Key Points
• Few studies suggested that mucinous breast carcinoma is a rare breast carcinoma with good prognostic factors. Therefore, in this study, biologic features and clinicopathological characteristics of pure mucinous breast carcinoma were investigated to determine its clinical outcome.
Introduction
Mucinous breast carcinoma (MBC) is relatively uncommon subtype of breast cancer, representing about 2% of all invasive breast cancers (1). In general, MBC presents at a mean age of 65 years, with 1% incidence in women under the age of 35 years. MBC patients are generally diagnosed through physical examination or mammography (2). MBC is characterized with the presence of tumor cells floating in extracellular mucin pools. Based on mucin contents, MBC is further divided into pure and mixed subgroups. Pure mucinous breast carcinoma (PMBC) contains a higher content of mucin than mixed mucinous breast carcinoma (MMBC). In this study, we considered tumors with more than 90% mucin content to be PMBC and less than 90% mucin contents to be MMBC (3). MBC patients have some features that differ from those of patients with invasive ductal carcinoma not otherwise specified. MBC has a lower incidence of nodal involvement, favorable histological grade (HG) and higher estrogen receptor (ER) and progesterone receptor (PR) expression (4). Breast carcinoma is a heterogeneous tumor with many clinical features that could be prognostic factors for patients. Despite the good prognosis of MBC, its clinical, histological, immunohistochemical characteristics and prognostic factors are still debatable. The purpose of this study was to report the last 18-year experience of the Department of Breast Surgery of the Istanbul Faculty of Medicine of Istanbul University regarding MBC with its histological and immune-histochemical characteristics and patient outcomes.
Materials and Methods
This study was based on an analysis of a large mono-institutional series of breast cancer patients treated in a high-volume reference center with widely standardized treatment and management. A multidisciplinary team had discussed each case individually after surgery, and all decisions about adjuvant treatment were made at these meetings.
Patient Selection and Follow-up
The study population was constituted at the Department of General Surgery, Breast Surgery Unit, and consisted of 87 female patients who had undergone surgical operations in the General Surgery Department. In addition, the PMBC diagnosis was assumed retrospectively. From the prospectively collected data between November 2004 and February 2022, we analyzed patients’ demographics and pathologic features.
All cases’ histological types were strictly controlled, and cases other than PMBC were excluded. Clinical and pathological factors, such as tumor size, surgical procedure, presence of loco-regional recurrence or distant metastasis, pathological characteristics, nodal staging, adjuvant treatment, and survival were analyzed. Personal contact with patients, including routine correspondence and telephone calls, was used to follow the patients. Follow-ups were performed at Istanbul University’s Department of General Surgery, Breast Surgery Unit, every three months for the first two years, every six months for the next two years, and once a year after that. Patients were treated with either mastectomy or lumpectomy and axillary lymph node dissection (ALND) or sentinel lymph node biopsy (SLNB) with local radiotherapy. After completion of the surgery, adjuvant treatments were administered as indicated based on international guidelines.
SLNB Method
Intraoperative visual blue dye (isosulfan blue) detection procedure was used. A frozen section procedure was employed, so if neoplasia was detected in the lymph node, a further lymph node dissection was performed. ALND was defined as a dissection of at least anatomical levels I and II including at least ten nodes, as shown in Figure 1.
The pathological tumor stage was assessed according to the American Joint Committee on Cancer’s 7th Staging System. PMBC was defined as having a mucinous component more than 90% and specialized pathologists with extensive experience in breast pathology performed a pathologic slide review. As recently revised (5, 6), the intrinsic subtypes of the tumor were defined as follows: luminal A, ER(+) or PR(+), human epidermal growth factor receptor 2 (HER2)-neu (-), Ki67 20%; luminal B, ER(+) or PR(-/+), HER2-neu (-/+), Ki67 >20%; HER2-enriched, ER(-) PR(-) HER2-neu (+); triple-negative, ER(-) PR(-).
Statistical Analysis
For statistical analysis, the Statistical Package for the Social Sciences (SPSS), version 25.0, was used (IBM Corp., Armonk, NY, USA). The data obtained from each continuous variable were analyzed using various descriptive, graphical, and statistical methods to determine whether or not they were normally distributed. In addition to descriptive statistical methods (number, percentage, mean, median, standard deviation, etc.), quantitative data was compared using the independent sample t-test. For qualitative comparisons between groups, the chi-square test (Pearson chi-square, continuity correction, Fisher’s Exact test) was used. The significance of the results was determined using a 95% confidence interval.
