Causes of Varied Internal Echo Patterns in Ultrasound Imaging of Breast Lymphoma

Causes of Varied Internal Echo Patterns in Ultrasound Imaging of Breast Lymphoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Causes of Varied Internal Echo Patterns in Ultrasound Imaging of Breast Lymphoma Yumi Kokubu, Tomo Osako, Takehiko Sakai, Yui Tomita, Chieko Kato, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7362488/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2026 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background Ultrasound (US) imaging of breast lymphoma often reveals a variety of internal echo patterns, making differentiation from breast cancer challenging. This study aimed to correlate pathological findings with US imaging features of breast lymphoma to enhance biopsy accuracy and diagnostic precision. Materials and methods We retrospectively analyzed 37 lesions (36 cases) with available US images and needle biopsy pathology specimens from breast lymphoma patients at our hospital between 2010 and 2021. The area ratios of tumor cells, mammary gland tissue, and adipose tissue in pathology specimens were compared with internal echo levels on US. Additionally, we assessed US images during the healing process in cases with complete resolution following treatment. Results US identified 34 of 37 lesions (92%) as masses. Of these, 23 (68%) exhibited mixed internal echoes, while 11 (32%) were hypoechoic. Among the mixed echo lesions, 8 (24%) displayed a mixed hyper-to-hypoechoic pattern, and 15 (44%) showed a mixed iso-to-hypoechoic pattern. Pathological analysis revealed that the tumor cell area ratio was highest in hypoechoic masses, mammary gland tissue ratio was highest in mixed iso-to-hypoechoic masses, and adipose tissue ratio was highest in mixed hyper-to-hypoechoic masses. During healing, the mass changed to non-mass abnormalities in 10 cases (77%) and decreased in size while retaining its shape in 3 cases (23%). Conclusion The internal echo patterns of breast lymphoma varied depending on three factors: the proportion of tumor cells; the presence of tumor cell low-density areas; and adipose tissue infiltration. Hypoechoic areas likely reflected tumor cells, isoechoic areas mammary gland tissue, and hyperechoic areas adipose tissue infiltration. These findings suggest that biopsy from hypoechoic regions is recommended for accurate diagnosis. breast lymphoma breast ultrasound high-resolution ultrasound internal echo pattern breast biopsy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Breast lymphoma is a rare disease accounting for 0.04–0.53% of malignant breast tumors [ 1 – 3 ].” Breast lymphoma can grow rapidly, necessitating prompt and accurate diagnosis. The treatment of breast lymphoma is mainly chemotherapy, while surgery may be the first choice for breast cancer. Despite the importance of distinguishing between the two, it is currently difficult due to the nonspecific images of breast lymphoma, which are similar to those of breast cancer [ 4 – 6 ]. While breast lymphoma has been reported to show a variety of internal echo patterns on ultrasound (US) [ 6 – 10 ], there are no reports in which the cause of this variation has been examined in detail. Since breast lymphoma is not surgically resected, it is not possible to compare US images with pathological findings. However, US images can be compared with pathological tissue findings obtained by needle biopsy. In recent years, high-resolution US devices have made it possible to observe the normal structure and lesions of the mammary gland in greater detail than before [ 11 – 13 ]. Slight differences in the internal echo level of lesions can be depicted, and lesions with truly homogeneous internal echoes are rare. It is becoming possible to obtain image findings that more closely reflect pathological macro-images. In general, internal echo patterns of breast cancer vary according to the components of the lesion such as tumor cells, adipose tissue, fibrous tissue, mucinous components, cystic components, and necrotic tissue. On the other hand, since lymphoma lesions are mainly composed of tumor cells and mammary gland tissue, tumor cell density may be associated with internal echo patterns. If the association between tumor cell density and internal echo patterns within the lesions is clarified, this would lead to more accurate biopsies and diagnoses. Furthermore, evaluating US changes during the healing process in cases that achieved complete remission may provide greater insight into lesion composition. In this study, we divided internal echo patterns into hypoechoic lesions and lesions with mixed echo levels. We then further divided the lesions with mixed echo levels into mixed hyper-to-hypoechoic lesions and mixed iso-to-hypoechoic lesions for evaluation. By evaluating the internal echo level of lesions in the above way and comparing them with histopathological findings from needle biopsy specimens, we were able to clarify the cause of internal echo patterns in breast lymphoma. Patients and methods Patients From 2010 to 2021, 12,522 lesions were diagnosed as malignant based on pathological diagnoses of breast needle biopsy. Of these, 45 lesions from 44 cases (0.4%) were diagnosed with breast lymphoma. In this study, US images and needle biopsy pathology specimens from 36 cases (37 lesions) were reviewed. In addition, when multiple lesions were present in the same breast, only the mass on which the biopsy was performed was evaluated. Equipment For US imaging, we used the Aplio 500, the AplioXG (Canon Medical Systems, Tokyo, Japan), and the LOGIQ E9 (GE Healthcare, Milwaukee, WI, USA), while the probes used were all linear transducers of 10 MHz or higher. Methods The following four items were evaluated: 1) The US images of lesions 2) The area ratios of tumor cells, mammary gland tissue, and adipose tissue in needle biopsy pathology specimens 3) The presence or absence of tumor cell low-density areas in needle biopsy pathology specimens 4) US images during the healing process in cases that achieved complete remission following treatment 1) Evaluation of the US images of lesions (Fig. 1 ) US images of lesions were evaluated in accordance with the Breast Ultrasound Guidelines [ 14 ] of JABTS. Lesions were classified into masses and non-mass abnormalities. Masses were evaluated for shape, margin, posterior echo, and internal echo pattern. Internal echo patterns of masses were classified into hypoechoic and mixed echo. Masses with a mixed echo were further classified into mixed hyper-to-hypoechoic and mixed iso-to-hypoechoic masses, and the US findings of each were evaluated. 2) Evaluation of the area ratios of tumor cells, mammary gland tissue, and adipose tissue in needle biopsy pathology specimens (Fig. 2 ) The area ratios of tumor cells, mammary gland tissue, and adipose tissue in hematoxylin and eosin staining (H&E) specimen of needle biopsy were evaluated, and the ratios were compared based on internal echo levels. If more than one biopsy specimen was collected, then the area ratio of the entire collected specimen was evaluated. A pathologist and a radiologist each evaluated the specimen, after which a decision was made by consensus. 