COVID-19 Vaccine-Related Axillary and Cervical Lymphadenopathy in Patients with Current or Prior Breast Cancer and Other Malignancies: Cross-Sectional Imaging Findings on MRI, CT, and PET-CT

Since the first COVID-19 vaccine was issued emergency use authorization by the U.S. Food and Drug Administration [1] and COVID-19 vaccination in the United States began in December, 2020, COVID-19 vaccine-related axillary and cervical adenopathy has been reported on the side of inoculation within 2–4 days after vaccination [2, 3]. After vaccination, migration of antigens from the injection site to the draining nodes can result in lymph node enlargement [4]. The median duration of adenopathy reported after Moderna vaccine (mRNA-1273) administration is 1–2 days and approximately 10 days duration after Pfizer vaccine (BNT162b2) administration [2, 3].

COVID-19 vaccination-induced lymphadenopathy is increasingly seen on breast imaging; management can be confounded by current or past cancer history. Management of vaccine-related adenopathy detected on breast MRI or other cross-sectional imaging currently varies across radiology practices. The management algorithm for adenopathy seen after recent COVID-19 vaccination in a high risk or known breast cancer patient might differ from an average risk patient with adenopathy seen on an otherwise benign-appearing screening mammogram. As the population continues to be vaccinated in larger numbers, adenopathy caused by COVID-19 vaccination will be increasingly seen by breast radiologists and could result in screening callbacks, additional workups, and false positive biopsies. In this article, we describe six patients with current or prior cancer history who had adenopathy seen on breast MRI, CT, or PET-CT after COVID-19 vaccination; the management approach used for each patient is discussed.

Given the prevalence of COVID-19 vaccine-related axillary adenopathy already encountered by breast radiologists, there is discussion within the breast imaging community regarding the potential for excessive callbacks or unnecessary biopsies. The Society of Breast Imaging guidelines issued in January, 2021, suggested that unilateral axillary adenopathy seen on screening mammogram be issued a Breast Imaging-Reporting and Data System (BI-RADS) 0 report to allow callback for further assessment of the ipsilateral breast and axilla [6]. More recent literature reveals that some centers consider recent COVID-19 vaccination a known inflammatory cause of unilateral axillary adenopathy and therefore recommend a benign assessment (BI-RADS category 2), if adenopathy is ipsilateral to the site of recent COVID-19 vaccination and not palpable [5]. Management recommendations vary by institution, although recommendations have been recently published that offer practical algorithms for management of adenopathy seen after COVID-19 vaccination [4, 5].

Management can be confounded by a concurrent or past cancer diagnosis; vaccine-related adenopathy in such patients can be indistinguishable from nodal metastasis. It is critical to correlate with thorough clinical history and vaccination details. When patients with current or prior history of breast cancer receive COVID-19 vaccination, we recommend that injection be given in the arm contralateral to the malignancy; this helps avoid unnecessary biopsy of a benign vaccine-related reactive lymph node which may overlap in imaging appearance with a metastatic node if ipsilateral to the breast cancer. Although ideal to schedule imaging exams prior to the first injection as this would eliminate vaccine-related findings, this is not always feasible due to scheduling constraints. Delay of screening or surveillance until at least 6 weeks after the 2nd dose may help minimize false positive findings; however, breast screening has already been delayed due to the ongoing pandemic. During the pandemic, the utilization of screening mammography dropped 99% and the number of new diagnosed cancers decreased; delayed diagnosis of these cancers could have detrimental impact on their prognosis [7]. Moreover, patients with a breast complaint require timely diagnostic workup and cannot be safely deferred. Physical exam should evaluate for palpable adenopathy or other suspicious clinical findings. Lehman et al. [8] suggest an approach for management of vaccine-related adenopathy based on clinical presentation, which encourages breast imaging regardless of vaccination status and acknowledges that in appropriate clinical scenarios, unilateral axillary adenopathy can be safely recognized as a benign finding after COVID-19 vaccination. To mitigate false positive nodal findings after COVID-19 vaccination, history of COVID-19 vaccination, number of doses and dates, along with site and laterality of injection should be documented at patient intake.

