Mucinous Micropapillary Carcinoma of Breast in a Developing World Setting: Case Series With Clinicopathological Insights and Survival Analysis From a Tertiary Care Hospital.

1. Introduction
Mucinous carcinoma (MC) of the breast is a rare subtype of breast cancer (BC), accounting for about 2% of all cases. It is classified as a special type with a predilection for older populations (> 55 years) and is generally associated with a favorable prognosis, low recurrence rates, and low incidence of lymph node (LN) metastasis [1].
World Health Organization (WHO) defines MC as an entity composed of small uniform clusters of tumor cells floating in large pools of extracellular mucin [2], (Figures 1 and 2). National Comprehensive Cancer Network (NCCN) also enlisted it among BC with favorable prognosis. The subsequent management and decision to administer chemotherapy varies with the diagnosis of pure mucinous carcinoma (PMC) [2].
At the other end of the spectrum is invasive micropapillary carcinoma (IMPC), which accounts for 1%–6% of BC and has a clinically aggressive course. It has strong predilection for lymphovascular invasion (LVI), LN metastasis and poorer outcomes [3]. Histologically, it is characterized by small, solid clusters of tumor cells arranged in a micropapillary, ring‐like structures (Figures 3 and 4), often highlighted by and better appreciated via immunohistochemistry (IHC) stain of epithelial membrane antigen (EMA) or Mucin‐1. It would show its characteristic inside–out pattern. Majority of this cohort of patients require aggressive management with the inclusion of chemotherapy [3].
Between these two extremes lies the much rarer “mucinous micropapillary carcinoma” (MMPC), which according to literature accounts for less than 1% of BC cases [4]. On gross examination, these tumors are lobulated with mucin evident on the cut section. Histologically, they combine features of MC and IMPC. These tumors show micropapillary clusters, hobnailing, occasional psammomatous calcifications, and characteristic reverse polarity in pools of extracellular mucin [5, 6] The nuclear grade of the tumor is usually intermediate to high [5, 6], (Figures 5 and 6). IHC is largely not required; however, EMA still can highlight the inside–out arrangement of tumor cell clusters (Figures 7 and 8).
The clinical–pathological features of this hybrid subtype are yet to be discovered. We have limited data, and studies show conflicting results. The majority of the literature favors MMPC, demonstrating at a younger age, higher nuclear grade, and increased propensity for LVI and LN metastasis (Figure 9). These features make the further management of patients with MMPC questionable; as to whether these patients need aggressive management or not [5–7].
Rarity of MMPC and uncertainty regarding its behavior and prognosis prompted us to study and assess its clinicopathological features presenting to our center. We are aimed at correlating tumor features with the clinical stage, overall survival (OS), and recurrence‐free survival (RFS). This will help us stratify MMPC patients at the time of initial diagnosis and address the disease more confidently.

2. Materials And Methods
Patients with histopathologically proven MMPC were identified from retrospectively maintained data of the histopathology section of the pathology department at our hospital from the last 6 years that is, Jan. 2017–Dec. 2022. Using ICD coding, MMPC cases were extracted from hospital records, and data were collected regarding age at diagnosis, tumor laterality, stage of BC at diagnosis, recurrence, and OS status from hospital records and the last visits of the patients reported in the system. The histopathological characteristics like tumor size, LVI, extranodal extension (ENE), LN metastasis, and tumor biology were also recorded for each patient. Standard surgical, chemotherapy, and radiation treatments were provided according to the institutional tumor stage and biology protocols. Quantitative age, tumor size, and OS variables are calculated as median with range (IQR), whereas qualitative variables are presented in percentages and frequencies. The research work has been reported in line with the PROCESS guidelines [8, 9].

3. Results
In the last 6 years, nine cases have been reported to our center with biopsy‐proven MMPC. The median age of BC diagnosis in our patients was 49 years with an age range between 27–74 years (IQR: 24 years). According to laterality, cancers were reported more on the right breast 5/9 (55.56%) than on the left side 4/9 (44.44%). At the time of diagnosis, 66.67% (6/9) of patients were diagnosed with Stage III, whereas 33.33% (3/9) were diagnosed with Stage II. Regarding histopathological features, the average reported tumor size in our cohort of cases was 4.5 cm with a range of 2.5–7 cm (I
Q
R = 2.9 c
m). The majority of tumors were Grade II, 77.78% (7/9) at the time of diagnosis; followed by Grade III, 22.22% (2/9). LVI was seen in 6/9 (66.67%) patients and ENE was appreciated in 3/9 that is, 33.33% of patients. LN metastases were present in 6/9 (66.67%), with an average of four nodes identified. The maximum number of positive LNs seen was 17 in a patient. Regarding tumor biology, 77.78% of MMPC patients were estrogen receptor (ER) and progesterone receptor (PR) positive (7/9), whereas only one patient was Her 2 neu receptor positive (11.11%). At the median follow‐up period of 3.5 years (IQR: 42 months or 3.5 years), recurrence was reported in two patients (22.22%). Both patients were initially diagnosed at Stage III, and one had Her 2 Neu positive status along with ER/PR positivity. Therefore, the RFS reported in our cohort is 77.78% (7/9). The OS reported at the time of the last data entry is seven out of nine patients (77.78%). The two patients who did not survive experienced distant metastasis of the disease/recurrence.

