limitations and strengths of the study
Our results are limited by the inherent weakness in retrospectively collected data. We adapted a strict definition for cCVAL and excluded cases with upper or bilateral neck nodes, and cases with nodes first noticed >14 days following vaccination. We believe this definition increased our specificity and confidence in our diagnosis but possibly have reduced the sensitivity and missed some cases presented in atypical ways. In our cohort, lymphadenopathy was spatially and temporally associated with COVID-19 vaccinations, however, it was difficult to ascertain a causality link. Our results could be useful and universally generalisable to members of cancer MDTs, including surgeons, radiologists, oncologists, and haematologists, in addition to primary care physicians, vaccinators, and the general public.

Conclusion

The widespread rollout of COVID-19 vaccination has important implications for clinicians and patients. Over the next few months, primary care and H&N cancer services will potentially encounter a rise in vaccine-related reactive lymphadenopathy referrals. Therefore, COVID-19 vaccination history must be included in all referrals. Reactive cervical CVAL can mimic malignant lymphadenopathy, and therefore might become challenging to correctly diagnose and manage. Furthermore, consideration should be given for alternative strategies and referral pathways for low-risk patients presenting with lymphadenopathy which have the COVID-19 vaccination as the most likely aetiology.

References

1-Medicines and Healthcare products Regulatory Agency. Public Assessment Report. Authorisation for Temporary Supply, COVID-19 mRNA Vaccine BNT162b2 (BNT162b2 RNA) concentrate for solution for injection. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/944544/COVID-19_mRNA_Vaccine_BNT162b2__UKPAR___PFIZER_BIONTECH__15Dec2020.pdf [Accessed 12/04/2021].
2-Medicines and Healthcare products Regulatory Agency. Public Assessment Report. Authorisation for Temporary Supply, COVID-19 Vaccine AstraZeneca, solution for injection in multidose container COVID-19 Vaccine (ChAdOx1-S [recombinant]). Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/963928/UKPAR_COVID_19_Vaccine_AstraZeneca_23.02.2021.pdf [Accessed 12/04/2021].
3-Medicines and Healthcare products Regulatory Agency. Public Assessment Report. Authorisation for Temporary Supply, COVID-19 Vaccine Moderna, 0.20 mg/mL dispersion for injection (COVID-19 mRNA Vaccine [nucleoside modified]). Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/962920/Public_Assessment_Report_for_Moderna_COVID-19_vaccine.pdf [Accessed 12/04/2021].
4-Medicines and Healthcare products Regulatory Agency. Coronavirus vaccine - weekly summary of Yellow Card reporting (09/12/2020 to 14/03/2021). Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/972844/Coronavirus_vaccine_-_summary_of_Yellow_Card_reporting_14.03.21.pdf [Accessed 12/04/2021].
5-Medicines and Healthcare products Regulatory Agency. COVID-19 mRNA Pfizer- BioNTech vaccine analysis print (09/12/2020 to 14/03/2021). Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/972832/COVID-19_mRNA_Pfizer-_BioNTech_Vaccine_Analysis_Print.pdf [Accessed 28/03/2021].
6-Medicines and Healthcare products Regulatory Agency. COVID-19 vaccine AstraZeneca analysis print (04/01/2021 to 14/03/2021). Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/975786/COVID-19_AstraZeneca_Vaccine_Analysis_Print.pdf [Accessed 28/03/2021].
7-Grimm L, Destounis S, Dogan B, et al. SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination: Society of Breast Imaging Patient Care and Delivery Committee;2021. Available from: https://www.sbi-online.org/Portals/0/Position%20Statements/2021/SBI-recommendations-for-managing-axillary-adenopathy-post-COVID-vaccination.pdf [Accessed 12/04/2021].
