Rare hepatic metastasis in classical adenoid cystic carcinoma of the breast: A case report

Introduction

Adenoid cystic carcinoma (ACC) of the breast (ACCB) is a rare subtype of triple-negative breast cancer (TNBC), with an incidence of ~0.92 per million individuals (1) and accounting for 0.06–0.1% of all breast cancers (2). Although the exact risk factors for ACCB remain unclear due to its rarity, the disease predominantly affects postmenopausal women, with rare cases reported in men, suggesting that age and hormonal status may play a role (3,4). While genetic alterations such as MYB-NFIB fusions have been implicated in ACC at other sites, their etiological significance in ACCB remains to be determined (5). ACCB shares histological features with ACC of the salivary glands and other sites (6), but differs from other TNBC subtypes (7). Typically, ACCB is localized and indolent, with minimal metastasis to axillary lymph nodes or distant organs (8,9). The prognosis of ACCB is generally favorable, with a 5-year overall survival (OS) rate of 98–100% and a 10-year OS rate of 85–100% (10). However, there is no standardized treatment for ACCB, and surgery remains the primary treatment strategy, followed by adjuvant radiotherapy (11). There is no consensus regarding the need for adjuvant chemotherapy. Therefore, understanding the unique biological behavior of ACCB and obtaining an accurate pathological diagnosis are crucial for proper clinical management and to avoid overtreatment. The present report describes a rare case of hepatic metastasis from classical ACCB.

Case report

A 70-year-old female patient was admitted to Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University (Zhuzhou, China) in March 2024, with a 1-month history of right upper abdominal pain.

In February 2016, the patient underwent a lumpectomy for a palpable mass located in the upper outer quadrant of the right breast. Intraoperative frozen section analysis revealed invasive carcinoma, and a modified radical mastectomy was subsequently performed. Postoperative routine pathology was performed. The tissue samples were fixed using 10% neutral buffered formalin at room temperature (20–25°C) for 24 h and then cut at a thickness of 4 μm. Hematoxylin and eosin staining was performed for 3 min and then the sections were examined using an Olympus BX53 optical microscope. The results indicated a classic cribriform architecture composed of dual-layered epithelial and myoepithelial cells, with outer basaloid cells surrounding pseudolumina filled with eosinophilic basement membrane-like material (Fig. 1A). Among the 12 axillary lymph nodes dissected, one was found to contain metastasis. The tumor measured 1.2×0.8×1.6 cm. For immunihistochemical analysis, paraffin-embedded tissues were fixed in 10% neutral buffered formalin at room temperature for 8 h before sectioning to 4 µm. Ready-to-use primary antibody (anti-ER, cat. no. 790-4325; anti-PR, cat. no. 790-4296; anti-HER-2, cat. no. 790-4493; all Roche Diagnostics GmbH; anti-E-cadherin, cat. no. ZM-0092; anti-p63, cat. no. ZM-0406; all Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.; anti-CD117, cat. no. kit-0029; Fuzhou Maixin Biotechnology Development Co., Ltd.) was incubated with the sections at 37°C for 1 h. DAB staining solution (Polymer method; Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) was then added to the sections at room temperature for 20 min. Hematoxylin counterstaining was applied at room temperature for 3 min and then the sections were examined using an Olympus BX53 optical microscope. The immunohistochemical results were as follows: Estrogen receptor (ER), negative (Fig. S1B); progesterone receptor (PR), negative (Fig. S1C); human epidermal growth factor receptor 2 (HER-2), score 0 (Fig. S1D); CD117, positive (Fig. 1B); p63, positive (Fig. 1C); and E-cadherin, positive (Fig. S1E). Based on histomorphological characteristics and the immunophenotype, the pathological diagnosis was grade II ACCB (12,13).

