Ipsilateral axillary diagnostic ultrasound is part of the initial staging for breast cancer to evaluate lymph nodes using a b-mode classification where certain aspects, when present, increase the level of suspicion for metastatic disease, such as cortical thickening and poor hilar visibility.1–3 Diagnostic ultrasound is also used as a method to guide biopsies of the suspicious lymph nodes.1
The majority of patients will have no suspicious lymph nodes findings at the time of diagnosis, the lymphatic system mapping after the injection of blue dye and/or a radioactive tracer followed by a surgical excision becomes the only way to determine the final stage of disease. However, these methods have limitations such as the use of radiation and lack of an imaging component.
In the past, ultrasound could not be used for lymphatic mapping, since mapping requires administration of a tracer. This changed with the use of contrast-enhanced ultrasound (CEUS) to detect lymph nodes after subcutaneous injections of microbubble-based ultrasound contrast agents (UCA), termed “lymphosonography”.4–6 The development of the lymphosonography technique addressed the limitations of the currently used lymphatic mapping techniques.
Our group conducted a clinical trial to evaluate the efficacy of CEUS lymphosonography in the identification of sentinel lymph nodes (SLN) in patients with breast cancer undergoing surgical excision following the injection of blue dye and radioactive tracer as part of their standard of care using pathology results for malignancy as a reference standard.6,7
In the clinical trial, 86 subjects were enrolled and 79 completed the study. The subjects received 4 subcutaneous injections of ultrasound contrast agent around the tumor, for a total of 1.0 ml. A clinical ultrasound scanner with CEUS capabilities was used to identify SLNs. After the ultrasound study examination, the subjects received blue dye and radioactive tracer for guiding SLN excision as part of their standard of care. The SLNs excised during the standard-of-care surgical excision were classified as positive or negative for presence of blue dye, radioactive tracer and UCA, and sent for pathology to determine presence or absence of metastatic involvement.
A total of 252 SLNs were excised from the 79 subjects. Of the 252 SLNs excised, 158 were positive for blue dye, 222 were positive for radioactive tracer and 223 were positive for UCA. Statistical comparison showed that compared with the reference standards, lymphosonography showed similar accuracy with radioactive tracer (p > 0.15) and higher accuracy (p < 0.0001). The pathology results showed that, of the 252 SLNs excised, 34 had metastatic involvement and were determined malignant by pathology. Of these 34 SLNs, 18 were positive for blue dye (detection rate of 53%), 23 were positive for radioactive tracer (detection rate of 68%) and 34 were positive for UCA (detection rate of 100%; p < 0.0001).
The conclusion of this study indicates that lymphosonography had similar accuracy as the standard-of-care methods for identifying SLNs in breast cancer patients, with the added advantage of an imaging component that allows for a preoperative evaluation of SLNs and that lymphosonography may be a more specific and precise approach to SLN identification in patients with breast cancer.6
Larger multicenter clinical trials are necessary to be able to translate this technique to the clinical setting and to be able to incorporate it as part of the breast cancer patients’ standard of care.
Voit CA, van Akkooi ACJ, Schäfer-Hesterberg G, et al. Rotterdam Criteria for sentinel node (SN) tumor burden and the accuracy of ultrasound (US)-guided fine-needle aspiration cytology (FNAC): can US-guided FNAC replace SN staging in patients with melanoma? J Clinical Oncol 2009; 27(30):4994–5000.
Dialani V, Dogan B, Dodelzon K, Dontchos BN, Modi N, Grimm L. Axillary imaging following a new invasive breast cancer diagnosis—A radiologist’s dilemma. J Breast Imaging 2021; 3:645–658.
Chang JM, Leung JWT, Moy L, Ha SM, Moon WK. Axillary nodal evaluation in breast cancer: state of the art. Radiology 2020; 295:500–515.
Goldberg BB, Merton DA, Liu J-B, Thakur M, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology 2004; 230:727–734.
Goldberg BB, Merton DA, Liu J-B, Murphy G, Forsberg F. Contrast‐enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med 2005; 24:953–965. doi: 10.7863/jum.2005.24.7.953.
Machado P, Liu J-B, Needleman L, et al. Sentinel lymph node identification in patients with breast cancer using lymphosonography. Ultrasound Med Biol 2023; 49:616–625. Epub 2022 Nov 26.
Machado P, Liu JB, Needleman L, et al. Sentinel lymph node identification in post neoadjuvant chemotherapy breast cancer patients undergoing surgical excision using lymphosonography. J Ultrasound Med 2023; 42:1509–1517. doi: 10.1002/jum.16164. Epub 2023 Jan 2.
