Essentials
With the rollout of mass COVID-19 vaccination across the world,
vaccine-induced lymphadenopathy is an important side effect for
clinicians, patients, and cancer researchers to be aware of.
Vaccine-induced lymphadenopathy can present as a diagnostic dilemma for
radiologists.
Evolving imaging guidelines are needed to address management strategies
of vaccine-induced lymphadenopathy in both the general population and
high-risk oncology patients.
Documentation of vaccination status is critical to decrease unnecessary
biopsies and alleviate patient anxiety.
Introduction
The COVID-19 pandemic has changed the landscape of society since February of 2020
with a significant and tragic impact on morbidity and mortality with 2.77 million
deaths across the world and 548,087 deaths in the United States as of March 26,
2021. Leading scientific minds have brought us a glimmer of hope with the
development of multiple vaccines that are currently being distributed throughout the
world. With the mass rollout of vaccination, both prevention of COVID-19 infection
and reduction in morbidity and mortality can be achieved with hopes of ending the
pandemic. Since February 27, 2021, three COVID-19 vaccines have been authorized by
the U.S. Food and Drug Administration for emergency use; the two-dose Pfizer and
Moderna mRNA vaccines and the most recently authorized single dose Johnson and
Johnson/Janssen adenovirus vector vaccine. Several other vaccines are in development
or being distributed in other countries including those developed by
Oxford-AstraZeneca (ChAdOx1 nCoV-19 or AZD1222), Gamaleya Research Institute of
Epidemiology and Microbiology (Sputnik V), and the CanSinoBIO-Beijing Institute of
Biotechnology (Convidicea or Ad5-nCoV). Through March 26, 2021, 526 million doses
of
vaccines have been distributed across the world.
With mass vaccination rollout, lymphadenopathy ipsilateral to the injected deltoid
muscle has become an important manifestation of an immune response to be aware of
as
it may present as a diagnostic dilemma on cancer imaging studies. We write this
editorial as a public service message at a time where other countries are starting
mass vaccination programs with the goal of preventing unnecessary nodal biopsies and
alleviating patient concern.
What are the side effects of COVID-19 vaccination?
The most common COVID-19 vaccine side effects include local injection site pain,
fever, chills, myalgias, headache and fatigue, with resolution usually in a few days
[1, 2]. However, palpable lymphadenopathy commonly involving the axilla as an immune
response to vaccination may present a clinical diagnostic dilemma especially in
persons with a history of malignancy. Patients may be concerned regarding
lymphadenopathy as a sign of malignancy, especially persons with a prior oncologic
history. This anxiety will only increase in patients with lymphadenopathy as
widespread rollouts of vaccination continue. In addition, lymphadenopathy may be
found incidentally on imaging examinations, such as routine screening or oncologic
surveillance examinations, presenting a diagnostic dilemma for radiologists.
How common is vaccine-induced axillary lymphadenopathy?
Although unilateral lymphadenopathy is a known side effect of vaccines, it is rarely
reported with vaccines such as the Bacillus Calmette–Guérin,
influenza, and human papillomavirus vaccines [3-5]. In a larger series examining 83
recipients of the influenza vaccine, four patients had unexpected fluorodeoxyglucose
axillary node accumulations on imaging [5]. In addition, lymph node uptake on
nuclear medicine studies after vaccination has been shown by multiple studies.
This is in contrast with the two-dose approved COVID-19 vaccines in the United
States, Pfizer-BioNTech and Moderna, which both have higher reported rates of
axillary swelling compared to prior vaccines. This may be due to a higher
immunogenic response to these mRNA vaccines, a type of vaccine that has not
previously been approved for use. As a solicited adverse event in the Moderna
clinical trials, axillary swelling or tenderness was reported in 11.6% of
patients (5.0% placebo) after Dose 1 and 16.0% (4.3% placebo)
after Dose 2 [1]. While not solicited as an adverse event in the Pfizer trials,
reports of lymphadenopathy from Dose 1 through 30 days after Dose 2 were imbalanced
with notably more cases in the Pfizer-BioNTech COVID-19 vaccine group (64) versus
the placebo group (6), which is plausibly
related to vaccination [2]. The true incidence of post-vaccination lymphadenopathy
may be higher given axillary swelling was only reported as an unsolicited adverse
event. Incidence of axillary lymphadenopathy visible at imaging is likely higher as
not all patients have clinical symptoms.
