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Introduction

Fibroadenoma is the most common benign tumor diagnosed in the breast, with a peak incidence in the female in their 20s and 30s worldwide (1,2). In principle, an asymptomatic fibroadenoma can be managed conservatively with regular breast imaging follow-up; however, in clinical practice, it may not be an optimal choice if the mass is enlarged or other atypical symptoms are present (3). Carcinoma arising in a fibroadenoma of the breast can be diagnosed by incidental biopsy or excision although it is present in only 0.1–0.3% of all cases (4).

To the best of our knowledge, only sporadic case reports and case series with a small sample size describing breast carcinoma occurring within a fibroadenoma have been published (3,5). Breast carcinoma arising within a fibroadenoma includes lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS) and, rarely, invasive carcinoma (6). Non-invasive breast carcinomas are more commonly found than invasive breast carcinomas (7). An epithelial malignancy within a fibroadenoma often mimics the features of a fibroadenoma clinically and radiologically; therefore, early detection remains clinically challenging. Although radiological examinations such as ultrasonography and mammography are valuable in diagnosing fibroadenoma, malignancy within a fibroadenoma may be indistinguishable from benign fibroadenoma on imaging (5). Moreover, few reports have documented the transition from fibroadenoma to breast cancer and little is known about its clinicopathological features and prognosis (5,8). To the best of our knowledge, no evidence-based guidelines for diagnosis and treatment of breast carcinoma arising within a fibroadenoma exist due to its low incidence rate. The present study reviews the literature and discusses the clinicopathological features and treatments of patients with breast carcinoma arising from a fibroadenoma diagnosed at The Third Hospital of Nanchang City (Nanchang, China) between January 2019 and December 2021.

Materials and methods

Patients

Between January 2019 and December 2021, 6,558 of breast carcinoma were admitted to The Third Hospital of Nanchang City (Nanchang, China). Of them, 6,550 cases were female. All cases diagnosed as breast carcinoma in situ or invasive carcinoma arising within fibroadenoma were included. All histopathological slides were reviewed by two pathologists independently to confirm the diagnosis. Data such as age, sex, menopausal status, primary complaint and treatment were also collected.

Pathological examination

All available hematoxylin and eosin (H&E)-stained breast carcinoma arising within a fibroadenoma sections were reviewed by two independent pathologists. Tumor morphology was assessed using recently described criteria (9), including nuclear grade, mitotic rate, presence and extent of associated carcinoma in situ and invasive carcinoma. Immunohistochemistry was performed on paraffin-embedded 4 µm tissue slides as described previously and fixed in 10% formalin for 6 h at room temperature (10). First incubate the slides at 65°C for 2 h, and then deparaffinize twice for 5 min. Antigen retrieval solution (10 mmol/l tris; 1 mmol/LEDTA; pH9.0) was 100°C for 5 min and blocked with 2% sheep serum (Biyangtian Biotechnology Research Institute) at room temperature. The slides were then incubated with primary antibodies overnight at 4°C and with horseradish peroxidase-labeled secondary antibodies and DAB for 1 h at 37°C. Tumor immunoreactivity was assessed independently by two pathologists. In addition, human epidermal growth factor receptor 2 (HER2) was detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) according to the latest HER2 testing recommendations from the American Society of Clinical Oncology and the College of American Pathologists. Status is determined. Breast Cancer 2018 (11). FISH analysis was performed as previously reported (12).

Follow-up

All patients are followed up regularly every 3–6 months at the Breast Disease Prevention and Treatment Center of Nanchang Third Hospital Routine physical and radiological examinations were performed to monitor recurrence and metastasis. The last date of follow-up was September 30, 2022.

Results

Clinical and pathological findings

Between January 2019 and December 2021, 16 patients were diagnosed with carcinoma arising in a fibroadenoma at The Third Hospital of Nanchang City. The age at diagnosis ranged between 19 and 58 years (median, 45 years). All patients were female and most were premenopausal (87.5%). The most common initial clinical presentation was an asymptomatic palpable mass (87.5%), followed by nipple discharge (6.3%). Notably, two patients (12.5%) presented because of abnormal imaging changes of fibroadenoma during follow-up (Table I).

Table I. Clinicopathological characteristics of breast carcinoma arising in a fibroadenoma.

Table I.

Clinicopathological characteristics of breast carcinoma arising in a fibroadenoma.

