Primary Mucinous Cystadenocarcinoma of the Breast: Clinicopathological Analysis of a Case and Difficulties Encountered in a Biopsy

Abstract

Background. With <40 case reports published in the English literature, mucinous cystadenocarcinoma of the breast is quite rare compared to its counterparts in the ovary, pancreas, and appendix. The purpose of this case report is to enrich scientific data by sharing the clinicopathological features of this new and extremely rare entity and present possible difficulties encountered in the biopsy materials. Case Report. A 34-year-old female patient presented with the complaint of white discharge from her left nipple lasting 8 months. Physical and radiological examination of the patient revealed a mass in the lower quadrant of the left breast and tru-cut biopsy was performed. The diagnosis of invasive breast carcinoma of no special type was reported. After neoadjuvant chemotherapy, left subcutaneous mastectomy and left sentinel lymph node biopsy were performed. Microscopic evaluation of the mastectomy material revealed a tumor consisting of stratified columnar cells with basally located nuclei and intracytoplasmic mucin, showing papillary structures and tufting toward the lumen. Peripheral myoepithelial cells were not identified with p63 and calponin immunohistochemistry. The diagnosis of mucinous cystadenocarcinoma was given through histomorphological and immunohistochemical evaluations. Conclusion. Clarifying unknown points about this rare malignancy of the breast and understanding the tumor biology is possible through evaluation of case reports. For this purpose, our case of primary mucinous cystadenocarcinoma is presented and its clinicopathological features are briefly discussed.

Introduction

Primary mucinous cystadenocarcinoma of the breast was first described by Koenig and Tavassoli in 1998 and is included in the latest edition of the World Health Organization Classification of The Breast Tumors published in 2019.^1,2 As of June 2023, with <40 case reports published in the English literature, mucinous cystadenocarcinoma of the breast is considered a rare tumor compared to its counterparts in the ovary, pancreas, and appendix. ³

Mucinous cystadenocarcinoma has different histomorphological characteristics than mucinous carcinoma, although it is included in the differential diagnosis. The presence of cystic spaces lined with tall stratified columnar cells, papillary structures, and tufting are characteristics of mucinous cystadenocarcinoma, though extracytoplasmic mucin can be encountered in these tumors.^1,4

When a tumor histologically compatible with mucinous cystadenocarcinoma is detected in the breast, the most important thing to consider before diagnosing primary mucinous cystadenocarcinoma is to rule out metastasis. Therefore, the clinic and radiological features and the immunohistochemical studies need to be evaluated in detail.^1,5 The aim of this case report is to enrich scientific data by sharing clinicopathological features of this new, extremely rare entity and present possible difficulties encountered in the biopsy materials.

Case Report

A 34-year-old female patient presented with the complaint of white discharge from her left nipple lasting 8 months. Upon physical examination, a palpable mass was detected in the lower quadrant of the left breast, located approximately 4 cm away from the nipple and measuring about 3 cm in diameter. Radiological imaging was planned for further evaluation. Bilateral contrast-enhanced magnetic resonance imaging (MRI) and breast ultrasonography revealed a dense fluid collection with lobulated contours of 16.5 × 7.5 mm in size, in the left breast outer quadrant at 5 o'clock, located 2 cm away from the nipple and an inflamed heterogeneous parenchymal area of 23.5 × 10 mm with no clear borders, located 4 cm away from the nipple. Additionally, an atypical lymph node measuring 28.5 × 14.5 mm with a cortex thickness of 7.5 mm and a discernible fatty hilum was detected in the left axilla. The radiological evaluation was considered compatible with an abscess. Cytological evaluation of nipple discharge, abscess drainage, and antibiotic therapy with tetracycline were planned. Patient's complaints regressed with antibiotic therapy and the cytological evaluation was compatible with an abscess. The patient was followed up.

During the follow-up period, the clear-white colored nipple discharge turned into bloody discharge, the size of the palpable mass increased and the lesion appeared to invade the breast skin. Subsequently, a tru-cut biopsy was planned. The microscopic evaluation revealed a well-circumscribed lesion with peripheral myoepithelial cells staining positively with p63 and calponin. The lesion consisted of stratified columnar cells with intracytoplasmic mucin and basally located nuclei and showed papillary structures and tufting toward the lumen. Additionally, an area of invasive tumor with focal intracytoplasmic mucin that did not reveal tubular formation was seen (Figure 1). The tumor was evaluated as invasive breast carcinoma of no special type and was compatible with a triple-negative immunohistochemical group. A broad immunohistochemical panel was performed to determine the origin of the tumor, as the histomorphological features did not resemble those of classical invasive breast carcinoma and as papillary growth pattern and cytological atypia were prominent in the metastatic tumor in the axilla (Figure 2). A possible pancreaticobiliary and ovarian metastasis was tried to be excluded. Tumor showed keratin 7 and mammaglobin positivity while estrogen receptor (ER), progesterone receptor (PR), keratin 20, CDX2, WT1, and PAX8 were negative.

Figure 1.

