Breast lymphoma (BL) is rare, accounting for 0.04–0.5% of malignant tumors of breast. Although implants associated anaplastic large cell lymphoma was not included in this study, with the popularity of implant transplantation, the incidence of BL will increase indirectly. The imaging findings of BL are similar to those of breast cancer, while the treatment regimens for BL and breast cancer are quite different. Therefore, an accurate diagnosis of BL is necessary, which can avoid unnecessary radical surgery, and is helpful for developing a reasonable treatment plan. Imaging features of BL have few reports to date. In order to determine the key imaging hallmarks of this disease, we retrospectively analyzed mammography and magnetic resonance imaging (MRI) findings of 15 cases with complete clinical data of BL.
2 Materials and methods
The institutional review board of The First Affiliated Hospital of Zhejiang Chinese Medical University approved this retrospective study and waived informed consent.
A total of 15 patients diagnosed with BL were collected with complete clinical and image data from March 2013 to June 2017 in The First Affiliated Hospital of Zhejiang Chinese Medical University. These patients included 14 females and 1 male. The age ranged from 24 to 85 years old. The average age is 48.4 ± 17.8 years old. About 5 cases out of the 15 patients underwent mammography and all cases underwent MRI examination. The clinical data and images of all patients were de-identified.
2.2 Imaging techniques
Craniocaudal and mediolateral oblique mammographic projections were obtained (Mammomat Inspiration, Siemens healthcare GmbH erlangen, Germany). Bilateral breast images were detected by a 16 channel special surface coil of bilateral mammary gland on 3T MR scanner (Magnetom Verio 3T, Siemens, Siemens healthcare GmbH erlangen, Germany). Scan sequences include fat-suppressed T2-weighted imaging (T2WI): TR: 4000 ms, TE: 70 ms, thickness: 4 mm, FOV: 360 mm × 360 mm, diffusion-weighted imaging (DWI): TR: 7000 ms, TE: 85 ms, thickness: 4 mm, B values of 50 s/mm2, 400 s/mm2, and 800 s/mm2 were selected, and the apparent diffusion coefficient (ADC) was reconstructed automatically after the scan, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The DCE-MRI was detected by three-dimensional dynamic imaging sequences with fast and small angle stimulation and used to scan 6 phases: TR: 4.51 ms, TE: 1.61 ms, thickness: 1.0 mm. At the end of the first 15.0 second interval, the high pressure injector was used to administer contrast injection of Gd-DTPA (Beijing Hokuriku Pharmaceutical Company Limited. Beijing China), administered intravenously via median cubital vein at a dose of 0.2 mmol/kg (15–20 mL), rate of 1.5–2 ml/s injection. The same injection rate was used to inject 20 mL saline to flushing pipe. Scan time of DCE-MRI is about 6 min 10 s.
2.3 Image analysis
The area of highest enhancement was selected as the region of interest (ROI) to measure the ADC value on ADC maps. Syngo random post-processing software was used for measurement. The ROI was selected to describe the time signal intensity curve. All mammography and MRI images were retrospectively reviewed by 2 senior radiologists, and the results were discussed and agreed upon. They reviewed the images by using the criteria of Breast Imaging Reporting and Data System Version 2013. The radiologists were blinded to the clinical data and the final diagnosis.
3.1 Clinical characteristics and pathological type
Fourteen cases of BL were confirmed by biopsy or surgical pathology, and 1 case of BL was confirmed by clinical treatment and follow-up observation. Fifteen patients including 13 cases of primary breast lymphoma (PBL) and 2 cases of secondary breast lymphoma (SBL) were enrolled. Thirteen cases of PBL included 10 cases of diffuse large B cell lymphoma (DLBCL), 2 cases of B cell lymphoma, and 1 case of a pregnant woman with Burkitt lymphoma. The two cases of SBL included 1 case of DLBCL and 1 case of peripheral T cell lymphoma. The clinical manifestations of the 3 cases of PBL were: rapid growth of the lesions, accompanied by breast pain with thickening, and edema of the skin. Another 10 cases of PBL were revealed from incidental breast mass findings and showed gradual enlargement to various degrees. The two cases of SBL were breast lumps found after diagnosis of lymphoma.
