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Novel coronavirus-19 (COVID-19) variants continue to spread worldwide with the development of highly transmissible strains. Several guidelines addressing management of cancer patients during the COVID-19 pandemic have been published, primarily based upon expert opinion. The COVID-19 pandemic has affected all aspects of breast cancer care including screening, diagnosis, treatment, and long-term follow-up. Recent reports indicate that mRNA COVID-19 vaccines can provoke lymphadenopathy in both cancer patients and healthy individuals. Unilateral axillary lymphadenopathy (UAL) post-COVID-19 vaccination is a challenging presentation for cancer patients because of the potential for misinterpretation as malignancy. The World Health Organization’s target to vaccinate 70% of the world’s population by mid-2023 is likely to increase the incidence of post-COVID-19 vaccination UAL. In this article, we review the published evidence regarding UAL post-COVID-19 vaccination and present diverse cases of breast cancer patients where false-positive UAL post-COVID-19 vaccination proved to be a therapeutic challenge. The United Arab Emirates (UAE) vaccination program is well ahead of other countries in the world, having accomplished the target of 100% vaccination of the population with at least one dose. Therefore, an increasing number of recently vaccinated patients are likely to present with UAL, detected by surveillance imaging, post-vaccination. We have therefore made recommendations regarding the management of cancer patients with UAL post-COVID-19 vaccination in order to avoid misdiagnosis and unnecessary imaging or invasive biopsy procedures.
© 2023 The Author(s). Published by S. Karger AG, Basel
IntroductionThe SARS-CoV-2 pandemic has caused a worldwide health crisis since 2019. Globally, according to the World Health Organization (WHO), there have been 510,270,667 confirmed cases of COVID-19 including 6,233,526 deaths as of April 2022 [1]. In the United Arab Emirates (UAE), there have been 898,571 diagnosed cases of COVID-19 with a total of deaths numbering 2,302 [2]. In December 2020, large-scale worldwide vaccination programs targeting COVID-19 were developed, and at least 13 different vaccines, with four different platforms, have since been administered [3]. As of October 2021, 46.5% of the total world population had received at least one dose of a COVID-19 vaccine [4]. Currently, there are five approved vaccines against the COVID-19 infection in the UAE: Sinopharm, Pfizer/BioNTech, Sputnik V, Oxford-AstraZeneca, and Moderna.
According to the Global Leadership Response in the COVID-19 crisis index [5], the UAE has been recognized to be among the top 10 countries for its leadership and proactive approach during the coronavirus disease outbreak. As of May 2022, a total of 24,729,282 vaccine doses have been administered in the UAE with 97.69% of the population being fully vaccinated [2]. Recently, UAE has moved to the top of the global rankings for vaccination rates, overtaking Israel. During this pandemic, cancer patients were classified as a higher risk group; therefore, the Center for Disease Control and Prevention (CDC) advised that the immunocompromised population should be offered mRNA-based vaccinations [6].
Unilateral axillary lymphadenopathy (UAL) post-COVID-19 vaccination is a new disease entity which requires special attention in this pandemic, particularly in cancer patients, because of the implications that this can have on cancer management. With the ongoing COVID-19 vaccination programs, radiologists will increasingly encounter UAL, and therefore, there is an urgent need for the development of protocols for managing this phenomenon. A breast clinic in Israel recently reported a 394% increase in reported lymphadenopathies when compared to previous years, largely due to the COVID-19 vaccination program [7]. Such important information about vaccination-related effects is needed in order to prevent misinterpretation of imaging and alleviate patient concern during staging or surveillance imaging procedures. This can be of special concern to patients with established malignancy during follow-up when imaging detects the new development of lymphadenopathy, which might be misinterpreted as progressive disease.
F-18 fluorodeoxyglucose positron emission tomography co-registered with computed tomography is an established nuclear medicine modality that has been extensively validated for staging newly diagnosed cancers and for monitoring the response to therapy [8]. A major attribute of F-18 fluorodeoxyglucose positron emission tomography-computed tomography is the ability to detect malignancy in lymph nodes based upon metabolic activity even when they are not enlarged; however, false positives can also result from infectious or inflammatory conditions.
