key: cord-0866132-4k7koc36
authors: Garreffa, Emanuele; Hamad, Ahmed; O’Sullivan, Ciara C.; Hazim, Antonious Z.; York, Joanne; Puri, Shama; Turnbull, Anne; Robertson, John F.; Goetz, Matthew P.
title: Regional lymphadenopathy following COVID-19 vaccination: Literature review and considerations for patient management in breast cancer care
date: 2021-10-11
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2021.09.033
sha: bd90ce1883d0b132e26c9516628a0b465a0bd447
doc_id: 866132
cord_uid: 4k7koc36

PURPOSE: Over 1 billion doses of COVID-19 vaccines have been already administered across the US, the UK and the EU at the time of writing. Furthermore, 1.82 million of booster doses have been administered in the US since 13(th) August, and similar booster programmes are currently planned or under consideration in the UK and the EU beginning in the autumn of 2021. Early reports showed an association between vaccine administration and the development of ipsilateral axillary and supraclavicular lymphadenopathy which could interfere with the diagnosis, treatment and follow-up of breast cancer patients. In this paper, we review the available evidence on vaccine-related lymphadenopathy, and we discuss the clinical implications of same on breast cancer diagnosis and management. METHODS: A literature search was performed - PubMed, Ovid Medline, Scopus, CINHAL, Springer Nature, Sciencedirect, Academic Search Premiere and the Directory of Open Access Journals were searched for articles reporting on regional palpable or image-detected lymphadenopathy following COVID-19 vaccination. Separately, we compiled a series of case studies from the University Hospitals of Derby and Burton, UK and the Mayo Clinic in Minnesota, USA to illustrate the impact that regional lymphadenopathy post-COVID-19 vaccination can have on the diagnosis and management of patients being seen in diagnostic and therapeutic breast clinics. RESULTS: From the literature search 15 studies met the inclusion criteria (n = 2057 patients, 737 with lymphadenopathy). The incidence of lymphadenopathy ranged between 14.5% and 53% and persisted for >6 weeks in 29% of patients. CONCLUSIONS: Clinicians managing breast cancer patients should be aware that the COVID-19 vaccination may result in regional lymphadenopathy in a significant number of patients which can result in unnecessary investigations, treatment and increased patient anxiety. An accurate COVID-19 vaccination history should be collected from all patients where regional lymphadenopathy is a clinical &/or an imaging finding and then combined with clinical judgment when managing individual cases.

During the first quarter of 2021, initial reports of patients developing regional lymphadenopathy, (palpable or image-detected), after receiving a COVID-19 vaccine (mostly mRNA vaccines) were published [16] [17] [18] [19] [20] and, more recently, guidance to aid the management of COVID-19 vaccinerelated lymphadenopathy in the primary care setting has been published [21] .

In this paper we review the available evidence on both palpable and image-detected regional lymphadenopathy attributed to recent receipt of the COVID-19 vaccination. By use of case studies we also discuss the clinical implications on the diagnosis and treatment of breast cancer.

A literature search was performed -PubMed, Ovid Medline, Scopus, CINHAL, Springer Nature, Sciencedirect, Academic Search Premiere and the Directory of Open Access Journals were searched for articles published between January 2021 and May 2021 using the following terms: ((((((covid- 19 ) OR (pfizer)) OR (astrazeneca)) OR (moderna)) OR (janssen)) AND (vaccine)) AND (lymphadenopathy). The PRISMA (preferred reporting items for systematic reviews and metaanalyses) guidelines were followed [22] . Only English language articles were reviewed, and their reference lists were cross-referenced until the search strategy was exhausted. Additional searches were carried out using Google Scholar and Researchgate. The most recent search was performed on 9 th May 2021.