3.2 Mammography and MRI findings
The mammography and MRI findings of our cases were summarized in Tables 1 and 2. Fifteen patients demonstrated lesions located in the right breast for 7 cases, 5 cases in left breast, and 3 cases in bilateral breast. Mammography was performed in 5 cases that included 4 cases with PBL and 1 case with SBL. Three cases of PBL showed a single, round, dense mass with well-circumscribed margin. One case of PBL showed focal asymmetry dense within a round, dense, and indistinct margin mass (Fig. 1A) accompanied by axillary lymph nodes. One case of SBL showed multiple, round, and highly dense masses with indistinct margins (Fig. 1B).
Fifteen cases were examined by MRI, including 13 cases of PBL with a diameter ranging from 2.3 cm to 15.1 cm with an average of 5.3 ± 3.8 cm, and 2 cases of SBL with a diameter ranging from 2.1 cm to 5.0 cm with an average of 3.5 ± 2.6 cm. MRI findings of all the lesions showed hyperintensity compared with breast parenchyma on T2WI and isointensity on T1-weighted imaging (T1WI). All the lesions showed hyperintensity on DWI and low ADC values. The average ADC value of PBL was (0.55 ± 0.08) × 10−3 mm2/s and the average ADC value of SBL was (0.54 ± 0.22) × 10−3 mm2/s. After intravenous administration of contrast medium, early rapid enhancement were seen in all lesions, and the kinetic curve was a Plateau or Washout. There were 8 cases of PBL with a unilateral single mass (61.5%, 8/13, Fig. 2A–D), which showed round, circumscribed margins. Four cases of PBL with multiple masses (30.8%, 4/13) were also found. One case of PBL showed diffuse infiltration (7.7%, 1/13, Fig. 3A–D) and the bilateral breast swelling with skin thickening and edema. The mass was characterized as a wide, partial nodular, and lumpy fusion mass. DCE-MRI showed heterogeneous enhancement of the lesion within penetrating vessels (Fig. 2C) and septal enhancement (Fig. 3B) in 5 patients. Seven cases of PBL showed unilateral or bilateral axillary lymph node enlargement. One case of SBL (Fig. 4Aand B) showed an unilateral, single, circumscribed margin mass, and DCE-MRI showed early homogeneous enhancement of the lesion with penetrating vessels (Fig. 4B). This was also accompanied by bilateral, multiple enlarged axillary lymph nodes. A single case of SBL showed bilateral, multiple, circumscribed margin masses, with homogeneous enhancement.
4.1 Diagnostic criteria and pathology of breast lymphoma
BL is divided into PBL and SBL. The clinical diagnosis of PBL refers to the diagnostic criteria proposed by Wiseman in 1972:
- (1) lymphoma should be confirmed by pathology,
- (2) microscopy should reveal infiltration in the breast duct and lobular tissue, in the breast epithelium with no malignant transformation, and at the junction of the specimen showing both normal breast tissue and invasion of lymphoma,
- (3) no lymph node and lymphoma occurring simultaneously except for involvement of ipsilateral axillary lymph node, and finally
- (4) no history of lymphoma in other organs or tissues.
In contrast, SBL refers to systemic lymphoma either along with PBL, or secondary to the breast. According to these rules, 13 patients were diagnosed as PBL, and 2 patients were diagnosed as SBL in this study. It is reported[3,4] that PBL accounts for 0.85% to 2.2% of extranodal lymphoma, with SBL being more common. However, most reports in literature and in study were cases of PBL. This may be due to the diagnostic criteria of SBL, which is based on clinical examination, leading to fewer imaging studies compared to PBL subjects. Studies[5,6] have shown that PBL has a higher incidence in pregnant and postpartum women who received estrogen replacement therapy. PBL also comes with an increased risk of lymphoma by 29%. These studies suggested that the growth of a tumor may be related to hormone stimulation. This group of patients included 14 females and 1 male, of which 1 female case showed progressive enlargement of the bilateral breast during pregnancy. Another female showed bilateral breast lumps during postpartum seventh month of lactation. Most of the clinical manifestations of BL are painless single or multiple masses, with or without axillary lymph node enlargement, involving unilateral and bilateral breast. The masses are tough and movable. A few of the breast diffuse enlargement with skin thickening and edema need to be differentiated from inflammatory breast cancer and acute mastitis. There are 3 cases of skin thickening and edema in this group, which are consistent with those reported in the literature.