Characteristic	Value
Age at diagnosis, years (%)
<35	5 (31.3)
35-50	10 (62.5)
>50	1 (6.3)
Median age (range), years	45.0 (19.0–58.0)
Sex (%)
Male	0 (0.0)
Female	16 (100.0)
Clinical presentation (%)
Mass	14 (87.5)
Nipple discharge	1 (6.3)
Laterality (%)
Left	8 (50.0)
Right	8 (50.0)
Bilateral	0 (0.0)
Fibroadenoma diameter, cm (%)
≤2	6 (37.5)
2-3	8 (50.0)
>3	2 (12.5)
Mean fibroadenoma diameter (range), cm	2.2 (1.0–3.7)
Malignant component subtype (%)
DCIS	10 (62.5)
LCIS	2 (12.5)
IDC	3 (18.8)
ILC	1 (6.3)
T stage (%)
Tis	12 (75.0)
T1	4 (25.0)
T2	0 (0.0)
T3	0 (0.0)
T4	0 (0.0)
Axillary lymph node involvement (%)
Yes	0 (0.0)
No	16 (100.0)

[i] T stage was classified according to the greatest dimension of malignant components within the fibroadenoma. DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; T, tumor; Tis, tumor in situ.

Consistent with a previous study (13), a small malignant tumor arising in a relatively large fibroadenoma was observed in 14 cases (87.5%). The mean tumor size (diameter of fibroadenoma containing the malignant component) ranged between 1.0 and 3.7 cm (mean, 2.2 cm). However, the malignant component in 12 of cases was non-invasive (75%). Thus, the majority of cases in the present study were tumor in situ (Tis) according to the latest TNM staging system (75%; Table I) (14).

Fibroadenoma harboring a carcinoma mimics benign fibroepithelial tumor radiologically. Ultrasonography revealed a circumscribed, homogenous, isoechoic or hypoechoic mass (Fig. 1). A total of 5 cases (31.3%) were categorized as breast imaging-reporting and data system (15) (BI-RADS) 4 on ultrasonography in the present study which indicated suspicious malignancy. Mammography findings were similar to those of benign tumors and revealed a lobulated well-defined mass. However, several indicators of malignant transformation, including indistinct borders and microcalcifications, were observed in three cases (18.8%) (16).

Figure 1. Ultrasonography of breast carcinoma arising within a fibroadenoma. A 26 mm large tumor in a 47-year-old female. Ultrasound examination revealing a regular and well-circumscribed hypoechoic mass.

Diagnosis, treatment and survival

In the present study, all cases received core needle or vacuum-assisted biopsy or excision to make a diagnosis. Pathologically, carcinoma in situ was more common than invasive carcinoma, with 12 non-invasive cases (75%) and four invasive cases (25%; Fig. 2A and B). Furthermore, DCIS was more common than LCIS (Table II; Fig. 2C and D). Invasive ductal and lobular carcinoma were diagnosed in three (81.3%) and one case (93.8%), respectively (Fig. 2E and F). When breast carcinoma arising within a fibroadenoma is suspected, immunohistochemical analysis (such as CK5/6 and α-SMA) is performed to confirm the diagnosis (Fig. S1). In immunohistochemical analyses, the majority of cases were hormone receptor (HR)-positive (15 cases, 93.8%) and HER2-negative (14 cases, 87.5%; Fig. 3A-C). Regarding molecular subtypes, luminal A and B, HER2-positive and triple-negative subtypes accounted for 10 (62.5%), 5 (31.3%), 1 (6.3%) and 0 (0.0%) cases, respectively.

Figure 2. Subtypes of breast carcinoma arising in a fibroadenoma. (A) Carcinoma in situ, (B) invasive breast carcinoma, (C) ductal and (D) lobular carcinoma in situ and (E) invasive ductal and (F) lobular carcinoma arising within a fibroadenoma. Representative images were observed at a magnification of ×100.

Figure 3. Immunohistochemical analysis of breast carcinoma arising in a fibroadenoma. (A) Estrogen and (B) Progesterone receptor. Human epidermal growth factor receptor (C) (1+) and (D) (3+). Representative images were observed at a magnification of ×200.

Table II. Immunohistochemical analysis.

Table II.

Immunohistochemical analysis.

Immunohistochemical marker	n (%)
ER status
Positive	15 (93.8)
Negative	1 (6.3)
PR status
Positive	14 (87.5)
Negative	2 (12.5)
HER2 status
-	3 (18.8)
1+	3 (18.8)
2+	8 (50.0)
3+	2 (12.5)
Ki67, %
≤14	12 (75.0)
>14	4 (25.0)
Molecular subtype
Luminal A	10 (62.5)
Luminal B	5 (31.3)
HER2 overexpression	0 (0.0)
TNBC	1 (6.3)

[i] A total of two cases positive for HER2 were classified as Luminal B subtype because they were HR-positive. ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer.

