Home Current issue Ahead of print Search About us Editorial board Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 36  |  Issue : 3  |  Page : 254-259

Predictors of occult nipple–areola complex involvement in breast cancer patients: clinicopathologic study


1 Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission03-Feb-2017
Date of Acceptance26-Mar-2017
Date of Web Publication27-Jul-2017

Correspondence Address:
Mohamed I Abdelhamid
El Shimaa St, EL Kawmia, Zagazig, Sharkia
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejs.ejs_17_17

Rights and Permissions
  Abstract 


Context
Although oncoplastic breast-conserving surgery is a standard approach for treatment of breast cancer patients, mastectomy is still performed in 20–30% of patients undergoing surgeries. Nipple-sparing mastectomy provides a cosmetic and psychological outcome for patients; however, the oncologic safety of nipple–areola complex (NAC) sparing is a major concern.
Aim
The focus of this study was to determine the predictive factors of NAC involvement to define the indicators for NAC preservation.
Patients and methods
We analyzed NAC involvement in 180 patients during the period between October 2013 and December 2016 as regards the relation between the pathological affection of the NAC and clinical criteria, pathological and molecular features of the tumor (size, site, tumor–nipple distant, nodal affection, and molecular classification of breast cancer).
Results
Among 180 patients, 38 (21.1%) demonstrated NAC involvement, and it was mostly associated with tumor size 4 cm (P=0.047), tumor–nipple distant of 2.5 cm (P=0.003), positive lymph node (P=0.05), negative estrogen receptor (P=0.00013), negative progesterone receptors (P=0.000001), and HER2 receptor overexpression (P=0.001). Triple-negative breast cancer was significantly associated with increased risk of NAC involvement followed by HER2/neu-enriched subtype (P=0.001).
Conclusion
Tumor–nipple distant, tumor size and state of lymph nodes are the most important clinical predictors of nipple involvement and should be considered as risk factors. At the pathological and molecular level, triple-negative breast cancer is the worst subtype. The presence of one or more of these factors indicates high risk of occult nipple invasion.

Keywords: nipple involvement, nipple-sparing mastectomy, predictive factors


How to cite this article:
Abdelhamid MI, Alkilany MM, Rashed HE. Predictors of occult nipple–areola complex involvement in breast cancer patients: clinicopathologic study. Egypt J Surg 2017;36:254-9

How to cite this URL:
Abdelhamid MI, Alkilany MM, Rashed HE. Predictors of occult nipple–areola complex involvement in breast cancer patients: clinicopathologic study. Egypt J Surg [serial online] 2017 [cited 2017 Dec 12];36:254-9. Available from: http://www.ejs.eg.net/text.asp?2017/36/3/254/211708




  Introduction Top


Although oncoplastic breast-conserving surgery is a standard approach for treatment of breast cancer patients, mastectomy is still performed in 20–30% of patients undergoing surgeries [1],[2].

Skin-sparing mastectomy and nipple-sparing mastectomy (NSM) are examples of mastectomy techniques that were originally employed for benign lesions [3],[4].

Skin-sparing mastectomy requires the removal of the nipple–areola complex (NAC) by considering the fact that the nipple contains the terminal ducts that may contain tumor cells or a certain amount of breast tissue that carry a risk of developing subsequent cancer [5].

There are many problems with reconstructed nipples, including lack of projection, shape, size, color mismatch, and position. Hence, there is increasing interest in preservation of the NAC in the hope of achieving better cosmetic and functional outcomes [6],[7],[8],[9].

NSM includes removal of all breast tissue with preservation of the entire skin of the breast and NAC [10],[11].

Risk factors for NAC involvement with tumor are still not well defined. Therefore, selection criteria for NSM in breast cancer patients have not been well established [12].

We intended to investigate the frequency of occult NAC involvement and the clinicopathologic factors most frequently associated with it.


  Aim Top


The focus of this study was to determine the predictive factors of NAC involvement to define the indicators for NAC preservation.


  Patients and methods Top


This study was conducted at Zagazig University Hospital between October 2013 and December 2016. The study was approved by local ethical committee of our faculty and the technique was discussed with all patients and informed consent was obtained. In this study, we analyzed NAC involvement in 180 patients as regards the relation between the pathological affection of the NAC and clinical criteria of the tumor [size, site, tumor–nipple distant (TND), and nodal affection].

Inclusion criteria

All female patients with breast cancer with healthy non invaded skin and grossly free NAC and who were not candidates for oncoplastic surgery.