Tru-cut biopsy material of the left breast. Well-defined lesions consisting of stratified columnar cells with basally located nuclei and intracytoplasmic mucin, showing papillary structures and tufting toward the lumen were observed (A, ×40, B, ×100, C and D, ×400). Nuclear p63 positivity in myoepithelial cells (E, ×100), and cytoplasmic calponin positivity in myoepithelial cells were seen (F, ×200).

Figure 2.

Tru-cut biopsy material of the left axillary lymph node. A tumoral lesion showing a papillary growth pattern and a cell with marked cytological atypia was seen. (A, ×200, B, ×400), Keratin 7 positivity in tumor cells (C, ×200), negative keratin 20 (D, ×200), negative WT1 (E, ×200), and negative CDX2 were seen (F, ×200).

As a result, neoadjuvant chemotherapy (doxorubicin [120 mg] and cyclophosphamide [120 mg]) was started. After chemotherapy, a left subcutaneous mastectomy and left sentinel lymph node biopsy were performed. In the macroscopic evaluation of the mastectomy material, a palpable gray-white discoloration area with a diameter of 4.5 × 2.5 cm was noticed. Anteromedially located in this area, a 4.2 × 3 cm cystic lesion including a brown mucous fluid and a smooth inner surface was observed.

Microscopic evaluation of the mastectomy material revealed a tumor consisting of stratified columnar cells with basally located nuclei and intracytoplasmic mucin, showing papillary structures and tufting toward the lumen. The tumor showed no peripheral myoepithelial cells with p63 and calponin immunohistochemistry (Figure 3A–C and E). In addition, carcinoma in situ around the tumor, constituting more than 25% of the tumor area, with histomorphological features similar to the tumor, and with peripheral myoepithelial cells expressing p63 and calponin, was observed. Besides the aforementioned invasive tumor, there were also numerous foci of invasive tumor, the largest accounting for 0.4 × 0.3 cm in diameter. These tumor foci did not show tubule formation, contained intracytoplasmic mucin, and had significant cytological atypia (Figure 3D). Immunohistochemical studies showed keratin 7 positivity, while ERBB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, also known as HER2), ER, PR, keratin 20, CDX2, WT1, PAX8, and keratin 5/6 staining was not observed. P53 staining was strong at 90% of the tumor and the ki-67 proliferation index was 20% (Figure 4). In the macroscopic evaluation of the left sentinel lymph node biopsy, 2 lymph nodes were dissected. Gross metastatic carcinoma was detected in one of the lymph nodes and isolated tumor cells were observed in the other. The lymph node containing gross metastasis was 2.1 cm in diameter and was completely infiltrated with a tumor (Figure 5). The patient was diagnosed with mucinous cystadenocarcinoma through histomorphological and immunohistochemical evaluations. A possible metastasis in the patient was pathologically excluded by immunohistochemical studies. However, the patient was further evaluated clinically and positron emission tomography/computed tomography (PET/CT) was performed. PET/CT showed increased metabolic activity at the degree of malignancy in the left breast and left axilla and moderately increased metabolic activity in the liver and skeletal system. No focus on metabolic hyperactivity was detected in any other localization. During the follow-up, a hereditary cancer panel was performed. No pathogenic variant was detected, but copy number variance (CNV) analysis in the PIK3CA gene revealed 3 copies in the PIK3CA_ex6 region with medium confidence, and multiplex ligation-based probe amplification was recommended. In addition, a disease-causing mutation in the ATM gene, c.2494C > T (p.Arg832Cys) heterozygous variant (NM_000051.3) has been identified in HGMD Professional 2022.1 and has been associated with clinical breast cancer (CM1620446).

Figure 3.

Left subcutaneous mastectomy material. Next to the normal breast parenchyma, a tumoral lesion was observed, consisting of large cystic spaces with tufting and papillary structures, and lined with columnar cells with basally located nuclei and intracytoplasmic mucin (A and B, ×40, C, ×100, E, ×200). Invasive tumor foci that did not form tubules contained intracytoplasmic mucin and had significant cytological atypia observed (D, ×400).

Figure 4.

Hematoxylin–eosin and immunohistochemical staining of 2 different tumors in the left subcutaneous mastectomy material. Hematoxylin–eosin of the invasive tumor area in which immunohistochemical studies were performed (A and F, ×200), negative keratin 20 (B and G, ×200), negative CDX2 (C and H ×200), Calponin negativity in invasive tumor foci (D, ×200), p63 negativity in invasive tumor foci (E, ×200).

Figure 5.

Left sentinel lymph node biopsy material. Findings consistent with metastatic carcinoma were observed in the biopsy material (A and B, ×200).

The patient has been followed up for 6 months and is alive and well.

Discussion

Breast cancer is the second most common malignancy in the world and consists of a heterogeneous group of tumors that have different biological and clinicopathological features as well as different clinical courses. These heterogeneous groups of tumors include frequently seen tumors such as invasive breast carcinoma of no special type, as well as very rare tumors such as mucinous cystadenocarcinoma. ¹ Mucinous cystadenocarcinoma generally presents in middle-old aged patients, such as 41–96 years of age. All cases reported in the English literature are female.^5,6 Our patient is a 34-year-old woman, which is lower than the age range in the available reported cases.