4. Discussion
Due to the rarity of MMPC in our clinical practice, that is around 0.1%–0.3% of total BC cases, we have limited data and information regarding its behavior and clinicopathological features. There is a high chance of misclassification of MMPC, which has implications on prognosis and treatment strategies [10]. The identification of just nine cases over 6 years′ time of the study further emphasizes its rarity. Our study, which was aimed at understanding the biological behavior, found out that the MMPC has predilection for younger age group (median age: 49 years) [7, 10, 11] with a slight tendency towards right side, 55.56%. This was also predicted in another study which showed 56.2% of right sided disease [11].
At presentation, the majority of patients (66.7%) had Stage III disease, and the average tumor size was 4.5 cm, T3. Histopathologically, most tumors were Grade II (77.8%), with high rates of LVI (66.7%), ENE (33.3%), and LN metastases (66.7%). Despite these high‐risk features, the observed clinical outcomes were relatively favorable.
If we compare our results with other sources, a study mentioned the majority of their patients having Stage 2 disease (47%), followed by Stage 1 BC. The variation between our results (i.e., 66.7% of patients having Stage III disease) could be due to differences in geographical regions in which research was carried out. High‐income nations have better screening options for their population which helps in identifying BC at the initial stages [10]. Similarly, the majority of patients in our cohort were T3, to begin with, which is in contrast to another research which showed T2 being the dominant pattern [11]. This study also states comparable results with respect to tumor grade and LVI [11].
Presence of extensive LN metastasis in our cohort (66.67%) emphasizes its aggressive nature as compared with LN metastasis in PMCs [10–13]. Having said this, it is important to know that LN metastasis directly correlates with the tumor size, which was already high in our data probably due to the late presentation of our patients in general.
Studies have also looked into molecular profiling at the cytogenetic level. They have inferred the importance of PIK3CA, GATA3, TP53, SF3B1, mTOR, and ErbB mutations along with the interplay of 1q, 6p, 8q, 10q, 16q, 11q, and 13q at the genetic level. This makes us more certain that MMPC is an overlapping entity between PMC and IMPC [11, 12]. It tells us that perhaps this newly acknowledged group of tumors is heterogeneous at the molecular level and may not make up one morphological type, but rather a convergent phenotype. GATA3, TP53, and SF3B1 are repeatedly seen to be mutated in MMPCs. MMPCs also display 17q, 20q gains, and 17p losses [10].
The significance of high ki‐67 levels is also reported in many studies which helps us in understanding its aggressive nature. We were unable to study these parameters in our cohort due to institutional limitations [10, 11].
Talking about hormone status and Her 2 Neu expression in our study, our results were comparable with other studies showing ER/PR predominance among their patients [5, 11, 12]. Although one of our patients had Her 2 Neu amplification detected who also had disease recurrence as Stage IV, it coincides with the predicted bad prognosis among MMPC patients who overexpress Her 2 Neu gene [10, 12, 14].
The fact that MMPC were ER/PR positive and Her2 neu negative and still possessed aggressive clinical and pathological features can mainly be assigned to tumor biology that is, presence of micropapillary component, which is known to have aggressive nature. Other than this, late presentation, poor understanding and deficient breast screening program has also contributed to increased tumor size, LVI, LN metastasis, and ENE.
The OS and RFS reported in our cohort are 77.78%, respectively, with a median follow‐up period of 3.5 years. One study reported that MMPC is associated with decreased OS and RFS compared with PMC, whereas when compared with IMPC, it has better OS and RFS [15]. Another study reported a favorable prognosis when compared with its counterparts, so the literature is showing mixed results for MMPC [12, 13]. Therefore, experts suggest that while considering special tumor subtypes, clinicians should take other prognostic factors like T size, LN status, and tumor biology into account to stratify the patients and devise management plans [16].
Our study has several limitations that must be acknowledged. Firstly, the small sample size limits the generalizability of our findings and may not represent the broader population of patients with MMPC. Secondly, the retrospective nature of the study relies on existing medical records, which may be incomplete or subject to reporting bias. We were also unable to perform detailed molecular profiling or assess ki‐67 levels due to institutional limitations, which could have provided deeper insights into tumor biology and potential prognostic factors. Lastly, the variation in diagnostic stages and treatment protocols over the study period could introduce heterogeneity in patient outcomes, making it difficult to draw definitive conclusions. Future studies with larger cohorts and prospective designs are needed to validate our findings and explore the molecular characteristics of MMPC thoroughly.

5. Conclusion
Our study highlights the rarity and aggressive nature of MMPC, which presents at a younger median age of 49 years with advanced stage and larger tumor size. Histopathological features include high‐grade tumor, frequent LVI, significant LN metastasis, and ENE. Despite these aggressive characteristics, the OS and RFS rates were 77.78% over a median follow‐up of 3.5 years.
These findings emphasize the need for early detection and tailored management strategies for MMPC. Future research with larger cohorts is necessary to validate our results and further understand MMPC′s molecular characteristics. In the developing world, enhancing BC awareness and screening programs is crucial to improve early diagnosis and outcomes for patients with this rare subtype.

Nomenclature
MMPCmucinous micropapillary carcinoma breast
BCbreast cancer
OSoverall survival
RFSrecurrence‐free survival
LVIlymphovascular invasion
ENEextranodal extension
LNlymph node
ERestrogen receptor
PRprogesterone receptor
NCCNNational Comprehensive Cancer Network
PMCpure mucinous carcinoma
IMPCinvasive micropapillary carcinoma
IHCimmunohistochemistry
EMAepithelial membrane antigen

Funding
No funding was received for this manuscript.

Ethics Statement
The authors have nothing to report.

Consent
Written informed consent was obtained from the patient for publication of this case series.

Conflicts of Interest
The authors declare no conflicts of interest.