For newly diagnosed cancer patients, false-positive UAL will imply more advanced disease resulting in increased patient anxiety because of the implication that more intense therapy may be required and also because of the necessity for further, potentially invasive, diagnostic procedures. For patients with known metastatic disease, new onset UAL post-COVID-19 vaccination can be falsely interpreted as disease progression potentially resulting in inappropriate changes in therapeutic strategy, which must be mitigated by clinician awareness and vigilance.
We therefore performed a detailed review of the published evidence pertaining to UAL post-COVID-19 vaccination, and we report 2 breast cancer cases where pathological diagnosis ruled out malignant involvement of the abnormal lymph nodes. The challenges when dealing with this presentation and the commonly associated pitfalls are discussed. In addition, we have discussed recommendations for the management of UAL post-COVID-19 vaccination with the objective of avoiding misdiagnosis and the use of unnecessary, invasive, investigations.
Case 1A 53-year-old woman was initially diagnosed with a high-risk locally advanced right breast cancer in 2008. Her treatment consisted of surgery, adjuvant chemotherapy, radiotherapy, and endocrine therapy with adjuvant tamoxifen for 5 years. In June 2019, she presented with a history of right shoulder pain and underwent a 18F-FDG PET-CT scan which showed areas of increased uptake in multiple bones, left breast, left axilla, and mediastinal lymph nodes consistent with metastatic breast cancer. Histopathology confirmed recurrent metastatic breast carcinoma which was strongly estrogen receptor positive 100%, progesterone receptor positive 90%, and human epidermal growth factor receptor 2 negative (immunohistochemistry score 0). A laparoscopic bilateral salpingo-oophorectomy was performed for ovarian suppression, and she was commenced on endocrine-based therapy with letrozole 2.5 mg once daily, palbociclib 125 mg for 3 weeks on, 1 week off, and denosumab 120 mg subcutaneously q4 weekly. Serial PET-CT scans were subsequently performed to monitor the patient’s progress, which revealed a complete metabolic response to treatment.
Follow-up PET-CT imaging in February 2021 revealed new FDG avid lymphadenopathy in the left axillary and subpectoral region (maximum SUV of 4) (Fig. 1a). These findings were reported as disease progression prompting further investigations. Ultrasound of the left axilla (Fig. 2) and axillary lymph node biopsy were performed. Histopathology revealed reactive changes and focal stromal fibrosis with no evidence of malignancy (Fig. 3a–c). The false-positive PET-CT scan findings in February 2021 were due to the patient having received her first dose of Pfizer COVID-19 vaccine in the left arm 12 days prior to the scan. Follow-up PET-CT scan performed in May 2021 (Fig. 1b) showed complete resolution of all abnormal metabolic activity. Three years following the initial diagnosis of metastatic breast cancer, the patient remains alive and well with no evidence of disease progression on first-line endocrine-based therapy.
Fig. 1.a, b FDG PET-CT images of case no. 1. a Multiple enlarged left axillary and subpectoral lymph nodes measuring at least 17 mm with increased uptake SUV max 4, 12 days’ post-first dose of Pfizer COVID-19 vaccine in the left arm. b Interval follow-up FDG PET-CT scan 2 months later showing complete resolution of lymphadenopathy. No other sites of metabolic active disease were identified on the scans.
Focused ultrasound study of left axilla of patient in case no. 1 (12 days’ post-first dose of Pfizer COVID-19 vaccine in the left arm) showing prominent lymph node with cortical thickening of 5 mm.
a–c Core biopsy of left axillary lymph node for case no. 1. a, b Hematoxylin and eosin staining showing reactive changes and focal stromal fibrosis with no evidence of metastatic carcinoma (original magnification ×4 and ×10, respectively). c Immunohistochemistry staining for general cytokeratin AE1/3 with no positive staining, confirming absence of metastatic carcinoma (original magnification ×10). Features consistent with COVID vaccine-associated lymphadenopathy in a patient with known breast cancer.