Histologically, BL can be divided into non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Most BL are of the NHL subtype, including DLBCL (56–84%), marginal zone lymphoma (MZL, 9–28%), follicular lymphoma (10–19%), and Burkitt lymphoma (<6%).[8–13] Burkitt lymphoma is relatively rare, occurring primarily in pregnant or lactating women and frequently involving the bilateral breast. The disease progresses rapidly and the prognosis is typically poor. In this group, 1 case was diagnosed as Burkitt lymphoma during pregnancy and the firstly diagnosis was misdiagnosed as mastitis.
4.2 Mammography and MRI findings of BL
There are few literature reports on BL, especially SBL. Sabaté and Liu et al[15,16] found that there was no significant difference between PBL and SBL analyzed by the findings of MRI. However, they found that the diameter of SBL lesions is smaller than PBL. Surov et al found that the number of lesions in SBL is more numerous than PBL, and the lesion of PBL was larger than SBL. Moreover, there were no differences between the PBL and SBL in the morphology and margin features of the lesions . In this study, the mean diameter of lesions in PBL group was larger than that of the SBL group, and no morphological difference were found between the two groups. However, a meaningful comparison cannot be made due to the limited number of cases. According to the mammography features of BL,[17,18] BL can be roughly divided into three types: nodular type, mass type, and infiltrative type. The nodular type typically shows non-calcified, clear or obscure margins, round or lobulated nodules, and spicule sign is rare; although lesions may be single or multiple. The mass type typically presents with a single, huge mass, well-defined border, and the skin adjacent to the lesion is not affected. The infiltrative type shows a high density shadow of the breast, invading a single quadrant or the entire breast with diffuse thickening of the skin. The subcutaneous tissue showed a grid-like change, and the affected breast rarely possessed a crater nipple.
Reports document MRI findings of BL are rare. Liu et al analyzed the MRI findings of 12 patients with PBL and 8 patients with SBL and found no meaningful difference between PBL and SBL on MRI. The main findings of MRI were irregular margins with heterogeneous enhancement. Some lesions showed separation, or non-entity like inhomogeneous enhancement. The time signal curves were dominated by plateau and washout types. Surov et al reported 8 cases of mostly smooth edge masses (81%), which showed homogeneous enhancement (82%), and the time signal curves was dominated by the plateau type (90%). The washout type was found in 1 case (5%). Wang et al analyzed 7 cases of BL. They found most cases of BL demonstrated homogeneous enhancement (87.5%) and time signal curves showed the washout type. However, 1 case revealed a ring-like enhancement and a plateau time signal curve. Histological features of BL are characterized by abundant, closely packed lymphocytes with small extracellular spaces, resulting in a significantly restricted and lower ADC value than that of breast cancer. Moreover, according to published literatures,[20,21] the ADC value of breast cancer ranged from 0.99 to 1.22, which was obviously higher than that of BL. This feature is helpful for differential diagnosis of BL and breast cancer. Wang et al analyzed 2 cases of BL and found the ADC value to be 0.876 × 10−3 mm2/s and 0.732 × 10−3 mm2/s, respectively. Our results showed that the ADC values of PBL and SBL were lower than the cases reported by Wang et al. Matsubayashi et al observed the findings of MRI and pathology of 3 patients with PBL. The results showed enhancement with penetrating vessels and septation in their lesions. In this study, five cases of PBL and 1 case of SBL had this characteristics.
Due to a lack of understanding of BL image features in the past, this often lead to misdiagnosis of breast cancer due to a poorly circumscribed lesion, thickening of skin, and enlargement of axillary lymph nodes. Although this study reported some findings, the major limitation of this study was the small sample of BL resulting from the rarity of BL, especially SBL. Meanwhile, the study is predominately a retrospective descriptive study, which was not designed to make specific comparisons between subgroups of BL or between BL and other breast pathology. Therefore, characteristics of BL need to be further investigated in future research.
Based on previous studies and data reported in this group, we observed several characteristics of BL:
- (1) BL can be roughly divided into the nodular type, mass type, and infiltrative type on mammography,
- (2) single mass BL does not involve the skin and the infiltrative subtype can present as extensive skin edema, and/or thickening,
- (3) in the early stage of enhancement, BL lesions were significantly enhanced with penetrating vessels and showed septation on DCE-MRI,
- (4) The ADC value of BL was observed to be lower than that of breast cancer.
These findings can be helpful in the diagnosis and differential diagnosis of BL.
Conceptualization: Changyu Zhou, Kun Lv.
