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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 2  |  Page : 232-237
Morphological predictors of nipple areola involvement in malignant breast tumors


1 Department of Pathology, North Bengal Medical College, India
2 Department of Community Medicine, North Bengal Medical College, India

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Date of Web Publication12-Jun-2010
 

   Abstract 

Context: Nipple areola (NA) sparing mastectomy has an acceptable complication rate, is oncologically safe and facilitates an improved cosmetic result, aiding greatly in reducing psychological trauma associated with breast loss. Questions regarding preoperative case selection for NA sparing mastectomy are pertinent. Aims: The principle objective was to develop a simple model based on correlation of malignant involvement of NA with morphological factors in breast cancer cases to accurately predict the cancerous involvement of nipple areola preoperatively. Settings and Design: The present cross-sectional study was carried out on 136 patients of breast cancer. The period of study spanned 3 years from 2004 to 2007. Materials and Methods: We evaluated 17 different morphological parameters which had proven prognostic significance in breast cancer cases for their relationship with NA involvement. Data regarding cytological parameters were available in 120 cases out of the total number of 136 cases. Simple and conventional methods appropriate for any under-resourced set-up were employed to enhance the economic viability and acceptability of the project. Statistical Analysis used: Statistical analysis in this study was mostly done using SPSS version: 14 software. P-value < 0.05 was considered significant when assessing correlation between two parameters. Results: The frequency of NA involvement detected in this study was 19.1%. In univariate analysis, 13 of the 17 morphological parameters were found to have strong statistical association (P<0.05) with NA involvement. In multivariate analysis, only four parameters-macroscopic NA changes, tumor-NA distance (<1.5cm), histological lymph node grade and extra capsular extension in lymph node were found to have independent role for NA involvement prediction. This multivariate Cox and Snell Regression model with Cox and Snell Regression Square of 0.551 can predict accurately 98.5% cases of nipple involvement using the 4 parameters as variables. Conclusions: By application of this simple multivariate model, accurate prediction of NA involvement would be possible preoperatively. NA sparing mastectomy may be performed on those cases predicted to have no NA involvement thus substantially reducing the burden of psychological morbidity.

Keywords: Breast Cancer, morphological parameters, nipple areola involvement, prognosis

How to cite this article:
Khan K, Chakraborti S, Mondal S. Morphological predictors of nipple areola involvement in malignant breast tumors. Indian J Pathol Microbiol 2010;53:232-7

How to cite this URL:
Khan K, Chakraborti S, Mondal S. Morphological predictors of nipple areola involvement in malignant breast tumors. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Nov 12];53:232-7. Available from: http://www.ijpmonline.org/text.asp?2010/53/2/232/64329


In multivariate analysis, four parameters-macroscopic NA changes, tumor-NA distance (< 1.5cm), histological lymph node grade and extra capsular extension in lymph node were found to play independent roles for NA involvement prediction. By application of this simple multivariate model, accurate prediction of NA involvement would be possible preoperatively. NA sparing mastectomy may be performed on those cases predicted to have no NA involvement thus substantially reducing the burden of psychological morbidity.


   Introduction Top


In the 20 th century battle against breast cancer, the focus is now on rapid and accurate diagnosis, less radical surgical approaches and increased patient participation in therapeutic decision making in order to fulfill the pristine aims of saving lives as well as reducing physical and psychological morbidity as a whole. [1] One of the stepping-stones in this noble effort, is the performance of nipple areola (NA) sparing mastectomies which have an acceptable complication rate, is oncologically safe and facilitates an improved cosmetic result, aiding greatly in reducing psychological trauma associated with breast loss. [2],[3],[4],[5] Questions regarding its preoperative case selection and economical viability are pertinent. Review of published literature revealed that estrogen receptor status, S-phase and other molecular factors had no correlation with NA involvement. [6] Even after diligent search, not a single study aiming at ascertaining correlation between cytomorphological parameters and nipple areola involvement was found.

The principle objective of the present study was to develop a simple model based on correlation of morphological factors in breast cancer cases with malignant NA involvement to accurately predict the cancerous involvement of the nipple areola preoperatively.