3) Evaluation of the presence or absence of tumor cell low-density areas in needle biopsy pathology specimens (Fig. 3 ) Needle biopsy H&E specimens that are clearly thought to have been taken from within a mass may contain areas of very low tumor cell density. These regions may contribute to the internal echo patterns observed on US images. If a tumor cell low-density area of 1 mm x 0.5 mm or larger was observed, it was considered as a tumor cell low-density area, and the presence or absence of this finding was evaluated. Furthermore, the frequency of lesions with a tumor cell low-density area was compared based on internal echo levels. 4) US images during the healing process in cases that achieved complete remission following treatment We evaluated how lesions disappeared for cases where US images were obtained during the course of treatment. The frequency of each pattern was evaluated: those that changed from mass to non-mass lesions, those that changed from non-mass to mass lesions, and those that shrank while remaining in the form of mass or non-mass lesion. Statistical analysis The normality of the data was assessed using the Shapiro–Wilk test. For variables determined to be normally distributed, unpaired t -tests were used for comparisons between two groups. For variables that were not normally distributed, the Wilcoxon rank-sum test (Mann–Whitney U test) was employed. Statistical analyses were performed using R version 4.5.1, and a p-value of < 0.05 was considered statistically significant. Code of Ethics This study was approved by the ethics committee of the institution, and the committee determined that informed consent could be simplified. [2022-GB-019]. Results Patient characteristics All 36 cases were female, with an average age of 58.3 years (range: 22–83 years); Of these, 30 cases were primary breast lymphoma (PBL), and 6 cases were secondary breast lymphoma (SBL). All 36 cases were untreated for breast lesions. One of the 36 patients had lesions on both breasts, resulting in a total of 37 lesions were targeted. The disease types were diffuse large B-cell lymphoma (DLBCL) in 30 patients (81%), mucosa-associated lymphoid tissue (MALT) lymphoma in 4 patients (11%), follicular lymphoma in 1 patient with bilateral breast lesions (5%), and T-cell lymphoma in 1 patient (3%). 1) US evaluation of lesions (Tables 1a, 1b) US findings for 37 lesions showed 34 mass lesions (92%) and 3 non-mass abnormalities (8%). There were 28 cases with a single mass and 6 cases with multiple masses. For those with multiple masses, only the site where the biopsy was performed was evaluated. The mean mass diameter of 34 mass lesions was 47.9 mm, with a median of 40.5 mm (range: 9-150 mm). Of the 34 mass lesions, 16 (47%) were round or oval in shape, 13 (38%) were lobular in shape, and 5 (15%) were irregular in shape. Mass margins were circumscribed in 7 lesions (20%), well-defined and rough in 23 lesions (68%), and indistinct in 4 lesions (12%). Posterior echoes showed accentuation in 27 lesions (79%) and no posterior features in 7 lesions (21%), with no lesions exhibiting attenuation of the posterior echo. Internal echo patterns indicated that 23 mass lesions (68%) had mixed echo levels, while 11 mass lesions (32%) had hypoechoic levels. Among the masses with mixed echo levels, 9 lesions (27%) were classified as mixed hyper-to-hypoechoic, while 14 lesions (41%) were classified as mixed iso-to-hypoechoic. No masses with echogenic foci due to calcification were observed. In addition, there were no lesions with cystic portions or architectural distortion. All three lesions appeared as hypoechoic areas on US. Two of these lesions (one MALT lymphoma and one DLBCL) presented with a geographic hypoechoic area, while the remaining MALT lymphoma lesion showed a mottled hypoechoic area. 2) Evaluation of the area ratios of tumor cells, mammary gland tissues, and adipose tissues in needle biopsy pathology specimens (Table 2) The area ratios of tumor cells, mammary gland tissue, and adipose tissue in the histopathology of biopsy specimens was evaluated. However, three lesions in which the boundary between the mass and the peripheral tissue in the pathology specimen could not be evaluated were excluded. The area ratios of tumor cells, mammary gland tissues, and adipose tissues in needle biopsy specimens with a hypoechoic mass was 87:10:3. For the needle biopsy specimens with a mixed iso-to-hypoechoic mass, the ratio was 70:26:4. For the needle biopsy specimens with a mixed hyper-to-hypoechoic mass, the ratio was 80:7:13. Among tumor cells with internal echo levels of hypoechoic, mixed iso-to-hypoechoic, and mixed hyper-to-hypoechoic, the average area ratio of tumor cells was highest in hypoechoic masses. The mean area ratio of mammary gland tissues was highest in mixed iso-to-hypoechoic masses. The mean area ratio of adipose tissue was highest in mixed hyper-to-hypoechoic masses. Regarding the area ratio of mammary gland tissues, there was a significant difference between mixed iso-to-hypoechoic masses and mixed hyper-to-hypoechoic masses, as well as between mixed iso-to-hypoechoic masses and hypoechoic masses, respectively ( p < 0.001, 0.002). In addition, in the area ratio of tumor cells, there was a significant difference between mixed iso-to-hypoechoic masses and hypoechoic masses ( p = 0.006). On the other hand, there was a statistically significant difference in the adipose tissue area ratio between mixed iso-to-hypoechoic and mixed hyper-to-hypoechoic masses ( p = 0.035). In addition, in pathological specimens of mixed hyper-to-hypoechoic masses, tumor cells infiltrating into adipose tissues were confirmed in 7 of 8 lesions (88%). 3) Evaluation of the presence or absence of tumor cell low-density areas in needle biopsy pathology specimens (Table 2) The proportion of lesions with island-like tumor cell low-density areas in the pathological tissue of biopsy specimens was evaluated. The number of lesions with tumor cell low-density areas at internal echo levels of mixed hyper-to-hypoechoic, mixed iso-to-hypoechoic, and hypoechoic were 2 lesions (29%), 11 lesions (85%), and 2 lesions (18%), respectively. The tumor cell low-density area was most common in mixed iso-to-hypoechoic masses and least common in hypoechoic masses. 4) US images during the healing process in cases that achieved complete remission following treatment (Figs. 4 , 5 ) 28 cases were completely resolved by treatment (28 lesions: 25 mass lesions, 3 non-mass abnormalities). US images of the healing process of 13 cases (11 mass lesions, 2 non-mass abnormalities) in which disappearance of lesions was confirmed were evaluated. Among the 11 mass lesions, 9 lesions (82%) changed to non-mass abnormalities during the healing process, while 2 lesions (18%) shrank centripetally while maintaining their shape as a mass. Two of the non-mass abnormalities (Case No. 36, 37) confirmed by US imaging of the healing process were also recognized as non-mass abnormalities during the healing process. Non-mass abnormalities did not change into masses during the healing process. Discussion It has been reported that US imaging of breast lymphoma is characterized by a round or oval shape, with internal echo patterns exhibiting hypoechoic or a variety of echo level mixes. 