Multicomponent metaplastic breast cancer with four histological components: A case report

Abstract

BACKGROUND

Mixed metaplastic breast cancer (MMBC) is an extremely rare subtype of breast malignancy characterized by aggressive biological behavior and a poor prognosis. Most patients with MMBC exhibit a triple-negative immunophenotype (ER-, PR-, HER2-), rendering them unresponsive to conventional endocrine therapy. Currently, no mature and effective targeted therapeutic agents are available for MMBC, and a universally accepted standard adjuvant chemotherapy regimen has not been established worldwide. Pathologically, most MMBC lesions contain only two histological components, whereas cases involving three or more distinct tumor components are extremely rare and have seldom been reported. Given its low incidence, high malignancy, limited clinical data, and lack of standardized treatment guidelines, we report a rare case of metaplastic breast cancer with three invasive components plus associated ductal carcinoma in situ (DCIS) components were identified. The patient underwent modified radical mastectomy for breast cancer and received 8 cycles of sequential chemotherapy: Pirarubicin plus cyclophosphamide, followed by docetaxel plus cisplatin. Herein, we share the relevant data regarding the patient’s diagnosis, individualized treatment, and prognosis.

CASE SUMMARY

A 60-year-old postmenopausal woman presented in August 2024 with a painless left breast mass noticed 3 days previously, without other symptoms. Preoperative ultrasonography indicated a breast lesion highly suspicious for malignancy. She underwent segmental mastectomy, and intraoperative frozen-section analysis confirmed high-grade invasive carcinoma, followed by modified radical mastectomy. Permanent pathological examination confirmed high-grade mixed metaplastic breast carcinoma. All 23 dissected axillary lymph nodes were negative for metastasis (0/23). Immunohistochemical analysis revealed a triple-negative phenotype (ER-, PR-, HER2-) and a Ki-67 index of 60%. Genetic testing identified TP53 and AKT1 mutations; however, no actionable targeted therapeutic options were identified. The patient received 8 cycles of sequential chemotherapy with Pirarubicin plus cyclophosphamide followed by docetaxel plus cisplatin, and grade 2-3 chemotherapy-related adverse reactions were alleviated with symptomatic treatment. No local recurrence or distant metastasis was observed during the 20-month postoperative follow-up, and the patient remains under regular surveillance.

CONCLUSION

This rare case of MBC with three invasive components plus associated DCIS components components expands the limited clinical evidence available for multicomponent metaplastic breast carcinoma. It also provides valuable clinical insights into the diagnosis, individualized comprehensive treatment, and long-term prognostic assessment of this rare and aggressive malignancy.

Key Words: Breast; Metaplastic breast cancer; Multicomponent; Triple-negative breast cancer; Case report

Core Tip: Metaplastic breast cancer (MMBC) is a rare breast malignancy with poor prognosis and a lack of standardized treatment strategies. We report a rare case of MMBC with three invasive components plus associated ductal carcinoma in situ components, a presentation that is seldom encountered in clinical practice. The tumor exhibits a triple-negative phenotype, a high Ki-67 proliferation index, and TP53 and AKT1 gene mutations. The patient completed 8 cycles of sequential Pirarubicin plus cyclophosphamide followed by docetaxel plus cisplatin adjuvant chemotherapy, with manageable grade 2-3 adverse reactions. No local recurrence or distant metastasis was observed during the 20-month follow-up period. This case provides clinical evidence for diagnosis, individualized therapy, and prognostic evaluation of multicomponent MMBC.

INTRODUCTION

Cancer development is primarily driven by oncogenic somatic and/or germline alterations in oncogenes and tumor suppressor genes. Advances in oncology have led to a wide range of therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy. However, treatment strategies should be tailored to the cancer type, tumor stage, and individual patient characteristics[1]. Breast cancer is the most common malignancy among women worldwide, with invasive ductal carcinoma being the predominant histological subtype. Mixed metaplastic breast cancer (MMBC) is a rare and distinct subtype, accounting for only 0.08%-0.2% of all breast malignancies[2]. Histologically, MMBC generally consists of two distinct tumor components, whereas cases involving three or more components are rarely reported. In addition, MMBC frequently exhibits a triple-negative immunophenotype (ER-, PR-, HER2-). Currently, no effective targeted or endocrine therapies are available for MMBC, and no universally accepted standard chemotherapy regimen has been established. Given the rarity, aggressive biological behavior, poor prognosis, limited clinical data, and lack of standardized treatment guidelines for MMBC, we report a rare case of MMBC with three invasive components plus associated ductal carcinoma in situ (DCIS) components components. This case provides clinical insights into the diagnosis, individualized treatment, and prognostic assessment of this uncommon malignancy.