   Materials and Methods Top


General

The present cross-sectional study was carried out on 136 patients with malignant breast tumors. All necessary information was collected. Simple and conventional methods appropriate for any under-resourced set-up were employed to enhance the economic viability and acceptability of the project.

Cytology

Fine needle aspiration of breast lump as well as palpable lymph nodes (LN) was performed on an outpatient basis without any local anesthetic or radiological guidance. Smears were subjected to Leishman, hematoxylin and eosin (H and E) as well as Papaniculaou (Pap) stain. Cytological features and nuclear grades were recorded for smears obtained from the primary tumor and for those from the LN. 3-tier modified Black grading system was used. Ohri et al.[7] suggested that in view of the precise correlation of cytological grade with histological grade, the Nottingham prognostic index (NPI) can be modified, replacing 3-tier histological grade with the 3-tier modified Black cytological grade. Modified NPI (NPI-C) was also evaluated in this study for its possible role as a predictor of NA involvement. Of the total number of 136 cases, cytological specimens were successfully obtained and assessed in 120 cases.

Histopathology

Nipple areola
- Several tissue blocks were taken longitudinally through the nipple and areola (bread loafing) including at least 2 cm of subcutaneous tissue. Whole mounts of each tissue block were processed in several separate blocks.

Lymph nodes - Whole mount tissue blocks were taken through the largest diameter of all lymph nodes. For every lymph node, a rim of adipose tissue (approximately 0.25 cm.) was included which facilitated the observation of extra capsular extension of the malignant process. Rest of the specimen was grossed routinely. Routine processing and paraffin embedding followed by H and E staining was performed. Histological typing was done based on the World Health Organization (WHO) classification of malignant breast tumors, 2003. Nottingham modified Scarff Bloom - Richardson grading system was followed for histological grading of the primary tumor. Metastatic tumor in the lymph nodes was also graded using the same Scarff Bloom - Richardson grading system as a modification.

Nipple areola Involvement was categorized as: [8] (a) Paget disease and (b) Direct malignant invasion, when tumor was found to involve the basal layer of the epidermis of nipple areola [Figure 1] A, B. On the basis of cancerous involvement of the nipple areola (NA), the study population was divided into two broad groups- (i) NA involved group and (ii) NA uninvolved group. The morphologically detectable proven prognostic parameters assessed in this study were - i) Histological Grade ii) Tumor size iii) Metastatic lymph node involvement iv) Extra capsular extension in LN (ECE) v) Cytological grade vi) NPI and vii) Lympho-vascular invasion (LVI). [9] ECE was considered to be positive if malignant cells were identified within the efferent lymph vessels and / or extra nodal adipose tissue. [6],[10] The macroscopic findings, prognostic parameters, histological type, cytological features and the NPI were individually assessed for the two broad groups of cases and their correlation studied.

Statistical methods

Statistical analysis in the present study was mostly done using SPSS version: 14 software. P-value < 0.05 was considered significant when assessing correlation between two parameters. The present study being a cross-sectional study, the odds ratio (OR) was considered for determination of the statistical significance of correlation between two parameters within the calculated 95% confidence interval (CI).


   Results Top


In this study, mean age of the study population was 43.21 years ± 10.58 (S.D.) (Range: 19 to 75 years). The mean interval between appearance of tumor and operation in the 136 cases studied was 6.55 months ± 3.5(S.D.) (Range: 2 to 24 months).The mean interval between fine needle aspiration cytology (FNAC) and operation in the 120 cases in which cytological specimens were available was 3.52 weeks ± 2.50 (S.D.) (Range: 1 to 16 weeks.) In this study, invasive ductal carcinoma, not otherwise specified (IDC, NOS) cases constituted the largest group with 120 patients and the frequency of occurrence was 88.3% which vastly outnumbered the other histological types of breast cancer. [Table 1]

The overall frequency of NA involvement, in this study, was found to be 19.1% (26 cases). The frequencies of occurrence of Paget's disease and direct malignant invasion were 2.94% (4 cases) and 16.17% (22 cases) respectively. [Table 2] In all the four cases of Paget's disease, the underlying invasive tumor was of the IDC, NOS type [Figure 2] a and b, [Figure 3] and [Figure 4].