Figure 1. Histopathological features of the breast lesion and liver metastasis. (A) Hematoxylin and eosin staining shows classic cribriform architecture composed of dual-layered epithelial and myoepithelial cells, with outer basaloid cells surrounding pseudolumina filled with eosinophilic basement membrane-like material (original magnification, ×200). (B) CD117-positive (magnification, ×200). (C) p63-positive (magnification, ×200). (D) Hematoxylin and eosin staining reveals a small number of cord-like epithelial cell nests with relatively uniform size, arranged in glandular and nested patterns (original magnification, ×100). (E) CD117-positive (magnification, ×100). (F) p63-positive (magnification, ×100). (G) Progesterone receptor-weakly positive (~1%; magnification, ×400). (H) Estrogen receptor-negative (magnification, ×400). (I) Human epidermal growth factor receptor 2-negative (magnification, ×400).

Postoperatively, the patient received chemotherapy consisting of three cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2), followed sequentially by three cycles of docetaxel (100 mg/m2). All drugs were administered via intravenous infusion, with each cycle lasting 21 days. Additionally, the patient received 25 sessions of local radiotherapy.

In 2019, the patient underwent a thyroid fine-needle aspiration biopsy, which was classified as Bethesda category VI (14). Total thyroidectomy was performed at Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, during which enlarged lymph nodes were observed anterior to the cervical trachea (maximum diameter, ~1.5 cm), and in the left cervical levels II, III, IV and V (maximum diameter, ~2.0 cm). After communication with the family of the patient, a total thyroidectomy and left cervical lymph node dissection were performed. Postoperative pathology, performed as aforementioned, indicated papillary thyroid carcinoma near the left isthmus, measuring 0.8×0.5×0.2 cm, with no evidence of metastasis in the dissected lymph nodes (Fig. S1A). The patient did not receive postoperative chemotherapy or radiotherapy.

The patient underwent routine chest imaging follow-up postoperatively, with the most recent CT scan in October 2020 showing no obvious abnormalities. However, no abdominal imaging had been performed until March 2024, when the patient experienced abdominal pain, and abdominal CT revealed multiple low-density lesions in the liver, with certain lesions demonstrating indistinct margins and central non-enhancing necrotic areas (Fig. 2A). These findings were suggestive of metastatic malignancy. A liver biopsy was performed, revealing a small number of cord-like epithelial nests in fibrous tissue, composed of uniform-sized cells with glandular and nested growth patterns, which was suggestive of malignancy (Fig. 1D). For immunohistochemical analysis, paraffin-embedded tissues were fixed in 10% neutral buffered formalin at room temperature for 8 h before sectioning to 4 µm. The sections were permeabilized with 0.1% Triton X-100 at room temperature for 10 min and blocked with 5% bovine serum albumin in PBS at room temperature for 30 min. Ready-to-use primary antibody (Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) was incubated with the sections at 37°C for 1 h. DAB chromogen solution (Polymer-based method; Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.) with HRP conjugate was applied to the sections at room temperature for 20 min. Hematoxylin counterstaining was performed at room temperature for 3 min, and the sections were then examined using an Olympus BX53 optical microscope. Immunohistochemical analysis revealed the following results: CD117, partially positive (Fig. 1E); p63, positive (Fig. 1F); PR, ~1%, weakly positive (Fig. 1G); ER, negative (Fig. 1H); HER-2, score 0 to negative (Fig. 1I); E-cadherin, positive (Fig. S1I); hepatocyte, negative (Fig. S1F); cytokeratin 19 (CK19), negative (Fig. S1G); thyroglobulin, negative (Fig. S1H); and thyroid transcription factor-1 (TTF-1), negative (Fig. S1J). Based on the clinical history, morphology and immunophenotype, the clinicopathological diagnosis was hepatic metastasis of ACCB.

Figure 2. Abdominal CT imaging of the liver. (A) March 2024: Multiple low-density hepatic lesions detected, with certain lesions demonstrating poorly defined borders and internal low-density non-enhancing necrotic areas. (B) May 2024: After two cycles of salvage adjuvant chemotherapy, the treatment response was evaluated as partial remission. (C) July 2024: After five cycles of salvage adjuvant chemotherapy, partial remission was maintained. (D) October 2024: Following six completed cycles of adjuvant chemotherapy and no additional treatment, the response remained partial remission.