92% of the lesions in this study exhibited mass lesions, while only 8% were non-mass abnormalities. The majority of the masses were round, oval, or lobular in shape. The boundaries were well-defined and rough. Posterior echoes indicated accentuation in 79% of cases and no posterior features in 21%, with no attenuation observed. This was thought to be due to the absence of fibrous component proliferation, which is the main cause of posterior echo attenuation. Similar findings with no posterior echo attenuation have been reported in the past [ 7 , 8 , 10 ]. Approximately 1/3 of the internal echo patterns exhibited hypoechoic, while the remaining 2/3 were a variety of echo level mixes. In this study, the internal echo patterns of masses were more likely to exhibit a variety of echo level mixes than hypoechoic. In contrast, previous reports found the frequency of hypoechoic lesions was higher than that of lesions with a variety of echo level mixes [ 5 , 7 – 9 , 15 ]. One possible reason for these differences is in the utilization of different equipment. In this study, a high-resolution device and a high-frequency probe made it possible to study internal echo patterns in three ways: hypoechoic, mixed iso-to-hypoechoic, and mixed hyper-to-hypoechoic. Mixed iso-to-hypoechoic lesions in this study may have been classified as heterogeneous hypoechoic masses in previous reports. Mixed hyper-to hypoechoic masses tended to have a higher area ratio of adipose tissues than hypoechoic or mixed iso-to-hypoechoic masses. On the other hand, in mixed iso-to-hypoechoic masses, the area ratio of mammary gland tissues was higher than that of other masses, with hypoechoic masses tending to have a higher area ratio of tumor cells than that of other masses. Lymphoma lesions have a very high tumor cell density, and areas with minimal non-tumor tissue appear hypoechoic on US images. On the other hand, if the background mammary gland is fatty or if subcutaneous adipose tissue is infiltrated by tumor cells, the mixed adipose tissue and tumor cells cause ultrasound backscattering, resulting in hyperechoic images. Additionally, if tumor cells are mixed within the interstitial tissue of the mammary gland, they are believed to produce isoechoic images. For this reason, we considered that the hyperechoic part reflected infiltration into adipose tissue, the iso-echoic part reflected mammary gland tissue, and the hypoechoic part reflected tumor cells. While some reports attribute hyperechogenicity in lymphoma masses to tumor cell infiltration into adipose tissue [ 16 – 18 ], other reports suggest that high tumor cell density is the cause [ 5 ]. In this study, the cause of iso-echoes can be inferred by dividing the mixed internal echo patterns into mixed hyper-to-hypoechoic and mixed iso-to-hypoechoic areas. A tumor cell low-density area was observed in more than 80% of mixed iso-to-hypoechoic and 50% of mixed hyper-to-hypoechoic lesions. A tumor cell low-density area was considered a factor indicating a variety of internal echo patterns. Lymphoma lesions are formed by cancerized lymphocytes, and the proliferation of fibrous tissue that is often observed in breast cancer is almost never observed. Therefore, the lesions themselves are formed by cancerized lymphocytes and normal mammary gland tissue. US findings of the lesions vary depending on the density of tumor cells and the component of the background mammary gland. Calcification was not observed in the biopsy pathology specimens of the lesions targeted. In addition, no hyperechoic foci suggesting calcification were observed in the target lesion even in US images. While there are similar reports of no calcification in lymphoma [ 1 , 3 , 6 – 9 , 19 ], there are also reports where calcification has been observed [ 4 , 10 ]. In addition, no spicula or architectural distortion was observed at the margins of the masses, similar to previous reports [ 1 , 8 , 19 ]. In lymphoma lesions, it was sometimes difficult to distinguish between masses and non-mass abnormalities. Fibrous capsules, which can be observed in breast cancer, are not formed around lymphoma masses. Rather, these masses are composed solely of tumor cells. When the tumor cell density at the margin of the mass was low, it was thought that the boundary with the normal structure was blurred. In this study, a hypoechoic area in the mammary gland was observed in the three patients with non-mass abnormalities. In this study, the three patients with non-mass abnormalities exhibited a hypoechoic area in the mammary gland. Because of their low tumor cell density throughout the lesion, they were not recognized as masses and are thought to have exhibited an image of non-mass abnormalities. When an increase in tumor cell density occurred, it was thought that their hypoechoic area could easily change into a mass. Interestingly, we found that 2 of the 3 non-mass abnormalities were MALT lymphomas. Because MALT lymphoma has a slow progression [ 20 ], it may have been diagnosed prior to the formation of masses. In the evaluation of images during the course of treatment, there were more masses that changed to non-mass abnormalities compared to those that shrank while maintaining the shape of the mass, accounting for 82% of the total. These lesions were thought to exhibit an image of non-mass abnormalities due to decreased tumor cell density. Limitations There are several limitations of this study. Specifically, it was a single-center study. Additionally, the pathological specimens were evaluated by needle biopsy rather than the entire lesion, and the area ratio of the pathological specimens contained elements that cannot be obtained by cell counting, only allowing for an approximate visual value. In addition, while there were 30 lesions for DLBCL, other lesions were much less common with only 4 for MALT lymphoma, 2 for follicular lymphoma, and 1 for T-cell lymphoma. This was insufficient to examine the difference in US imaging by disease type. Conclusion Approximately 2/3 of the internal echo patterns in the mass of breast lymphoma were mixed hyper-to-hypoechoic or mixed iso-to-hypoechoic, while approximately 1/3 were hypoechoic. It was thought that internal echo patterns varied depending on three factors: the proportion of tumor cells; the presence of tumor cell low-density areas; and adipose tissue infiltration. Hypoechoic areas were thought to correspond to tumor cells, iso-echoes areas were thought to correspond to mammary gland tissue, and hyperechoic areas were thought to correspond to tumor cell infiltration into adjacent adipose tissue. From the above, it is considered desirable that biopsies be performed from the hypoechoic part that reflects a high tumor cell density. Declarations Acknowledgments The authors are deeply grateful to Dr. Kengo Takeuchi and Dr. Naoko Tsuyama of the Cancer Research Institute Pathology Department for their cooperation in collecting the case list and pathological specimens for this study. Conflict of interest The authors declare that they have no conflict of interest. References Sabaté JM, Gómez A, Torrubia S, Camins A, Roson N, De Las Heras P, et al. Lymphoma of the breast: clinical and radiologic features with pathologic correlation in 28 patients. Breast J. 2002 Sep-Oct;8(5):294-304. Giardini R, Piccolo C, Rilke F. 