Exclusion criteria

  1. Grossly and radiologically involved NAC.
  2. Inflammatory breast cancer.
  3. Breast cancer patient subjected to chemotherapy or radiotherapy.
  4. Skin involvement.


All patients diagnosed with breast cancer by history taking, clinical examination and investigation in the form of breast ultrasound, mammography and biopsy [Fine needle aspiration cytology (FNAC), true cut or excisional]. For staging of the disease chest radiography, pelvic abdominal ultrasound and bone scan were carried out. MRI was performed for all patients to measure TND (distant between the center of the nipple and nearest margin of the lesion).

After diagnosis of early breast cancer, our patients were prepared and consented for modified radical mastectomy (MRM).

Clinical criteria of the patients that were taken into consideration throughout our study included age, tumor size, tumor site, lymph node status (palpable or not palpable) and TND. Breast ultrasonography plays an important and more precise role in determining tumor size and infiltration of axillary lymph nodes.

The resulting specimens after MRM were subjected to histopathological examination for nipple invasion (lymphatic and vascular invasion of the subareolar region) ([Figure 1]) shows histological type [Invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), ductal carcinoma insitu (DCIS) or any combination], tumor grade (I, II or III), pathological lymph node affection (positive or negative) and immunohistochemistry for molecular classification: (i) luminal A tumors that showed an IHC profile of high Estrogen receptors (ER), progesterone receptors (PR) expression, negative HER2 and low Ki67; (ii) luminal B is ER+, PR+, HER2− and Ki67 greater than or equal to 14%; (iii) luminal HER2 is ER+, PR+ and HER2+; (iv) HER2-enriched subtypes are ER−, PR−, HER2+ and (v) triple-negative breast cancer (TNBC): ER-, PR- and HER2-. Immunohistochemistry was performed on paraffin sections using anti-ER antibody (clone D07, DAKO) and anti-PR antibody ((PR 636, Dako at 1 : 50 dilution). Polyclonal HER2 antibody in the Herceptin kit (HercepTest, DAKO) was used according to the manufacturer’s instructions and Ki67 antibody (clone MIB-1, 1 : 50 dilution; Dako) was utilized by using the Envision system for detection. For ER and PR expression, moderate to strong nuclear staining in ≥1% of tumor cells was considered positive. HER2/neu was considered positive if at least 10% of tumor cells exhibited 3+‏ cell membrane staining. Cutoff point for ki67 expression was 14%.
Figure 1 A: Skin of NAC are infiltrated by malignant ductal epithelial cells (H&E x400). B: Skin of NAC are infiltrated by malignant ductal epithelial cells (IHC, Her2-neu x400).

Click here to view


Statistical analysis was performed to compare tumors with or without nipple involvement.


  Results Top


Patient age

Age distribution along the examined group is shown in [Table 1]
Table 1 Age distribution along the examined group

Click here to view


Lymph nodes examination

In our study, preoperative examination of axillary lymph nodes revealed that the majority of cases had impalpable nodes, but on testing the relation of having infiltrated axillary LNs to having an NAC devoid of malignancy, this relation was found to be strongly statistically significant as P value was less than 0.05 (χ2 test was used) ([Table 2]).
Table 2 State of lymph nodes

Click here to view


Tumor–nipple distant

In our study, preoperative measuring of the distant from the outer mass margin to the center of the nipple was recorded in a trial to find the safe distance at which the NAC was devoid of malignancy. Patients were divided into groups as shown in the following table; thereafter, every 2 successive groups were compared statistically to record this safe distance, and at least 2.5 cm was found to be the statistically significant safe distant for having an NAC free of malignancy. P value was 0.003 (χ2 test was used) ([Table 3]).
Table 3 Tumor–nipple distant

Click here to view


Tumor size

In our study, tumor size at the maximal diameter was recorded in a trial to find the safe size at which the NAC was devoid of malignancy. Patients were divided into groups as shown in the following table; thereafter every 2 successive groups were compared statistically to record this safe size and 4 cm at maximal diameter for the tumor mass was found to be the statistically significant safe size for having an NAC free of malignancy. P value was 0.047 (χ2 test was used) ([Table 4]).
Table 4 Tumor size

Click here to view


Other pathological features

In our study, certain pathological factors were recorded in a trial to outline the pathological features at which the NAC was devoid of malignancy. These factors were as follows:
  1. Histopathological type of the tumor.
  2. Histological grade.
  3. Histopathological status of lymph nodes.
  4. Molecular classification of breast cancer.


