key: cord-0953211-zgur5sa0 authors: Özütemiz, Can; Krystosek, Luke A.; Church, An L.; Chauhan, Anil; Ellermann, Jutta M.; Domingo-Musibay, Evidio; Steinberger, Daniel title: Lymphadenopathy in COVID-19 Vaccine Recipients: Diagnostic Dilemma in Oncology Patients date: 2021-02-24 journal: Radiology DOI: 10.1148/radiol.2021210275 sha: 91c923e2f22c034bd128f842b1fbccaec0e0834e doc_id: 953211 cord_uid: zgur5sa0 We present five cases of axillary lymphadenopathy which occurred after COVID-19 vaccination and that mimicked metastasis in oncologic patients. Initial radiologic diagnosis raised concerns for metastasis. However, further investigation revealed that patients received COVID-19 vaccinations in the ipsilateral arm prior to imaging. In two cases, lymph node biopsy confirmed vaccination related reactive lymphadenopathy. Ipsilateral axillary swelling / lymphadenopathy was reported based on symptoms and physical examination in COVID-19 vaccine trials. Knowledge of the potential for COVID-19 vaccine-related ipsilateral adenopathy is necessary to avoid unnecessary biopsy and change in therapy. The United States Food and Drug Administration issued emergency use authorization for two vaccines, Pfizer-BioNTech and Moderna COVID-19 vaccines, to help decrease COVID-19 infection and death in December 2020. As of February 6, 2021, about 28.9 million people in the United States had received one or more vaccine doses. (1) (2) (3) . In conjunction with the rapid administration of these vaccines, we have started to observe secondary effects on diagnostic imaging. In clinical studies, axillary lymphadenopathy was reported on the ipsilateral injection side (4, 5) . Ipsilateral axillary swelling/tenderness was the second most frequently reported local reaction to the Moderna COVID-19 vaccine, occurring in 11.6% and 16.0% of recipients following first and second dose respectively. In the Moderna cohort, clinically detected axillary and supraclavicular lymphadenopathy was reported in 1.1% of study participants within 2-4 days after vaccination, as an unsolicited adverse event (4) . In the Pfizer-BioNTech COVID-19 vaccine trial, the rate of ipsilateral axillary and supraclavicular lymphadenopathy was reported to be 0.3% among vaccine recipients versus <0.1% among placebo group (5). In the above vaccine trials, abnormal lymphadenopathy was reported based on physical examination rather than using imaging. In our center, we have observed unilateral axillary lymphadenopathy in five patients using different imaging modalities including PET/CT, MRI and ultrasonography. Initial diagnosis was concerning for metastasis; however, further investigation revealed that these patients had received COVID-19 vaccinations prior to imaging. A description of these patients is below. I n p r e s s Materials and Methods: An institutional review board waiver was obtained for this HIPAA compliant retrospective case series. Cases were identified from our institution from 12.21.2020 to 1.27.2021. In two cases diagnosis was confirmed by histopathology. In three, diagnosis was made based on combination of clinical and radiologic information. For Cases 1-4, the lymphadenopathy was discovered incidentally on radiologic imaging. Case 5 presented for evaluation of left breast and left axillary pain. pseudoprogression secondary to immunotherapy. Given that the biopsy proven index tumor showed complete response to treatment and true progression could not be excluded, a biopsy was recommended. However, further investigation revealed that the patient received the second I n p r e s s dose of Pfizer-BioNTech COVID-19 vaccine six days prior to PET/CT and there was triangular intramuscular FDG uptake in the left arm at the injection site ( Figure 1 ). Based on this information, left axillary lymphadenopathy was attributed to recent vaccination. Findings were discussed with the patient, and the patient opted for observation instead of biopsy. Follow up of the lymphadenopathy will be obtained as part of the patient's three-month follow-up PET/CT for melanoma surveillance. We have highlighted five cases with ipsilateral axillary lymphadenopathy following administration of Pfizer-BioNTech vaccine. Ipsilateral axillary lymphadenopathy following vaccinations has been previously reported with vaccinations other than COVID-19. For example, ipsilateral axillary and supraclavicular lymphadenopathy was clinically reported in a patient following HPV vaccine administration (6) . Radiologically, hypermetabolism in the ipsilateral lymph nodes was reported with 18-FDG PET/CT exams following seasonal H1N1 Influenza-A vaccines (7-9). Shirone et al reported hypermetabolic ipsilateral lymphadenopathy in 4 of 83 patients (4.8%) following seasonal influenza vaccination and all these reported cases were within I n p r e s s seven days following vaccination (9) . On January 22, 2021, the Society of Breast Imaging issued a statement for management recommendations of ipsilateral axillary lymphadenopathy following COVID-19 vaccinations. A recent ultrasonography case series of four patients, demonstrated ipsilateral asymmetrical lymphadenopathy following vaccination with both Pfizer-BioNTech and Moderna vaccines (10, 11) . None of these were confirmed as reactive lymphadenopathy on histopathology; but based on clinical and radiological findings, follow-up was recommended. Although lymphadenopathy related to vaccination has been known in breast cancer imaging, the unprecedented administration of COVID-19 vaccines is affecting almost all modalities of imaging. To our knowledge, a single PET/CT case was published similar to our fourth patient, although this case was without pathologic confirmation (12) . In two cases, we had pathologic confirmation of benign reactive lymphadenopathy secondary to vaccination and to our knowledge, these are the first pathologically proven cases in the literature. Although, the remaining three cases are not confirmed as reactive benign lymph nodes with histopathological evaluation, as we described above, it is more plausible to attribute these findings to recent vaccine administration. At present, no data is available regarding the duration of radiologically evident lymphadenopathy or appropriate follow-up intervals. Until data becomes available, management will be guided by clinical context, particularly in patients with history of cancers with specific propensity towards axillary lymphadenopathy. Due to widescale vaccination of the majority of the U.S. population, axillary lymphadenopathy due to COVID-19 vaccination is likely to be encountered in oncologic patients. In addition, in this limited series, a triangle of intramuscular inflammation was demonstrated at the injection site I n p r e s s on MRI and PET/CT, as also described by Eifer and Eshet (12) , suggesting vaccine-related inflammation. Overall, our findings are important, particularly for cancer patients. Radiologists, oncologists, and internists should be aware of this secondary effect of vaccination to obviate unnecessary changes in management, unnecessary patient emotional stress or biopsy. Moderna COVID-19 Vaccine. US Food & Drug Administration Web site COVID-19 Vaccine. US Food & Drug Administration Web site Covid data tracker. US Center for Disease Control and Prevention Web site Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine. US Center for Disease Control and Prevention Web site Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Development of unilateral cervical and supraclavicular lymphadenopathy after human papilloma virus vaccination FDG uptake in axillary lymph nodes after vaccination against pandemic (H1N1) Duration of 18F-FDG avidity in lymph nodes after pandemic H1N1v and seasonal influenza vaccination Axillary lymph node accumulation on FDG-PET/CT after influenza vaccination SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination. Society of Breast Imaging Web site Unilateral axillary Adenopathy in the setting of COVID-19 vaccine Imaging of COVID-19 Vaccination at FDG PET/CT. Radiology We would like to thank Dr Bruce C. Trautman for his help with the histopathologic evaluation, and Dr Katherine Chang for informing us about one of the cases. I n p r e s s