COVID-19 Vaccine-Associated Lymphadenopathy in Breast Imaging Recipients: A Review of Literature

The unpredictability of the coronavirus disease 2019 (COVID-19) pandemic has created an ongoing global healthcare crisis. Implementation of a mass vaccination program to accelerate disease control remains in progress. Although injection site soreness, fatigue, and fever are the most common adverse reactions reported after a COVID-19 vaccination, ipsilateral lymph node enlargement has increasingly been observed. In patients undergoing routine screening and surveillance for breast cancer, interpreting lymphadenopathy (LAP) is challenging in the setting of a recent COVID-19 vaccination. With a growing proportion of the population receiving the vaccine, a multifaceted approach is necessary to avoid unnecessary and costly workup. In this comprehensive review, we summarize the existing literature on COVID-19 vaccine-associated LAP in breast imaging patients.

A comprehensive literature search was performed by three authors (RTA, JR, JD) using scientific databases including PubMed, Google Scholar, and Science Direct. Search strings included "COVID-19" AND "vaccine" AND "lymphadenopathy" AND "mammogram" OR "mammography" OR "breast imaging" OR "breast MRI." No MeSH terms were utilized. The following study designs were included in our final review: retrospective, case series, and case reports. Pre-existing literature reviews and systematic reviews were excluded. All articles were reviewed for relevancy by reading the title and abstract. After removing duplicate articles, we included data from 26 studies relevant to our topic. We included retrospective observational studies, case series, and case reports published in English. Many of these articles included patients with breast imaging such as mammography (MMG), breast ultrasounds (US), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). The table in Appendices comprises a list of articles used in this report and briefly describes each.

Data Collection
Data extraction was completed independently by three authors (RTA, JR, JD). These studies examined characteristics such as age, prior history of breast cancer, malignant findings, and adenopathy location in addition to variables such as imaging type, vaccination type, days since the last COVID-19 vaccination, and whether patients received the first or second dose of the vaccine.

Results
In our literature review, 26 published (11 retrospective studies, eight case reports, and seven case series) articles were included (Tables 1; table in the Appendices). An analysis of these articles can be seen in Table  1.

Discussion
LAP reports will likely increase as the COVID-19 vaccine reaches a broader patient population. With increasing vaccination rates, side effects from vaccination are expected to become more noticeable, and thus more likely to be reported. The purpose of this literature review was to summarize the available data related to LAP after receiving at least one dose of the COVID-19 vaccine. It is essential to consider time variation, the number of vaccinations received, and personal patient characteristics when LAP is reported on breast imaging.

LAP Characteristics
Across the 26 studies reviewed, a total of 5,162 patients received at least one dose of the COVID-19 vaccine, with 1,906 patients (36.92%) showing signs of post-vaccination LAP [7,. Axillary LAP was seen across all studies, while supraclavicular, intramammary, and subpectoral LAP was also noted, though less frequently [7,17,29,32]. LAP was found through various imaging modalities, including MMG, US, MRI, and PET/CT, with and without fluorodeoxyglucose (FDG) tracing.

Timing
Studies that reported the number of days since the last COVID-19 vaccination showed that LAP typically occurs within a month after vaccination. Considering the close timing after vaccine administration, LAP found on breast imaging after COVID-19 vaccination may not merit an aggressive workup. A thorough history and last vaccination date should therefore be taken before an aggressive workup is initiated. A retrospective case series by Robinson et al. found that patients who had received a COVID-19 vaccination within 90 days had a higher incidence of axillary adenopathy present on MMG [19]. The study identified 23 out of 750 cases of axillary adenopathy (3%), much higher than the 0.02-0.04% rate of adenopathy reported in normal MMG, particularly in the first two weeks following vaccination. Additionally, no instances of axillary adenopathy were identified in those who were observed 28 days post-vaccination [19].

Vaccine Type
While vaccinations against HIN1 Influenza, tuberculosis (TB), smallpox, measles, and human papillomavirus (HPV) are associated with regional LAP to varying degrees, post-vaccination LAP is an infrequent adverse effect in the aforementioned vaccinations [9,[36][37][38]. Meanwhile, this effect has been observed with higher frequency in SARS-CoV-2 mRNA vaccine recipients [39]. The two mRNA COVID-19 vaccines, Pfizer and Moderna, were the first mRNA vaccines to be granted authorization by the FDA. Most vaccinations work by using a killed or weakened version of a pathogen to trigger the immune system to recognize and respond to it in the future. Messenger RNA (mRNA) vaccines work differently by using genetically engineered mRNA instead of part of an actual bacteria or virus. When mRNA is introduced into the body, it is displayed on antigen-presenting cells and then travels to regional axillary lymph nodes and initiates a large T-and B-cell response for the development of cellular and humoral immunity. As a result, the mRNA vaccination, unlike previous protein-based vaccinations, elicits a more robust immune response within lymph node germinal centers during antigen presentation [10]. The mRNA vaccinations, Moderna and Pfizer, were the two most frequently administered in the studies included in our review. Studies in which patients were administered AstraZeneca, a viral vector vaccine, and J&J, an adenovector vaccine, were less frequently mentioned.