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Supplementary Files YumiKokubuTables.pptx Cite Share Download PDF Status: Published Journal Publication published 07 Apr, 2026 Read the published version in Breast Cancer → Version 1 posted Editorial decision: Major Revision 10 Sep, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers invited by journal 14 Aug, 2025 Editor assigned by journal 14 Aug, 2025 First submitted to journal 13 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7362488","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":500339593,"identity":"e45e6317-0ab5-4597-b5d5-8b2086750709","order_by":0,"name":"Yumi 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Research","correspondingAuthor":false,"prefix":"","firstName":"Chikako","middleName":"","lastName":"Takahata","suffix":""},{"id":500339601,"identity":"b4a15b3f-abc6-4b08-a1c4-61e0d4334bc0","order_by":8,"name":"Takayuki Ueno","email":"","orcid":"","institution":"Cancer Institute Hospital, Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Ueno","suffix":""},{"id":500339602,"identity":"f8a7c499-89ca-4485-b971-e662a5db21f9","order_by":9,"name":"Kiyoshi Matsueda","email":"","orcid":"","institution":"Cancer Institute Hospital, Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Kiyoshi","middleName":"","lastName":"Matsueda","suffix":""}],"badges":[],"createdAt":"2025-08-13 08:18:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7362488/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7362488/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12282-025-01820-5","type":"published","date":"2026-04-07T15:59:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89640386,"identity":"972fd585-507f-408e-8711-fe58a13ab09e","added_by":"auto","created_at":"2025-08-22 08:04:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1051809,"visible":true,"origin":"","legend":"\u003cp\u003eExamples of internal echo evaluations of masses\u003c/p\u003e\n\u003cp\u003ea: Hypoechoic mass\u003c/p\u003e\n\u003cp\u003eb: Mixed iso-to-hypoechoic mass\u003c/p\u003e\n\u003cp\u003ec: Mixed hyper-to-hypoechoic mass\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/eee80d0b8113c85c08dd55ae.png"},{"id":89642557,"identity":"873ded3f-d0fb-4f19-8efd-0b127ad037ef","added_by":"auto","created_at":"2025-08-22 08:20:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4396661,"visible":true,"origin":"","legend":"\u003cp\u003eExamples of evaluating the area ratios of tumor cells, mammary gland tissue, and adipose tissue in needle biopsy pathology specimens\u003c/p\u003e\n\u003cp\u003ea: The area ratio of tumor cells, mammary gland tissue, and adipose tissue is 100:0:0\u003c/p\u003e\n\u003cp\u003eb: The area ratio of tumor cells, mammary gland tissue, and adipose tissue is 60:40:0\u003c/p\u003e\n\u003cp\u003ec: The area ratio of tumor cells, mammary gland tissue, and adipose tissue is 65:0:35\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/ef54ec9e3b049f9553493666.png"},{"id":89640392,"identity":"9a7ef116-8192-4734-bd8a-7d00d3702793","added_by":"auto","created_at":"2025-08-22 08:04:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2249169,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluation of tumor cell low-density areas in needle biopsy pathology specimens\u003c/p\u003e\n\u003cp\u003eSeveral tumor cell low-density areas were found in the biopsy specimen. Since the tumor cell low-density area was observed in the central area of the tissue and measured at least 1 mm x 0.5 mm, it was determined that there was a tumor cell low-density area.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/a33e3e20b76147b6d502a076.png"},{"id":89642101,"identity":"752534f1-87d7-4abb-9d49-77bb9097c94d","added_by":"auto","created_at":"2025-08-22 08:12:47","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":445753,"visible":true,"origin":"","legend":"\u003cp\u003eChange in the maximum diameter during the healing process in a completely resolved cases\u003c/p\u003e\n\u003cp\u003eThis diagram illustrates the change in the maximum diameter over time in 13 lesions in which the US image of the healing process was confirmed. The shape of the lesion is shown as a circle (〇) for masses and a cross (×) for non-mass abnormalities. Many of the masses had changed to non-mass abnormalities at an early stage after the start of treatment.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/d1a220bf558a752a4e842554.png"},{"id":89642103,"identity":"e02c57bb-0be5-42f3-8f1e-ea014d8ae656","added_by":"auto","created_at":"2025-08-22 08:12:47","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1743108,"visible":true,"origin":"","legend":"\u003cp\u003eFemale in her 50s with DLBCL (Case No. 17): US images of a case of complete remission case with chemotherapy\u003c/p\u003e\n\u003cp\u003ea. At symptom onset. Masses are seen as huge masses occupying left breast (arrowhead). The size of the mass is 75 x 70 x 21 mm and the internal echo pattern exhibits a mixed iso-to-hypoechoic pattern.\u003c/p\u003e\n\u003cp\u003eb. 7 months after the start of chemotherapy. The boundary of the mass is indistinct and has changed to a hypoechoic area (arrowhead). Part of the hypoechoic area is lumpy.\u003c/p\u003e\n\u003cp\u003ec. 8 months after the start of chemotherapy. The lesion is observed as a hypoechoic area (arrowhead). Echo levels have slightly increased throughout.\u003c/p\u003e\n\u003cp\u003ed. 12 months after the start of chemotherapy. The hypoechoic area has disappeared, and no abnormalities are detectable at the site where the lesion was previously located.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/6bb0c6633f6be4144ad99f2a.png"},{"id":106809187,"identity":"1728533e-940f-4c91-b0c6-88d5f231ad5f","added_by":"auto","created_at":"2026-04-13 16:07:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":15412135,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/4e926b1a-2b52-49db-af06-828ac2cbeeb9.pdf"},{"id":89640384,"identity":"65eea77d-3c0a-4601-8fe3-c9b80ee1e799","added_by":"auto","created_at":"2025-08-22 08:04:47","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":66291,"visible":true,"origin":"","legend":"","description":"","filename":"YumiKokubuTables.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7362488/v1/c9b1c1f756ac0f1e1b976bf1.pptx"}],"financialInterests":"","formattedTitle":"Causes of Varied Internal Echo Patterns in Ultrasound Imaging of Breast Lymphoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast lymphoma is a rare disease accounting for 0.04\u0026ndash;0.53% of malignant breast tumors [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u0026rdquo; Breast lymphoma can grow rapidly, necessitating prompt and accurate diagnosis.