Regional lymphadenopathy following COVID-19 vaccination: Literature review and considerations for patient management in breast cancer care

Abstract

Purpose: Over 1 billion doses of COVID-19 vaccines have been already administered across the United States, the United Kingdom and the European Union at the time of writing. Furthermore, 1.82 million booster doses have been administered in the US since 13th 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 the same on breast cancer diagnosis and management.

Methods: A literature search was performed - PubMed, Ovid Medline, Scopus, CINHAL, Springer Nature, ScienceDirect, Academic Search Premier 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, United Kingdom and the Mayo Clinic in Minnesota, United States of America, 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 and/or an imaging finding and then combined with clinical judgement when managing individual cases.

Keywords: Breast cancer; COVID-19; Cancer diagnosis; Cancer follow-up; Lymphadenopathy; Vaccine.

Fig. 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) flow diagram.

Fig. 2

(Case 1): A 70-year-old woman was recalled following a screening mammogram for an ill-defined malignant-appearing mass in the left breast. The mass measured 17 mm on digital breast tomosynthesis and 16 mm on ultrasound scan. On ultrasound assessment of the axilla, there was an enlarged lymph node with a 3 mm cortex of indeterminate nature (U3). The patient reported having received the 1st dose of the Pfizer-BioNTech COVID-19 vaccine in the left arm four weeks prior to the ultrasound date. Ultrasound-guided core biopsy of the breast mass showed a grade II invasive mixed ductal and lobular cancer, while ultrasound-guided fine-needle aspiration (FNA) of the lymph node demonstrated small and intermediate size lymphocytes with no obvious metastatic carcinoma cells (C2). The benign FNA result was accepted, and the patient underwent left-sided breast-conserving surgery and a left-sided sentinel node biopsy that was negative for metastasis.

Fig. 3

(Case 2): A 38-year-old woman, with no personal or family history of breast cancer, presented with a 4-week history of a palpable lump inferior to the left clavicle, which was first noticed approximately one week after receiving the first dose of the Pfizer-BioNTech COVID-19 vaccine in the left arm. Ultrasound of the left axilla and supraclavicular fossa (SCF) revealed normal-appearing axillary lymph nodes and a couple of lymph nodes up to 8 mm in size in the area of interest, with appearances favouring benign reactive nodes. A bilateral mammogram showed no abnormalities. As the patient was due to have her 2nd vaccine dose in 5 weeks' time, she was advised to return for a 10-week follow-up ultrasound scan and clinical examination to ensure resolution. The patient reported that in the following weeks, the adenopathy progressively improved. Two days after receiving the 2nd vaccine dose, she again developed palpable SCF adenopathy that had resolved completely by the time of her follow-up appointment.

Fig. 4

(Case 3): A 76-year-old woman presented with a palpable lump in her left axilla and no breast symptoms. She received the 1st dose of AstraZeneca COVID-19 vaccine in her left arm 8 weeks prior. Ultrasound of the left axilla demonstrated a large abnormal appearing lymph node, suspicious of malignancy (left). Mammography showed no breast abnormalities. Lymph node core biopsy demonstrated non-specific reactive changes. A 6-week follow-up ultrasound scan demonstrated no significant change in size and appearance of the node. However, the patient had the 2nd vaccine dose administered in the left arm the previous week, and therefore, biopsy was not repeated, and a further ultrasound scan was arranged in 6 weeks. This showed marked improvement, both clinically and radiologically, and the patient was reassured and discharged (right).