A 39-year-old woman presented with a 4-week history of a lump in the left breast. Mammography, ultrasound, and breast magnetic resonance imaging were performed which revealed a 10 × 13 × 20-mm left breast lower inner quadrant lesion associated with pleomorphic calcifications. Multiple enlarged left axillary lymph nodes were noted with a thickened cortex of approximately 6 mm suggestive of malignant involvement. Biopsy from the left breast revealed invasive ductal carcinoma, grade 3, estrogen receptor negative 0%, progesterone receptor negative 0%, and human epidermal growth factor receptor 2-positive immunohistochemistry score 3+. Although the imaging was suggestive of node-positive breast cancer, core biopsy from the left axillary lymph node revealed reactive follicular hyperplasia with no evidence of malignancy (Fig. 4a, b). On further enquiry into the patient’s history, it was noted that she had received the Pfizer SARS-CoV-2 vaccine 7 days prior to the mammogram. It was therefore concluded that this was as a false-positive imaging result for the axillary lymph nodes. She received neo-adjuvant therapy with anthracyclines followed by paclitaxel, trastuzumab, and pertuzumab for 24 weeks followed by left-sided mastectomy and sentinel lymph node biopsy. Surgical pathology revealed complete pathological response in the breast (ypT0) along with 2 benign lymph nodes in the axilla (ypN0). She was continued on adjuvant trastuzumab maintenance therapy for 12 months. Adjuvant chest wall radiotherapy was omitted because she had lymph node-negative breast cancer. Diligent history taking with an emphasis upon previous COVID-19 vaccination is essential for known or suspected breast cancer patients in order to avoid disease over-staging and the potential therapeutic consequences thereof.
Fig. 4.a, b Core biopsy of left axillary lymph node, hematoxylin and eosin staining, for case 2 showing reactive lymphoid hyperplasia and no evidence of metastatic carcinoma (original magnification ×4 (a) and. ×10 (b)). Features consistent with COVID vaccine-associated reactive lymphadenopathy in a patient with known breast cancer.
In order to identify case studies, we conducted searches in PubMed, Scopus, and Web of Science via Covidence. We included all case studies that reported UAL in patients with solid tumors and were published in English. Editorials, letters, commentaries, review articles, and studies on healthy subjects were excluded from the analysis.
Two investigators worked independently, completing separate screenings of the literature. The same reviewers used the inclusion and exclusion criteria to independently assess the full eligibility of studies identified in the databases. Once the relevant full-text articles were identified, the two reviewers achieved consensus regarding eligibility and extracted data onto a standardized extraction form.
Data ExtractionWe extracted the following data from the studies: author and year of publication, study design (i.e., case report and case series), country of study, population (i.e., healthy or cancer patient), type of COVID vaccine, type of lymphadenopathy developed, number of cases described, and imaging techniques. Data entry was compared, and discordant information was resolved by consensus through data checks and discussion between the data extractors.
Overview of Included StudiesWe identified a total of 439 records through the initial search in three databases: Scopus, Web of Science, and PubMed. 264 duplicated records and 75 articles were excluded. 96 full-text articles were screened for eligibility, and patients with no proven malignancy were excluded. A total of 26 studies, including 21 case reports and 5 case series, met our inclusion criteria and were included for our qualitative analysis (Fig. 5).
Fig. 5.PRISMA flow diagram of literature review process for studies on the COVID 19 vaccine-associated lymphadenopathy.
Of the 26 reported studies (Table 1), fifteen (58%) were carried out in the USA and the remaining in Europe (n = 7), Canada (n = 1), Israel (n = 1), Taiwan (n = 1), and Korea (n = 1). The patient population (n = 40) in these studies had a median age of 60 years (range 32–83 years), with female preponderance (n = 15). The most common diagnosis was breast cancer (n = 15), followed by melanoma (n = 8), lung cancer (n = 3), prostate cancer only (n = 3), head and neck cancers (n = 3), sarcoma (n = 2), renal cell carcinoma (n = 1), bladder cancer (n = 1), and colon cancer (n = 1). In addition, 2 patients had dual malignancies, one with thyroid and renal cell cancer and the second patient with tongue and prostate cancer.