Priscilla Machado, MD, FAIUM, is a Research Assistant Professor in the Department of Radiology at Thomas Jefferson University in Philadelphia, PA.
Interested in learning more about ultrasound? Check out these posts from the Scan:
Can you please raise your arm? A few enlarged and unilateral axillary lymph nodes come into view. The cortex is eccentrically or diffusely thickened, they are enlarged, and they are hypervascular. Spotting an abnormal lymph node is not often the challenge, but knowing what to do with the lymph nodes can certainly be. First, I have a confession to make. I am a breast radiologist by training, and I am also fortunate to work in the body division in our department. This opportunity puts me in a unique position to explore both of the worlds and allows for collaboration and the exchange of knowledge.
Any radiologist who performs or interprets ultrasound exams knows that the patient history is of paramount importance along with available previous imaging exams. For example, a recently diagnosed breast cancer, unilateral cellulitis, and lymphoma all influence the management of axillary adenopathy. Similarly, cervical adenopathy can be seen as a reactive finding with head and neck infection, as well as in the setting of known malignancy like head/neck and thyroid cancers, which are prone to metastasize to neck lymph nodes. Vaccination history is also important when considering unexplained adenopathy, and it becomes particularly important with the introduction of the COVID-19 vaccines, which is a mass vaccination undertaking.
The COVID-19 vaccination is administered in the deltoid muscle. As a result, the reactive locoregional adenopathy in the axilla and cervical region has been observed (1). Axillary and/or cervical adenopathy as unsolicited adverse events for the Pfizer-BioNTech vaccine were reported in up to 0.3% among vaccine recipients (as opposed to 0.1% in the placebo group) (2). This adenopathy had onset about 2 to 4 days after vaccination and lasted an average of about 10 days. In the Moderna trial, 1.1% of the vaccination group versus 0.6% of the placebo group reported axillary and/or cervical adenopathy within 2 to 4 days after vaccination (3). However, the median duration of adenopathy with the Moderna vaccine was reported to be 1 to 2 days. It is important to note that these trials did not pursue the incidence of adenopathy via imaging such as ultrasound or regular physical examinations by a practicing physician after vaccination. Therefore, true incidence of axillary or cervical adenopathy remains unknown and is likely much higher than reported.
A total of 0.02% to 0.04% of otherwise normal screening mammograms present with unilateral adenopathy (4-6). During the early months of 2021, it was surprising to encounter a higher frequency of screening mammograms demonstrating unilateral adenopathy, which subsequently required a screening callback for further evaluation. As word spread in the breast imaging community, the Patient Care and Delivery Committee of the Society of Breast Imaging (SBI) issued a set of management guidelines in January 2021 for axillary adenopathy following the COVID-19 vaccination (7).
The dilemma of unilateral adenopathy extended beyond just screening mammograms. Any exams covering the anatomical regions of the axilla and lower neck started to show enlarged lymph nodes. Some examples of these exams include soft tissue ultrasound in the setting of a palpable mass, screening ultrasound exams for indications such as thyroid cancers, and cross-sectional examinations including MRI shoulder exams, CT Chest, and PET-CT.
Locoregional adenopathy has been encountered in the setting of other vaccines like influenza and shingles. However, unlike other vaccines with documented adenopathy among adults, the COVID-19 vaccine is a mass-scale vaccination program and the incidence of adenopathy is expected to be very high in numbers. Furthermore, the vaccination history is not routinely available in the medical chart, at least in early 2021, presumably due to a lack of automated connection between state health departments and unique health center-based electronic medical records. Therefore, effort should be made to document vaccination history either at the time of scheduling or at the time of imaging. At our Institution, the COVID-19 vaccine history including the timing of dose(s) is now routinely reviewed and documented for all breast exams including mammography (both screening and diagnostic), ultrasound, and MRI exams as well as ultrasound exams evaluating the axillary and/or neck regions.
Cancer screening is an important and challenging responsibility. Early detection is important in order to improve mortality and reduce morbidity. The COVID-19 vaccination campaign continues, and the race to protect as many people as possible is more important than ever. As radiologists, it is imperative to follow the data and carefully evolve in order to appropriately diagnose vaccine-related reactive adenopathy while avoiding the unintentional consequence of missing a cancer diagnosis.