Results
Patients and Tumors Characteristics
The patients were all female, with a median (range) age of 63 (28–90) years. The median tumor size was 23 (5–100) mm. Out of 87 patients, 60 (69%) had breast-conserving surgery (BCS), while 27 (31%) had mastectomy (Table 1). Only 15 of the patients with axillary staging had lymph node metastasis, 11 of which were N1 and four of which were N2.
As can be seen in Table 1, 58 patients (66.7%) had SLNB, and 24 had axillary dissection due to positive SLNB or positive clinical axilla. Only two of the 15 patients who had a positive SLNB and underwent axillary dissection had non-sentinel positivity. Due to age and comorbidities, five patients were not suitable for axillary surgery.
From all the tumors that were included in this study, 11 (12.6%) had lympho-vascular invasion (LVI), whereas 37 tumors (42.5%) were HG 1, 45 tumors (51.7%) were HG 2, and only 5 tumors (5.7%) were HG 3. Necrosis was seen in only six (6.9%) of the patients. Almost all patients were in the luminal group (95.4%).
Only five patients (5.7%) had HER2-neu positive tumors, while 83 tumors (95.4%) were ER-positive and 77 tumors (88.5%) were PR-positive. The majority of patients with Ki67 index (n = 56) had a Ki67 score less than 20% (71.4%).
Adjuvant Systemic Therapy
Adjuvant chemotherapy was given to only 23 patients (26.4%). With the exception of four patients, all patients had hormone therapy since their tumors were ER negative.
Outcome Analysis
The median follow-up time was 53 (6–207) months. None of the patients had a local or systemic recurrence. Only 10 out of 87 patients (11.5%) died during the follow-up and treatment period due to non-cancer causes.
As shown in Table 2, in this study we found that tumor diameter and LVI were statistically significantly higher in grade II/III tumors (p = 0.039 and p = 0.021, respectively). Also, we found that necrosis was only seen in grade II/III tumors (p = 0.036). Additionally, tumor diameter was larger (p = 0.027) and lymph node metastasis was more likely (p = 0.013) in patients younger than 50 years. Moreover, HER2 positivity was statistically significantly more common in patients younger than 50 years (p = 0.026). In a similar way, Ki67 less than 20% was statistically significant in grade I tumors and in patients older than 50 (p = 0.006 and p = 0.033, respectively). Furthermore, patients who had not received chemo/radiotherapy were older than 50 years (p = 0.002).
Radiological Investigation Results
Our radiological investigations were the same as reported in previous studies. Mammographically, PMBC tends to present as a well-circumscribed lesion (7, 8, 9), which is echogenic to the breast fat on ultrasonography (10). Thus, a significant number of lesions could be misinterpreted as benign on screening mammograms (10, 11).
Interestingly, a delay in the diagnosis may not cause a significant adverse outcome for most women (2). On magnetic resonance imaging, PMBC is associated with a very specific appearance, showing a gradually enhancing contrast pattern with rim or heterogeneous enhancement and a very high signal intensity on T2-weighted images (12, 13), as we show in Figure 2.
Discussion and Conclusion
Mucinous carcinoma is a rare type of cancer that can arise in mucin-producing epithelial tissues. MBC is rarely seen in clinical practice, comprising approximately 2% of all invasive breast cancers (1). In the literature, Di Saverio et al. (14) and Vo et al. (15) presented multivariate analysis results. These studies indicate that independent factors such as age, tumor size, lymph node status, and ER status are associated with a particularly good prognosis in MBC patients. PMBC is a cancer of older women, with only 1% of PMBC patients being under the age of 35 years (2, 16). The median age of the patients included in this study was 63, which is similar to a study done by Zhou et al. (17).
