Seven-month persistence of COVID-19 vaccine-induced lymphadenopathy: a case report

Abstract

Background

Lymphadenopathy is a known side effect of both messenger RNA and viral vector coronavirus disease-2019 vaccines and can cause a spectrum of findings. Coronavirus disease-2019 vaccine-associated lymphadenopathy typically resolves within 60 days after administration of the dose.

Case presentation

A 59 year old Chinese woman underwent routine mammographic screening that revealed scattered areas of fibroglandular densities in the lower-inner quadrant of the left breast and abnormal lymph nodes. A core biopsy of the breast identified ductal carcinoma in situ. A biopsy of the lymph nodes was performed, and histological findings and immunophenotype were consistent with lymphoid hyperplasia. This patient had sought medical attention after she detected swelling in her left supraclavicular fossa 7 months earlier. She had received the first dose of the Pfizer coronavirus disease-2019 vaccine in the left deltoid muscle 7 days prior to presenting with left supraclavicular fossa swelling.

Conclusion

After reviewing the history, imaging, and pathology, it was concluded through a diagnosis of exclusion that the observed enlarged left axillary lymph nodes with reactive histology were probably related to the coronavirus disease-2019 vaccine administration and not to ductal carcinoma in situ or an undetected invasive cancer. Clinicians and radiologists need to be aware of the potential for abnormal presentations of persistent lymphadenopathy that may interfere with the diagnosis and follow-up of cancers.

Background

Lymphadenopathy is a known side effect of both mRNA and viral vector coronavirus disease-2019 (COVID-19) vaccines and can cause a spectrum of findings, including, but not limited to, a single enlarged lymph node, multiple enlarged lymph nodes, or adenopathy with soft tissue stranding [1, 2]. In the initial randomized trial of the Pfizer COVID-19 vaccine, 0.3% of vaccinated individuals reported the development of lymphadenopathy [3]. Lymphadenopathy was identified on the basis of self-report, which may have resulted in an underestimate of the true incidence. For the Moderna mRNA vaccine, “axillary swelling or tenderness” was the second most commonly reported local reaction and was more frequent among individuals aged 18–64 years than among those aged ≥ 65 years (16.0% versus 8.4% after dose two, respectively) [4]. However, in a study of patients undergoing computed tomography-positron emission tomography (CT/PET) scans of the chest for various clinical indications, 66% of individuals who had received a COVID-19 vaccination within the past 32 days were found to have ipsilateral increased activity in axillary lymph nodes [5]. A review of published studies on COVID-19 vaccine-related lymphadenopathy suggests that lymphadenopathy typically resolves within 60 days after administration of the vaccine [1,2,3,4]. In this patient, enlarged nodes persisted for 7 months, which complicated the diagnosis of ductal carcinoma in situ (DCIS) because it raised the possibility of an unrecognized focus of invasive cancer.

Case presentation

A 59 year old Chinese woman underwent routine mammographic screening that revealed scattered areas of fibroglandular densities with microcalcifications developing in the lower inner quadrant of the left breast and prominent lymph nodes (Fig. 1a, b). Magnification mammographic views of the left breast demonstrated amorphous heterogeneous calcifications in a segmental distribution, spanning an area approximately 70 mm in maximal anterior–posterior dimension (Fig. 1c, d). No associated mass was identified on mammography or ultrasound. A 14 gauge (G) ultrasound-guided, spring-loaded core biopsy of the left breast lesion revealed low-to-intermediate grade ductal carcinoma in situ (DCIS) (with associated microcalcifications).

Fig. 1

Mammogram of the left breast; A left craniocaudal view; B left mediolateral oblique view; C left magnified craniocaudal view; D left magnified lateromedial view

The patient was gravida 3 para 3, postmenopausal approximately 1 year previously, with no family history of breast cancer and in good health. She had no history of malignancy and was a lifetime nonsmoker.

Ultrasound of the left axilla showed normal morphology level I lymph nodes and one to two abnormal level II lymph nodes with focally increased cortical thickness measuring up to 5 mm and an eccentrically displaced and partially flattened fatty hilum. This clinical scenario raised the question of why this patient had enlarged nodes in the apparent presence of only DCIS.

In addition, 10 months prior to presentation, she had acute upper respiratory tract symptoms consistent with a viral illness, with a negative nasopharyngeal swab reverse transcription polymerase chain reaction test for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This patient had sought medical attention after she detected swelling in her left supraclavicular fossa 7 months earlier. In addition, 7 days prior to presenting with left supraclavicular fossa swelling, she had received the first dose of the Pfizer COVID-19 vaccine in the left deltoid muscle. Just prior to her vaccination, serologic testing for total antibodies to SARS-CoV-2 nucleocapsid and spike proteins were negative.

Physical examination at the time of her presentation revealed a cluster of three soft nontender lymph nodes in the left supraclavicular fossa, each approximately 1–1.5 cm in diameter. There was no detectable cervical or axillary lymphadenopathy. Breast exam was normal, with no palpable masses. A chest X-ray revealed no abnormalities. The enlarged lymph nodes were attributed to the COVID-19 vaccine. Over the next 4 weeks, the left supraclavicular lymph nodes decreased in size and became barely palpable.

