References Chao C; Edwards MJ; Abell T et al. Palpable Breast Carcinomas: a hypothesis for clinically relevant lymphatic drainage in sentinel lymph node biopsy. The Breast Journal : Chua B; Ung O; Taylor R; et al. Frequency and predictors of axillary lymph node metastases in invasive i breast cancer. ANZ J Surg : Cunningham, JE; Jurj AL; Oman L et al. Is the risk of axillary lymph node metastasis associated with proximity of breast cancer to the skin. Breast Cancer Res Treat : Brenin DR; Manasseh DM; El-Tamer Mahmoud et al. Factors correlating with lymph node metastases in patients with T1 breast cancer. Annals of Surgical Oncology : Martin C; Cutuli B; Velten M. Predictive Model of axillary lymph node involvement in women with small invasive breast carcinoma. Cancer : Olivotto IV; Jackson JSH; Mates, D et al. Prediction i of axillary lymph node involvement of women with invasive breast carcinoma. Cancer :

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