Once the tumor was confirmed to be malignant, breast-conserving surgery (BCS) as well as sentinel lymph node biopsy (SLNB) were advised. A total of seven patients (43.6%) received BCS and nine patients (56.3%) received mastectomy (Table III). SLNB was performed in all cases and no axillary lymph node involvement was observed. Of seven patients who received BCS, six underwent radiation therapy; one 19-year-old female patient diagnosed with DCIS arising within a fibroadenoma rejected radiotherapy because of personal reasons. Furthermore, chemotherapy was administered in two patients diagnosed with invasive carcinoma. Anti-HER2-targeted therapy was administered concurrently with chemotherapy in one of these patients, since the immunohistochemical staining revealed HER2-positive invasive carcinoma (Fig. 3D).

Table III. Treatment of breast carcinoma arising in a fibroadenoma.

Table III.

Treatment of breast carcinoma arising in a fibroadenoma.

Treatment	n (%)
Surgery
BCS or lumpectomy	7 (43.8)
Mastectomy	9 (56.3)
Surgery of axillary lymph nodes
SLNB	16 (100)
ALND	0 (0.0)
Chemotherapy
Yes	2 (12.5)
No	14 (87.5)
Radiotherapy
Yes	6 (37.5)
No	10 (62.5)
Endocrine therapy
Yes	15 (93.8)
No	1 (6.3)
HER2-targeted therapy
Yes	1 (6.3)
No	15 (93.8)

[i] BCS, breast conserving surgery; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; HER2, human epidermal growth factor receptor-2.

Follow-up data were available for all patients. In the follow-up period, no signs of recurrence or relapse were observed and all patients were in good health at the last follow-up.

Discussion

Carcinoma arising from a fibroadenoma is a poorly understood disease of the breast, with only a few reported cases (17,18). Unlike benign fibroadenoma, malignant transformation within a fibroadenoma is most reported in patients in their 40s (6,13), although it can occur at any age. Consistent with these reports, the age of patients at diagnosis in the present study ranged between 19 and 58 years, with a median age of 45 years. Notably, five of the 16 patients (31.3%) were <35 years old, with the proportion of young patients with breast cancer markedly higher than that in the whole breast cancer population (19). This indicated that malignant transformation within a fibroadenoma may be stimulated by high estrogen levels in young women. Notably, the youngest patient in the present study was a 19-year-old female patient who was diagnosed with low-grade DCIS arising with a fibroadenoma. To the best of our knowledge, this is the youngest case reported in the literature so far. Therefore, it is important for clinicians to be cognizant of potential malignant transformation within a fibroadenoma even if the patient is young.

Breast cancer arising in fibroadenomas is difficult to diagnose because its oncogenic components may be masked by fibroadenoma components and has a low incidence rate.. In the present study, the most common clinical presentation was a well-defined, movable, asymptomatic mass (87.5%), which was similar to a benign breast tumor. Furthermore, observations in the radiological examinations, including ultrasonography and mammography, are usually non-specific (20). Only five patients (31.3%) in the present study were categorized as BI-RADS 4 on ultrasonography. Additionally, malignant transformation indicators in mammography, such as microcalcifications and distortion of surrounding tissue, were only observed in three cases (18.8%) (21). As the carcinoma component may be hidden by other components in fibroadenoma, and thus, may not be detected by imaging examinations (16), it is difficult to differentiate benign fibroadenomas from their counterparts with malignant transformation within them. Therefore, tumor biopsy or excision should potentially be suggested to make a diagnosis in this situation. Notably, a recent study evaluated the role of dynamic contrast-enhanced MRI in diagnosing cancerous lesions developing within fibroadenomas (21) and revealed that relatively low diffusion of the apparent diffusion coefficient value suggested a malignant transformation within a fibroadenoma. Novel potential imaging methods with high accuracy and efficiency are clinically warranted.

Here, non-invasive carcinoma was the predominant type of malignancy within a fibroadenoma (75%). Theoretically, the occurrence of a breast carcinoma within a fibroadenoma has two potential etiologies: The breast carcinoma may arise from epithelial components of the fibroadenoma or tumors may coexist separately (22). Previous studies have produced inconsistent results: Several studies found that LCIS is more common compared with DCIS since fibroadenoma is of lobular origin (23,24), while other reports demonstrated that LCIS and DCIS present with approximately equal frequency within a fibroadenoma because they both originate from the terminal duct-lobular units of the breast (25,26). However, in the present study, DCIS was more frequent than LCIS. These inconsistent results indicate that the exact cell origin of the carcinoma within a fibroadenoma remains unclear.