\u003c/p\u003e\u003cp\u003eThe treatment of breast lymphoma is mainly chemotherapy, while surgery may be the first choice for breast cancer. Despite the importance of distinguishing between the two, it is currently difficult due to the nonspecific images of breast lymphoma, which are similar to those of breast cancer [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile breast lymphoma has been reported to show a variety of internal echo patterns on ultrasound (US) [\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], there are no reports in which the cause of this variation has been examined in detail. Since breast lymphoma is not surgically resected, it is not possible to compare US images with pathological findings. However, US images can be compared with pathological tissue findings obtained by needle biopsy.\u003c/p\u003e\u003cp\u003eIn recent years, high-resolution US devices have made it possible to observe the normal structure and lesions of the mammary gland in greater detail than before [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Slight differences in the internal echo level of lesions can be depicted, and lesions with truly homogeneous internal echoes are rare. It is becoming possible to obtain image findings that more closely reflect pathological macro-images. In general, internal echo patterns of breast cancer vary according to the components of the lesion such as tumor cells, adipose tissue, fibrous tissue, mucinous components, cystic components, and necrotic tissue. On the other hand, since lymphoma lesions are mainly composed of tumor cells and mammary gland tissue, tumor cell density may be associated with internal echo patterns. If the association between tumor cell density and internal echo patterns within the lesions is clarified, this would lead to more accurate biopsies and diagnoses. Furthermore, evaluating US changes during the healing process in cases that achieved complete remission may provide greater insight into lesion composition. In this study, we divided internal echo patterns into hypoechoic lesions and lesions with mixed echo levels. We then further divided the lesions with mixed echo levels into mixed hyper-to-hypoechoic lesions and mixed iso-to-hypoechoic lesions for evaluation.\u003c/p\u003e\u003cp\u003eBy evaluating the internal echo level of lesions in the above way and comparing them with histopathological findings from needle biopsy specimens, we were able to clarify the cause of internal echo patterns in breast lymphoma.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003ePatients\u003c/p\u003e\u003cp\u003eFrom 2010 to 2021, 12,522 lesions were diagnosed as malignant based on pathological diagnoses of breast needle biopsy. Of these, 45 lesions from 44 cases (0.4%) were diagnosed with breast lymphoma. In this study, US images and needle biopsy pathology specimens from 36 cases (37 lesions) were reviewed. In addition, when multiple lesions were present in the same breast, only the mass on which the biopsy was performed was evaluated.\u003c/p\u003e\u003cp\u003eEquipment\u003c/p\u003e\u003cp\u003eFor US imaging, we used the Aplio 500, the AplioXG (Canon Medical Systems, Tokyo, Japan), and the LOGIQ E9 (GE Healthcare, Milwaukee, WI, USA), while the probes used were all linear transducers of 10 MHz or higher.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eThe following four items were evaluated:\u003c/p\u003e\u003cp\u003e1) The US images of lesions\u003c/p\u003e\u003cp\u003e2) The area ratios of tumor cells, mammary gland tissue, and adipose tissue in needle biopsy pathology specimens\u003c/p\u003e\u003cp\u003e3) The presence or absence of tumor cell low-density areas in needle biopsy pathology specimens\u003c/p\u003e\u003cp\u003e4) US images during the healing process in cases that achieved complete remission following treatment\u003c/p\u003e\u003cp\u003e\u003cspan\u003e\u003cp\u003e1) Evaluation of the US images of lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eUS images of lesions were evaluated in accordance with the Breast Ultrasound Guidelines [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] of JABTS. Lesions were classified into masses and non-mass abnormalities. Masses were evaluated for shape, margin, posterior echo, and internal echo pattern. Internal echo patterns of masses were classified into hypoechoic and mixed echo. Masses with a mixed echo were further classified into mixed hyper-to-hypoechoic and mixed iso-to-hypoechoic masses, and the US findings of each were evaluated.\u003c/p\u003e\u003cp\u003e2) Evaluation of the area ratios of tumor cells, mammary gland tissue, and adipose tissue in needle biopsy pathology specimens (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe area ratios of tumor cells, mammary gland tissue, and adipose tissue in hematoxylin and eosin staining (H\u0026amp;E) specimen of needle biopsy were evaluated, and the ratios were compared based on internal echo levels. If more than one biopsy specimen was collected, then the area ratio of the entire collected specimen was evaluated. A pathologist and a radiologist each evaluated the specimen, after which a decision was made by consensus.\u003c/p\u003e\u003cp\u003e3) Evaluation of the presence or absence of tumor cell low-density areas in needle biopsy pathology specimens (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNeedle biopsy H\u0026amp;E specimens that are clearly thought to have been taken from within a mass may contain areas of very low tumor cell density. These regions may contribute to the internal echo patterns observed on US images. If a tumor cell low-density area of 1 mm x 0.5 mm or larger was observed, it was considered as a tumor cell low-density area, and the presence or absence of this finding was evaluated. Furthermore, the frequency of lesions with a tumor cell low-density area was compared based on internal echo levels.\u003c/p\u003e\u003cp\u003e4) US images during the healing process in cases that achieved complete remission following treatment\u003c/p\u003e\u003cp\u003eWe evaluated how lesions disappeared for cases where US images were obtained during the course of treatment. The frequency of each pattern was evaluated: those that changed from mass to non-mass lesions, those that changed from non-mass to mass lesions, and those that shrank while remaining in the form of mass or non-mass lesion.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe normality of the data was assessed using the Shapiro\u0026ndash;Wilk test. For variables determined to be normally distributed, unpaired \u003cem\u003et\u003c/em\u003e-tests were used for comparisons between two groups. For variables that were not normally distributed, the Wilcoxon rank-sum test (Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test) was employed. Statistical analyses were performed using R version 4.5.1, and a p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003eCode of Ethics\u003c/p\u003e\u003cp\u003eThis study was approved by the ethics committee of the institution, and the committee determined that informed consent could be simplified. [2022-GB-019].