Studies were included only if the lymphadenopathy was diagnosed in one of the following scenarios: a symptomatic presentation with palpable lymphadenopathy; at breast screening examinations; as an incidental finding during other imaging exams or lymphadenopathy detected during breast cancer staging or follow-up exams. No study was excluded based on the design, given they all reported at least the following data: number of patients, age, location of the lymphadenopathy, modality of detection, vaccine dose details (1 st 

The following information was retrieved from the studies: study design/phase; number of patients included; number of patients with adenopathy; mean age and sex of patients; type of vaccine administered and number of doses; site of the adenopathy and number of nodes identified; modality of presentation (symptomatic or image-detected); method of detection; time from vaccine to symptom onset/node detection; history of COVID-19 infection; degree of clinical suspicion; further diagnostic exams/biopsies; length of follow-up and time to resolution.

Case Studies -Case studies of patients presenting at either of our institutions have been compiled to illustrate the varying clinical scenarios that regional lymphadenopathy secondary to Covid-19 vaccination may impact the clinical care of patients attending breast clinics for diagnostic and therapeutic purposes.

The search strategy identified 49 articles ( Fig. 1 ) [22] . After inclusion of records identified through the additional searches and removal of duplicates, 60 records were screened. The primary reason for exclusion at the screening stage was lack of relevance to the topic. A total of 42 full-text articles were assessed for eligibility. Of these, 27 were excluded, most commonly because they were small PET-CT scan studies (n=17) or did not report the minimum amount of data (n=9). This left 15 studies eligible for inclusion [16, 17, [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] (Fig.1, Table 1 ). These studies included 2057 patients, with a sample size ranging from 1 to 728, and of those patients, 737 had vaccine-related lymphadenopathy.

All of the selected articles were retrospective studies. Most lymphadenopathies (n=657) were J o u r n a l P r e -p r o o f identified during imaging for cancer staging or follow-up and of those, almost all were identified on a PET-CT scan (n=654). The remaining cases of lymphadenopathy presented as follows: 37 symptomatic patients with palpable adenopathy; 22 patients with incidental adenopathy identified during imaging performed for other reasons and 21 patients with adenopathy identified during breast screening exams (Table 1) .

All patients in the selected studies received an mRNA vaccine (mostly the Pfizer-BioNTech vaccine) and the incidence of post-vaccination lymphadenopathy among the included studies that reported this information ranged between 14.5% (after a single dose) and 53% ( Table 2 ). Receipt of a single dose of vaccine, older age (≥64 years) and an immunocompromised status have been associated with lower rates of lymphadenopathy, whereas higher rates of lymphadenopathy have been found in younger (<64 years), immunocompetent and fully vaccinated patients (Table 2) .

Among the patients with non-palpable lymphadenopathy, the enlarged nodes were mostly identified in the axilla (n = 688; 98.3%), whereas only 2 (0.3%) had supraclavicular fossa (SCF) adenopathy; 10 patients (1.4%) had both axillary and SCF adenopathy. On the contrary, palpable lymphadenopathies were mostly detected in the SCF (n 32; 86.5%), with only 4 patients (10.8%) presenting with axillary adenopathy and 1 patient (2.7%) presenting with both axillary and SCF adenopathy ( Table 2) .

On balance, the degree of suspicion of such lymphadenopathies was considered to be low, with only 10 biopsies performed (1.3%) and little need for further workup imaging studies (Table 3) . For palpable adenopathy, the average time to clinical resolution (when reported) was approximately 7-8 days. However, in 9 patients (25%), palpable nodes persisted for > 21 days. Evidence from the PET-CT scan studies suggested that the lymphadenopathy can persist for longer than 21 days (and even beyond 6 weeks) in 29% of cases.

Adverse events reported in the randomised controlled trials of the COVID-19 vaccines include data J o u r n a l P r e -p r o o f on lymphadenopathy. [36] [37] [38] [39] . For the Moderna vaccine, the reported rate of ipsilateral axillary lymphadenopathy or tenderness (symptoms were not reported separately) was ~ 11.6% and 16% after the first and second dose respectively. A small number of cases of neck lymphadenopathy were also reported. [36] . For the other vaccines, the incidence of ipsilateral axillary lymphadenopathy was reported to be lower: <1% for the Pfizer-BioNTech and AstraZeneca vaccines, and 0.1% for the Janssen vaccine [37] [38] [39] . However, it is worth noting that in these trials, unlike the Moderna one, lymphadenopathy was only reported as an unsolicited adverse event and hence the true incidence rate is likely to be higher.