What has been reported in the literature so far regarding COVID-19
vaccine-related lymphadenopathy?
As of March 2021, at least 20 articles have been published illustrating or discussing
COVID-19 vaccine-related lymphadenopathy, with 18 of these articles published in
imaging journals. The earliest publications occurred in the field of breast imaging,
where vaccine-induced lymphadenopathy was cited as a cause of unilateral axillary
lymphadenopathy. Other imaging subspecialities citing this side effect included nine
articles in nuclear medicine, and one article in cardiothoracic imaging. In most
publications so far, there has only been one or a very small number of patients
reported on; one of the largest groups of patients reported on is 23 patients with
axillary adenopathy who had undergone breast imaging [6]. Journals which have
published on this subject include Radiology, American Journal of
Roentgenology, European Journal Nuclear Medicine and Molecular Imaging, Clinical
Nuclear Medicine and Journal of the American College of
Radiology (JACR). The majority of these articles reported
lymphadenopathy as a side effect after the two-dose COVID-19 Pfizer or Moderna
vaccines with two recent articles citing vaccine-induced lymphadenopathy with the
Oxford-AstraZeneca vaccine, currently only given as one-dose in the United Kingdom,
with the second dose planned for delayed administration. The location of the
lymphadenopathy was primarily axillary with four articles reporting cervical
lymphadenopathy. The lymphadenopathy can be visualized on multiple modalities with
most published cases demonstrated on US, followed by PET, MRI, mammography, and
CT.
What are the current imaging guidelines related to vaccine-induced axillary
lymphadenopathy?
The Society of Breast Imaging (SBI) was the first imaging society to propose
guidelines addressing axillary lymphadenopathy seen on imaging [7], with the
Canadian Society of Breast Imaging (CSBI) endorsing the SBI recommendations. There
have now been multiple publications suggesting guidelines for unilateral axillary
lymphadenopathy with focus on different modalities or oncologic subspecialities. We
summarize these below divided in terms of different phases of care.
Clinical history:
Vaccination dates, injection site/laterality and vaccine type should be
documented on patient intake forms or electronic medical record [7].
Scheduling exams:
To mitigate the diagnostic dilemma of vaccine-induced lymphadenopathy, the SBI
recommends that patients should “consider scheduling screening exams
prior to the first dose of a COVID-19 vaccination or 4-6 weeks following the
second dose of a COVID-19 vaccination” [7]. This recommendation has been
followed by a similar guideline published in Radiology from a
multi-disciplinary panel from oncologic centers, recommending for non-urgent
indications such as routine surveillance, screening, or staging imaging to be
scheduled prior to vaccination or to postpone imaging “at least 6 weeks
after final vaccination dose” [8]. McIntosh et al also [9] suggested
performing PET/CT “at least two weeks after vaccination in patients with
a cancer for which interpretation is anticipated to be potentially impacted by
the vaccination, though optimally 4-6 weeks after vaccination”. However,
like other imaging exams, if there is an urgent clinical indication such as
treatment planning, active treatment monitoring, or assessment of new symptoms
or potential complications, imaging should not be delayed, regardless of
vaccination status.
An additional strategy to mitigate confounding findings would be to administer
COVID-19 vaccinations “on the side contralateral to the primary
cancer” [8].