CASE PRESENTATION

Chief complaints

A 60-year-old postmenopausal woman presented with a painless lump in her left breast that had been present for 3 days.

History of present illness

The lump remained unchanged in size and shape during this period, and the patient reported no associated symptoms, including nipple discharge, skin changes, axillary discomfort, or systemic symptoms. She had received no prior treatment or intervention and was admitted to our hospital on August 1, 2024, for further evaluation and treatment.

History of past illness

She had a history of essential hypertension for 8 years, the patient takes amlodipine tablets regularly with well-controlled blood pressure. No long-term use of other medications. No family history of hereditary diseases. She had also undergone cholecystectomy for cholelithiasis 10 years earlier, with an uneventful recovery. She denied a history of diabetes mellitus or coronary heart disease, as well as any allergies to medications or contrast media, and any history of hormone replacement therapy. She underwent menopause at the age of 55 years and reported no history of menstrual abnormalities before menopause. Gravida 2, Para 2, breastfed, no history of breast disease, and no history of radiation exposure. The patient had no hereditary germline genetic testing considered or performed.

Personal and family history

The patient had no history of smoking or alcohol consumption. No history of hormone medication use, and no exposure to radiation. Her mother, sister, and daughter had no history of breast cancer.

Physical examination

The patient was in good general condition, with stable vital signs (temperature, 36.5 °C; pulse, 78 beats/minute; respiratory rate, 18 breaths/minute; blood pressure, 132/86 mmHg). No obvious abnormalities were noted on general physical examination. Breast examination revealed symmetrical breasts without nipple retraction, nipple discharge, or skin changes, including dimpling or an orange-peel appearance. A firm, irregular mass measuring 3.5 cm × 2.5 cm was palpable at the 2-3 o’clock position of the left breast. The mass had relatively well-defined borders, moderate mobility, and no tenderness. No palpable mass was detected in the right breast, and no enlarged axillary lymph nodes were palpable bilaterally. Other systemic examinations revealed no significant abnormalities.

Laboratory examinations

Routine blood tests, liver and renal function tests, electrolyte levels, coagulation parameters, and infectious disease screening results were all within normal limits. Breast cancer-related tumor markers, including carcinoembryonic antigen (1.8 ng/mL) and cancer antigen 15-3 (12.5 U/mL), were also within the normal ranges.

Imaging examinations

Breast ultrasonography performed on August 1, 2024, revealed a 3.0 cm × 3.0 cm hypoechoic mass in the upper outer quadrant of the left breast. The mass had an irregular shape, heterogeneous echogenicity, multiple microcalcifications, and moderate blood flow signals, with a resistance index of 0.72, and was classified as BI-RADS 5, indicating a high suspicion of malignancy. Mammography performed on August 2, 2024, showed a high-density nodule with clustered microcalcifications in the left breast (BI-RADS 5) and mild benign hyperplasia in the right breast (BI-RADS 2). Preoperative chest and abdominal computed tomography (CT) performed on August 2, 2024, revealed no evidence of distant metastasis in the chest, abdomen, and retroperitoneum. No enlarged axillary lymph nodes were identified bilaterally.

FINAL DIAGNOSIS

High grade mixed metaplastic carcinoma of the left breast (triple-negative, pT2N0M0), with an associated highgrade DCIS component (Figure 1); mammary hyperplasia of the right breast; and essential hypertension.

