Abstract
Secretory carcinoma of the breast (SCB) is a rare and specific type of breast cancer. Owing to its rarity, the number of SCB reports available is limited, with most of them focusing on clinical and pathological characteristics but no reports on its multimodal ultrasound (US) features. Thus, we present a rare case of SCB, retrospectively analyzing manifestations of US and contrast-enhanced US, as well as its pathological basis, aiming to enhance the understanding of US image features of SCB and provide more valuable information for clinical diagnosis. Moreover, the treatment strategy adopted for this patient may serve as a template for future management of SCB.
Introduction
Secretory carcinoma of the breast (SCB) is a special type of rare, low-grade invasive carcinoma, characterized by intracytoplasmic secretory vacuoles and extracellular eosinophilic secretory material [1, 2]. Ultrasound (US) is a significant tool in detection of breast disease and provides valuable information to guide clinical decision-making [3–6]. Therefore, preoperative multimodal US assessment is critical for clinical diagnosis and treatment of SCB. We present a 45-year-old female patient diagnosed with SCB, focusing on the features of multimodal US in combination with pathological characteristics, aiming to enhance the understanding of US image features of SCB, which may provide more valuable information for clinical diagnosis.
Case presentation
The 45-year-old female patient detected a mass in the left breast for more than 4 years. The mass caused slight pressure pain, but exhibited no redness or swelling, no nipple discharge, and no visible enlargement. The patient underwent a breast US examination at other hospital before admitting to hospital. The 11 o’clock directional mass in the left breast was classified as the Breast Imaging Reporting and Data System (BI-RADS) 4B and multiple masses in bilateral breasts were classified as BI-RADS 3. The specialist examination after admission showed that a lump was detected in the upper inner quadrant of the left breast at a distance of 2.8 cm from the nipple, with a tough texture, clear border, smooth surface, and poor mobility. No nipple discharge was observed during left nipple compression. Enlarged lymph nodes were not detected in the left axilla and subclavian fossa. Besides, the patient denied any family history of similar disease.
In mammographic evaluation, masses in bilateral breasts were categorized as BI-RADS 3 (Fig. 1). In the two-dimension (2D) US, a 2.1 cm×1.6 cm homogeneous hypoechoic mass was detected in the direction of 11 o’clock on the left side of the breast, with regular morphology, burr and angular edges, as well as parallel growth (Fig. 2a). Color Doppler flow imaging (CDFI) detected abundant internal blood flow signal (Fig. 2b), with visible arterial spectrum, peak flow velocity measuring about 10.3 cm/s, and resistance index of blood flow measuring about 0.85. US elastography revealed an elasticity score of 5 (Fig. 2c). Additionally, contrast-enhanced ultrasound (CEUS) highlighted that the lesion displayed centripetal inhomogeneous hyperenhancement, with an enlargement enhancement in range compared to the 2D US, and filling defects within. Radial enhancement was observed in the periphery as well (Fig. 2d). The combination of conventional US, US elasticity, and CEUS suggested that the solid lesion located at 11 o’clock position in the left breast was graded as BI-RADS 4 C and the others in bilateral breast were graded as BI-RADS 3. Moreover, regarding automated breast volume scanning (ABVS), the hypoechoic mass located at 11 o’clock in the left breast was categorized as BI-RADS 4 C and the others in bilateral breast were categorized as BI-RADS 3 (Fig. 3).
Mammogram of the left breast showed localized nodular-like changes with no distinct mass. a: The craniocaudal (CC) view. b: The mediolateral oblique (MLO) view.
US displayed a solid breast mass positioned at 11 o’clock on the left breast. a: Grey-scale US exhibited that the morphology of the lesion was irregular, with angular and burr margin. b: CDFI revealed a rich flow signal within the lesion. c: US elastography suggested that both the tissue within and the periphery of the lesion were hard. d: CEUS showed that the enhancement range of the lesion was increased compared to that of the 2D range.
The ABVS manifestations of the left breast. The scan captured four different views: anteroposterior coronal and medial coronal in a and b respectively, which display the “convergence sign”; as well as anteroposterior sagittal and medial sagittal in c and d respectively, which show an irregular mass morphology with burrs and angular margins.
The patient underwent resection of the mass in her left breast, and the intraoperative pathology indicated invasive carcinoma. Subsequently, the tissue samples of the mass at 3, 6, 9, and 12 o’clock positions, as well as the surface and basal margins of the mass, and the left axillary anterior sentinel lymph nodes were examined. However, no cancerous tissue was detected. Finally, the patient underwent a segmental mastectomy of the left breast.