After a multidisciplinary discussion, an advanced breast cancer salvage treatment plan was developed. The patient began adjuvant chemotherapy in March 2024, consisting of intravenous albumin-bound paclitaxel (150 mg/m2) and oral capecitabine (1,000 mg/m2), administered in 21-day cycles for a total of six cycles. Following two cycles of chemotherapy, the patient experienced a reduction in right upper abdominal pain, with noticeable improvement compared with before treatment, although the symptom did not completely resolve. The patient returned regularly for subsequent cycles of chemotherapy, completing a total of six cycles by July 2024. Abdominal CT performed after the second (Fig. 2B) and fifth (Fig. 2C) chemotherapy cycles indicated partial remission. Moreover, follow-up CT in October 2024 (Fig. 2D), indicated slight shrinkage of the liver metastases. The general condition of the patient remained stable, and the quality of life of the patient was satisfactory, with ongoing follow-up. Follow-up included abdominal CT scans every 3 months to monitor hepatic metastasis and detect any new lesions. Mammography and chest CT were performed every 3 months to assess for locoregional recurrence, metastasis and pulmonary involvement. Liver function tests, complete blood counts and tumor marker analysis (such as analysis of carcinoembryonic antigen and CA15-3) were conducted every 3 months. Physical examinations and symptom assessments were performed to evaluate the patient's general condition, pain, fatigue or any new symptoms. Quality of life assessments included patient-reported outcomes regarding physical function, psychological state and social participation.

Discussion

ACC is most commonly found in the salivary glands and is rare in the breast (1). The reported rates of lymph node metastasis for ACCB are <2%, and the distant metastasis rate is 2.2% (6). The most common site for distant metastasis is the lung (6). According to the 2020 World Health Organization classification, ACCB is categorized into classic, solid and high-grade transformation types. Among these, the classic type is the most common, with the most favorable biological behavior and a low rate of metastasis. The solid and high-grade transformation types are more prone to local recurrence and distant metastasis. Pathological grading of ACCB is based on the cellular architecture and the proportion of solid components: Tumors composed almost entirely of cribriform and/or tubular structures with no solid areas are classified as grade I; those primarily cribriform and/or tubular with ≤30% solid components are classified as grade II; and those with >30% solid components, notable cytological atypia and increased mitotic activity are classified as grade III. The higher the proportion of solid components, the worse the prognosis (12,13). The present case report describes a rare instance of distant metastasis in classical grade II ACCB. The patient had undergone radical surgery, followed by adjuvant chemotherapy and radiotherapy, but later developed hepatic metastasis.

ACCB has a complex pathological structure. Fine-needle aspiration biopsy is associated with a high risk of missed or incorrect diagnosis. Around half of ACCB cases are misdiagnosed as other breast diseases (15). Clinical and imaging findings are often insufficient for definitive diagnosis, and histopathological examination combined with immunohistochemistry remains the gold standard for diagnosis. ACCB is mainly composed of epithelial, myoepithelial and basaloid cells. Co-expression of CD117 (c-kit) in luminal epithelial cells and p63 in myoepithelial/basaloid cells is recognized as the immunophenotypic hallmark of ACCB (1,16). In a study by Mastropasqua et al (17), CD117 and p63 were positive in 95 and 85% of ACCB cases, respectively, but not in common cribriform or tubular breast carcinomas. In the present case, the breast lesion exhibited typical cribriform architecture composed of dual-layered epithelial and myoepithelial cells, with outer basaloid cells surrounding pseudolumina filled with eosinophilic basement membrane-like material. The immunophenotype was triple-negative, with positive CD117 and p63 staining, supporting the diagnosis of ACCB. Moreover, a liver mass was detected 8 years after breast surgery. Liver biopsy revealed small cord-like epithelial nests with uniform cells exhibiting glandular and nested growth. Negative hepatocyte and CK19 staining ruled out primary liver cancer, and negative thyroglobulin and TTF-1 staining excluded thyroid cancer. Based on the clinical history, morphology and immunophenotype, the diagnosis was hepatic metastasis from ACCB.

