A retrospective review with long term follow up of 11,400 cases of pure mucinous breast carcinoma
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- Di Saverio, S., Gutierrez, J. & Avisar, E. Breast Cancer Res Treat (2008) 111: 541. doi:10.1007/s10549-007-9809-z
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Background Pure mucinous breast carcinoma (PMBC) is a rare histologic type of mammary neoplasm. It has been associated with a better short-term prognosis than infiltrating ductal carcinoma (IDC) but identical long-term survival curves have been reported. The value of tumor size for TNM staging has been challenged because of the mucin content of the lesions. This study presents a large PMBC series with 20 years follow up as compared to IDC. The relative significance of a variety of common prognostic factors is calculated for this uncommon histology. Materials and methods A retrospective analysis of all PMBC cases reported in the SEER database between 1973 and 2002 was conducted. Overall survival (OS) and disease specific survival (DSS) were calculated at 5, 10, 15 and 20 years of follow up. Those curves were compared with all the IDC cases reported into the database during the same period. The prognostic significance of gender, race, laterality, age at diagnosis, T and N status, estrogen and progesterone receptors and administration of radiation therapy was calculated by univariate and multivariate analysis. Results There were 11,422 PMBC patients reported. The median age at diagnosis was 71 years (Range 25–85). Fifty three percent of the tumors were well differentiated, 38% were moderately differentiated and the remaining 9% were poorly differentiated or anaplastic. The majority of the tumors were located in the upper outer quadrant (44%) the other 56% were roughly evenly divided between the upper inner, lower inner, lower outer and central quadrants. Eighty six percent of the patients had only localized disease at the time of surgery without nodal or distant disease while 12% had regional nodal involvement and 2% had distant metastases. The PMBC cases showed a better differentiation with lesions of lesser grade and more frequent ER/PR expression, smaller size and lesser nodal involvement when compared to the IDC cases of the same period. Kaplan Meier survival curves revealed a 5 years. breast cancer specific survival rate of 94%. Although slowly decreasing with time, 10, 15 and 20 years survival were 89%, 85% and 81% respectively compared to 82% (5 year), 72% (10 year), 66% (15 year) and 62% (20 year) for IDC. There were no significant differences in overall survival. Multivariate analysis by Cox regression revealed the nodal status (N) to be the most significant prognostic factor followed by age, tumor size (T), progesterone receptors and nuclear grade. Disease specific survival curves stratified for nodal status revealed a highly significant difference between node negative and node positive patients. The addition of radiation therapy after surgery did not significantly improve overall survival. Conclusions This large retrospective comparative analysis confirms the less aggressive behavior of PMBC compared to IDC. This favorable outcome is maintained after 20 years. This tumor presents typically in older patients and is rarely associated with nodal disease. Positive Nodal status appears to be the most significant predictor of worse prognosis.
KeywordsBreast neoplasmsPure mucinous breast carcinomaInfiltrating ductal carcinomaLymph node statusRisk factorsPrognosis
Background and aims
Pure mucinous breast carcinoma (PMBC) is a rare histologic type of mammary neoplasm, representing 1–4% of all breast cancers and associated with a better prognosis than infiltrative ductal carcinoma (IDC) [1–3]. In the elderly, a slightly higher incidence rate of 6–7% was reported . PMBC has to be distinct from the histologically mixed forms of ductal carcinoma with a mucinous component (occurring in 2% of cases) because those tumors carry a prognosis identical to the non-mucinous component [3, 5]. The classification of the mucinous histology and the distinction between the two subgroups of pure and mixed mucinous carcinomas is based upon the quantification of cellularity , mucinous neoplasms being defined as having a mucinous component of more than 50% of the lesion. The “pure” type consists exclusively of tumor tissue with extracellular mucin production, while the “mixed” form of mucinous carcinoma also contains infiltrating ductal epithelial component without mucin . A precisely defined percentage of mucinous component for the classification and distinction of pure and mixed lesions is however not yet clearly established. [8–10]. Although, the pure mucinous subtype has been associated with a better short term prognosis than IDC , long term survival curves have been reported as identical, noting a worsening of prognosis after longer follow up  . PMBC tends to grow very slowly but can reach large diameters at diagnosis  . Those lesions are frequently associated with estrogen receptors positivity  and despite large tumor sizes, the axillary lymph nodes are rarely involved [3, 10, 16] [17, 18] accounting for the better biological behavior. Axillary nodal involvement, although rare, seems to affect and worsen the prognosis [19, 20].