It was found that histopathological type of the tumor, histological grade or histopathological status of lymph nodes cannot affect the malignancy-free condition of the NAC, as P values for them were 0.687, 0.084, and 0.08, respectively. In contrast, estrogen and progesterone receptors status and HER2 overexpression were found to strongly and significantly affect the malignancy-free condition of the NAC, as P values for them were 0.00013, 0.000001 and 0.001, respectively (χ2 test was used), as shown in [Table 5]. TNBC was significantly associated with increased risk of NAC involvement followed by HER2/neu-enriched subtype (P=0.001) as shown in [Table 6].
Table 5 Pathological finding

Click here to view
Table 6 Molecular classification of the cases

Click here to view



  Discussion Top


Surgical treatment of early breast cancer has rapidly evolved from radical mastectomy to more cosmetic procedures like breast-conserving surgery and NSM with NAC preservation.

All patients in our study were subjected to MRM, because we included patients who were not candidates for oncoplastic surgery (patient preference was the main cause) and to enable us for NAC resection and histopathological examination.

Most breast cancer patients ask for both better cosmetic appearance and oncological safety. The majority of patients are interested in preserving the nipple during surgical resection of the tumor.

Preoperative detection of NAC invasion helps the surgeon to choose the most suitable surgical procedure that achieves both cosmetic and oncological satisfaction.

Factors that predict NAC invasion are not fixed in all studies, and to preserve the NAC we must be sure that it is free from malignancy.

The rate of NAC involvement has shown a wide range of involvement varying from 0 to 58% [13],[14]; hence, the safety of the NSM remains controversial. NAC involvement was defined by the presence of invasive carcinoma and/or ductal carcinoma in situ at the subareolar margin. In this work we tried to predict factors that determine NAC involvement. In the current study NAC involvement was 21.1%; however, Andersen and Pallesen [15] have reported a rate of 50% of NAC involvement.

Many studies reported a lower rate of recurrence; Laronga et al. [16], have reported a 5.6% rate of recurrence, whereas Jianli et al. [17] reported a 9.5% rate of recurrence. This discrepancy between different rates of recurrence may be due to a peripherally located tumor in some studies and the sampling technique of the nipple, whether it was a sagittal section, or multiple coronal or vertical sections.

Site of the tumor, size of the tumor, and the state of the lymph nodes are the most important clinical factors associated with NAC involvement [18],[19]; this was confirmed in the current study.

In our study, TND was the most important risk factor for nipple invasion; tumor distance less than 2.5 cm from the nipple was predictive for NAC involvement, and this is in agreement with Gerber et al. [9] and Vyas et al. [20], but in contrast with Sacchini et al. [7] who report that the cutoff value of TND was 1 cm.In this study, the risk of NAC invasion is directly proportionate with tumor size; tumor size less than 4 cm in our study was predictive for NAC involvement, and this is in agreement with Garcia-Etienne et al. [21].

In our study, breast ultrasonography plays an important and more precise role in determining axillary lymph nodes infiltration; positive lymph nodes were predictive for NAC involvement.

Breast cancer is a heterogeneous tumor that reveals several different molecular profiles with different biological behaviors; triple-negative subtypes present poorly differentiated tumors lacking ER, PR, and HER2 on immunohistochemical assay, and they are characterized by an increased rate of proliferation and increased invasiveness. In this work, this subtype was associated with increased risk of NAC involvement followed by HER2/neu-enriched subtype and this is in agreement with Petit et al. [22].


  Conclusion Top


Tumor nipple distant, tumor size and state of lymph nodes are the most important clinical predictors of nipple involvement and should be considered as risk factors. At the pathological and molecular level, TNBC is the worst subtype. The presence of one or more of these factors indicates high risk of occult nipple invasion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Morrow M, Bucci C, Rademaker A. Medical contraindications are not a major factor in the underutilization of breast conserving therapy. J Am Coll Surg 1998; 186:269–274.  Back to cited text no. 1
    
2.
Baum M, Budzar A, Cuzick J, Forbes J, Houghton JH, Klijn JG et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131–2139.  Back to cited text no. 2
    
3.
Freeman B. Subcutaneous mastectomy for benign breast lesions with immediate or delayed prosthetic replacement. Plast Reconstr Surg Transplant Bull 1962; 30:676–682.  Back to cited text no. 3
    
