Computed Tomography Imaging of COVID-19 Vaccination–related Axillary Lymphadenopathy: Updated Review of Literature

Correspondence: papers@team.qeios.com — Qeios will forward to the authors

The systematic review was performed as per the PRISMA guidelines and checklist. Since this was a systematic review, institutional review board approval was not needed. PubMed database was searched for relevant English language articles up till September 2022. The search terms “Vaccine" OR "Vaccination" AND "Axillary Lymphadenopathy" OR "Axillary Lymph node" AND "Covid-19″ AND “CT Chest”. 7 studies or reports were identified using the predefined keywords. One of them described myocardial perfusion imaging findings and others described PET/CT imaging findings. Only 1 study was initially found to describe exclusively CT chest findings of covid 19 associated axillary lymphadenopathy. From the “similar articles section” of this paper few additional studies were found describing CT chest findings in covid 19 associated axillary lymphadenopathy. Studies that described findings on ultrasound or mammography or PET/ CT or MRI were included only if Chest CT images were also described. Studies describing non-axillary lymphadenopathy were excluded. Letter to Editors, conference abstracts, and non-research articles (such as opinions and commentaries) were excluded. Identical articles and abstracts were identified to avoid duplication. Similar studies published by the same institution were analyzed and only the most recent comprehensive study was included to avoid data duplication. Data extraction was performed by 3 investigators independently and results were cross-checked and merged for analysis.

Ahn et al. describe Axillary Lymphadenopathy after mRNA COVID-19 Vaccination on CT Chest images ^[9]. It occurred 7 days after the second dose of mRNA COVID-19 in a 32-year-old man. The lymph node measured 15mm in its short axis. Axial CT Chest imaging in a 39-year-old woman initially revealed normal lymph nodes. However, 8 days after vaccination with mRNA Covid-19 vaccine patient demonstrated left axillary lymph nodes measuring 1.4 cm on the short axis. All patients were asymptomatic.

Lane et al. describe COVID-19 Vaccine-Related Axillary Lymphadenopathy in Patients with Current or Prior Breast Cancer and Other Malignancies on Cross-Sectional Imaging including MRI, CT, and PET-CT. They found that vaccination can cause level I-III axillary lymphadenopathy ^[10]. They found axillary adenopathy in the left level II axilla lymph node in a 70-year-old female with a history of right breast cancer and bilateral mastectomy. Enlarged lymph nodes were seen five days after the second COVID-19 vaccine. Follow-up ultrasounds showed an enlarged lymph node with focal cortical bulge and loss of fatty hilum.

Viana et al. ^[11] describe the first Brazilian case report of post-COVID-19 adenopathy within 24 hours of the COVID-19 vaccine. The patient developed fever, axillary discomfort, and also a convulsion episode after administration of the Pfizer BioNTech COVID-19 vaccine in the right arm. He underwent Chest computer tomography on the same day which showed axillary fat standing with lymph node enlargement.

Nishino et al.. ^[11] utilized prevaccine and postvaccine chest CT data of lung cancer patients who had received two doses of mRNA-based COVID-19 vaccinations. The incidence rate was found to be 9%. The median time of development of lymph node enlargement was 1.7 weeks after the second booster shot. Vaccine type (mRNA1273 vaccine) and female sex were revealed to be predisposing factors. The median number of enlarged nodes was four and the median short-axis diameter of the largest node was 7 mm.

Yu et al.. present a misdiagnosed case of lymphadenopathy after COVID-19 vaccination from SinoVac. 34-year-old lady presented with left axillary pain and fever. She received her first and second doses of the SinoVac COVID-19 vaccine five and four months ago respectively. Both doses were administered to the left arm. She developed left axillary swelling and pain. Computer tomography demonstrated left axillary lymphadenopathy. Follow-up was performed using ultrasound which showed an initial increase in the size of the lymph nodes. Initial ultrasounds misreported necrotic lymph nodes and fine needle aspiration cytology was negative for tuberculosis or malignancy. Follow-up ultrasound showed a decrease in the size of the lymph nodes and eventual resolution after 8 months. The lymphadenopathy was attributed finally to side effects of the COVID-19 vaccine based on clinical, imaging, and histopathological findings, and this was confirmed in the prognosis as it resolved on its own.

Placke et al. ^[12] studied 8 patients with melanoma or Merkel cell carcinoma who underwent lymph node excision and received Covid-19 vaccination within 6 weeks before surgery. They found that the lymphadenopathy images of Covid-19 were similar to lymph nodal metastasis.

Wolfson et al. ^[13] studied 1217 patients who had taken Covid-19 vaccine and had undergone breast imaging. 9% (29 patients) had lymph node enlargement identified with mammography alone, 61% (203 patients) hade lymph node enlargement detected on sonography. 44 % (537 patients) had lymph node enlargement on atleast one imaging. The average lymph node size was 1.8 cm. Lymphadenopathy was typically seen within 14 days of vaccination and was rare after 50 days of second dose.

The majority of lymphadenopathy after Moderna vaccination occurred within 2 to 4 days and radiological observations lasted between 4 days to 10 weeks. The lymphadenopathy that occurred with Sinovac vaccine occurred at 4 months and resolved at 8 months. All the studies discussed above had initial CT chest imaging. The CT features of Covid axillary lymphadenopathy in all these studies were similar to lymph nodal metastasis or any other infectious cause of lymph node enlargement. Follow-up by ultrasound was done, which showed resolution of lymphadenopathy in all the studies without any treatment, confirming COVID-19 as the etiology.