Under microscopic examination postoperatively, the tumor cells were observed to be arranged in a sieve-like and glandular structure, with mucus-containing sieve pores (Fig. 4a). There was no clear evidence of vascular or nerve bundle invasion. The immunohistochemistry results of ER, AR, PR, and Her-2 were negative. CK5/6 and CD117 were partially positive, while SMMHC, P63, and E-ca were negative. CgA was negative, but S100 was positive. Fluorescence in situ hybridization (FISH) showed a positive result for the ETV6-NTRK3 fusion gene (Fig. 4b). The proliferation index of Ki-67 was about 15%. Finally, the resultant diagnosis was SCB.
The microscopic features. a: Hematoxylin-eosin staining (HE,×400) showed a sieve-like and glandular tube-like pattern of tumor cells. b: FISH detected approximately 40% of abnormal cells with the ETV6-NTRK3 gene fusion signaling type, in which the ETV6 gene was labelled with red fluorescence and the NTRK3 gene was labelled with green fluorescence.
Following the surgery, the patient received a radiotherapy and chemotherapy regimen. The patient has successfully completed treatment and has been under follow-up since then. No signs of recurrence or metastasis have been detected.
SCB is a low-grade malignant breast tumor that is classified by the World Health Organization as a rare subtype of breast cancer, accounting for approximately 0.15% of breast cancer incidence [1, 2]. McDivitt first reported and proposed SCB in 1966 [7], and it had been previously referred to as juvenile breast cancer due to its occurrence in children. Subsequent research has indicated that SCB can present in individuals of various ages [8]. In 1980, Tavassoli et al. [9] formally named it secretory carcinoma, supported by both the histological morphology of the tumor and the properties of the intracellular and extracellular secretions produced by the tumor cells.
On histopathology of SCB, microscopic tumor cells may generate milky or thyroglossal secretions distributed inside and outside the cytoplasm. Hematoxylin-eosin staining (HE) appears pale red. Tumor cells often exhibit a microcystic, solid, tubular arrangement [1], with a few appearing papillary [2] and frequently showing a combination of morphologies. Moreover, its immunohistochemical expression is characteristic of basal-like cells, which are negative for ER, PR, and human epidermal growth factor receptor 2 (HER2) [1]. Recent literature has identified cases with weaker ER/PR positivity [10] and variable Ki-67 proliferation index, which tends to be below 20% [2]. On the other hand, a chromosome t(12;15)(p13;q25) translocation and resulting expression of the ETV6-NTRK3 fusion gene were found in SCB patients [11], leading to specific molecular pathological changes.
Currently, the majority of SCB research focuses on clinical and pathological characteristics. However, there is a limited number of US studies, with no reports on its multimodal US features. In the US, SCB presents a solid mass with rounded shape and well-delimited border, which correlates with the expanding growth characteristics of tumor cells under pathological microscopy. Additionally, the varying growth rates of these cells can lead to small lobular changes in the surrounding tissues at the edge. In individual cases, tumor cells could infiltrate into the adjacent adipose tissue. When the interstitial response is not obvious, the US may show blurred borders [12]. There have been isolated cases of lesion margins featuring burrs [13]. According to Jeh et al. [14], these burr-like margins are associated with the low density of tumor cells, abundant collagen matrix, and surrounding fibroproliferative reaction. In the present case, the margins were burr and angular, but there was no evidence of lymph node metastasis, which suggests that the tumor may be predominantly locally invasive.
The relationship between the internal and posterior echogenicity of the lesion and the composition of the tumor tissue is evident, with a sizeable percentage of tumor cells demonstrating hypoechoic internal echogenicity and enhanced or unaltered posterior echogenicity. A high proportion of fibrous components display attenuated posterior echogenicity. When significant amounts of milky or thyroid gelatinous secretions are produced within and outside the cytoplasm of the cancer cells, the US image can show cystic-like echogenicity. In this case, the lesion’s internal portion appeared hypoechoic, with no observable change in the posterior echoes. Pathological microscopy revealed the presence of dense tumor cells and their secretions, along with a minor proportion of stromal ingredient. Meanwhile, immunohistochemistry confirmed the triple-negative subtype. Prior research indicated that such cancers are predominantly hypoechoic internally, with enhanced or unaltered posterior echoes [15].