Fig. 5

(Case 4): A 73-year-old female who was referred to the symptomatic breast clinic with a one-month history of a left-sided breast mass. Clinical examination revealed a 25 mm suspicious breast mass and no clinically palpable axillary or supraclavicular lymph nodes. On breast imaging, the mass was also suspicious of malignancy, measuring 26 mm on mammography and 24 mm on ultrasound scan. Axillary ultrasound at that time demonstrated no lymphadenopathy (left). The breast biopsy showed evidence of squamous cell carcinoma (SCC). Due to the unusual histology, a whole-body PET-CT scan was performed to rule out primary SCC from other sites. This did not show evidence of another primary malignancy, however, clustered left axillary and subpectoral nodes, measuring <1 cm, were identified. Those were judged as presumably inflammatory in nature, although malignant infiltration could not be excluded (middle). There was also uptake noticed within the left deltoid muscle (right). The patient had the 1st dose of the AstraZeneca COVID-19 vaccine in the left arm one day prior to the PET-CT scan. The lymphadenopathy was considered likely to be vaccine-related and the patient underwent a left mastectomy and left sentinel node biopsy, which was negative for lymph node metastasis.

Fig. 6

(Case 5): A 71-year-old woman, with a history of a right-sided breast cancer 9 years ago, attended the symptomatic breast clinic with a new lump in her left breast. Mammogram and breast ultrasound identified a 29 mm malignant appearing lesion in the lower inner quadrant of the left breast. Ultrasound of the left axilla was normal. A core biopsy of the left breast mass showed grade 2 invasive ductal cancer, which was ER positive, and HER2 positive. Breast MRI confirmed the presence of a 31 mm spiculated mass in the left breast. Staging CT scans of chest, abdomen and pelvis showed no evidence of metastatic disease, with only small volume para-aortic lymphadenopathy seen, and no pathological lymphadenopathy in the axilla or SCF/ICF bilaterally (left). The patient was started on neoadjuvant chemotherapy to downsize the cancer and facilitate breast conserving surgery. A repeat CT scan was performed after 3 months of neoadjuvant systemic treatment, which identified the interval emergence of prominent right-sided axillary nodes, of uncertain clinical significance (right). The patient had the first dose of the AstraZeneca COVID-19 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 that showed complete pathological response in the breast and no evidence of lymph node metastasis or fibrosis.

Fig. 7

(Case 6): A 58-year-old woman with a history of a stage III right-sided breast cancer receiving extended adjuvant endocrine treatment with exemestane was found to have new palpable axillary lymphadenopathy during a follow-up visit. Three weeks prior, she received the 2nd dose of the Pfizer-BioNTech Covid-19 vaccine to her left arm. Ultrasound of left axilla (left) and a chest CT scan (middle) demonstrated new multiple abnormal-appearing left axillary and subpectoral lymph nodes, the largest measuring 2 cm. A core biopsy of the largest lymph node revealed reactive changes with mild follicular and paracortical lymphoid hyperplasia, including an increased number of polytopic B-immunoblasts (right). Cytokeratin stain was negative for metastatic disease.

Fig. 8

(Case 7): A 41-year-old female with a prior history of locally advanced left breast cancer at the age of 33, presented to the Mayo Clinic Neurology service with the slow onset numbness of the 4th and 5th digits of her left hand, progressing to weakness in the left hand and forearm. In 2003, she presented with a T2, N3 breast cancer (ER+/HER2-) treated with bilateral mastectomies and left axillary node dissection followed by adjuvant chemotherapy, radiotherapy and hormonal therapy. She received sequential doses of the Moderna COVID-19 vaccine to her right arm, with the last dose two weeks prior to her presentation to the Mayo Clinic. A PET-CT scan identified hypermetabolic right axillary, retropectoral and retro-clavicular lymph nodes, most consistent with nodal metastasis, as well as local and linear areas of FDG uptake along the left brachial plexus at the level of C7-T1 paravertebral region also extending to intervertebral neural foramen and probably to the spinal canal. A non-diagnostic FNA of the pathological right axillary lymph node was followed by a core biopsy that was negative for malignancy (lymphocytes consistent with sampled lymph node). Neurosurgical exploration of left brachial plexus demonstrated nodular enlargement and swelling of C8 and two fascicular biopsies demonstrated perineural space involved by metastatic carcinoma, consistent with a breast primary.