\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\u003cp\u003eAll 36 cases were female, with an average age of 58.3 years (range: 22\u0026ndash;83 years); Of these, 30 cases were primary breast lymphoma (PBL), and 6 cases were secondary breast lymphoma (SBL). All 36 cases were untreated for breast lesions. One of the 36 patients had lesions on both breasts, resulting in a total of 37 lesions were targeted. The disease types were diffuse large B-cell lymphoma (DLBCL) in 30 patients (81%), mucosa-associated lymphoid tissue (MALT) lymphoma in 4 patients (11%), follicular lymphoma in 1 patient with bilateral breast lesions (5%), and T-cell lymphoma in 1 patient (3%).\u003c/p\u003e\u003cp\u003e1) US evaluation of lesions (Tables\u0026nbsp;1a, 1b)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eUS findings for 37 lesions showed 34 mass lesions (92%) and 3 non-mass abnormalities (8%). There were 28 cases with a single mass and 6 cases with multiple masses. For those with multiple masses, only the site where the biopsy was performed was evaluated. The mean mass diameter of 34 mass lesions was 47.9 mm, with a median of 40.5 mm (range: 9-150 mm).\u003c/p\u003e\u003cp\u003eOf the 34 mass lesions, 16 (47%) were round or oval in shape, 13 (38%) were lobular in shape, and 5 (15%) were irregular in shape. Mass margins were circumscribed in 7 lesions (20%), well-defined and rough in 23 lesions (68%), and indistinct in 4 lesions (12%). Posterior echoes showed accentuation in 27 lesions (79%) and no posterior features in 7 lesions (21%), with no lesions exhibiting attenuation of the posterior echo. Internal echo patterns indicated that 23 mass lesions (68%) had mixed echo levels, while 11 mass lesions (32%) had hypoechoic levels. Among the masses with mixed echo levels, 9 lesions (27%) were classified as mixed hyper-to-hypoechoic, while 14 lesions (41%) were classified as mixed iso-to-hypoechoic. No masses with echogenic foci due to calcification were observed. In addition, there were no lesions with cystic portions or architectural distortion.\u003c/p\u003e\u003cp\u003eAll three lesions appeared as hypoechoic areas on US. Two of these lesions (one MALT lymphoma and one DLBCL) presented with a geographic hypoechoic area, while the remaining MALT lymphoma lesion showed a mottled hypoechoic area.\u003c/p\u003e\u003cp\u003e2) Evaluation of the area ratios of tumor cells, mammary gland tissues, and adipose tissues in needle biopsy pathology specimens (Table\u0026nbsp;2)\u003c/p\u003e\u003cp\u003eThe area ratios of tumor cells, mammary gland tissue, and adipose tissue in the histopathology of biopsy specimens was evaluated. However, three lesions in which the boundary between the mass and the peripheral tissue in the pathology specimen could not be evaluated were excluded.\u003c/p\u003e\u003cp\u003eThe area ratios of tumor cells, mammary gland tissues, and adipose tissues in needle biopsy specimens with a hypoechoic mass was 87:10:3. For the needle biopsy specimens with a mixed iso-to-hypoechoic mass, the ratio was 70:26:4. For the needle biopsy specimens with a mixed hyper-to-hypoechoic mass, the ratio was 80:7:13.\u003c/p\u003e\u003cp\u003eAmong tumor cells with internal echo levels of hypoechoic, mixed iso-to-hypoechoic, and mixed hyper-to-hypoechoic, the average area ratio of tumor cells was highest in hypoechoic masses. The mean area ratio of mammary gland tissues was highest in mixed iso-to-hypoechoic masses. The mean area ratio of adipose tissue was highest in mixed hyper-to-hypoechoic masses. Regarding the area ratio of mammary gland tissues, there was a significant difference between mixed iso-to-hypoechoic masses and mixed hyper-to-hypoechoic masses, as well as between mixed iso-to-hypoechoic masses and hypoechoic masses, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 0.002). In addition, in the area ratio of tumor cells, there was a significant difference between mixed iso-to-hypoechoic masses and hypoechoic masses (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). On the other hand, there was a statistically significant difference in the adipose tissue area ratio between mixed iso-to-hypoechoic and mixed hyper-to-hypoechoic masses (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.035). In addition, in pathological specimens of mixed hyper-to-hypoechoic masses, tumor cells infiltrating into adipose tissues were confirmed in 7 of 8 lesions (88%).\u003c/p\u003e\u003cp\u003e3) Evaluation of the presence or absence of tumor cell low-density areas in needle biopsy pathology specimens (Table\u0026nbsp;2)\u003c/p\u003e\u003cp\u003eThe proportion of lesions with island-like tumor cell low-density areas in the pathological tissue of biopsy specimens was evaluated. The number of lesions with tumor cell low-density areas at internal echo levels of mixed hyper-to-hypoechoic, mixed iso-to-hypoechoic, and hypoechoic were 2 lesions (29%), 11 lesions (85%), and 2 lesions (18%), respectively. The tumor cell low-density area was most common in mixed iso-to-hypoechoic masses and least common in hypoechoic masses.\u003c/p\u003e\u003cp\u003e4) US images during the healing process in cases that achieved complete remission following treatment (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e28 cases were completely resolved by treatment (28 lesions: 25 mass lesions, 3 non-mass abnormalities). US images of the healing process of 13 cases (11 mass lesions, 2 non-mass abnormalities) in which disappearance of lesions was confirmed were evaluated.\u003c/p\u003e\u003cp\u003eAmong the 11 mass lesions, 9 lesions (82%) changed to non-mass abnormalities during the healing process, while 2 lesions (18%) shrank centripetally while maintaining their shape as a mass. Two of the non-mass abnormalities (Case No. 36, 37) confirmed by US imaging of the healing process were also recognized as non-mass abnormalities during the healing process. Non-mass abnormalities did not change into masses during the healing process.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIt has been reported that US imaging of breast lymphoma is characterized by a round or oval shape, with internal echo patterns exhibiting hypoechoic or a variety of echo level mixes. 92% of the lesions in this study exhibited mass lesions, while only 8% were non-mass abnormalities. The majority of the masses were round, oval, or lobular in shape. The boundaries were well-defined and rough. Posterior echoes indicated accentuation in 79% of cases and no posterior features in 21%, with no attenuation observed. This was thought to be due to the absence of fibrous component proliferation, which is the main cause of posterior echo attenuation. Similar findings with no posterior echo attenuation have been reported in the past [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eApproximately 1/3 of the internal echo patterns exhibited hypoechoic, while the remaining 2/3 were a variety of echo level mixes. In this study, the internal echo patterns of masses were more likely to exhibit a variety of echo level mixes than hypoechoic. In contrast, previous reports found the frequency of hypoechoic lesions was higher than that of lesions with a variety of echo level mixes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. One possible reason for these differences is in the utilization of different equipment. In this study, a high-resolution device and a high-frequency probe made it possible to study internal echo patterns in three ways: hypoechoic, mixed iso-to-hypoechoic, and mixed hyper-to-hypoechoic. Mixed iso-to-hypoechoic lesions in this study may have been classified as heterogeneous hypoechoic masses in previous reports.