Ipsilateral axillary lymphadenopathy is a well-documented finding associated with COVID-19 vaccination. Varying guidelines have been published for the management of asymptomatic patients who have a history of recent vaccination and present with incidental lymphadenopathy at screening mammography. Some experts recommend follow-up imaging, and others suggest that clinical management, rather than repeat imaging or biopsy, is appropriate. Symptomatic patients with lymphadenopathy and/or additional abnormal imaging findings should be treated differently depending on risk factors and clinical scenarios. Although ipsilateral lymphadenopathy is well documented, ipsilateral breast edema after COVID-19 vaccination has been rarely reported. The combination of ipsilateral lymphadenopathy and diffuse breast edema after COVID-19 vaccination presents a clinical management challenge because edema can obscure underlying abnormalities at imaging. For symptomatic patients with lymphadenopathy and associated breast parenchymal abnormality, prompt action is appropriate, including diagnostic evaluation and consideration of tissue sampling. This approach may prevent delays in diagnosis and treatment of patients with malignancy masked by symptoms from the vaccination.
The Pfizer-BioNTech and Moderna COVID-19 vaccines represent a new class of messenger RNA (mRNA) vaccines that have not previously been used to prevent illness. Since the emergency use authorization of these vaccines in the United States on December 11, 2020, the medical community has continued to learn about vaccination-related local and systemic side effects, including ipsilateral lymphadenopathy. Vaccine-related lymphadenopathy had been occasionally documented with influenza, human papillomavirus, and bacille Calmette-Guerin vaccines, but it is far less prevalent than the lymphadenopathy associated with COVID-19 vaccination [1–3]. The highly immunogenic nature of mRNA vaccines leads to both local and systemic side effects. In the Moderna COVID-19 vaccine trial , ipsilateral axillary swelling or tenderness was well documented in 10.2% of patients (4.8% in the placebo group) after the first dose and 14.2% of patients (3.9% in the placebo group) after the second dose. In the younger cohort (18–64 years old), axillary symptoms were even more prevalent (16.0%). The Pfizer clinical trials  documented lower rates of axillary swelling and tenderness. This symptom, however, was reported as an unsolicited adverse event and was not prospectively documented. The CDC reported that the mean duration of clinically evident lymphadenopathy in the arm and neck associated with the Pfizer vaccine was 10 days  and that the median duration associated with the Moderna vaccine was 1–2 days . Both trials likely underestimated the actual prevalence and duration, because ipsilateral lymphadenopathy can be asymptomatic.
Evidence of ipsilateral lymphadenopathy after COVID-19 vaccination, which predominantly involves the axillary, supraclavicular, and cervical nodes, is often incidentally detected on multimodality imaging [8, 9]. Sonographic findings include enlarged nodes with cortical thickening, loss of normal fatty hilum, and possible hypervascularity [8, 10]. MRI and CT findings include enlarged nodes with thickened cortex, some with mild surrounding fat stranding . FDG PET/CT shows hypermetabolic activity with increased FDG avidity in ipsilateral nodes, which may or may not be enlarged according to size criteria [8, 10].
The duration of COVID-19 vaccine–related lymphadenopathy is variable. In one series, all five patients who underwent fine-needle aspiration of lymphadenopathy detected up to 33 days after COVID-19 vaccination had reactive benign findings . In another study, which included 23 women , COVID-19 vaccine–associated axillary lymphadenopathy was found on breast imaging 2–29 days after vaccine administration; 87% of patients had no symptoms. Data from FDG PET/CT indicate that vaccine-associated lymphadenopathy persists longer than 4–6 weeks after administration [12, 13], and one study  showed that ipsilateral lymphadenopathy may last as long as 10 weeks. With high rates of vaccination in the U.S. population, ipsi-lateral lymphadenopathy is now frequently detected on imaging.
Although abundant literature has documented COVID-19 vaccine–associated lymphadenopathy, such literature has overwhelmingly not reported any breast parenchymal abnormalities, to our knowledge. However, two recent publications [15, 16] did report findings of COVID-19 vaccination–associated axillary and breast edema that subsequently resolved. In addition, we encountered a patient at our institution who presented with breast swelling and ipsilateral lymphadenopathy after recent COVID-19 vaccination and was subsequently diagnosed with invasive lobular breast cancer. It is important to recognize this clinical scenario and to manage these patients accordingly. We propose that patients presenting with axillary lymphadenopathy and with other breast symptoms or additional abnormal imaging findings be considered in a high-risk category and undergo prompt diagnostic evaluation and consideration of tissue sampling. If no focal abnormality is identified on initial workup (i.e., in association with the breast edema), then close-interval diagnostic imaging follow-up, preferably within 4 weeks, is recommended with consideration of breast MRI, referral for breast surgical consultation, and tissue sampling with punch biopsy.