Incidentally detected unilateral lymphadenopathy on imaging:
For subclinical unilateral lymphadenopathy detected on imaging, vaccination
history including injection site and date is now a key piece of clinical
information to obtain. In cases of unilateral axillary lymphadenopathy on
screening mammography, the SBI recommends a BI-RADS 0 designation to bring the
patient back for assessment of the ipsilateral breast and additional
documentation of medical and vaccination history [7]. After an otherwise
negative diagnostic workup, and if a COVID-19 vaccine was given on the
ipsilateral side in the past 4 weeks, a BI-RADS 3 (Probably Benign) assessment
is then assigned with consideration for a short term follow up in 4-12 weeks
after the second vaccination dose. If lymphadenopathy persists at follow up,
then consider a BI-RADS 4 (Suspicious) assessment with biopsy to exclude
malignancy. As these recommendations were first announced in January 2021 based
on very early experience with COVID-19 vaccinations, they are necessarily meant
to be conservative. In an update (March 9, 2021), the SBI notes that individual
practices may wish to establish their own guidelines based on local expertise
and resources.
A different approach was suggested by a recent publication in
JACR proposing use of “BI-RADS 2 Benign”
assessment with clinical follow-up for isolated unilateral lymphadenopathy after
recent COVID-19 vaccination in the ipsilateral arm [10]. This is consistent with
the American College of Radiology BIRADS recommendations for unilateral
lymphadenopathy in the setting of a known inflammatory cause [10]. In comparison
with the more conservative SBI recommendations, this “pragmatic”
approach would result in fewer follow-up examinations.
In terms of management of clinically evident post-vaccination lymphadenopathy,
the multi-disciplinary panel recommended “observing for at least 6 weeks
until resolution before referring for diagnostic imaging evaluation or biopsy of
the nodes” [8]. The multidisciplinary panel also recommended
“expectant management strategy without default follow-up imaging”
in patients whom pre-test probability of adenopathy is much more likely to due
to vaccination rather than malignancy. In higher-risk situations, either a
short-term imaging follow up with ultrasound and/or tissue diagnosis can be
considered, especially in patients with a high-risk oncologic history (e.g.
ipsilateral breast or head/neck cancer, melanoma or lymphoma) [8]. The expected
duration of post-vaccination lymphadenopathy is not yet determined.
What are the implications for patients?
Widespread patient education regarding vaccine-induced lymphadenopathy is needed,
especially as this may be mistaken as a sign of malignancy. Imaging societies,
clinicians, and news media outlets should spread awareness to educate the public
regarding this side effect to minimize patient anxiety. When vaccines are
administered, side effects such as axillary swelling should be highlighted and
normalized as an immune response initiated by the vaccine. Patients should be aware
of the best times to schedule routine imaging exams with more infographics such as
the SBI mammography recommendations for women receiving the COVID-19 vaccine being
widely distributed. In patients with palpable lymphadenopathy after vaccination,
another suggestion may be to proceed with clinical follow-up by a clinician or the
patient themselves rather than imaging, resulting in cost-savings to the system.
Care should also be taken to ensure clinical and/or imaging follow-up for those with
lymphadenopathy that does not resolve, those with potentially causative malignancies
(such as breast or head/neck cancer, lymphoma, or melanoma), and those with
additional sites of lymphadenopathy.
Figure 1A:
69-year-old female with a history of lung adenocarcinoma and recent left arm
COVID-19 vaccination three days prior (first dose). (A) Axial images from
chest CT show left axillary and subpectoral lymphadenopathy (arrows) (B)
Comparison chest CT images from one-year prior show normal left axillary
lymph nodes.
69-year-old female with a history of lung adenocarcinoma and recent left
arm COVID-19 vaccination three days prior (first dose). (A) Axial images from
chest CT show left axillary and subpectoral lymphadenopathy (arrows) (B)
Comparison chest CT images from one-year prior show normal left axillary lymph
nodes.
Figure 1B:
69-year-old female with a history of lung adenocarcinoma and recent left arm
COVID-19 vaccination three days prior (first dose). (A) Axial images from
chest CT show left axillary and subpectoral lymphadenopathy (arrows) (B)
Comparison chest CT images from one-year prior show normal left axillary
lymph nodes.
69-year-old female with a history of lung adenocarcinoma and recent left
arm COVID-19 vaccination three days prior (first dose). (A) Axial images from
chest CT show left axillary and subpectoral lymphadenopathy (arrows) (B)
Comparison chest CT images from one-year prior show normal left axillary lymph
nodes.