Because of its relative rarity, most reported PMBC series have a low number of patients and a limited long term follow up. The significance and prognostic value of the clinico-pathological factors commonly used for IDC is also not well established and therefore the best treatment guidelines for optimal local regional and systemic control of this neoplasm are mostly extrapolated from the treatment of IDC without clear validation in a PMBC series of patients.
The objective of this study was to evaluate the long term disease specific and overall survival as well as the significance of the available clinical and pathological prognostic factors for PMBC in a large and robust database. The retrospective analysis also included a comparison between PMBC and IDC recorded in the SEER database in the same period as well as a comparative evaluation of their demographic, clinical and pathological features and the outcomes in terms of Disease Specific and Overall survival.
Patients and methods
A retrospective comparative analysis of all PMBC and IDC cases reported in the SEER database between 1973 and 2002 was conducted. The SEER (Surveillance Epidemiology and End Results) is a cancer registry held by the cancer statistics branch of the surveillance program promoted by the National Cancer Institute. It is an authoritative source of information on cancer incidence and survival in the Unites States. SEER collects and publishes cancer incidence and survival data from population-based cancer registries covering approximately 26% of the US population. The population covered by SEER is epidemiologically comparable and representative of the US population. The SEER database includes and records all the tumor cases from 18 cancer registries from several states and is considered the standard for quality among cancer registries around the world. It began collecting data on cancer cases in 1973 and recorded several demographics, clinical and pathological variables as well as follow up and survival data . Overall survival (OS) and disease specific survival (DSS) were calculated at 5, 10, 15 and 20 years of follow up. Those curves were compared with the 338,479 IDC cases reported into the database during the same period. The prognostic significance of gender, race, laterality, age at diagnosis, T and N status, nuclear grade, estrogen and progesteron receptors and administration of radiation therapy was calculated by univariate and multivariate analysis.
The statistical analysis has been carried out using a statistical software package (SPSS 13.0 SPSS Inc. Chicago. IL). The association between the discrete variables were evaluated by χ2 or Fisher exact test as appropriate. For means in case of continuous numerical data, we used the independent samples t-test and the Mann–Whitney test, respectively for data normally and non-normally distributed. The data was previously tested for normality by the Kolmogorov–Smirnov test. A statistical analysis of the breast cancer-specific survival and overall survival for each group (obtained by Kaplan–Meier curves for univariate analysis and Cox logistic regression for multivariate analysis) was conducted. The comparison for statistically significant differences between survival curves was performed by the log rank test (Mantel Cox). Statistical significance was considered to be reached at a level of P < 0.05.
Clinico-pathologic features of 11,422 PMBC patients (SEER database 1973–2002) and comparison with 338,479 IDC patients (SEER database 1973–2002)
T size (mm)
Prognostic significance of 10 clinico-pathological factors and influence on survival
Covariates (Ca = Categorical; Co = Continous; D = Dichotomous)
Multivariate analysis Cox regression of survival
Age at diagnosis (Co)
T size (Co)
N pathological status (D)
Nuclear grade (Ca)
ER status (Ca)
PR status (Ca)
Adjuvant radiotherapy (D)
The pure histotype of mucinous breast carcinoma is rare. The few and small series described in the literature indicate an indolent biological behavior and a better long-term prognosis than Invasive Ductal Carcinoma [3, 6, 10, 12, 13, 18, 19, 22]. Recently Fujii et al. investigated the genomic features of PMBC and demonstrated that it does not have the extensive genomic alterations typically found in the more common variants of breast cancer. Moreover mucinous carcinoma has less genetic instability than the other forms of breast cancer and its molecular pathogenesis seems substantially different compared to the usual breast carcinoma . Other studies carried out histochemical and immunohistochemical examinations of mucin revealing that the mucinous growth and the pure type of mucinous carcinoma may originate from intraductal carcinoma . Mammographically PMBC tends to present as a well circumscribed lesion [25–27], isoechogenic to the breast fat on ultrasonography . For that reason a significant number of lesions could be misinterpreted as benign on screening mammograms. Interestingly, a delay in diagnosis however may not cause a significant adverse outcome for most women . A careful diagnostic investigation of the radiological characteristics may be helpful in the identification of PMBC. On Magnetic Resonance Imaging, PMBC is associated with a very specific appearance showing a gradually enhancing contrast pattern and a very high signal intensity on T2-weighted images [30, 31]. Although fine needle aspiration cytology (FNA) can diagnose mucinous carcinoma and can demonstrate nicely the mucin component, the sensitivity of FNA is 56%  while the histology from core biopsy achieved 100% sensitivity and accuracy [33, 34].
