Mucinous Breast Carcinoma

Etiology

The origin of mucinous breast cancer is multifactorial and involves diet, reproductive factors, and hormones.

Epidemiology

Mucinous breast carcinoma prevails in postmenopausal women with a median age of 70 years [3]. Pure mucinous carcinoma is rarely encountered in young patients under 35 (1%)[2]. 

Pathophysiology

Transcriptomic studies have demonstrated that mucinous tumors are of luminal A molecular subtype [4]. The transcriptomic features of mucinous A are distinct from those of mucinous B tumors, the latter showing a gene expression pattern similar to neuroendocrine carcinomas [4]. Pure mucinous carcinomas harbor a low level of genetic instability and rare recurrent amplifications, and the genomic profiles of the tumor components of mixed mucinous tumors are remarkably similar to those of pure mucinous carcinomas. More than 90% of pure mucinous carcinomas are diploid, whereas only 42% of mixed mucinous carcinomas are diploid [5].

Histopathology

Macroscopic findings:

A gross examination of mucinous carcinoma of the breast shows a glistening gelatinous lesion with pushing margins and a readily recognizable soft consistency. The tumors range from less than 1 cm to over 20 cm (mean = 3 cm).

Microscopic findings:

Histologically, mucinous carcinoma is characterized by nests of cells floating in lakes of mucin partitioned by delicate fibrous septae containing capillary blood vessels. The cell clusters are variable in shape and size with an occasional tubular arrangement. Nuclear atypia is generally low in classic mucinous carcinoma, but in rare cases, atypia and mitoses may prevail [6]. A micropapillary or cribriform intraepithelial component is rarely seen. Mucinous carcinoma presenting with large cell clusters, reported by Capella as hypercellular or type B mucinous carcinoma, shows frequent neuroendocrine differentiation [7]. Type A mucinous carcinoma with larger quantities of extracellular mucin represents the classic non-endocrine variety. Pure and mixed variants have been described [8]. The most common admixture is with invasive carcinoma of no special type. A pure tumor must be composed of more than 90% mucinous carcinoma [6]. The in situ component may have a papillary, micropapillary, or cribriform pattern. In some cases, the in situ carcinoma may exhibit prominent luminal mucin production. Neuroendocrine differentiation can sometimes be identified using immunohistochemistry and special stains (Grimelius). 

Immunohistochemistry:

Typically, mucinous carcinoma is positive for estrogen and progesterone receptors [9], while androgen receptors are expressed at a low level, and HER2 is not amplified [10]. Pure and mixed mucinous carcinomas are reported to express WT [11]. Mucinous breast carcinoma expresses predominantly MUC2 and MUC6 among the family of MUC genes [12].

History and Physical

Mucinous carcinoma usually grows slowly and can reach a large size during diagnosis. This can be explained by the fact that the mucinous content of the tumor does not feel firm or solid upon examination [13]. Most patients with mucinous breast carcinoma present with a palpable breast mass. Fixation to the skin or chest wall is rare but is reported in large lesions. With widespread screening, many patients are diagnosed because of a mammographic abnormality [14].

Evaluation

Mammography:

On mammography, circumscribed and lobulated breast lesions are common findings for a mucinous carcinoma. A circumscribed margin would favor the diagnosis of a pure mucinous carcinoma [15].

Ultrasonography:

On ultrasonography, mucinous carcinoma is usually a complex mass with cystic and solid components, including microlobulation, vascularity, and distal enhancement. The histologic subtype of mucinous carcinoma can be predicted based on echogenicity. Isoechoic masses are found in pure mucinous carcinoma, whereas hypoechoic masses are found in mixed mucinous carcinoma [16].

Magnetic resonance imaging:

On an MRI, mucinous carcinoma has a lobular shape, rim or heterogeneous enhancement, a persistent pattern on the time-intensity curve, and homogeneous strongly high signal intensity on T2-weighted images [17] [15]. 

Tissue biopsy:

Tissue biopsy is mandatory in the evaluation of mucinous breast carcinoma. Tissue specimens can be obtained by core biopsy, fine needle aspiration cytology, and incisional or excisional biopsy.

Treatment / Management

The treatment of mucinous breast carcinoma is based on surgery associated with post-operative hormone therapy in hormone-responsive (estrogen/progesterone) tumors. A recent study recommended axillary staging by sentinel lymph node biopsy and administration of adjuvant radiotherapy and hormone therapy after breast-conservation for mucinous carcinoma [9][18]. Since most mucinous carcinomas are negative for the protein HER2/neu, they are not treated with trastuzumab. Trastuzumab is approved for both the treatment of advanced breast cancer and as adjuvant therapy for early-stage HER2-positive tumors [19]. Some authors have stated that adjuvant chemotherapy can be omitted in cases with favorable risk factors [20].(B2)

Differential Diagnosis

Histological differential diagnosis:

• Mucocele-like-lesion
• Metastatic mucinous carcinoma

Radiological differential diagnosis:

• Myxomatous fibroadenoma

Treatment Planning

The following factors may impact treatment decisions:

• Tumor biology: Since mucinous carcinoma is more prevalent in the older population, estrogen and progesterone receptors are expressed more often than in younger women. Similarly, there are lower rates of HER-2 overexpression. This impacts the selection of appropriate therapy.
• General health status: A higher prevalence of comorbidity, frailty, and cognitive decline in elderly patients are considered limiting factors when selecting treatment.
• Functional status: This refers to the ability to perform routine daily tasks. Functional limitation is independently associated with worse life expectancy and hence determines the overall survival of the patients. Comprehensive Geriatric Assessment (GCA) can be utilized to evaluate elderly patients and optimize mucinous cancer treatment. 

Staging

Staging of mucinous breast carcinoma is determined clinically by physical examination and imaging studies. The stage is determined pathologically by histological examination of the tumor and lymph nodes after surgery. The TNM classification system is used to classify mucinous breast carcinoma based on:

• Primary tumor size (T)
• Regional lymph node status (N)
• Distant metastasis (M)

The system that is most recently used is that of the American Joint Committee on Cancer (8th edition).

Prognosis

Mucinous carcinoma has a favorable prognosis and infrequent lymphatic metastasis compared to invasive ductal carcinoma. Axillary lymph node metastases occur in 12%-14% of the cases [19]. Pure mucinous carcinoma has a better prognosis than mixed mucinous breast carcinoma [3]. The 5-year disease-free survival rates range from 81% to 94% (the latter if lymph nodes are negative). Late distant metastases may occur in pure mucinous carcinoma [21]. In a multivariate analysis of 11,422 patients with pure mucinous carcinoma, tumor size was found to be an independent prognostic indicator but less significant than nodal status [2]. Other studies have found that tumor size is not a significant prognostic factor and does not affect survival since most tumor volume consists of mucin[13].

Complications

Complications of breast mucinous carcinoma include:

• Axillary lymph node metastases
• Late distant metastases
• Recurrence after surgical excision