Figure 1 Tumor and histopathological features. A: Gross specimen obtained after segmental resection of the breast mass, showing the cut surface of the lesion after central incision; B: Histopathological features of mixed metaplastic breast cancer; C: Histopathological features of squamous cell carcinoma (× 100); D: Histopathological features of high-grade ductal carcinoma in situ (× 100); E: Histopathological features of invasive ductal carcinoma (× 100); F: Histopathological features of spindle cell carcinoma (× 100); G: Immunohistochemical staining showing negative expression of estrogen receptor in breast cancer tissue (× 200); H: Immunohistochemical staining showing negative HER2 expression in breast cancer tissue (× 200); I: Immunohistochemical staining showing negative PR expression in breast cancer tissue (× 200); J: Immunohistochemical staining showing positive CK5/6 expression in breast cancer tissue (× 20); K: Immunohistochemical staining revealed positive expression of P40 in breast cancer tissues (× 20); L: Immunohistochemical staining revealed positive expression of P63 in breast cancer tissues (× 20).

Pathological diagnosis and immunohistochemistry: Specimen type: Modified radical mastectomy specimen of the left breast specimen size: 20 cm × 16 cm × 7 cm. Tumor location: Approximately 3 cm from the nipple, upperouter quadrant. Tumor size: 3 cm × 2.5 cm. Tumor type (Figure 1A): Mixed metaplastic carcinoma invasive ductal carcinoma (Figure 1E) + spindlecell carcinoma (Figure 1F) + squamous cell carcinoma (Figure 1C), high-grade. Associated ductal carcinoma (Figure 1D) in situ: Present (high-grade) Invasive involvement: Infiltration into surrounding adipose tissue. Vascular tumor thrombus: Absent perineural invasion: Absent resection margin status: Negative margins at the nipple and basal resection margin. Lymph nodes: No metastatic carcinoma (0/23); resected axillary lymph nodes (0/20); no lymph nodes identified in the submitted “left subclavian lymph node” specimen; submitted “left axillary lymph nodes” (0/3). Pathological tumor stage (American Joint Committee on Cancer 8^th edition): PT2N0M0.

Immunohistochemistry: ER (-) (Figure 1G), PR (-) (Figure 1I), Her2 (-) (Figure 1H), ECadherin (+), P120 (membranous +), focal P40 (+) (Figure 1K), focal P63 (+) (Figure 1L), CK5/6 (+) (Figure 1J), GCDFP15 (-), Calponin (-), Ki67 (+): 60%.

Breast cancer 68-Gene Test Report Summary (FFPE tissue, Shanghai Daen Medical Technology Center). Note: This is a structured transcription of the test results, not clinical advice, and does not replace your attending physician’s interpretation. No germline testing was performed in this case, so somatic vs germline origin cannot be distinguished.

TP53: Variant details. Gene: TP53. Exon: Exon 5. Nucleotide change: C.A488G.

Protein change: P.Y163C (missense mutation). Pathogenicity interpretation. ClinVar classification: Pathogenic, gene type: Tumor suppressor gene. This missense mutation disrupts p53’s tumor-suppressive function. Loss of p53 impairs DNA damage repair, apoptosis, and cell-cycle surveillance, promoting tumor initiation and progression. It is a common somatic driver mutation in breast cancer. Evidence classification: Class II variant (level D evidence - clinical case-report level). AKT1. Variant 1: P.E17K (c.G49A, exon 4). Protein change: P.E17K, missense mutation. Variant allele frequency (VAF): 41.22%. ClinVar classification: Pathogenic. Pathway: Hotspot activating mutation in the PI3K-AKT-mTOR pathway core gene, leading to sustained AKT activation that drives tumor proliferation and survival. In HR-positive breast cancer, this mutation is often associated with resistance to endocrine therapy. Evidence classification: Class II variant (Level D evidence - clinical case-report level). Variant 2: P.E40Q (c.G118C). Protein change: P.E40Q, missense mutation. VAF: 46.59%. Classification: VUS (Variant of Uncertain Significance), Class III - current evidence is insufficient to determine whether it is harmful or benign; it should not be used to guide therapy. Key notes. This is a somatic (tissue/FFPE) test; no germline sequencing was performed, so it cannot determine whether these mutations are inherited germline alterations. The coexistence of a TP53 pathogenic mutation and the AKT1 p.E17K hotspot activating mutation indicates activation of the PI3K-AKT-mTOR pathway. Combined evaluation by a medical oncologist - integrating IHC results (ER/PR/HER2, Ki-67), staging, and prior treatment history - is needed to determine targeted and endocrine therapy options.