In this study after univariate analysis, 13 parameters: tumor laterality, tumor size, macroscopic NA changes, macroscopic tumor - NA distance, histological grade, LVI, number of lymph nodes involved, LN grade, ECE in LN, Cytological tumor grade, Cytological LN grade, NPI and NPI-C were found to have statistically significant correlation with microscopic NA involvement. On the other hand, four parameters: patient's age, tumor location (Quadrant of breast involved), histological tumor type and presence or absence of metastatic LN involvement was found to have no statistically significant correlation with cancerous NA involvement. [Table 3]

Following multivariate analysis, only four parameters: macroscopic NA changes, macroscopic tumor - NA distance, lymph node grade and extra capsular extension in lymph node turned out to be statistically significant (P < 0.05). [Table 4] and were detected as the parameters which are independent indicators or predictors of cancerous NA involvement.

Overall, during univariate analysis, in 136 cases, mean tumor - NA distance was 1.516 cm ± 0.999 (S.D.) and it ranged from 0 cm. to 5.5cms. Mean tumor - NA distance in the NA involved and uninvolved groups were 0.327 cm ± 0.662 (S.D.) and 1.797 cms ± 0.848 (S.D.) with a mean difference of 1.47cm. The difference turned out to be highly significant statistically - P value = 0.001(<0.05). Based on the tumor - NA distance, the study population was divided into two categories - one with tumor NA distance < 1.5 cm and the other with the same ≥ 1.5 cm. Multivariate analysis was performed with this parameter arrived at during univariate analysis.

With the use of the multivariate Cox and Snell regression model developed in this study, 98.5% cases of nipple involvement can be predicted correctly with the use of variables listed in [Table 4]. The Cox and Snell regression Square was found to be 0.551. [Table 5]

Moreover, in the present study it was found that, cases with gross NA changes were more than 58 times (OR= 58.33; 95% CI = 7.84 to 1204.24) more likely to have NA involvement by the malignant process; cases with macroscopic tumor-NA distance < 1.5 cm. were about 26 times more at risk for malignant involvement of the NA (OR= 25.71; 95% CI = 5.42 to 167.11) and presence of ECE in LN made the cases 13 times (OR=13.09; 95% CI = 4.2 to 42.12) more likely to have NA involvement by the malignant process.


   Discussion Top


The frequency of occurrence of malignant involvement of the NA observed in this present study (19.1%) closely corroborated with the observations of several previous studies by Lambert et al,[6] McCarty et al.[11] Vyas et al,[12] Crowe et al,[13] Smith et al,[14] Simmons et al,[15] Quinn et al,[16] Parry et al,[17] Laronga et al,[18] and Enomoto et al.[19] The frequency of NA involvement, in few other studies was found to be considerably higher or lower than that observed in this study. In all these studies either the study population was too small (Menon et al.[20] - 33 cases; Andersen et al.[21] - 40 cases; Suehiro et al.[22] - 65 cases; Cucin et al.[23] - 50 cases; Verma et al.[24] - 26 cases); the mean age was too high (Andersen et al.[21] - 61 years); majority of the cases studied were high risk on screening (Cucin et al.[23] - 46% patients were high risk); all the cases studied had tumors > 4 cms from the NA (Verma et al[24] : 0% frequency reported) or presence of tumor even at 1 cm distance from the NA was also reported as NA positivity (Menon et al.[20] - 58% reported frequency). The observations regarding existence of correlation, in this study, after univariate and multivariate analysis are individually in agreement with one or several of the previously published studies.

The findings of the present study regarding macroscopic NA changes and its correlation with NA involvement are in absolute agreement with the observations reported by Parry et al.[17] Smith et al.[14] and Cucin and co-workers. [23] Parry et al.[17] even commented that clinically normal nipples are not likely to contain cancer. Millard et al.[25] commented that 90% or more of all breast cancers do not involve the nipple and if they do, this is evident clinically as well as pathologically.

The observations of the present study regarding correlation of macroscopic tumor-NA distance with NA involvement are in absolute agreement with the published observations of Vyas et al,[12] Suehiro et al,[22] Quinn et al,[16] Enomoto et al.[19] and Verma et al.[24] Vyas and co-workers [12] recommended that in cases where the tumor is over 2.5 cm from the areola, preserving the NA for reconstruction would be worthwhile; as this distance, in their study emerged as an independent risk factor and predictor for NA involvement.