So, where do we go from here now that we know adenopathy has been reported with both the Moderna and Pfizer vaccines? Initial consensus statement from a multidisciplinary panel specifically highlights the benefit of prioritizing COVID vaccination among patients with known cancer history, as the protection offered by the vaccine outweighs the unintended side effect of adenopathy (1).
Here, we would like to discuss possible solutions highlighted by the Society of Breast Imaging (SBI) and multi-institutional cancer imaging specialists, along with solutions based on our anecdotal institutional experience, that might be of benefit when faced with the dilemma of adenopathy in your clinical practice following COVID-vaccination.
Collaborate with your colleagues in other divisions and departments. Coordinate and establish a consistent algorithm to assist with the management of unexpected adenopathy in the context of recent COVID-19 vaccination.
Document COVID-19 vaccination history. This could consist of three phases: 1) The collected information could possibly include date of vaccine doses, laterality of the arm receiving the vaccine, and the brand of the vaccine) prior to a screening exam, particularly when it involves a head/neck or axillary evaluation. 2) Once set up, this strategy of vaccination documentation could then be expanded to all modalities including cross-sectional imaging exams, either at the time of scheduling or at the time of patient’s intake on the day of the exam. 3) The final phase would consist of documentation across your entire hospital system at the time of scheduling of various appointments or using online secured tools to encourage patients to document the same on a voluntary basis. Inter-connection between different systems already existing on many Electronic Medical Record (EMR) systems would be a powerful tool in this regard. Organized COVID vaccination history in a standard location within the EMR could improve accessibility for all healthcare providers.
Consider the timing of a routine screening exam. If the screening exam is non-urgent, consider scheduling the exam at a minimum of 4–6 weeks following the second dose of the COVID vaccine (SBI). However, a longer interval of 6 weeks has also been advised in this setting given preliminary evidence of adenopathy persisting at 4 weeks (1). The patient’s existing risk factors and anxiety should also be considered while pursuing delaying the exam.
Keep your patients informed. Discuss the known reports of adenopathy following vaccination. Review short-term follow-up as a reasonable initial option in this situation and when biopsy may be indicated.
Know when tissue diagnosis may be indicated. According to SBI, in the absence of any other suspicious mammographic finding or contributing history beyond the vaccine, short-term follow-up in 4–12 weeks following the second vaccine dose can be considered. If axillary adenopathy persists after that period of time, tissue diagnosis is warranted to exclude breast and non-breast malignancy. However, for patients with a newly diagnosed breast cancer, it may be more appropriate to rule out metastasis with a biopsy instead of short-interval imaging follow-up.
Identify clearly abnormal lymph nodes. Reactive lymph nodes typically present as diffuse enlargement while maintaining their reniform shape. Fatty hilum is present, although could be thinned out. Ultrasound exams might show tiny hypoechoic (not anechoic) areas, indicative of prominent germinal centers. On PET-CT exams, the standardized uptake values (SUVs) of >7.0 have been reported within the lymph nodes as opposed to the typical scenario of reactive lymph nodes in the neck showing SUVs between 2 and 3. However, heterogeneous distribution of SUVs within lymph nodes, clearly necrotic or cystic areas within lymph nodes across all modalities, calcifications on CT and echogenic foci on ultrasound would indicate clearly abnormal lymph nodes, and tissue sampling in these cases will be indicated irrespective of COVID vaccine administration.
It is important to keep in mind that new knowledge and data continue to contribute to evolving guidelines and that current recommendations may change as we learn more.
Dr. Noelle Hoven is an Assistant Professor in the breast imaging division and Dr. Anil Chauhan is an Associate Professor in the thoracoabdominal division in the diagnostic radiology department at the University of Minnesota.
Becker AS, Perez-Johnston R, Chikarmane SA, et. al. Multidisciplinary Recommendations Regarding Post-Vaccine Adenopathy and Radiologic Imaging: Radiology Scientific Expert Panel. [published online ahead of print February 24, 2021] Radiology. doi: 10.1148/radiol.2021210436.
Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020; 383(27):2603–2615.
Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021; 384(5):403–416.
Patel T, Given-Wilson RM, Thomas V. The clinical importance of axillary lymphadenopathy detected on screening mammography: revisited. Clin Radiol. 2005; 60:64–71.
Lim ET, O’Doherty A, Hill AD, Quinn CM. Pathological axillary lymph nodes detected at mammographic screening. Clin Radiol. 2004; 59:86–91.
Chetlen A, Nicholson B, Patrie JT, Harvey JA. Is screening detected bilateral axillary adenopathy on mammography clinically significant? Breast J. 2012; 18:582–587.