Previous studies have shown that sentinel lymph node metastasis is the most important prognostic factor for disease-free survival (1, 18, 19). In this study, a small number of patients (15/87) had lymph node metastasis, and a favorable prognosis was noted for patients who had no metastasis to lymph nodes. Compared to the other studies, nodal positivity was detected in 17.2% of our study patients whereas in other series, this percentage ranged from 2% to 20% (17, 18, 19, 20). Only two of the 15 patients (2/15; 13.3%) who had a positive SLNB and underwent axillary dissection had non-sentinel positivity. According to the findings of the ACOSOG Z0011 study, axillary curettage would be unnecessary for patients with sentinel lymph node positivity in the pure mucinous carcinoma patient group (21).
We found that tumor diameter in PMBC was significantly larger in grade II/III tumors and in patients under the age of 50, which was consistent with the findings of Tahmasebi et al. (22). In a group of 111 patients with MBC, Diab et al. (23) observed a correlation between the size of the primary tumors and the status of the lymph nodes. When the tumor size was less than 2 cm, metastasis to lymph nodes was not indicated in 90% of the patients, which is in agreement with our study results of 83%. Another study by Skotnicki et al. compared the clinical characteristics and treatment results of 70 patients with PMBC and 40 patients with MMBC, treated at a single institution for 25 years. Their results demonstrated that the only difference between PMBC and MMBC was nodal status, as MMBC showed a significantly higher incidence of axillary nodal metastasis compared to PMBC (25% versus 10%) (17).
Furthermore, a recent study found that PMBC and MMBC were clinicopathologically distinct in terms of gross findings and lymph node status. The average length of follow-up was 24.5 months. MMBCs were highly proliferative, with more complications compared to PMBC. Lymph node involvement is the most important prognostic factor, and it is independent of other prognostic factors, such as tumor size, patient age, and hormonal receptor status (24). According to our findings, lymph node involvement, mean tumor diameter, high Ki67 expression, and HER2 positivity were all significantly increased in the group under 50 years old. These findings are consistent with the earlier reports of young-age aggressive tumor structure. However, no local, regional, or systemic recurrence was found in this study. This could be explained by the distinctive structure of mucinous carcinomas.
The PMBC data shows a high percentage of hormone receptor expression. These findings are consistent with Saverio’s findings from large data, which reported a rate of positivity of 94% for ER and 81% for PR (14). A high rate of hormone receptor expression and old age were associated with a favorable prognosis in patients. Patients over the age of 50 did not receive chemo/radiotherapy, which explains their high sensitivity to hormone therapy and lack of lymph node metastasis.
Compared to other breast carcinoma forms, mucinous carcinoma has less genetic instability (25). Several studies have shown that PMBC has clinicopathological heterogeneity (26), but 95.4% of patients in this study were in the luminal subgroups. We couldn’t classify luminal subgroups because we didn’t have the values for Ki67 expression for all patients. Moreover, it is genetically heterogeneous and lacks any sort of pathognomonic genetic alterations (26, 27). Further clinical trials with larger sample sizes, as well as molecular and genetic studies, need to be conducted to get a better understanding of the molecular biology and clinical outcomes of PMBC.
In conclusion, MBC is a rare type of breast cancer with a favorable prognosis. Patients with MBC have a low rate of lymph node metastasis and almost all patients are in the luminal subgroups. PMBC has a lower incidence, smaller tumor size, benign lesion-like characteristics, low axillary lymph node metastasis, low grade, low recurrence rate, and a higher survival rate. We believe that minimal axillary surgery would be the most appropriate approach during patient treatment due to the low rate of lymph node involvement and favorable prognosis in PMBC patients.
Acknowledgement
The authors would like to express their heartfelt gratitude to Mr. Atilla Bozdogan for conducting the statistical analysis for this study.
Ethics Committee Approval: This study was based on an analysis of a large mono-institutional series of breast cancer patients treated in a high-volume reference center with widely standardized treatment and management.
Informed Consent: Retrospective study.
Peer-review: Externally and internally peer-reviewed.
Authorship Contributions
Concept: S.E., N.C., E.O.; Design: S.E., S.K., N.C., E.O., M.M.; Data Collection and/or Processing: S.E., M.T., S.O., M.M.; Analysis and/ or Interpretation: S.E., M.T., S.K., H.K., S.O., V.O., N.C., E.O., R.Y., M.M.; Literature Searching: S.E.; Writing: S.E., M.T., S.K.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declare that this study received no financial disclosure.