As COVID-19 vaccines are administered intramuscularly to the deltoid muscle, vaccinationassociated adenopathy typically occurs in the axilla and supraclavicular region. Recognition of this association is crucial in patients with cancer, where it can lead to under-or over-diagnosis, under-or over-treatment and increased patient anxiety. This is especially relevant for breast cancer patients, (but also for patients with head and neck cancers, lymphoma, and melanoma of the back and upper extremities as these malignancies have a predilection for metastasizing to these lymph node stations. As shown by the data from Israel, the true incidence of image-detected ipsilateral lymphadenopathy after an mRNA COVID-19 vaccine appears to be at least 2-3 times higher than previously reported in the Moderna trial [23, 28, 33] and, during the current mass vaccination campaign, patients should be routinely asked about their vaccination history when they are assessed for breast conditions. In the following paragraphs we present some considerations regarding the potential impact of vaccine-related lymphadenopathy on the management of breast patients in different settings: from breast cancer screening to post-treatment cancer surveillance.

The first cases of subclinical unilateral axillary lymphadenopathy following COVID-19 vaccinations were identified by breast imagers in women undergoing breast screening exams such as magnetic resonance imaging (MRI), mammography, and ultrasound [16, 31] . The Society of Breast Imaging, as well as other groups in the US, responded by publishing different management J o u r n a l P r e -p r o o f recommendations [29, 40, 41] . Even though there was a general consensus that COVID-19 vaccination should not be postponed due to the need for imaging in patients undergoing breast cancer screening or surveillance, the recommendations regarding the timing of imaging and management of the lymphadenopathy varied. According to the Society of Breast Imaging, patients with unilateral axillary adenopathy identified during screening exams should be recalled for further assessment of the ipsilateral breast and documentation of relevant medical history, including prior COVID-19 vaccination. Imaging follow-up 4-12 weeks after the second vaccine dose is recommended for patients with isolated axillary adenopathy [40] . They also recommend that routine screening exams should be postponed until 6 weeks after completion of the vaccination course [40] . Contrary to the US, where the general advice has been to perform breast screening exams either before receiving the COVID-19 vaccine or 6-10 weeks after the second dose, no specific recommendations regarding the timing of breast screening in relation with COVID-19 vaccination have been issued in the UK or in Europe [42] . In England, advice regarding the scheduling of mammograms has not altered. There is currently no requirement for women to wait for a predefined time period following a COVID-19 vaccination before attending a screening appointment.

A recently published retrospective case series analysed the mammograms of 750 patients with history of administration of at least 1 dose of a COVID-19 vaccine within the previous 90 days and identified 23 cases of axillary adenopathy (3%), which is higher than reported rates of axillary adenopathy in otherwise normal mammography (0.02-0.04%). The incidence of adenopathy was found to be higher in the first 2 weeks following the vaccination, with no cases identified beyond 28 days from vaccine administration [43] .

The finding of isolated axillary lymphadenopathy during a screening mammogram requires a recall for ultrasound assessment of lymph node morphology. In patients with suspicious or frankly malignant appearing nodes, a needle biopsy would be performed irrespective of their vaccination history, whereas patients with fatty or normal appearing lymph nodes (i.e. BIRADS 1) would be discharged. It is in patients with probably benign/reactive nodes with regular cortical thickening that COVID-19 vaccination history becomes relevant, even though this information should be used in the context of an overall patient's risk assessment. Patients who received a recent COVID-19 vaccination (<6 weeks) in the ipsilateral arm and who are at low risk of malignancy (i.e. fatty mammogram and no relevant family history) can be discharged and instructed to return in case they develop a palpable abnormality, whereas in patients with a significant family history of breast cancer and/or dense mammogram a 3-6 months follow-up would be advisable, based on clinical judgement.