Data curation: Dongya Lin, Yangyang Bu.
Formal analysis: Yinxing Yu, Maosheng Xu.
Investigation: Dongya Lin.
Writing – original draft: Changyu Zhou, Kun Lv.
Writing – review & editing: Yangyang Bu.
. Jeanneret-Sozzi W, Taghian A, Epelbaum R, et al. Primary breast lymphoma
: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study. BMC Cancer 2008;8:86.
. Wiseman C, Liao KT. Primary lymphoma
of the breast. Cancer 1972;29:1705–12.
. Avilés A, Delgado S, Nambo MJ, et al. Primary breast lymphoma
: results of a controlled clinical trial. Oncology 2005;69:256–60.
. Surov A, Holzhausen HJ, Wienke A, et al. Primary and secondary breast lymphoma
: prevalence, clinical signs and radiological features. Br J Radiol 2012;85:e195–205.
. Joks M, Myśliwiec K, Lewandowski K. Primary breast lymphoma
– a review of the literature and report of three cases. Arch Med Sci 2011;7:27–33.
. Teras LR, Patel AV, Hildebrand JS, et al. Postmenopausal unopposed estrogen and estrogen plus progestin use and risk of non-Hodgkin lymphoma
in the American Cancer Society Cancer Prevention Study-II Cohort. Leuk Lymphoma
. Walker R. Rosen's breast pathology. Prog Obstet Ginecol 2002;45:316.
. Ryan G, Martinelli G, Kuper-Hommel M, et al. Primary diffuse large B-cell lymphoma
of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma
Study Group. Ann Oncol 2008;19:233–41.
. Validire P, Capovilla M, Asselain B, et al. Primary breast non-Hodgkin's lymphoma
: a large single center study of initial characteristics, natural history, and prognostic factors. Am J Hematol 2009;84:133–9.
. Martinelli G, Ryan G, Seymour JF, et al. Primary follicular and marginal-zone lymphoma
of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma
Study Group. Ann Oncol 2009;20:1993–9.
. Talwalkar SS, Miranda RN, Valbuena JR, et al. Lymphomas involving the breast: a study of 106 cases comparing localized and disseminated neoplasms. Am J Surg Pathol 2008;32:1299–309.
. Negahban S, Ahmadi N, Oryan A, et al. Primary bilateral Burkitt lymphoma
of the lactating breast: a case report and review of the literature. Mol Diagn Ther 2010;14:243–50.
. Savvari P, Matsouka C, Barbaroussi D, et al. Burkitt's lymphoma
in pregnancy with bilateral breast involvement: case report with review of the literature. Onkologie 2010;33:461–4.
. Aviv A, Tadmor T, Polliack A. Primary diffuse large B-cell lymphoma
of the breast: looking at pathogenesis, clinical issues and therapeutic options. Ann Oncol 2013;24:2236–44.
. Liu K, Xie P, Peng W, et al. The features of breast lymphoma
on MRI. Br J Radiol 2013;86: 20130220.
. Sabaté JM, Gómez A, Torrubia S, et al. Lymphoma
of the breast: clinical and radiologic features with pathologic correlation in 28 patients. Breast J 2002;8:294–304.
. Ganjoo K, Advani R, Mariappan MR, et al. Non-Hodgkin lymphoma
of the breast. Cancer 2007;110:25–30.
. Liberman L, Giess CS, Dershaw DD, et al. Non-Hodgkin lymphoma
of the breast: imaging characteristics and correlation with histopathologic findings. Radiology 1994;192:157–60.
. Wang L, Wang D, Chai W, et al. MRI features of breast lymphoma
: preliminary experience in seven cases. Diagn Interv Radiol 2015;21:441–7.
. Bogner W, Gruber S, Pinker K, et al. Diffusion-weighted MR for differentiation of breast lesions at 3.0 T: how does selection of diffusion protocols affect diagnosis? Radiology 2009;253:341–51.
. Ei Khouli RH, Jacobs MA, Mezban SD, et al. Diffusion-weighted imaging improves the diagnostic accuracy of conventional 3.0-T breast MR imaging. Radiology 2010;256:64–73.
. Matsubayashi RN, Inoue Y, Okamura S, et al. MR imaging of malignant primary breast lymphoma
: including diffusion-weighted imaging, histologic features, and a literature review. Jpn J Radiol 2013;31:668–76.