TREATMENT

Surgical resection was performed on August 3, 2024. Left breast segmental mastectomy was initially performed, and intraoperative frozen-section analysis confirmed invasive carcinoma. Left modified radical mastectomy was subsequently completed at the patient’s request.

Postoperatively, the patient received 8 cycles of adjuvant Pirarubicin plus cyclophosphamide followed by docetaxel plus cisplatin (Table 1) chemotherapy, consisting of four cycles of pirarubicin plus cyclophosphamide followed by four cycles of docetaxel plus cisplatin[3-6]. Grade 2-3 chemotherapy-related toxicities were managed with symptomatic treatment. Endocrine therapy was not indicated because of the triple-negative phenotype, and no targeted therapy was available because the identified TP53/AKT1 mutations were not actionable. Regular follow-up was arranged. The patient declined postoperative radiotherapy due to economic constraints. Surveillance protocols were scheduled as follows: Tumor markers, breast and axillary ultrasonography, hepatobiliary ultrasonography, and chest CT were to be performed every 3 months within the first 2 years after surgery.

Table 1 Pirarubicin plus cyclophosphamide followed by docetaxel plus cisplatin.

Cycle	Treatment date	Drug	Dose (mg/m2)	Actual total dose per cycle (mg)	Route	Dose adjustment	Adverse event	CTCAE 5.0 grade1	Management	Reason for the delay
1	August 31, 2024	Pirarubicin cyclophosphamide	40; 200	62; 310	Infusion	No	-	-	-	-
2	September 27, 2024	Pirarubicin cyclophosphamide	40; 200	62; 310	Infusion	No	-	-	-	Respiratory infection
3	October 20, 2024	Pirarubicin cyclophosphamide	40; 200	62; 310	Infusion	No	Leukopenia	Grade 2	G-CSF2	Leukopenia
4	November 11, 2024	Pirarubicin cyclophosphamide	40; 200	62; 310	Infusion	No	Nausea/vomiting neutropenia alopecia	Grade 2	5-HT3 receptor antagonist3; G-CSF	-
5	December 1, 2024	Docetaxel cisplatin	75; 20 (d1-d3)	116; 93	Infusion	No	Anorexia nausea/vomiting leukopenia	Grade 2	Nutritional support; 5-HT3 receptor antagonist+Dexamethasone	-
6	December 22, 2024	Docetaxel cisplatin	75; 20 (d1-d3)	116; 93	Infusion	No	Anorexia nausea/vomiting leukopenia	Grade 2	Nutritional support; 5-HT3 receptor antagonist+Dexamethasone; G-CSF	-
7	January 13, 2025	Docetaxel cisplatin	75; 20 (d1-d3)	116; 93	Infusion	No	Anorexia nausea/vomiting leukopenia	Grade 3	Nutritional support; 5-HT3receptor antagonist+Dexamethasone	-
8	February 4, 2025	Docetaxel cisplatin	75; 20 (d1-d3)	116; 93	Infusion	No	Anorexia nausea/vomiting leukopenia	Grade 2	Nutritional support; 5-HT3receptor antagonist+Dexamethasone	-

¹CTCAE 5.0, Common Terminology Criteria for Adverse Events version 5.0.

²G-CSF, Granulocyte Colony-Stimulating Factor.

³5-HT3 receptor antagonist, 5hydroxytryptamine type 3 receptor antagonist.

OUTCOME AND FOLLOW-UP

The patient was alive and free of recurrence at the 20-month follow-up (as of May 1, 2026) after surgery. Regular physical examinations, imaging tests (breast ultrasound, chest and abdominal CT), and tumor marker assessments showed no local recurrence or distant metastasis. The patient remained in good health, with well-controlled blood pressure, and continued to undergo regular long-term follow-up.