In this study, 23 cases (16.9%) revealed microscopic ECE in one or more lymph nodes. Statistically significant correlation (P<0.05) was observed between NA involvement and presence of ECE in LN as well as number of lymph nodes with ECE. Fisher and colleagues reported statistically significant association of NA involvement with ECE in axillary LN metastases and ≥ 4 positive lymph nodes which is in absolute agreement with the findings of this study. [26] But in this study after multivariate analysis, however, only LN grade and not positivity or number of positive axillary lymph nodes was found to have statistical significance with a p value of 0.044 (< 0.05). Similar observations were reported by Lambert et al.[6] In their series also, LN status correlated with NA involvement in univariate analysis, but failed to show significant correlation in multivariate analysis.

The potential for spread and hence the natural course of a tumor depends on the interplay between the inherent malignant characteristics of the tumor cells and the host tumor immunity. Higher LN grade and presence of ECE in LN indicates a shift in this balance in favor of the malignant process and hence more aggressive spread of the tumor. These parameters may be more informative in this regard than the unilateral tumor characteristics only. Correlations with clinical involvement of the NA and proximity of the tumor to the NA were found in this study due to obvious reasons.

Even after extensive search, no contemporary study was found, which aimed at ascertaining the correlation between LN grade and NA involvement. As mentioned earlier, no previous study was also found which aimed at ascertaining the correlations of cytological parameters with NA involvement; but, the observations in this study stand evidence to the fact that cytological grade can act as a significant predictor of malignant involvement of the NA.


   Conclusion Top


Using the multivariate Cox and Snell regression model (Cox and Snell regression square = 0.551) developed in this study, the accurate preoperative prediction of malignant involvement of the NA would be possible in 98.5% cases of malignant breast tumors. Moreover, it would be technically simple and easy to perform. The only invasive procedure needed to be performed is a fine needle aspiration of the axillary lymph node or axillary lymph node dissection. Along with that, a thorough clinical examination and a preoperative high-resolution ultrasonogram of the primary breast tumor should suffice.


   Recommendations Top


In order to improve both the objectivity as well as reproducibility of cytological and histological grading of the primary tumor as well as those of the lymph nodes, automated or morphometric analysis of the respective specimens may be employed.

Multi-centric studies involving a larger population should be undertaken with similar aims and objectives as that of the present study for validation of the conclusions reached in this study. Prospective, multi-centric and long-term follow-up studies should be undertaken involving the cases in which NA-sparing mastectomy is performed following use of this multivariate model, to establish the oncological safety and viability of the whole process.