Vaccine-Associated Axillary and Breast Edema
Both Pfizer-BioNTech  and Moderna  report injection site swelling and redness as a possible side effect of COVID-19 vaccines. This finding is reflected by studies [8, 17] showing increased signal in the deltoid muscle and skin at the site of injection on T2-weighted and STIR MRI caused by local inflammation and edema after vaccine administration.
A case study from 2012  showed marked upper extremity lymphedema after vaccination in two patients with prior treated breast cancer. One patient who had undergone left mastectomy and axillary lymph node dissection had extensive left arm lymphedema after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; poliovirus; yellow fever; hepatitis A; and typhoid fever vaccinations before travel. The other patient with a history of treated left breast cancer (type of surgery not reported) had left arm edema 6 hours after administration of tetanus vaccine. Neither patient had a history of upper extremity lymphedema before vaccinations or recurrence during follow-up. Although the mechanism of this phenomenon is unknown, the authors hypothesized that it may be related to increased lymphatic flow from inoculated vaccine immunogens and activated dendritic cells that compromise the previously adequate lymphatic flow. No breast abnormalities were documented in these patients.
Cases of COVID-19 vaccine–associated axillary or breast edema have been reported [15, 16]. One patient without a history of breast cancer developed axillary edema in addition to cortical thickening of ipsilateral axillary lymph nodes 1 day after COVID-19 vaccination, as found at screening breast MRI . This patient was evaluated with ultrasound 4 days after vaccination, which also showed the lymphadenopathy but also showed marked reduction in the axillary edema, which the authors thus attributed to an acute process. In a case series from the Mayo Clinic , three patients developed axillary and breast edema 1–11 days after COVID-19 vaccination. Two asymptomatic patients had findings of focal asymmetry on screening mammography due to trabecular thickening in the ipsilateral breast; one of these patients also had mild skin thickening. In these two patients, the abnormality had resolved at diagnostic breast imaging evaluation 4 days and 4 weeks, respectively, after the screening examinations. The third patient, who had symptoms, presented with a palpable and tender axillary lump. Trabecular thickening of the breast tissue in the right axillary tail was found at diagnostic mammography, and corresponding ultrasound showed lymphadenopathy with cortical thickening and subcutaneous edema. This patient noted clinical resolution of symptoms in less than 4 weeks and had normal findings at subsequent targeted ultrasound. All three patients had findings consistent with inflammatory changes and edema.
At our institution, an 81-year-old woman presented with 3 days of diffuse left breast swelling. She had received the first dose of COVID-19 vaccination (Pfizer-BioNTech) in the left arm 12 days before presentation and had no personal or family history of breast cancer or ovarian cancer. Digital diagnostic mammography with tomosynthesis (Fig. 1) and complete left breast ultrasound (Fig. 2) showed diffuse left breast swelling, skin thickening, parenchymal edema, and ipsilateral left axillary lymphadenopathy. Screening mammography performed 7 years previously had been un-remarkable (BI-RADS category 1). The patient had no findings to suggest a systemic cause or fluid overload on chest CT (Fig. 3), and there was no evidence of cardiac abnormality at recent echocardiography. The patient returned for biopsy 6 weeks after the diagnostic imaging (biopsy was delayed by patient-related factors rather than a clinical recommendation). At biopsy, the patient had interval clinical resolution of the left breast edema and skin thickening, but a new lump in the left upper outer breast was found that corresponded to a 10.8 × 7.1 × 10.0 mm irregular hypoechoic mass on targeted ultrasound (Fig. 4). Ultrasound-guided core biopsy of the breast mass yielded estrogen receptor–positive, progesterone receptor–positive, HER2-negative invasive lobular carcinoma, and fine-needle aspiration biopsy of the left axillary lymph node yielded metastatic invasive lobular carcinoma. Breast MRI (Fig. 5) performed 3 weeks after breast biopsy showed the index malignancy and multiple abnormal left axillary lymph nodes.
Management of Vaccine-Associated Lymphadenopathy
Postvaccine lymphadenopathy presents unique challenges in the care of patients with a history of malignancy or suspected malignancy. This is especially relevant for imaging performed for cancer surveillance or diagnosis of suspected malignancy. Guidelines developed by a group of experts from multiple tertiary care centers  call for a 6-week interval of between completion of vaccination and screening imaging studies. However, these recommendations do not apply to patients with acute symptoms or those who need urgent treatment planning.