Patients who have concurrent breast cancer and ipsilateral indeterminate node may require nodal biopsy for accurate staging and treatment plan; the need to initiate oncologic treatment does not allow time to assess resolution of possible vaccine-related adenopathy, so we recognize that some false positive biopsies will be inevitable in these vaccinated patients. Biopsy in Patient 1 who had asymptomatic round lymph nodes was required due to ipsilateral breast cancer; the need to initiate oncologic treatment did not allow time for imaging follow-up. Even though adenopathy in Patient 4 was contralateral to the patient’s original breast malignancy, biopsy was pursued due to palpable nature of adenopathy and history of stage IIIC breast cancer. Contralateral nodal breast cancer metastases have rarely been reported [9, 10], and therefore if patients have history of more aggressive, higher stage, or locally advanced breast cancer, a lower threshold to biopsy an indeterminate node may be appropriate, even if contralateral to the original malignancy. In contrast, Patients 2 and 3 were considered low risk for nodal metastasis due to negative axillary lymph node status on the side ipsilateral to primary malignancy; the contralateral lymph nodes could therefore be safely assumed benign without biopsy.

Vaccination has been cited as a potential cause of false-positive results in FDG PET-CT imaging, previously reported after vaccination against influenza, H1N1, and human papillomavirus [11]. An early case report of FDG uptake in axillary nodes after COVID-19 vaccination described a patient with history of breast cancer and moderately increased FDG uptake in normal-sized axillary nodes 10 days after COVID-19 vaccination [12]. A second case report described a new cluster of subcentimeter axillary nodes with FDG uptake 2 days after COVID-19 vaccination [13]. Our Patient 6 demonstrates similar findings of increased FDG uptake in normal sized axillary nodes 15 days after ipsilateral injection of 1st dose Moderna vaccine. While there are now multiple studies describing COVID-19 vaccination-related adenopathy on FDG PET-CT [14, 15], the duration of vaccine-related FDG-avid nodal uptake remains not clearly defined. FDG nodal uptake has been previously reported up to 7 days after influenza vaccination and 1–14 days after H1N1 vaccination [11, 16, 17]. However, abnormal nodal appearance may persist longer on FDG-PET after COVID-19 vaccination, even in nonenlarged nodes [4]. The current mRNA vaccines might require longer time for resolution of adenopathy compared to other vaccines [18]. One study reports that 29% mRNA vaccine recipients have persistent FDG uptake between 7 to 10 weeks after second dose [19].

COVID-19 vaccines may cause a higher incidence of axillary adenopathy on breast MRI than other vaccines. Although little data exists regarding duration of vaccine-related adenopathy on breast MRI, it has been suggested that the time course of adenopathy seen on breast MRI might mirror the duration of increased nodal uptake seen on FDG PET-CT [20]. A published study regarding unilateral axillary adenopathy caused by COVID-19 vaccination and seen on breast MRI [20] described two patients with axillary adenopathy 13 days and 16 days after vaccination, respectively. The authors suggest that COVID-19 vaccine-related adenopathy visible on breast MRI may occur as early as 1–2 days after injection [20]. Indeed, review of our patients with known or prior history of breast cancer agrees that early onset of adenopathy can be seen on breast MRI after COVID-19 vaccination. Patient 1 showed axillary adenopathy on breast MRI only 4 days after receiving the 1st dose of Pfizer vaccine. Patient 5 had adenopathy on MRI 2 days after 2nd vaccine dose. Consistent with previous reports [20, 21], we have also observed that vaccine-related adenopathy seen on breast MRI can involve multiple levels of the axilla (seen in Patient 5) and can be more extensive than that seen on mammography, which only visualizes the level I axilla. COVID-19 vaccination can also cause cervical adenopathy on the side ipsilateral to injection, as demonstrated in Patient 4, who had adenopathy involving the level II axilla and supraclavicular region seen on neck CT.

In summary, as the population becomes increasingly vaccinated, more incidental axillary and cervical adenopathy is anticipated on imaging studies. Radiologist and referring clinician awareness is critical to avoid a large number of false positive biopsies. Axillary or cervical adenopathy after recent COVID-19 vaccination should be interpreted with knowledge of COVID-19 vaccination details and in the context of patient’s risk for nodal metastasis, potential limitations of the imaging modality, and impact on clinical treatment plans. In general, we favor a conservative management plan if possible, but recognize that false positive nodal biopsy may be inevitable in some breast cancer patients. Correlation with injection site and pathology of known malignancy may help minimize false positives. Further study regarding duration of COVID-19 related adenopathy is needed, and as it becomes available over the next months, timing guidelines for follow-up may be amended. Documentation of COVID-19 information will prove important for other radiology subspecialties as well, as they read cross-sectional imaging of studies that include the axilla and neck, where vaccine-related adenopathy may be seen.