ACCB is a unique form of TNBC. Surgery combined with adjuvant chemotherapy is typically recommended for most patients with TNBC; however, this approach may not be suitable for ACCB. Moreover, to date, there is no consensus on the treatment of ACCB (7). A previous study suggested that breast-conserving surgery is the preferred treatment, with adjuvant radiotherapy recommended after the surgery (18). Macias et al (6) performed a systematic review of 4,370 ACCB cases, and surgery was the primary treatment in 3,984 patients, underscoring the importance of surgical management. Surgical options for ACCB include both breast-conserving surgery and radical surgery (19). In a retrospective analysis of 583 patients with early-stage ACCB, Huang et al (20) reported that breast-conserving surgery resulted in improved 10-year OS and disease-specific survival rates compared with modified radical mastectomy. Furthermore, a recent study reported that breast-conserving surgery combined with radiotherapy is the main treatment modality for ACCB (21). Sun et al (11) also reported that adjuvant radiotherapy could improve the 5-year cancer-specific survival rate of patients with ACCB by 4.3%.

The role of adjuvant chemotherapy remains unclear, and its benefit in terms of survival has not been well established (7). Certain clinicians treat ACCB as TNBC, predominantly using chemotherapy (6). Yang et al (22) reported that patients with ACCB did not benefit from adjuvant chemotherapy. Moreover, Li et al (7) reported that adjuvant chemotherapy did not improve the survival of patients with ACCB, even in subgroups at high risk for recurrence and metastasis. Due to the absence of hormone receptor (HR) and HER-2 expression, ACCB is insensitive to endocrine and targeted therapies (23). Certain studies have reported HR-positive ACCB; however, the clinical features and prognosis of this subtype are still unclear compared with those of HR-negative ACCB (1,6). Wenig and Birhiray (24) described cases of ACCB with isocitrate dehydrogenase [NADP(+)] 2 and fibroblast growth factor receptor 2 mutations, which responded to targeted therapies with enasidenib and erdafitinib, suggesting the importance of genetic testing for rare malignancies. Additionally, Massé et al (25) identified NOTCH as a potential therapeutic target in 30% of solid-type ACCB cases.

In the present case, the patient underwent radical surgery rather than breast-conserving surgery, followed by chemotherapy and radiotherapy. The chemotherapy regimen, which was three cycles of fluorouracil, epirubicin and cyclophosphamide, followed by three cycles of docetaxel, was consistent with recommended protocols for TNBC (26). Despite the generally good prognosis of ACCB, the rare occurrence of distant metastasis in the current case highlights the potential overtreatment associated with radical surgery and adjuvant chemotherapy in ACCB. Currently, treatment strategies for ACCB vary widely in clinical practice due to the lack of specific guidelines. Therefore, further studies with larger sample sizes and longer follow-up are required to elucidate the optimal treatment approach for ACCB.

In summary, ACCB is a rare TNBC subtype with distinct clinical and pathological characteristics. The prognosis of ACCB is generally favorable, and breast-conserving surgery combined with radiotherapy may be the ideal treatment option. The efficacy of chemotherapy requires further evaluation. Therefore, differentiating ACCB from other TNBC subtypes is crucial to avoid unnecessary treatments, such as radical surgery and overtreatment with chemotherapy.

Supplementary Material

Supporting Data

Acknowledgements

Not applicable.

Funding

The present study was supported by the Youth Project of Hunan Natural Science Foundation (grant no. 2024JJ7654).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

XH, YO, LT and WZ collected the clinical, imaging and pathological data of the patient, and wrote the manuscript. MT and TW conceived and designed the study, and revised the manuscript. MT and TW confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent was obtained from the patient for publication of the images and data.

Competing interests

The authors declare that they have no competing interests.

References