Guidelines and algorithms for management of lymphadenopathy in current setting of Covid-19 vaccinations - Current Society of Breast Imaging Guidelines ^[14]:

1. For average-risk women with screening-detected ipsilateral lymphadenopathy and no other suspicious mammographic findings: Assess as BI-RADS 2, no dedicated follow-up
2. At short-term imaging follow-up (≥12 weeks): If improving lymphadenopathy, assess as BI- RADS 2
3. At short-term imaging follow-up (≥12 weeks): If unchanged lymphadenopathy, assess as BI-RADS 3, consider additional 6-month follow-up If increased lymphadenopathy, then consider lymph node sampling

Schiaffino et al. ^[15] recommended in European Society of Breast Imaging that 1) vaccination should be administered in the contralateral arm or in the thigh in cases with previous history of breast cance, (2) all vaccination data has to be collected for all patients referred to breast imaging services (3) breast imaging examinations should be performed before vaccination or at least 12 weeks after the last vaccine dose; (4) apply standard imaging protocols regardless of vaccination status in newly diagnosed breast cancer, (5) in any case of symptomatic or imaging‐detected axillary lymphadenopathy before vaccination or at least 12 weeks after, examine with appropriate imaging the contralateral axilla and both breasts to exclude malignancy; (6) perform standard work‐up in case of axillary lymphadenopathy contralateral to the vaccination side, (7) Lymphadenopathy only ipsilateral to the vaccination side within 12 weeks after vaccination can be considered benign or probably‐benign, in patients without breast cancer history and no suspicious breast imaging findings, (8) post‐vaccination lymphadenopathy coupled with suspicious breast finding requires standard work‐up, including biopsy when appropriate in patients without breast cancer history, (9) interpret lymphadenopathy considering the timeframe from vaccination and overall nodal metastatic risk in patients with breast cancer history, interpret and manage post‐vaccination (10) complex or unclear cases should be managed by the multidisciplinary team.

Zhang et al. ^[16] have state in their paper that risk-based management algorithm scan significantly reduced unnecessary biopsies in low-risk patients. They also describe the imagin features to differentiate benign from malignant lymphadenopathy. In axilla not only the size but the morphology of the lymph node including its shape, cortical thickness, uniformity, and presence or absence of central fatty hila are considered important criteria for differentiating normal from abnormal lymph nodes. Normal and benign nodes appear oval or reniform, with cortical thickness less than or equal to 3 mm and a preserved fatty hilum. Ultrasound evaluation and classification of axillary lymph nodes based on the cortical thickness and appearance of the hilum have been found to be more accurate in predicting malignancy than overall size of the lymph node. Nodal vascularity at color Doppler US also helps distinguish benign from metastatic lymph nodes, with benign nodes demonstrating hilar perfusion and most metastatic nodes demonstrating eccentric or peripheral perfusion. Patients with active breast cancer should be evaluated with standard imaging protocols regardless of vaccination status.

Ryogo Minamimoto et al. ^[17] describe in their paper the imaging features of FDG-PET/CT imaging after Covid-19 vaccination. There is normal to moderate increase in lymph node size with thickening of cortex and fatty hilum, suggesting benign lesions. Sometimes the lymph node can show abnormal size or loss of fatty hilum shortly after vaccination that can be confused for malignancy. FDG uptake has been shown in axillary lymph nodes following vaccination. It tends to occir within 7 dasy of vaccination and resolves by 12-14 days. It can even persisit for 10 weeks. Generally ipsilateral lymph nodes are involvd however contralateral lymph nodes can also be affected.

Cohen et al.. ^[18] categorized vaccine-associated hypermetabolic lymphadenopathy (VAHL) according to the intensity and area of FDG uptake in axial lymph nodes as follows: grade 1, mild FDG-uptake intensity (SUVmax < 2.2); grade 2, moderate FDG-uptake intensity (2.2 ≤ SUVmax < 4); grade 3, high FDG- uptake intensity (SUVmax ≥ 4) in normal-size nodes; and grade 4, high FDG-uptake intensity (SUVmax ≥ 4) in enlarged nodes. The incidence of VAHL was 36.5% among all subjects who were vaccinated but was significantly higher after the 2nd vaccination (45.8%) compared with the 1st vaccination (26.3%). Node size, FDG uptake in axial lymph nodes beyond level 1, and the site of vaccination were all more prominent after the 2nd vaccination. After the first vaccination, the incidence of VAHL was higher at 6-12 days after vaccination compared with that in the first 5 days and at 13 days. After the second vaccination, the incidence and grade of VAHL were highest in the first 6 days, decreased gradually over time, and were significantly low at more than 20 days after vaccination. VAHL was recognized in 29% of vaccinated patients at 3 weeks after the second vaccination, but only 7% had grade 3 or 4 VAHL. After the first vaccination, there was a higher incidence and higher grade of VAHL in subjects aged ≤ 62 years than in others; whereas after the second vaccination, there was a higher incidence and higher grade of VAHL in subjects aged ≤ 64 years than in others (26). Regarding FDG uptake in lymph nodes, greater uptake was associated with second vaccination; in contrast, lower uptake was associated with older age, immunosuppressive treatment, and hematologic disease (30).

Conclusions

Vaccine-related lymphadenopathy in patients with lung cancer can lead to diagnostic dilemmas. In the initial stage, axillary lymphadenopathy can alter staging and can result in unnecessarily invasive procedures. Second, it can make the evaluation of the effectiveness of neo-adjuvant therapy difficult. Finally, new lymph node enlargement in post-operative patients makes it difficult to distinguish it from recurrence.

List of Abbreviations

• Chest CT: Chest Computed Tomography
• MRI: Magnetic Resonance Imaging.
• PET / CT: Positron Emission Tomography / Computerized Tomography.

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