Pure Mucinous Breast Carcinoma is a disease of older women and only 1% of PMBC patients are younger than 35 years [4, 12]. Our series confirms this finding demonstrating significantly older age at diagnosis for PMBC compared to IDC.
Our large series of PMBC from SEER demonstrates a high percentage of hormone receptor expression, indicating a better differentiation than the ductal lesions. Those findings are in agreement with Komenaka's findings reporting a rate of positivity of 91% and 79% for estrogen and progesteron receptors respectively .
Although the size of PMBC lesions at diagnosis varies widely and has been described from non-palpable lesions to as large as 20 cm [18, 35–40], the median size of PMBC lesions in our study was significantly smaller than IDC lesions. A potential explanation could be the relatively slow growth of PMBC usually allowing diagnosis at a smaller size.
The prognostic significance of tumor size is an especially interesting point with PMBC. Komenaka et al. did not find size to be a significant prognostic factor in their series suggesting that because the majority of the tumor volume consists of mucin it may not impact survival . In our multivariate analysis of a large number of PMBC, tumor size was an independent prognostic indicator but it was less significant than nodal status and age. Although some authors found that the incidence of node positivity was directly related to tumor size , other studies did not find any correlation between tumor size and the incidence of axillary nodal metastases [17, 42]. In this study we did find a significant correlation between tumor size and incidence of nodal involvement in PMBC.
Nodal positivity is rare and was detected in 12% of the patients in our review. The same percentage was noticed by Avisar et al. , with the rate being 14% in the series from Komenaka et al., and ranging from 2% to 14% in other series [5, 9, 10, 28, 43] compared to 46% to 64% for mixed mucinous lesions [3, 5, 43].
Previous studies have shown the nodal status to be the strongest predictor of disease-specific survival [1, 18, 35] and the majority of patients presenting with axillary metastases proceeded to develop distant metastases . Our multivariate analysis confirms those findings and supports the important prognostic value of sentinel node biopsy in those patients despite the relatively low rate of nodal involvement.
Finally the prognosis of PMBC and the overall and disease specific survival are very favorable. Previous series have suggested that the observed favorable five years survival is temporary and that PMBC tends to recur after 10 years similarly to IDC . Komenaka et al. reported disease-specific survival rates of 95% and 79% respectively at 5 and 10 years . Our study clearly shows that the DSS is significantly higher for PMBC compared to IDC and that survival advantage is maintained after 20 years.
Diab et al. demonstrated a significantly better disease-free survival for the mucinous lesions versus the NOS carcinomas even in the subset of node negativity . Also Thurman et al.  compared ductal NOS carcinomas, tubular and mucinous carcinomas and confirmed a better prognosis, lesser nodal involvement and wider Estrogen and Progesteron receptors expression associated with the mucinous lesions. This series confirms a highly statistically significant DSS advantage for PMBC compared to IDC for localized, regional and even for metastatic disease claiming for a truly better tumor biology.
This large retrospective comparative analysis confirms the less aggressive behavior of PMBC compared to IDC. This favorable outcome is maintained after 20 years. This tumor typically presents in older patients and is rarely associated with nodal disease. Positive Nodal status appears to be the most significant predictor of worse prognosis. An axillary staging by sentinel lymph node biopsy could guarantee a reliable staging of disease, identification of the more aggressive lesions and planning of further therapies.