4.
Toth B, Lappert P. Modified skin incisions for mastectomy: the need for plastic surgical input in preoperative planning. Plast Reconstr Surg 1991; 87:1048–1053.  Back to cited text no. 4
    
5.
Cense H, Rutgers E, Lopes Cardozo M, Van Lanschot J. Nipple-sparing mastectomy in breast cancer: a viable option? Eur J Surg Oncol 2001; 27:521–526.  Back to cited text no. 5
    
6.
Gerber B, Krause A, Reimer T. Skin-sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction is an oncologically safe procedure. Ann Surg 2003; 238:120–127.  Back to cited text no. 6
    
7.
Sacchini V, Pinotti J, Barros A. Nipple-sparing mastectomy for breast cancer and risk reduction: oncologic or technical problem? J Am Coll Surg 2006; 203:704–714.  Back to cited text no. 7
    
8.
Petit J, Veronesi U, Orecchia R. Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years’ experience at the European Institute of Oncology of Milan (EIO). Breast Cancer Res Treat 2009; 117:333–338.  Back to cited text no. 8
    
9.
Gerber B, Krause A, Dieterich M, Kundt G, Reimer T. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study. Ann Surg 2009; 249:461–468.  Back to cited text no. 9
    
10.
Murthy V, Chamberlain R. Nipple-sparing mastectomy in modern breast practice. Clin Anat 2013; 26:56–65.  Back to cited text no. 10
    
11.
Long L. The use of nipple-sparing mastectomy in patients with breast cancer. Clin J Oncol Nurs 2013; 17:68–72.  Back to cited text no. 11
    
12.
Wagner J, Fearmonti R, Hunt K, Hwang R, Meric-Bernstam F, Kuerer HM et al. Prospective evaluation of the nipple-areola complex sparing mastectomy for risk reduction and for early-stage breast cancer. Ann Surg Oncol 2012; 19:1137–1144.  Back to cited text no. 12
    
13.
Gomez C. The role of radiation therapy after nipple-sparing mastectomy. Ann Surg Oncol 2014; 21:2237–2244.  Back to cited text no. 13
    
14.
Bistoni G. Nipple-sparing mastectomy: preliminary results. J Exp Clin Cancer Res 2006; 25:495–497  Back to cited text no. 14
    
15.
Andersen J, Pallesen R. Spread to the nipple and areola in carcinoma of the breast. Ann Surg 1979; 189:367–372.  Back to cited text no. 15
    
16.
Laronga C, Kemp B, Johnston D, Robb G, Singletary S. The incidence of occult nipple-areola complex involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol 1999; 6:609–613.  Back to cited text no. 16
    
17.
Jianli W, Xiuli X, Jianmin W, Naazneen I, Laurie B, Kristin A. Predictors of nipple-areola complex involvement by breast carcinoma: histopathologic analysis of 787 consecutive therapeutic mastectomy specimens. Ann Surg Oncol 2012; 19:1174–1180.  Back to cited text no. 17
    
18.
Cense H, Rutgers E, Lopes Cardozo M, Van Lanschot J. Nipple-sparing mastectomy in breast cancer: a viable option? Eur J Surg Oncol 2001; 27:521–526.  Back to cited text no. 18
    
19.
Simmons R, Brennan M, Christos P, King V, Osborne M. Analysis of nipple/areola involvement with mastectomy: can the areola be preserved? Ann Surg Oncol 2002; 9:165–168.  Back to cited text no. 19
    
20.
Vyas J, Chinoy R, Vaidya J. Prediction of nipple and areola involvement in breast cancer. Eur J Surg Oncol 1998; 24:15–16.  Back to cited text no. 20
    
21.
Garcia-Etienne C, Cody H III, Disa J, Cordeiro P, Sacchini V. Nipple-sparing mastectomy: initial experience at the Memorial Sloan-Kettering Cancer Center and a comprehensive review of literature. Breast J 2009; 15:440–449.  Back to cited text no. 21
    
22.
Petit J, Veronesi U, Orecchia R, Curigliano G, Rey P, Botteri E et al. Risk factors associated with recurrence after nipple-sparing mastectomy for invasive and intraepithelial neoplasia. Ann Oncol 2012; 23:2053–2058.  Back to cited text no. 22
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Aim
Patients and methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed64    
    Printed0    
    Emailed0    
    PDF Downloaded28    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]