In patients presenting with lymphadenopathy associated with an ipsilateral breast abnormality and recent COVID-19 vaccine history, the management will vary according to the appearances of the breast lesion. A lymph node biopsy will be performed only in cases where the breast abnormality looks suspicious or frankly malignant (i.e. , whereas in patients with benign appearing breast lesions (i.e. BIRADS 2-3) only a breast biopsy will be performed in the first instance (Fig. 2) .

Axillary metastatic carcinoma without detection of a primary breast lesion (occult primary) is rare, occurring in only 0.3-1% of all breast cancer patients [44] . Therefore, in patients presenting to J o u r n a l P r e -p r o o f University Hospitals of Derby and Burton (UHDB) with palpable unilateral axillary/supraclavicular lymphadenopathy, normal breast imaging and a history of recent COVID-19 vaccination in the ipsilateral arm, short-term follow-up (4-5 weeks) is generally preferred to a potentially unnecessary and costly lymph node biopsy (Fig. 3) . Though In patients with a personal or family history of breast cancer, or if another malignancy (i.e. lymphoma) is suspected, a lymph node biopsy may still be considered, depending on the degree of clinical concern (Fig. 4) . In patients where a suspicious abnormality is identified in the ipsilateral breast, a lymph node biopsy should be routinely performed.

Incidental detection of enlarged lymph nodes in breast cancer patients undergoing staging or restaging scans could not only confound the accurate assessment of disease extent and/or treatment response but may also increase patient anxiety and lead to additional and unnecessary interventions.

At UHDB, the detection of ipsilateral enlarged regional lymph nodes in patients with newly diagnosed breast cancer during staging exams such as breast MRI or CT scan would mandate a targeted ultrasound and lymph node biopsy with fine needle aspiration (FNA), unless the adenopathy could be confidently attributed to the COVID-19 vaccine (i.e. uptake at the site of injection in the deltoid muscle seen on PET-CT scan) (Fig. 5 ). For patients with benign appearing lymph nodes (low suspicion), a benign FNA result is accepted, whereas a core biopsy would be J o u r n a l P r e -p r o o f performed in all patients with highly suspicious nodes. COVID-19 vaccination history becomes relevant for those patients with an intermediate grade of suspicion for malignancy, as we would tend to accept a benign FNA result in those patients with recent (previous 6 weeks) vaccination in the ipsilateral arm, whereas a core biopsy would be requested for those with no recent history of vaccination. This approach is supported by the published literature, as vaccine-related lymphadenopathies were generally associated with a low or intermediate degree of suspicion, and only a small minority of cases (6 out of 737, 0.81%) were described as highly suspicious (Table 3) .

Contralateral axillary metastasis is a rare occurrence in breast cancer (reported incidence between 1.6% and 6%) [45] , and in those patients with a history of recent COVID-19 vaccination in the contralateral arm and image-detected lymphadenopathy, omission of a lymph node biopsy would be reasonable, especially if there is no adenopathy on the side of the patient's prior/current breast cancer. The biopsy of highly suspicious lymph nodes should not be omitted in those circumstances.

It is of paramount importance that breast cancer patients who are waiting to receive one or more of the vaccine doses, including any future booster doses, are instructed to do so in the contralateral arm to their breast cancer. Administration of the vaccine to the ipsilateral arm could cause confusion when assessing the response to neoadjuvant chemotherapy as the appearance of enlarged axillary and/or supraclavicular nodes could mimic cancer progression (Fig. 6 ).

Vaccine-related lymphadenopathy could also negatively affect the quality of breast cancer care by resulting in more extensive axillary surgery. Similar considerations have been recently published by Ko et al., who advised vaccine administration at least one week prior to surgery or one to two weeks after (to avoid confusion in the causality attribution of symptoms such as fever) and in the arm opposite to the affected breast [46] . It is worth noting however, that the maximum levels of protection following COVID-19 vaccine administration are achieved in 3 to 4 weeks [47] and therefore, it would be preferrable to perform the surgery after this time interval, especially in elderly patients or in those who have been treated with neo-adjuvant chemotherapy.