Clinical presentation is usually with the complaint of a palpable mass. It may be accompanied by complaints such as ulcers on the breast skin, skin retraction, and nipple discharge. The average size of a mass is 3 cm, but tumors ranging from 0.8 to 19 cm in size have been reported.^7,8 The maximum diameter of our patient's primary tumor is 8.7 cm, which is within the reported range.

Mucinous cystadenocarcinoma usually presents as a well-circumscribed multilobular mass with medium–high density on mammography, an isoechoic–hypoechoic well-defined mass on ultrasonography and as a well-circumscribed solid-cystic lesion on MRI. It is possible that lesions, especially those consisting of cystic and solid components, can be radiologically confused with papillary neoplasms. ⁹

Grossly, the tumor is usually well-circumscribed containing multiple cysts filled with gelatinous material. It is not possible to distinguish the tumor from mucinous carcinoma with the gross findings. ⁷ Histologically, it presents as a well-circumscribed tumor including stratified columnar cells with intracytoplasmic mucin and basally located nuclei, showing tufting and papillary structures towards the lumen and having no peripheral myoepithelial cells. Mucinous cystadenocarcinoma may be in pure form, or it may be accompanied by ductal carcinoma in situ, invasive ductal carcinoma, or invasive pleomorphic lobular carcinoma. Additionally, tumors containing a metaplastic component, such as squamous cell carcinoma or high-grade sarcoma, have also been reported.^8,10 Evaluation of a limited tumor area in biopsy materials can cause difficulty in achieving an accurate diagnosis, especially for rare tumors such as mucinous cystadenocarcinoma. Especially in the case of a nonpure form mucinous cystadenocarcinoma, taking a biopsy specimen from an area that does not represent mucinous cystadenocarcinoma may pose a problem. Lack of clinical and radiological findings may also lead to an incorrect or incomplete diagnosis. This may be caused by the patient herself, the lack of communication between the clinician and the pathologist, or by the malignancies whose first clinical presentation is metastasis to the breast. It is possible to prevent misdiagnosis with a complete and detailed clinicoradiological examination as well as a detailed histopathological and immunohistochemical evaluation. ¹¹

Mucinous cystadenocarcinoma is usually ER, PR, and ERBB2 negative with immunohistochemical studies, but a rare ER and PR positive case is reported. In some tumors, keratin 5/6, epidermal growth factor receptor, and p53 immunoexpression can be seen. These features distinguish mucinous cystadenocarcinoma from mucinous carcinomas. Differentiation from a possible ovarian or pancreatic metastasis is achievable when tumor cells show positive staining with keratin7, GATA3, gross cystic disease fluid protein-15, and mammaglobin, and do not stain with keratin 20, CDX2, WT1, Villin, or PAX8. The ki-67 proliferation index is generally high, ranging between 20.5% and 90%. When neoplasia with mucinous features is encountered, especially in small biopsy samples, a panel consisting of the aforementioned immunohistochemical studies will facilitate correct diagnosis.^1,7,12 Our case had a triple-negative immune profile. P53 positivity was detected at a rate of 90% and the ki-67 proliferation index was 20%.

Mucinous cystadenocarcinomas have a good prognosis despite a triple-negative immune profile, which is generally considered a poor prognostic indicator. Death related to disease has not been reported yet. However, local recurrence and distant metastasis have been reported in 1 case. Metastasis to axillary lymph nodes is rare, but a case with more than 3 metastatic lymph nodes has not been reported.^3,6,13,14 Evaluation of the axillary lymph nodes may pose a problem, especially in cases in which tru-cut biopsy is performed. This may be due to a biopsy sample containing a small or limited tumor area, or due to fragmented tissue depending on the way it is embedded in the block or the way the biopsy was taken. Fragmented biopsy materials may also suggest a possible contamination. In such instances, it would be appropriate to evaluate the material with consecutive sections as well as with immunohistochemical studies. In our case, metastasis in one of the ipsilateral axillary lymph nodes was seen.

Our knowledge about the genetic or molecular alterations occurring in mucinous cystadenocarcinomas is quite limited. Recurrent mutations in PIK3CA, KRAS, MAP2K4, RB1, KDR, PKHD1, TERT, and TP53 were identified in 2 cases with reported gene analyses. ¹⁵ The hereditary cancer panel of our case revealed no pathogenic variant but, CNV analysis in the PIK3CA gene showed 3 copy reads in the PIK3CA_ex6 region with medium-confidence levels and a c.2494C > T (p.Arg832Cys) heterozygous variant in the ATM gene. Clarifying the unknown points about this rare breast tumor and understanding the tumor biology is possible through evaluation of case reports. For this purpose, our case of primary mucinous cystadenocarcinoma is presented and its clinicopathological features are briefly discussed with data from the literature.