In addition, typical breast cancer displays thickened and irregularly shaped blood vessels with increased flow velocity. In this present case, the lesion exhibited abundant blood flow signal. Furthermore, an arterial spectrum was observed, highlighting a peak flow velocity and a high resistance index. This may be related to the abundance of tumor cells, as well as the increased number of neovasculature found among the nests of the solid carcinoma. Otherwise, based on the modified US elastography 5-point scale suggested by professor Luo [16], the current case achieved a score of 5. The result indicated that the lesion and its surrounding tissues presented malignant features of hard in texture.
CEUS revealed centripetal inhomogeneous hyperenhancement of the lesion, with an increased enhancement range compared to the 2D. Filling defects were observed within the lesion, with radial enhancement evident in the periphery. These findings were consistent with previous studies [17]. It may be attributed to the uneven distribution of neovascularization within the lesion, and necrosis or haemorrhage observed in certain areas. In conclusion, the combination of 2D US, US elasticity, and CEUS resulted in a diagnosis of BI-RADS 4 C.
ABVS is capable of capturing coronal images using three-dimension (3D) US, which is hard to obtain through traditional US, so as to provide a comprehensive 3D assessment of the breast mass in transversal, longitudinal and coronal perspectives. In this case, the coronal plane of the left breast lesion displayed a “convergence sign” with a radial collection of medium to high echoes and low echoes at the periphery of the mass and the diagnosis was BI-RADS 4 C.
Due to the rarity of SCB, there is no standard treatment protocol, and surgery is considered the primary treatment option. Since SCB in children has a favorable prognosis and is less prone to metastasis, it is recommended to preserve the breast buds as much as possible while ensuring negative margins [18]. Whereas SCB in adults carries a risk of poor prognosis. Factors linked to poor prognosis were (1) a tumor diameter≥2 cm with poorly defined boundary, (2) patient age≥20 years, (3) male gender, (4) family history of breast cancer, and (5) positivity for the immune marker Vimentin and a high proliferative index of Ki-67 [19]. Richard et al. [20] suggested that modified radical surgery was recommended for patients who were over 20 years old and had tumors with diameters greater than 2 cm. While Li et al. [21] recommended performing local excision and sentinel lymph node biopsy for patients with tumors smaller than 2 cm in diameter. If the sentinel lymph nodes and margins were negative, breast-conserving surgery could be performed without axillary lymph node dissection.
Therefore, US offers significant benefits for timely detection of small suspicious lesions due to its non-invasive nature, real-time imaging, and ease of operation. Moreover, breast-conserving surgery can be effectively carried out when lymph node metastasis is absent, thus lowering patient trauma to a larger extent. In this case, margin tissues and axillary sentinel lymph nodes were negative. Additionally, the patient had low proliferation index of Ki-67 and no family history of breast cancer. Despite the diameter measured over 2 cm and the triple-negative ones diagnosed, research has established that it is an indolent tumor with a favorable prognosis [22]. Thus, breast-conserving mastectomy with postoperative radiotherapy and chemotherapy was finally adopted. Further evaluation and monitoring of this patient on a long-term basis are necessary owing to the limited number of cases and the unclear treatment guidelines.
It is well known that mammography is a recognized and effective imaging technique for early breast cancer screening. Nevertheless, the missed diagnosis in this case may be attributed to the low-density resolution of the mammography, which makes it hard to detect small lesions in dense breasts. On the other hand, triple-negative breast cancers are more likely to present with smooth margins and few calcifications [23]. The 2D US findings showed no definitive malignancy, but the elastography indicated the lesion and its surrounding tissues were hard. Moreover, both CEUS and ABVS revealed typical malignant features, which significantly increased the diagnostic accuracy of US. Therefore, the department of ultrasonography at our institution upgraded BI-RADS 4B diagnosed at other hospital to BI-RADS 4 C. This case enhances comprehension of the US characteristics of SCB through the application of multimodal US techniques and demonstrating the unique advantages of combining multiple US methods for preoperative examination. Multimodal US can provide a comprehensive and objective evaluation in breast masses, particularly small suspicious malignant breast lesions in dense breasts. Additionally, this case can provide more valuable information for the diagnosis and management of SCB, thus assisting with clinical diagnosis and treatment of this rare type of breast cancer.
Funding
This work was supported by the Science and Technology Bureau Project of Zhanjiang [Grant No. 2020A01036] and the “Three-Aspected Education” Special Project of the First Clinical Medical College of Guangdong Medical University.