8-Özütemiz C, Krystosek LA, Church AL, et al. Lymphadenopathy in COVID-19 Vaccine Recipients: Diagnostic Dilemma in Oncology Patients. Radiology. 2021:210275. doi: 10.1148/radiol.2021210275. PMID: 33625300.
9-McIntosh LJ, Bankier AA, Vijayaraghavan GR, Licho R, Rosen MP. COVID-19 Vaccination-Related Uptake on FDG PET/CT: An Emerging Dilemma and Suggestions for Management. AJR Am J Roentgenol. 2021 Mar 1. doi: 10.2214/AJR.21.25728. PMID: 33646823.
10-Becker AS, Perez-Johnston R, Chikarmane SA, et al. Multidisciplinary Recommendations Regarding Post-Vaccine Adenopathy and Radiologic Imaging: Radiology Scientific Expert Panel. Radiology. 2021:210436. doi: 10.1148/radiol.2021210436. PMID: 33625298.
11- Seely JM, Barry MH. The Canadian Society of Breast Imaging/ Canadian Association of Radiologists’ Recommendations for the Management of Axillary Adenopathy in Patients With Recent COVID-19 Vaccination. Can Assoc Radiol J. 2021:846537121998949. doi: 10.1177/0846537121998949. PMID: 33622040.
12-Fernández-Prada M, Rivero-Calle I, Calvache-González A, Martinón-Torres F. Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021. Euro Surveill. 2021(10):2100193. doi: 10.2807/1560-7917.ES.2021.26.10.2100193. PMID: 33706861.
13-Hiller N, Goldberg SN, Cohen-Cymberknoh M, Vainstein V, Simanovsky N. Lymphadenopathy Associated With the COVID-19 Vaccine. Cureus. 2021;13(2):e13524. doi: 10.7759/cureus.13524. PMID: 33786231.
14-Mitchell OR, Dave R, Bekker J, Brennan PA. Supraclavicular lymphadenopathy following COVID-19 vaccination: an increasing presentation to the two-week wait neck lump clinic? Br J Oral Maxillofac Surg. 2021;59(3):384-385. doi: 10.1016/j.bjoms.2021.02.002. PMID: 33685772.
15-Cunnane M, Cheung L, Moore A, di Palma S, McCombe A, Pitkin L. Level 5 Lymphadenopathy Warrants Heightened Suspicion for Clinically Significant Pathology. Head Neck Pathol. 2016;10(4):509-12.
16-National Institute for Health and Care Excellence. Suspected cancer: recognition and referral. [London]: NICE; 2015 [updated 2021 Jan]. (NICE guideline [NG12]). Available from: https://www.nice.org.uk/guidance/ng12/ [Accessed 12/04/2021].
17-von Elm E, Altman DG, Egger M, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335(7624):806-8. doi: 10.1136/bmj.39335.541782.AD. PMID: 17947786.
18-Coates EE, Costner PJ, Nason MC, et al. Lymph node activation by PET/CT following vaccination with licensed vaccines for human papilloma viruses. Clinical Nuclear Medicine. 2017;42(5):329-334. DOI: 10.1097/RLU.0000000000001603. PMID: 28288041.
19-Burger IA, Husmann L, Hany TF, Schmid DT, Schaefer NG. Incidence and intensity of F-18 FDG uptake after vaccination with H1N1 vaccine. Clin Nucl Med. 2011;36(10):848-53. DOI: 10.1097/RLU.0b013e3182177322. PMID: 21892032.
20-Mortazavi S. Coronavirus Disease (COVID-19) Vaccination Associated Axillary Adenopathy: Imaging Findings and Follow-Up Recommendations in 23 Women. AJR Am J Roentgenol. 2021. doi: 10.2214/AJR.21.25651.PMID: 33624520.
21-Cohen D, Krauthammer SH, Wolf I, Even-Sapir E. Hypermetabolic lymphadenopathy following administration of BNT162b2 mRNA Covid-19 vaccine: incidence assessed by [18F]FDG PET-CT and relevance to study interpretation. Eur J Nucl Med Mol Imaging. 2021:1–10. doi: 10.1007/s00259-021-05314-2. PMID: 33774684.
22-Mehta N, Sales RM, Babagbemi K, et al. Unilateral axillary Adenopathy in the setting of COVID-19 vaccine. Clin Imaging. 2021;75:12-15. doi: 10.1016/j.clinimag.2021.01.016. PMID: 33486146.
23-Ying M, Ahuja A. Sonography of neck lymph nodes. Part I: normal lymph nodes. Clin Radiol. 2003;58(5):351-8. doi: 10.1016/s0009-9260(02)00584-6. PMID: 12727162.
24-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:S1546-1440(21)00212-X. doi: 10.1016/j.jacr.2021.03.001. PMID: 33713605.