DISCUSSION

Breast cancer is the most commonly diagnosed malignancy among women worldwide. In 2024, it accounted for 32% of all newly diagnosed malignancies, with invasive ductal carcinoma being the most common histological subtype[7]. MMBC is a rare subtype of breast cancer, accounting for 0.08%-0.2% of breast malignancies, and is generally associated with an unfavorable prognosis[2,8]. Most patients are older adults and typically present with larger breast masses, a low incidence of axillary lymph node metastasis, and a high risk of distant metastasis[9]. Clinically, MMBC most commonly presents as a painless breast mass.

Most reported cases of MMBC contain only two distinct pathological components[10,11], while cases involving three or more components are extremely rare. The current standard treatment primarily consists of surgical resection, including mastectomy or modified radical mastectomy, followed by adjuvant chemotherapy. The reported 5-year disease-free survival and overall survival rates for MMBC are only 45.6% and 53.7%, respectively, which are significantly lower than those reported for triple-negative breast cancer[12]. PIK3CA and TERT promoter mutations have been frequently identified in metaplastic breast carcinoma, with TP53 being the most frequently mutated gene[13]. Previously reported cases of mixed metaplastic breast carcinoma have predominantly involved two histological components, most commonly spindle cell carcinoma combined with invasive ductal carcinoma, followed by a smaller number of cases involving invasive ductal carcinoma and squamous cell carcinoma[14,15]. In the present case, the tumor consisted of four distinct components: Invasive ductal carcinoma, spindle cell carcinoma, squamous cell carcinoma, and a high-grade DCIS component. The triple-negative phenotype and high Ki-67 proliferation index in this case may indicate a highly proliferative and potentially aggressive tumor phenotype.

At present, no effective targeted or endocrine therapy has been established for MMBC[16], and no universally accepted standard chemotherapy regimen has been defined. Therefore, individualized surgical planning and postoperative systemic therapy are particularly important[17-19]. Considering the squamous cell carcinoma component and referring to the relevant recommendations of the National Comprehensive Cancer Network Guidelines, we selected pirarubicin plus cyclophosphamide for the initial four cycles of adjuvant chemotherapy. Given the reported efficacy of docetaxel plus cisplatin in the treatment of primary squamous cell carcinoma of the breast, the regimen was subsequently changed to docetaxel plus cisplatin for an additional four cycles, with a 3-week interval between cycles. After completing all 8 cycles of chemotherapy, the patient entered routine follow-up.

Intraoperative frozen-section analysis suggested invasive ductal carcinoma; therefore, modified radical mastectomy was performed at the patient’s request. Although all dissected axillary lymph nodes were negative for metastasis, adjuvant chemotherapy was administered because of the aggressive biological behavior of MMBC. Once recurrence or distant metastasis occurs, treatment options may be limited. MMBC is characterized by a relatively low incidence of axillary lymph node metastasis but a high propensity for distant metastasis, and lymph node involvement may be associated with a more aggressive clinical course. In this case, segmental resection was performed rather than conventional lumpectomy to achieve an adequate tumor-free surgical margin.

With advances in multimodal cancer therapy, the 5-year survival rate of patients with conventional breast cancer has continued to improve. Nevertheless, MMBC remains a rare and highly aggressive malignancy, with most tumors exhibiting an ER- and PR- negative phenotype and limited sensitivity to endocrine therapy. To date, no optimal treatment strategy has been established for MMBC. Therefore, early detection, appropriate surgical management, and individualized adjuvant therapy are crucial to improve clinical outcomes.

CONCLUSION

This case highlights the diagnostic and therapeutic challenges associated with multicomponent MMBC. The presence of three invasive components plus associated DCIS components within a single tumor is exceptionally rare. Despite the triple-negative phenotype and high proliferative index, the patient achieved a favorable clinical outcome during 20 months of follow-up following individualized surgical management and adjuvant pirarubicin plus cyclophosphamide followed by docetaxel plus cisplatin chemotherapy. Continued long-term follow-up and the accumulation of additional cases are warranted to establish optimal treatment strategies for this rare entity.