Since few case reports have been published to date (27,28), the immunohistochemical characteristics as well as molecular subtype distribution of breast carcinoma arising within a fibroadenoma remain to be determined. A retrospective study reported that most cases are HR-positive (25). However, the study was reported in the ‘pre-adjuvant anti-HER2 therapy era’ and HR status was determined few cases, which introduced possible elements of bias. In the present immunohistochemical examination, the majority of cases were positive for HR (93.8%) and negative for HER2 (87.5%). The luminal A and B, HER2-positive and triple-negative molecular subtypes accounted for 10 (62.5%), five (31.3%), 0 (0.0%) and 0 (0.0%) and one (6.3%) cases, respectively. To the best of our knowledge, this is the first case series reporting molecular subtype distribution in detail. Since DCIS cases have diverse clinical and prognostic features for different molecular subtypes, accurate diagnosis, including determination of molecular subtype, is required for prompt treatment and prognosis.

Following diagnosis of carcinoma, BCS was performed in seven patients and mastectomy was performed in nine patients based on the personal preference of the patient. Although the majority of cases were non-invasive on core needle biopsy, SLNB was performed in all cases in case of tumor upstaging on final pathology. A previous study (29) reported the rate of upstaging to invasive breast cancer in patients with DCIS identified on core needle biopsy; 36% of patients with DCIS were ultimately diagnosed with invasive carcinoma (29). Additionally, in the present study, no axillary node involvement was observed. The present results indicated that SLNB may be unnecessary in carcinoma arising within a fibroadenoma, particularly in non-invasive cases.

Although differences between breast carcinoma arising from fibroadenoma and breast cancer remain unknown, a tumor bed boost after postoperative whole breast irradiation in patients with DCIS following conservative surgery can be recommended, as evidenced by the BIG 3–07/TROG 07.01 trial (30). Regarding radiotherapy following BCS, six out of seven patients completed the treatment as planned; one 19-year-old female with DCIS refused post-operative radiotherapy for personal reasons. Adjuvant chemotherapy was administered to one HER2-positive invasive breast cancer case. Upregulation of HER2 in DCIS is associated with adverse clinicopathological parameters, including higher grade, comedo necrosis, as well as worse clinical outcome (31). To the best of our knowledge, however, the therapeutic role of anti-HER2-targeted therapy in HER2-positive DCIS has not been established. Therefore, another patient diagnosed with HER2-positive DCIS arising within a fibroadenoma was treated with post-operative radiotherapy only.

At the end of follow-up, all 16 patients included in the present study were alive and no progression was observed. A limitation of the present study is the follow-up period was relatively short; further follow-up and prognosis should be assessed in future. A second limitation of the study is the genetic analysis of breast carcinoma arising within a fibroadenoma is not routinely performed in daily clinical practice, therefore genetic information of these cases was not collected. Previous studies have demonstrated that carcinoma arising within a fibroadenoma is associated with a favorable prognosis with adequate local therapy (3,32), regardless of whether it is biologically in situ or not. However, clinicians should be alert to potentially enclosed cancerous lesions in a fibroadenoma since they can radically alter both prognosis and treatment outcome.

In conclusion, carcinoma arising within a fibroadenoma is a rare malignancy of the breast. In clinical practice, it is often encountered incidentally during pathological examination of a benign breast mass. Non-invasive carcinoma was the predominant type of malignancy within a fibroadenoma, although the cell origin of the carcinoma remains to be elucidated. Notably, the present report described the youngest case to date, although malignant changes within fibroadenomas are typically identified in older patients. Aggressive molecular phenotypes, including HER2-positive or triple-negative subtypes, were identified in the present case series. Surgical excision with or without postoperative radiotherapy should be recommended once the malignancy is diagnosed. Additionally, systemic treatment, such as chemotherapy and endocrine therapy, were also suggested, especially in the presence of invasive carcinoma with unfavorable tumor biology or axillary lymph node metastases.

Supplementary Material

Supporting Data

Acknowledgements

The authors would like to thank Professor Jianhong Tu (Department of Pathology, The Third Hospital of Nanchang City, Nanchang, China) for technical assistance in preparing histology tissue sections.

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81860467, 82060482 and 81860546) and Key Science and Technology Support Project of Nanchang (grant no. 2019-258-13).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

LX, WQ, SL and YC conceived and designed the study. LX and QM wrote the manuscript. LL collected data. QM, YG and LL analyzed the data. WQ performed the pathological examination and provided experimental technical support. SL and YC wrote and revised the manuscript. LX and YC confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The present study was approved by the Institutional Review Boards of The Third Hospital of Nanchang City (Nanchang, China; approval no. K-ky2023005). Written informed consent was obtained from all patients according to The Declaration of Helsinki.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References