Interpretation of the significance of lymphadenopathy after COVID-19 vaccination in breast cancer (or other malignancies that tend to involve axillary and supraclavicular lymph nodes) can be challenging. Of the 332 vaccinated patients with ipsilateral hypermetabolic axillary and/or SCF lymph nodes detected during PET-CT scan in the study by Cohen et al., the lymphadenopathy was described as equivocal in 49 cases (14.8%) and of those 20 (40.8%) were women with an ipsilateral breast cancer [28] . Among the 728 vaccinated patients who underwent PET-CT scans in the aforementioned study, 113 (15.5%) were breast cancer patients [28] . A recently published study from the US (although with limited sample size and follow-up) also found that women might be more likely to develop reactive nodes following COVID-19 vaccination, with 7 out of 9 (78%) patients with lymphadenopathy (in a cohort of 68 vaccinated patients undergoing PET-CT scan for oncological indications) being female [48] . However, the usefulness of this approach could be questioned, when considering the recent findings of an Israeli study which included 169 patients undergoing a PET-CT scan 7 to 10 weeks after J o u r n a l P r e -p r o o f receiving the second dose of the Pfizer-BioNTech vaccine; persistent unilateral lymphadenopathy was observed in 29% of patients [32] .

The appropriate management strategy for these patients should be determined on a case-by-case basis taking into account characteristics of the cancer, COVID-19 vaccination history and the degree of clinical suspicion. If the lymphadenopathy is felt unlikely to be malignant, then clinical judgement could be used to attribute the findings to the vaccination, and no further follow-up would be needed. In the case of indeterminate or confounding lymphadenopathy (i.e. a vaccine administered on the same side as the breast cancer or known prior axillary metastases), then management would be determined by the relevance of the clinical findings. If clinically irrelevant (i.e. will not change disease stage), then no further imaging is recommended, and attention should be given on follow-up. If clinically relevant, then a lymph node biopsy should be considered (Fig.   7,8) .

The real-world experience from the mass-COVID-19 vaccination campaign shows that a higher proportion of vaccinated people will develop regional lymphadenopathy than what was originally reported in vaccine randomised clinical trials, and this could last beyond 6 weeks. This has important implications for the diagnosis and/or management of patients with a known or suspected breast cancer diagnosis. Accurate information regarding COVID-19 vaccination history should be collected from all patients and combined with clinical judgment when managing individual cases.

Clinicians should provide patients with clear information and advice regarding the potential onset of vaccine administered into the right arm 4 weeks prior. On imaging review, the left breast cancer showed signs of interval response to treatment compared to the previous CT scan. In view of this, and due to the patient's vaccine history, it was felt that the right axillary adenopathy was unlikely to represent metastatic disease, and a 6-month follow-up with an ultrasound of the right axilla was advised. The patient completed neoadjuvant chemotherapy and underwent left breast conserving surgery and sentinel node biopsy which showed complete pathological response in the breast and no evidence of lymph node metastasis or fibrosis. A non-diagnostic FNA of the pathological right axillary lymph node was followed by a core biopsy which was negative for malignancy (lymphocytes consistent with sampled lymph node).

UK Government. Coronavirus (COVID-19) in the UK. Available at

European Centre for Disease Prevention and Control. COVID-19 Vaccine Tracker

COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. Food and Drug Administration

Covid-19: Booster vaccine to be rolled out in autumn as UK secures 60m more Pfizer doses

MHRA statement on booster doses of Pfizer and AstraZeneca COVID-19 vaccines. Medicines and Healthcare products Regulatory Agency

ECDC and EMA highlight considerations for additional and booster doses of COVID-19 vaccines

CombiVacS Study Group. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre

Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study

Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination

Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination

Evaluating COVID-19 vaccine boosters

Delayed Heterologous SARS-CoV-2 Vaccine Dosing (Boost) After Receipt of EUA Vaccines

Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination

SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination

Unilateral axillary Adenopathy in the setting of COVID-19 vaccine

Lymphadenopathy in COVID-19 Vaccine Recipients: Diagnostic Dilemma in Oncology Patients

Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F]Choline PET/CT-not only an FDG finding

Unilateral Axillary Lymphadenopathy After Coronavirus Disease (COVID-19) Vaccination

Supraclavicular lymphadenopathy following COVID-19 vaccination: an increasing presentation to the two-week wait neck lump clinic?