 
   References Top

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2.Greenway RM. Fifteen year series of skin-sparing mastectomy for stage 0 to 2 breast cancer. Am J Surg 2005;190:918-22.  Back to cited text no. 2      
3.Margulies AG, Hochberg J, Kepple J, Henry-Tillman RS, Westbrook K, Klimberg VS. Total skin-sparing mastectomy without preservation of the nipple-areola complex. Am J Surg 2005;190:907-12.   Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Petit JY, Veronesi U, Luini A, Orecchia R, Rey PC, Martella S, et al. When mastectomy becomes inevitable: The nipple-sparing approach. Breast 2005;14:527-31.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Rashid M, Ilahi I, ur Rehman Sarwar S, ul Haq E, Aslam R, Islam ZU, et al. Skin sparing mastectomy and immediate breast reconstruction. J Coll Physicians Surg Pak 2005;15:467-71.  Back to cited text no. 5  [PUBMED]    
6.Lambert PA, Kolm P, Perry RR. Parameters that predict nipple involvement in breast cancer. J Am Coll Surg 1996;191:44-50.  Back to cited text no. 6      
7.Ohri A, Jetly D, Shukla K, Bansal R. Cytological grading of breast neoplasia and its correlation with histological grading. Indian J Pathol Microbiol 2006;49:208-13.  Back to cited text no. 7  [PUBMED]    
8.Wood WC, Muss HB, Solin LJ, Olapade OI. Malignant Tumors of the Breast. In: De Vita Jr. VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. p. 1415-77.   Back to cited text no. 8      
9.Elston CW, Ellis IO, Goulding H, Pinder SE. Role of pathology in the prognosis and management of breast cancer. In: Elston CW, Ellis IO, editors. The Breast, Systemic Pathology, Volume 13. 3 rd ed. London: Churchill Livingstone; 1999. p. 385-433.   Back to cited text no. 9      
10.Haybittle JL, Blamey RW, Elston CW, Johnson J, Doyle PJ, Campbell FC, et al. A prognostic index in primary breast cancer. Br J Cancer 1982;45:361-6.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.McCarty KS, Kesterson GH, Barton TK, Seigler HF, Georgiade NG. Selection of patients for heterotopic implantation of the areola and nipple. Surg Gynecol Obstet 1980;150:545-7.  Back to cited text no. 11      
12.Vyas JJ, Chinoy RF, Vaidya JS. Prediction of nipple and areola involvement in breast cancer. Eur J Surg Oncol 1998;24:15-6.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Crowe JP Jr, Kim JA, Yetman R, Banbury J, Patrick RJ, Baynes D. Nipple-sparing mastectomy: technique and results of 54 procedures. Arch Surg 2004;139:148-50.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Smith J, Payne WS, Carney JA. Involvement of the nipple and areola in carcinoma of the breast. Surg Gynecol Obstet 1976;143:546-8.  Back to cited text no. 14  [PUBMED]    
15.Simmons RM, Brennan M, Christos P, King V, Osborne M. Analysis of Nipple/Areolar involvement With Mastectomy: Can the Areola be preserved? Ann Surg Oncol 2002;9:165-8.  Back to cited text no. 15  [PUBMED]    
16.Quinn RH, Barlow JF. Involvement of the nipple and areola by carcinoma of the breast. Arch Surg 1981;116:148-50.  Back to cited text no. 16      
17.Parry RG, Cochran TC Jr, Wolfort FG. When is there nipple involvement in carcinoma of the breast? Plast Reconstr Surg 1977;59:535-7.  Back to cited text no. 17  [PUBMED]    
18.Laronga C, Kemp B, Johnston D, Robb GL, Singletary SE. The incidence of occult nipple-areola complex involvement in breast cancer patients receiving skin-sparing mastectomy. Ann Surg Oncol 1999;6:609-13.  Back to cited text no. 18  [PUBMED]    
19.Enomoto K. Breast preserving surgery. Gan To Kagaku Ryoho 1990;17:732-6.  Back to cited text no. 19  [PUBMED]    
20.Menon RS, van Geel AN. Cancer of the breast with nipple involvement. Br J Cancer 1989;59:81-4.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
21.Andersen JA, Pallesen RM. Spread to the nipple and areola in carcinoma of the breast. Ann Surg 1979;189:367-72.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]  
22.Suehiro S, Inai K, Tokuoka S, Hamada Y, Toi M, Niimoto M, et al. Involvement of the nipple in early carcinoma of the breast. Surg Gynecol Obstet 1989;168:244-8.  Back to cited text no. 22  [PUBMED]    
23.Cucin RL, Guthrie RH, Luterman A, Gray G, Goulian D. Screening the nipple for involvement in breast cancer. Ann Plast Surg 1980;5:477-9.  Back to cited text no. 23      
24.Verma GR, Kumar A, Joshi K. Nipple involvement in peripheral breast carcinoma: a prospective study. Indian J Cancer 1997;34:1-5.  Back to cited text no. 24  [PUBMED]    
25.Millard DR Jr, Devine J Jr, Warren WD. Breast reconstruction: a plea for saving the uninvolved nipple. Am J Surg 1971;122:763-4.  Back to cited text no. 25  [PUBMED]    
26.Fisher ER, Gregorio RM, Redmond C, Kim WS, Fisher B. Pathologic findings from the national surgical adjuvant breast project. (protocol no. 4). III. The significance of extranodal extension of axillary metastases. Am J Clin Pathol 1976;65:439-44.  Back to cited text no. 26      

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Correspondence Address:
Kalyan Khan
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DOI: 10.4103/0377-4929.64329

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    Figures

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    Tables

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

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