Initial ultrasound-guided 25G and 22G fine needle aspiration of the level II axillary lymph node yielded insufficient lymphoid sample and was unsatisfactory for evaluation.

Dynamic contrast enhanced magnetic resonance imaging (MRI) was performed to further assess the breasts and lymph nodes. There was corresponding focally increased non-mass enhancement at the site of the left breast biopsy proving DCIS but no MRI evidence of grossly invasive disease (Fig. 2). In the left axilla, there was an enhancing mass measuring 1.3 cm in diameter, deep to the pectoralis major muscle. An ultrasound-guided core biopsy of this mass was performed. Pathology revealed lymphoid tissue with interfollicular areas containing small lymphocytes, plasma cells, and rare eosinophils (Fig. 3a, b). No aberrant expression of CD20, CD3, BCL2, BCL6, kappa, lambda, or AE1/AE3 was identified. These histologic findings and the immunophenotype were consistent with lymphoid hyperplasia.

Fig. 2

Dynamic contrast enhanced magnetic resonance imaging of the breasts and axillary lymph nodes

Fig. 3

A Core biopsy of lymph node including fragment of skeletal muscle (bottom right). The stars and arrows point to follicles and an expanded paracortical zone; B the lymph node demonstrates lymphoid hyperplasia with multiple follicles (arrow) present within an expanded paracortical zone (star)

Lymphadenopathy can be caused by various etiologies, including malignancies, infections, autoimmune disorders, or miscellaneous conditions such as certain medications, foreign bodies, or vaccinations. In this case, many etiologies could be eliminated from consideration on the basis of the patient’s history, physical exam, and investigations. The patient had no known infections and no findings suggestive of an infection. She had no history of or symptoms suggestive of an autoimmune disorder. The patient was only taking hormone replacement therapy, steroid inhaler, and chronic antihypertensive medications in the 7-month period between vaccination and diagnosis of DCIS, none of which are associated with lymphadenopathy. There was no history of any implanted device or foreign body. After reviewing imaging and pathology, the clinical team concluded that the enlarged left axillary lymph nodes with reactive histology were not due to a malignancy or benign tumor. Thus the team determined by diagnosis of exclusion that the lymphadenopathy was most likely due to the prior ipsilateral upper extremity COVID-19 vaccine administration.

Because of the extent of the DCIS, the final recommendation was to do a total mastectomy of the left breast with sentinel node removal and immediate reconstruction with a deep inferior epigastric artery perforator (DIEP) flap.

Surgical pathology revealed multifocal intermediate grade DCIS that was positive for estrogen receptor protein and progesterone receptor protein, with the largest area spanning 59 mm on histology. The left axilla sentinel lymph node was negative for malignancy. The patient had an uneventful recovery and received no additional treatment.

Discussion and conclusion

Lymphadenopathy as a result of COVID-19 vaccine can lead to additional diagnostic tests, which are often anxiety-provoking and unpleasant for the patient, which in turn can reduce quality of life. In this patient, the presence of abnormal level II lymph nodes with no abnormal level I lymph nodes on ultrasound imaging was a diagnostic clue that the abnormal lymphadenopathy was likely unrelated to the presence of either DCIS or an undetected invasive breast cancer. There are three levels of axillary lymph nodes: level I nodes are below the lower edge of the pectoralis minor muscle, and are usually the first affected nodes in invasive breast cancer (sentinel nodes are level I nodes); level II nodes are located underneath the pectoralis minor muscle; and level III nodes are above the pectoralis minor muscle.

A case series of five patients reported axillary lymphadenopathy that mimicked metastases in oncologic patients, which complicated diagnosis and treatment [6]. Unlike this patient, all the cases presented were within 15 days of a recent vaccination. Another recent report of axillary lymphadenopathy in a woman with breast cancer also described resolution after 9 days of receipt of second COVID vaccine [7]. In addition, two large retrospective studies, one with 750 women and the other with 1217 women, reported axillary lymphadenopathy in 3% and 9% of women undergoing screening mammography [1, 8]. The longest duration between COVID-19 vaccination and presence of lymphadenopathy was up to 10 weeks [8]. The 7-month duration of persistent vaccine-related lymphadenopathy is highly unusual, especially with widespread vaccination of the population and ongoing booster vaccinations. Because of the frequency of COVID-19 vaccine-related lymphadenopathy, Wolfson et al. suggest that screening mammograms should not be delayed owing to prior administration of COVID-19 vaccinations. Instead, results should be interpreted in the context of various risk factors, including prior vaccination, and other mammographic abnormalities [8]. On the basis of our case, clinicians and radiologists need to be aware of the potential for abnormal presentations of persistent lymphadenopathy that may interfere with the diagnosis and follow-up of cancers.

This case should not lead physicians to underestimate the risk of cancer, particularly upon abnormal imaging. Instead, primary care providers should continue the practice of clinical follow-up of lymphadenopathy 6–8 weeks after COVID-19 vaccination in patients without a history of cancer and prompt imaging in patients with recent cancer diagnoses or a history of cancer [9]. Most importantly, physicians should continue to collect information about COVID-19 vaccination status, type of vaccine, dates of vaccination, and site (especially laterality) of vaccination, as well as provide this information to interpreting radiologists should imaging be scheduled.