\u003c/p\u003e\u003cp\u003eMixed hyper-to hypoechoic masses tended to have a higher area ratio of adipose tissues than hypoechoic or mixed iso-to-hypoechoic masses. On the other hand, in mixed iso-to-hypoechoic masses, the area ratio of mammary gland tissues was higher than that of other masses, with hypoechoic masses tending to have a higher area ratio of tumor cells than that of other masses. Lymphoma lesions have a very high tumor cell density, and areas with minimal non-tumor tissue appear hypoechoic on US images. On the other hand, if the background mammary gland is fatty or if subcutaneous adipose tissue is infiltrated by tumor cells, the mixed adipose tissue and tumor cells cause ultrasound backscattering, resulting in hyperechoic images. Additionally, if tumor cells are mixed within the interstitial tissue of the mammary gland, they are believed to produce isoechoic images. For this reason, we considered that the hyperechoic part reflected infiltration into adipose tissue, the iso-echoic part reflected mammary gland tissue, and the hypoechoic part reflected tumor cells.\u003c/p\u003e\u003cp\u003eWhile some reports attribute hyperechogenicity in lymphoma masses to tumor cell infiltration into adipose tissue [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], other reports suggest that high tumor cell density is the cause [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this study, the cause of iso-echoes can be inferred by dividing the mixed internal echo patterns into mixed hyper-to-hypoechoic and mixed iso-to-hypoechoic areas.\u003c/p\u003e\u003cp\u003eA tumor cell low-density area was observed in more than 80% of mixed iso-to-hypoechoic and 50% of mixed hyper-to-hypoechoic lesions. A tumor cell low-density area was considered a factor indicating a variety of internal echo patterns. Lymphoma lesions are formed by cancerized lymphocytes, and the proliferation of fibrous tissue that is often observed in breast cancer is almost never observed. Therefore, the lesions themselves are formed by cancerized lymphocytes and normal mammary gland tissue. US findings of the lesions vary depending on the density of tumor cells and the component of the background mammary gland.\u003c/p\u003e\u003cp\u003eCalcification was not observed in the biopsy pathology specimens of the lesions targeted. In addition, no hyperechoic foci suggesting calcification were observed in the target lesion even in US images. While there are similar reports of no calcification in lymphoma [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], there are also reports where calcification has been observed [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition, no spicula or architectural distortion was observed at the margins of the masses, similar to previous reports [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn lymphoma lesions, it was sometimes difficult to distinguish between masses and non-mass abnormalities. Fibrous capsules, which can be observed in breast cancer, are not formed around lymphoma masses. Rather, these masses are composed solely of tumor cells. When the tumor cell density at the margin of the mass was low, it was thought that the boundary with the normal structure was blurred.\u003c/p\u003e\u003cp\u003eIn this study, a hypoechoic area in the mammary gland was observed in the three patients with non-mass abnormalities. In this study, the three patients with non-mass abnormalities exhibited a hypoechoic area in the mammary gland. Because of their low tumor cell density throughout the lesion, they were not recognized as masses and are thought to have exhibited an image of non-mass abnormalities. When an increase in tumor cell density occurred, it was thought that their hypoechoic area could easily change into a mass. Interestingly, we found that 2 of the 3 non-mass abnormalities were MALT lymphomas. Because MALT lymphoma has a slow progression [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], it may have been diagnosed prior to the formation of masses.\u003c/p\u003e\u003cp\u003eIn the evaluation of images during the course of treatment, there were more masses that changed to non-mass abnormalities compared to those that shrank while maintaining the shape of the mass, accounting for 82% of the total. These lesions were thought to exhibit an image of non-mass abnormalities due to decreased tumor cell density.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThere are several limitations of this study. Specifically, it was a single-center study. Additionally, the pathological specimens were evaluated by needle biopsy rather than the entire lesion, and the area ratio of the pathological specimens contained elements that cannot be obtained by cell counting, only allowing for an approximate visual value.\u003c/p\u003e\u003cp\u003eIn addition, while there were 30 lesions for DLBCL, other lesions were much less common with only 4 for MALT lymphoma, 2 for follicular lymphoma, and 1 for T-cell lymphoma. This was insufficient to examine the difference in US imaging by disease type.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eApproximately 2/3 of the internal echo patterns in the mass of breast lymphoma were mixed hyper-to-hypoechoic or mixed iso-to-hypoechoic, while approximately 1/3 were hypoechoic. It was thought that internal echo patterns varied depending on three factors: the proportion of tumor cells; the presence of tumor cell low-density areas; and adipose tissue infiltration. Hypoechoic areas were thought to correspond to tumor cells, iso-echoes areas were thought to correspond to mammary gland tissue, and hyperechoic areas were thought to correspond to tumor cell infiltration into adjacent adipose tissue. From the above, it is considered desirable that biopsies be performed from the hypoechoic part that reflects a high tumor cell density.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are deeply grateful to Dr. Kengo Takeuchi and Dr. Naoko Tsuyama of the Cancer Research Institute Pathology Department for their cooperation in collecting the case list and pathological specimens for this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSabat\u0026eacute; JM, G\u0026oacute;mez A, Torrubia S, Camins A, Roson N, De Las Heras P, et al. Lymphoma of the breast: clinical and radiologic features with pathologic correlation in 28 patients. Breast J. 2002 Sep-Oct;8(5):294-304.\u003c/li\u003e\n\u003cli\u003eGiardini R, Piccolo C, Rilke F. Primary non-Hodgkin\u0026apos;s lymphomas of the female breast. Cancer. 1992 Feb 1;69(3):725-35.\u003c/li\u003e\n\u003cli\u003eLiberman L, Giess CS, Dershaw DD, Louie DC, Deutch BM. Non-Hodgkin lymphoma of the breast: imaging characteristics and correlation with histopathologic findings. Radiology. 1994 Jul;192(1):157-60.