Table 1.Case reports and series of lymphadenopathy secondary to SARS-CoV-2 vaccination
Reference, yearCountryDiagnosis/age/gender, yearsVaccine/number of days post-vaccinationDiagnostic technique(s)Injection siteBiopsy/FNA doneSite of lymphadenopathyAalberg et al., 2021 [9]USARenal cell carcinoma/73/MModerna/2 days18F-FDG PET/CTLeft armYesLeft axillaAvner et al., 2021 [10]IsraelMelanoma/57/MPfizer/BioNTech/6 days18F-FDG PET/CTPfizer (n = 12) and Moderna (n = 11) were the most commonly administered vaccines followed by Oxford-AstraZeneca (n = 7) and Janssen (n = 1). The type of vaccine used was not mentioned in 8 cases (Table 1). In addition to the axilla, in some cases abnormal lymphadenopathy was noted in the subpectoral, supraclavicular, and lower cervical lymph nodes.
18F-FDG PET-CT imaging was the most common modality used to identify lymphadenopathy, although PET-CT with radio labeled choline or somatostatin analogues, mammography, and ultrasound were also used in some cases. The median interval between vaccination and identification of UAL was 6.5 days (range 1–30 days). Only 11 out of 39 cases (28%) had a confirmatory core biopsy or fine-needle aspiration of the axillary lymph nodes to rule out malignant involvement and to confirm the inflammatory response. Pathology results from all biopsied lymph nodes were reported as showing benign or reactive hyperplasia [9, 12, 14, 26, 34]. For patients that did not undergo lymph node biopsy, the diagnosis of UAL post-COVID-19 vaccination was made based on the history of preceding vaccination and regression of lymphadenopathy on follow-up. The time to resolution of UAL ranged from 7 days to 3 months [17, 19, 26, 30, 31].
DiscussionThe COVID-19 pandemic, now at its 2-year mark, has significantly altered the health-care landscape by impeding the management of chronic disease and by raising significant concerns for cancer management [35]. The goal of the COVID-19 vaccination strategy is to minimize deaths, severity of disease, overall disease burden and to reduce the risk of new variants. Patients with cancer have a higher risk of COVID-19 and associated mortality than the general population [36]. Therefore, patients with cancer have more recently been prioritized for COVID-19 vaccination globally, although these patients were not included in the pivotal clinical trials [37]. For cancer patients, there remains uncertainty about vaccine efficacy and the risks of vaccine-related adverse events.
Lymph node enlargement is a common side effect of vaccinations that evoke a strong immune response, and this has more recently been described in a few case reports and series as UAL post-COVID-19 vaccination [38]. In the phase III trial of the Pfizer-BioNTech vaccine, UAL was only reported in 0.3% of recipients, occurring within a median of 2–4 days [39]. However, in the phase III Moderna vaccine trial, the incidence of palpable UAL was higher at 11.6% and 16% following the first and second dose, respectively [40]. The reporting of lymphadenopathy in these studies was based only on physical examination potentially excluding subclinical lymph node abnormalities which might be detected by imaging alone. As the worldwide COVID-19 vaccination campaigns have intensified, the incidence of UAL post-COVID-19 vaccination is likely to rise.
Humoral and cell-mediated immunities are two types of adaptive immune responses to defense against any foreign body such as viral infections. CD4+ T cells help activate B lymphocytes, thereby producing antibodies and CD8+ T cells to eliminate viral infected cells. Reactive lymphadenopathy can be seen as a sign of successful immunization because it implies activation of the immune systems including SARS-CoV-2 neutralizing antibodies; furthermore, activation of the immune system enhances the uptake of PET-CT scan tracers [39, 41]. Vaccination has provided protection through successful production of neutralizing antibodies and seroconversion that has reached up to 100%, including in cancer patients [42–44]. COVID-19-specific IgG and IgA seroconversion is proof of a generated immune response following vaccination. The vaccine usually stimulates multiple B lymphocyte clones in order to produce neutralizing antibodies specific to the viral spike glycoprotein, which mediates host cell attachment and viral entry [45]. However, viral neutralizing antibodies alone are not sufficient to protect humans from severe COVID-19 infection and T cell activation is also required [46].
A study conducted in the Czech Republic found out that participants were at a higher risk of developing lymphadenopathy after vaccination if they were female, young adults, suffered from allergies, bowel disease, cardiac disease, chronic obstructive pulmonary disease, diabetes mellitus type 2, and neurologic diseases [47]. However, cancerous conditions were not among the conditions that contribute to increased incidence of UAL.