Patient Characteristics
In this literature review, it appears that the women with adenopathy were predominantly between 30 years and 60 years of age. According to the United States Preventive Services Task Force (USPSTF), it is recommended for women 50-74 years old to get MMG every two years [40]. Do clinical professionals have an obligation to pursue aggressive workups if women receive MMG that reveals LAP in the setting of recent vaccination? Before the pandemic, women with LAP on breast imaging were recommended for further evaluation. However, vaccine-associated LAP should be considered to avoid unnecessary workup in this patient population.

Conservative Approach
In our literature review, 21 studies investigated whether patients with LAP following COVID-19 vaccination showed evidence of new malignant findings. As a whole, new malignancy findings were rarely reported. These 21 studies identified 1,172 patients with LAP, 28 of whom (2.4%) showed new malignancies on imaging. More specifically, in Horvat et al., among 104 patients with LAP and COVID-19 vaccinations, only three were newly diagnosed with breast cancer [26]. In the study by Cohen et al., 17 out of 332 women had a new breast cancer diagnosis [32]. A majority of the patients undergoing aggressive workup (e.g., biopsy) in these studies did not have evidence of malignancy. Follow-up US is less invasive than other imaging modalities and also did not reveal evidence of malignancy in most cases. Despite being less invasive, ultrasound is, however, less sensitive than biopsy for diagnosing malignancy. Therefore, it is important to acknowledge that false negatives can occur.

Management and Recommendations
In response to the original guidelines suggested by the Society of Breast Imaging, a large, multidisciplinary team of experts at three of the leading tertiary cancer centers in the United States have come forward with recommendations regarding radiographic imaging and post-vaccination imaging LAP. Their recommendations included the following: whenever possible, cancer-related imaging and screening should be performed before vaccination. As mortality rates due to infection are more significant than the reduction in mortality rates seen from screening, they suggested that patients being screened for cancer who are at increased risk or patients with a known history of cancer should not delay vaccination due to scheduled imaging, as these patients are at higher risk for serious COVID-19 infection and complications. In line with the recommendations by the Society of Breast Imaging in 2021, they suggested that screening MMG should either be scheduled before a patient's first dose or four to six weeks after the second dose of the vaccine. In addition, the team recommended extending this interval to six weeks after the final vaccination dose, stating that it is common for LAP to remain detectable on imaging at four weeks. Imaging should not be delayed in an acute situation [41].
If a patient has cancer or has a known history of cancer, all vaccinations should be administered contralateral to the affected side, in the same location on the arm [32]. Whenever new-onset LAP follows vaccination, Becker et al. recommend observation for six weeks before a thorough diagnostic workup and consider US follow-up if there is a history of cancer. A tissue biopsy should be performed only if there is a concern for metastatic nodal cancer, where prompt identification and treatment are required [41].
Since their initial recommendations in the winter of 2021, the Society of Breast Imaging updated its guidelines as of February 2022 for managing and screening individuals with post-vaccination LAP. It is no longer recommended to delay screening MMG for four to six weeks after the COVID-19 vaccination. A Breast Imaging Reporting and Data System (BI-RADS) category 1 was previously assigned to patients with unilateral axillary LAP on screening MMG with a recent history of COVID-19 vaccination. The latest guidelines recommend categorizing these patients as BI-RADS category 2 (benign), requiring further routine screening. If given a BI-RADS category 3 (probably benign), previous recommendations suggested a followup interval of four to twelve weeks. As post-vaccine LAP may persist for a prolonged period, the guidelines now suggest a follow-up interval of longer than twelve weeks. Patients with persistent axillary LAP were previously considered for biopsy. According to the Society of Breast Imaging, patients with improved axillary LAP should be assigned a BI-RADS category 2, or if the condition remains unchanged, a BI-RADS category 3, which will warrant continued follow-up at six months. A lymph node biopsy should only be considered if adenopathy increases [42].
It is essential to consider tissue sampling and prompt diagnostic evaluation in patients with LAP and associated breast parenchymal abnormalities. This refined approach may prevent delays in diagnosis and treatment for patients with malignancy masked by symptoms from vaccination. A review by Hao et al. highlights an instance in which a patient with ipsilateral LAP and associated breast parenchymal change (breast edema) seen on MMG twelve days post-vaccination was found to have a metastatic invasive lobular carcinoma on biopsy [43]. Hence, clinical judgment and consideration of associated symptoms are essential when determining whether to perform breast imaging.

Limitations
The study's design must be viewed in light of some limitations. A significant limitation is the insufficient sample size for a meaningful statistical analysis. Most of the literature available are case reports and case series. Therefore, we recognize that their findings lack generalization. Furthermore, the minimal cohort studies we found target different variables. This manuscript places all the available literature to date in one article for easy readability. Considerations for future studies with potential for generalizability may include prospective observational studies following patients with post-COVID-19 vaccine LAP over time.  Thirty-four women had benign results, and 9 had concern for malignancy. Four patients were diagnosed with metastatic breast cancer.  underwent a lumpectomy, and a pathological examination of the excised tissue showed ductal carcinoma in situ (DCIS) with a single focus of microinvasion. Given upgrade to invasive disease, a sentinel lymph node biopsy was performed for staging, and two sentinel nodes were negative, consistent with the diagnosis of vaccination-associated reactive LAP. 26 Bernstine et al. [35] Axillary lymph nodes

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.