Management guidelines are particularly important in breast imaging given the wide range (20–56%) of malignancy rates associated with axillary lymphadenopathy of unknown causation on mammograms [20–22]. According to the 2013 BI-RADS atlas , BI-RADS category 0 should be used for axillary lymphadenopathy without an infectious or inflammatory cause, and BIRADS category 2 is appropriate when a benign cause is known. The Society of Breast Imaging  published new guidelines to assist with BI-RADS categorization in the setting of COVID-19 vaccination that call for a conservative approach to vaccine-related lymphadenopathy found at screening mammography. In this approach the lymphadenopathy is assessed BI-RADS category 0, and appropriate diagnostic workup and short-term (4–12 weeks) follow-up are provided after the final vaccine dose. Other institutions have suggested clinical management with an emphasis on the individual patient's overall risk profile and pretest probability of malignancy . These centers consider COVID-19 vaccination a known inflammatory cause and support assignment of BIRADS category 2 with clinical follow-up and further imaging only if symptoms persist or worsen after 6 weeks [25, 26]. These recommendations apply only to asymptomatic patients who have isolated ipsilateral lymphadenopathy. It is crucial that the care of patients with breast symptoms or breast abnormalities on imaging be managed differently. In the algorithm suggested by Lehman et al. , management of symptomatic axillary lymphadenopathy and additional imaging findings within the breast that could be related to lymphadenopathy is based on the discretion of the radiologist, the patient's clinical evaluation, and the imaging characteristics of the lymphadenopathy [25, 26]. We support this differentiation and recommend treating patients with breast symptoms or with abnormalities on breast imaging in a separate category regardless of COVID-19 vaccination status.
Management of Vaccine-Associated Lymphadenopathy With Diffuse Breast Edema
Although ipsilateral breast edema associated with COVID-19 vaccination appears to be rare, it is important to recognize this clinical scenario and to treat these patients carefully. All four patients with COVID-19 vaccination–associated axillary and breast edema reported in two studies [15, 16] had interval resolution of abnormalities within 4 weeks. The patient at our institution, however, was subsequently diagnosed with invasive lobular breast cancer. Although the cause of the patient's breast edema cannot be determined, the onset after vaccination with interval clinical resolution at follow-up suggests a probable vaccine-related reaction.
When a patient has diffuse edema, it is important to consider the broad differential diagnosis of unilateral breast edema, including both malignant and benign causes. Initial history, physical examination, and diagnostic workup should exclude possible benign causes, including mastitis, congestive heart failure, venous occlusion, and trauma, and iatrogenic causes, such as prior surgery or radiation treatment [27–29]. Managing clinicians must then consider the possible malignant causes, including inflammatory breast cancer, primary or metastatic breast cancer obstructing lymphatic drainage, and breast lymphoma [27, 28]. Appropriate diagnostic evaluation with mammography and breast ultrasound should be performed. Because breast edema can limit imaging evaluation, if no focal abnormality is identified at initial workup, close-interval diagnostic imaging follow-up, preferably within 4 weeks, is recommended. If abnormalities persist, breast MRI, referral for breast surgical consultation, and tissue sampling with punch biopsy should be considered for further evaluation. This approach is especially important if there is any concern about inflammatory breast cancer, because patients often present with skin changes and edema that can mask underlying lesions in addition lymphadenopathy . Therefore, patients who have symptomatic lymphadenopathy and associated breast parenchymal abnormalities, including breast edema, must be differentiated from those who have isolated symptomatic lymphadenopathy; the former are considered in a high-risk category.
We have reviewed the limited literature to date on the combination of axillary lymphadenopathy and breast edema after COVID-19 mRNA vaccination. We incorporate into this presentation a unique case of symptomatic lymphadenopathy confounded by profound unilateral breast swelling after recent vaccination with subsequent biopsy revealing invasive lobular carcinoma and nodal metastasis. Although ipsilateral axillary and breast edema associated with COVID-19 vaccination is uncommon, it is critical to exclude causes such as inflammatory breast cancer and underlying masses obscured by the edema. Patients presenting with axillary lymphadenopathy and with other breast symptoms or additional abnormal imaging findings should be considered in a high-risk category and need prompt diagnostic evaluation and consideration of tissue sampling.
Newfield L, Naschitz JE, Yeshurun D. BCG-induced axillary lymph-adenitis in the adult [in Hebrew]. Harefuah 1990; 119:199–200
Studdiford J, Lamb K, Horvath K, Altshuler M, Stonehouse A. Development of unilateral cervical and supraclavicular lymphadenopathy after human papilloma virus vaccination. Pharmacotherapy 2008; 28:1194–1197
Brown A, Shah S, Dluzewski S, et al. Unilateral axillary adenopathy following COVID-19 vaccination: a multimodality pictorial illustration and review of current guidelines. Clin Radiol 2021; 76:553–558
Eshet Y, Tau N, Alhoubani Y, Kanana N, Domachevsky L, Eifer M. Prevalence of increased FDG PET/CT axillary lymph node uptake beyond 6 weeks after mRNA COVID-19 vaccination. Radiology 2021; 300:E345–E347
Lehman CD, D'Alessandro HA, Mendoza DP, Succi MD, Kambadakone A, Lamb LR. Unilateral lymphadenopathy after COVID-19 vaccination: a practical management plan for radiologists across specialties. J Am Coll Radiol 2021; 18:843–852
Lehman CD, Lamb LR, D'Alessandro HA. Mitigating the impact of coronavirus disease (COVID-19) vaccinations on patients undergoing breast imaging examinations: a pragmatic approach. AJR 2021; 217:584–586