Compared to other types of vaccines, mRNA vaccines offer effective protection against COVID-19 symptoms, mediated by a combined humoral and cell-mediated immunity with a relatively low incidence of serious adverse effects [48]. Patients with cancer had a greatly increased risk of COVID-19 infection estimated to be between 7 and 12 odds value, and an increased risk of mortality compared to the general population [49].
In our case series, case no. 1 had metastatic breast cancer and had remained stable on endocrine-based therapy for several years until a follow-up PET-CT scan suggested disease progression due to false-positive UAL post-COVID-19 vaccination. If there had been true disease progression, the patient would have needed a change in therapy with second-line endocrine therapy or chemotherapy. This resulted in a significant degree of patient anxiety because the phenomenon of post-COVID-19 UAL was not well recognized at that time. Core biopsy of the axillary lymph node confirmed reactive changes with no evidence of malignancy, and follow-up imaging showed complete resolution of the lymphadenopathy. Case no. 2 presented with a small T1 breast cancer and was thought to have nodal involvement based on false-positive imaging. Core biopsy of the axillary lymph node showed reactive changes with no evidence of malignancy suggestive of UAL post-COVID-19 vaccination.
Irrespective of the stage of malignancy, post-COVID-19 vaccination UAL, especially in breast cancer patients, poses a diagnostic dilemma and can result in significant patient anxiety. The CARE Checklist has been completed by the authors for this case series, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529913).
Management and RecommendationSince COVID-19 vaccination programs are likely to continue, even after the reduction of cases worldwide, there are considerations for the management of axillary lymphadenopathy in patients with recent or booster COVID-19 vaccinations. We therefore support the following recommendations by the European Society of Breast Imaging [50].
1) In cases of pre-existing breast cancer, vaccination should be given on the arm contralateral to the site of cancer or anterolateral thigh whenever possible.
2) Patients should schedule breast examinations prior to the first dose or 12 weeks following the second or subsequent booster doses.
3) Prior to any imaging, we encourage detailed documentation of vaccination status including date(s) of vaccination(s), type of vaccine, injection site (left or right; arm/thigh), and any recent history of palpable nodules.
4) In patients with pre-existing breast cancer, UAL post-COVID-19 vaccination should be interpreted with caution, keeping in view the time since vaccination and overall nodal metastatic risk. For patients with low risk of nodal metastases, interval clinical reassessment may be appropriate. For patients with high risk of nodal metastases, short-interval follow-up imaging or nodal biopsy should be considered.
ConclusionRecent studies have shown targeted efforts to accelerate COVID-19 vaccinations, particularly in developing countries with encouraging results. Radiologists and other health-care workers will increasingly encounter COVID-19 vaccination-induced lymphadenopathy detected by multiple imaging modalities. Furthermore, there is an anticipated increase in the number of SARS-CoV-2 variants and also an uncertainty as to the duration of vaccine protection. Therefore, COVID-19 vaccination may become seasonal in future.
It is therefore of paramount importance that the management of these clinical cases with UAL post-COVID-19 vaccination becomes standardized in order to avoid unnecessary additional imaging and invasive procedures. For breast cancer patients presenting with UAL post-COVID-19 vaccination, risk stratification for nodal metastases based on clinical parameters and radiological findings is essential to decide on whether follow-up imaging or lymph node biopsy is warranted.
Statement of EthicsThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The subjects have given their written informed consent to publish their medical cases and accompanying images. This study was reviewed and approved by Abu Dhabi Health Research and Technology Ethics Committee, Department of Health, Reference no. DOH/CVDC/2021/991 on July 7, 2021.
Conflict of Interest StatementThe authors declare no conflict of interest.
Funding SourcesNo external funding to declare.
Author ContributionsConceptualization, original draft preparation, and methodology: J.A., Z.A., and S.Z. Software analysis, investigation, and data curation: Z.A. and S.Z. Review of radiology: H.A. and S.M.K. Pathology review: I.S. Case analysis and preparation: M.A., A.Y., M.M.H., and M.S.H. Review and editing: S.Z., Z.A., A.Y., M.A., M.M.H., M.S.H., S.M.K., H.A., I.S., K.B., F.A., A.S., E.D., and J.A. Supervision of manuscript: J.A., Z.A., and K.B. Critical review of manuscript: E.D., K.B., A.S., and F.A. All authors read and approved the final manuscript prior to submission.
Data Availability StatementAll data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.
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