Regional lymphadenopathy following COVID-19 vaccination: considerations for primary care management

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Covid-19 mRNA Vaccination: Age and Immune Status and its Association with

Axillary Lymph Node PET/CT Uptake

Unilateral axillary lymphadenopathy following COVID-19 vaccination: A case report and imaging findings

Lymphadenopathy after BNT162b2 Covid-19 Vaccine: Preliminary Ultrasound Findings

Lymphadenopathy Associated With the COVID-19 Vaccine. Cureus

Axillary Lymphadenopathy After mRNA COVID-19 Vaccination. Radiol Cardiothorac Imaging

Hypermetabolic lymphadenopathy following administration of BNT162b2 mRNA Covid-19 vaccine: incidence assessed by

FDG PET-CT and relevance to study interpretation

Unilateral Lymphadenopathy After COVID-19 Vaccination: A Practical Management Plan for Radiologists Across Specialties

Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique

Management of Unilateral Axillary Lymphadenopathy Detected on Breast MRI in the Era of Coronavirus Disease

Vaccination

Prevalence of Increased FDG PET/CT Axillary Lymph Node Uptake Beyond 6 Weeks after mRNA

Axillary Lymph Nodes Hypermetabolism After BNT162b2 mRNA COVID-19 Vaccination in Cancer Patients Undergoing 18F-FDG PET/CT: A Cohort Study

COVID-19) Vaccination Associated Axillary Adenopathy: Imaging Findings and Follow-Up Recommendations in 23 Women

Adenopathy Following COVID-19 Vaccination

Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine

Systemic Reactions, Adverse Events, and Serious Adverse Events: Pfizer-BioNTech COVID-19 Vaccine

Public Assessment Report for AstraZeneca COVID-19 vaccine. Medicines and Healthcare products Regulatory Agency

Public Assessment Report for COVID-19 Vaccine Janssen

SBI Recommendations for the Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination: Society of Breast Imaging Patient Care and Delivery Committee

Pharmacovigilance evidence review: the effect of covid-19 vaccines on breast screening

Incidence of Axillary Adenopathy in Breast Imaging After COVID-19 Vaccination

Occult breast cancer: Where are we at? Breast

Contralateral Axillary Lymph Node Metastases from Breast Carcinoma: Is it Time to Review TNM Cancer Staging?

COVID-19 vaccination and breast cancer surgery timing

Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study

Association of COVID-19 mRNA Vaccine With Ipsilateral Axillary Lymph Node Reactivity on Imaging

Method of detection Eifer [23] Retrospective 426 170 67 (20-95) 207 219 Cancer staging/Follow-up PET-CT Dominguez [24] Case-report 1 1 38 (38) 0 1 Image-detected CT Granata [25] Retrospective 18 18 46 (26-63) 13 5 -Symptomatic (10) -Image-detected (8) -Patient (10) -US (8) Hiller [26] Case-report 3 3 45 (42-47) 3 0 -Symptomatic (2) -Screening (1) -Patient (2) -MRI (1) Ahn [27] Case-report 3 3 35 (32-39) 2 1 -Screening (2) -Image-detected (1) -CT (1) -MRI (2) Cohen [28] Retrospoective [33] Low No N/A NK NK Legends: NK: not known; N/A: not applicable; US: ultrasound; MMG: mammography; MRI: magnetic resonance imaging; CT: computed tomography; PET-CT: positron emission tomography and computed tomography.