\u003c/li\u003e\n\u003cli\u003ePicasso R, Tagliafico A, Calabrese M, Martinoli C, Pistoia F, Rossi A, et al. Primary and Secondary Breast Lymphoma: Focus on Epidemiology and Imaging Features. Pathol Oncol Res. 2020 Jul;26(3):1483-1488. \u003c/li\u003e\n\u003cli\u003eAdrada B, Wu Y, Yang W. Hyperechoic lesions of the breast: radiologic-histopathologic correlation. AJR Am J Roentgenol. 2013 May;200(5):W518-30. \u003c/li\u003e\n\u003cli\u003eRaj SD, Shurafa M, Shah Z, Raj KM, Fishman MDC, Dialani VM. Primary and Secondary Breast Lymphoma: Clinical, Pathologic, and Multimodality Imaging Review. Radiographics. 2019 May-Jun;39(3):610-625. \u003c/li\u003e\n\u003cli\u003eYang WT, Lane DL, Le-Petross HT, Abruzzo LV, Macapinlac HA. Breast lymphoma: imaging findings of 32 tumors in 27 patients. Radiology. 2007 Dec;245(3):692-702.\u003c/li\u003e\n\u003cli\u003eLyou CY, Yang SK, Choe DH, Lee BH, Kim KH. Mammographic and sonographic findings of primary breast lymphoma. Clin Imaging. 2007 Jul-Aug;31(4):234-8.\u003c/li\u003e\n\u003cli\u003eSurov A, Holzhausen HJ, Wienke A, Schmidt J, Thomssen C, Arnold D, et al. Primary and secondary breast lymphoma: prevalence, clinical signs and radiological features. Br J Radiol. 2012 Jun;85(1014):e195-205.\u003c/li\u003e\n\u003cli\u003eChen Y, Zhou JH, Fan HX, Luo Y, Peng YL, Ma BY. Ultrasound Diagnosis of Breast Lymphoma and the Identification of Breast Infiltrating Ductal Carcinoma. J Ultrasound Med. 2020 Jun;39(6):1203-1211. \u003c/li\u003e\n\u003cli\u003eIzumori A, Horii R, Akiyama F, Iwase T. Proposal of a novel method for observing the breast by high-resolution ultrasound imaging: understanding the normal breast structure and its application in an observational method for detecting deviations. Breast Cancer. 2013 Jan;20(1):83-91.\u003c/li\u003e\n\u003cli\u003eUematsu T. Non-mass-like lesions on breast ultrasonography: a systematic review. Breast Cancer. 2012 Oct;19(4):295-301.\u003c/li\u003e\n\u003cli\u003eWang LC, Sullivan M, Du H, Feldman MI, Mendelson EB. US appearance of ductal carcinoma in situ. Radiographics. 2013 Jan-Feb;33(1):213-28.\u003c/li\u003e\n\u003cli\u003eGuideline for Breast Ultrasound: Management and Diagnosis, 4th Edition. Japan Association of Breast and Thyroid Sonology,2020.\u003c/li\u003e\n\u003cli\u003eBalu-Maestro, J. N. Bruneton, A. Rogopoulos, P. Y. Marcy, T. Guidicelli, C. Raffaelli et al. Mammographic and ultrasonographic appearances of lymphoma of the breast. Eur Radiol.\u003cem\u003e \u003c/em\u003e1992;2(6):565-569.\u003c/li\u003e\n\u003cli\u003eTomita M, Oura S, Nishiguchi H, Makimoto S. A Case of Diffuse Large B Cell Lymphoma of the Breast with Predominantly High-Level Internal Echoes. Case Rep Oncol. 2020 Mar 25;13(1):309-313.\u003c/li\u003e\n\u003cli\u003eMatsuzaki M, Nomizu T, Katagata N, Sakuma T, Momma T, Tachibana K, Andoh J, et al. A case of primary malignant lymphoma of the breast with an unusual ultrasound image. Fukushima J Med Sci. 2010 Dec;56(2):145-50.\u003c/li\u003e\n\u003cli\u003ePark SY, Park JY, Park JW, Kim WH, Park JY, Kim HJ. Unexpected hyperechoic lesions of the breast and their correlations with pathology: a pictorial essay. Ultrasonography. 2022 Jul;41(3):597-609. \u003c/li\u003e\n\u003cli\u003eShim E, Song SE, Seo BK, Kim YS, Son GS. Lymphoma affecting the breast: a pictorial review of multimodal imaging findings. J Breast Cancer. 2013 Sep;16(3):254-65.\u003c/li\u003e\n\u003cli\u003eShibahara Y, Delabie JMA, Kulkarni S, Grant A, Prica A, McCready DR, et al. Primary MALT lymphoma of the breast: pathological and radiological characteristics. Breast Cancer Res Treat. 2024 Jun;205(2):387-394.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"breast lymphoma, breast ultrasound, high-resolution ultrasound, internal echo pattern, breast biopsy","lastPublishedDoi":"10.21203/rs.3.rs-7362488/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7362488/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUltrasound (US) imaging of breast lymphoma often reveals a variety of internal echo patterns, making differentiation from breast cancer challenging. This study aimed to correlate pathological findings with US imaging features of breast lymphoma to enhance biopsy accuracy and diagnostic precision.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMaterials and methods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed 37 lesions (36 cases) with available US images and needle biopsy pathology specimens from breast lymphoma patients at our hospital between 2010 and 2021. The area ratios of tumor cells, mammary gland tissue, and adipose tissue in pathology specimens were compared with internal echo levels on US. Additionally, we assessed US images during the healing process in cases with complete resolution following treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUS identified 34 of 37 lesions (92%) as masses. Of these, 23 (68%) exhibited mixed internal echoes, while 11 (32%) were hypoechoic. Among the mixed echo lesions, 8 (24%) displayed a mixed hyper-to-hypoechoic pattern, and 15 (44%) showed a mixed iso-to-hypoechoic pattern. Pathological analysis revealed that the tumor cell area ratio was highest in hypoechoic masses, mammary gland tissue ratio was highest in mixed iso-to-hypoechoic masses, and adipose tissue ratio was highest in mixed hyper-to-hypoechoic masses. During healing, the mass changed to non-mass abnormalities in 10 cases (77%) and decreased in size while retaining its shape in 3 cases (23%).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe internal echo patterns of breast lymphoma varied depending on three factors: the proportion of tumor cells; the presence of tumor cell low-density areas; and adipose tissue infiltration.\u003c/p\u003e\n\u003cp\u003eHypoechoic areas likely reflected tumor cells, isoechoic areas mammary gland tissue, and hyperechoic areas adipose tissue infiltration. These findings suggest that biopsy from hypoechoic regions is recommended for accurate diagnosis.\u003c/p\u003e","manuscriptTitle":"Causes of Varied Internal Echo Patterns in Ultrasound Imaging of Breast Lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 08:04:42","doi":"10.21203/rs.3.rs-7362488/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-09-10T08:41:32+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-08-14T07:06:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T06:58:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-14T05:23:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2025-08-13T09:41:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cbaf90ae-bbec-4fa8-a038-f7ad1caccb95","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:04:54+00:00","versionOfRecord":{"articleIdentity":"rs-7362488","link":"https://doi.org/10.1007/s12282-025-01820-5","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2026-04-07 15:59:23","publishedOnDateReadable":"April 7th, 2026"},"versionCreatedAt":"2025-08-22 08:04:42","video":"","vorDoi":"10.1007/s12282-025-01820-5","vorDoiUrl":"https://doi.org/10.1007/s12282-025-01820-5","workflowStages":[]},"version":"v1","identity":"rs-7362488","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7362488","identity":"rs-7362488","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}