Soon after the initiation of the anti-SARS-CoV-2 vaccination campaigns, it appeared that the injection of mRNA vaccines may induce swelling of lymph nodes draining the injection site. Although considered as benign, this vaccine reaction sometimes complicated the interpretation of 18F-FDG PET/CT imaging for suspicion of a neoplastic process affecting lymph nodes (3). When a lymph node biopsy was performed to exclude a malignant process, the pathological picture showed reactive benign changes with prominent germinal centers (3, 8). The differential diagnosis with lymphoma was occasionally complicated by the development of hypermetabolic sites at distance of the injection site, including contralateral lymph nodes or spleen (9, 10). In a patient with mantle lymphoma, PET/CT was suggestive of a relapse but was eventually excluded (11).
Published studies on hypermetabolic lymphadenopathy after SARS-CoV-2 vaccination were recently reviewed and the subject of a meta-analysis (8, 12). Most observations were reported after injection of approved nucleoside-modified mRNA vaccines, namely BNT162b2 (Pfizer-BioNTech) or mRNA-173 (Moderna) (8). Nevertheless, hypermetabolic lymphadenopathies were also observed in 31 health workers following injection of the adenovirus-vectored Vaxveria vaccine (13).
Considering oncologic patients, the most informative study was conducted in a series of 728 patients having received the BNT162b2 mRNA vaccine (14). PET/CT revealed hypermetabolic lymph nodes in the axillary and supraclavicular regions draining the vaccine injection site in 36% of the subjects having received the first dose and 54% of those studied after the 2nd dose. The hypermetabolic lymph nodes were enlarged in 7% of 1st dose vaccinees and 18% of 2nd dose vaccinees. Both differences were statistically significant, demonstrating that the impact on draining lymph nodes was greater after the booster dose, confirming data from the meta-analysis above (12). Regarding the relationship with the underlying malignancy, hypermetabolic lymph nodes were considered as malignant in 5% of the patients while no conclusion regarding the malignant nature could be drawn in 15% of the vaccinees including 16 patients with lymphoma. Interestingly, in none of these studies, the possibility that the mRNA vaccines could have played a role in the development of malignant lymph nodes was considered. Indeed, the consensus so far is that the occurrence of hypermetabolic lymphadenopathies should not question the safety of mRNA vaccines, neither in healthy individuals nor in patients with neoplastic conditions (15).
To the best of our knowledge, this is the first observation suggesting that administration of a SARS-CoV-2 vaccine might induce AITL progression. Several arguments support this possibility. First, the dramatic speed and magnitude of the progression manifested on two 18F-FDG PET-CT performed 22 days apart. Such a rapid evolution would be highly unexpected in the natural course in the disease. Since mRNA vaccination is known to induce enlargement and hypermetabolic activity of draining lymph nodes, it is reasonable to postulate that it was the trigger of the changes observed. Indeed, the increase in size and metabolic activity was higher in axillary lymph nodes draining the site of vaccine injection as compared to their contralateral counterparts. However, pre-existing lymphomatous nodes were also clearly enhanced as compared to the first test. Moreover, new hypermetabolic lesions most likely of lymphomatous nature clearly appeared at distance of the injection site.
In fact, the supposed enhancing action of the vaccine on AITL neoplastic cells is fully consistent with previous observations identifying TFH cells within germinal centers as key targets of nucleoside-modified mRNA vaccines both in animals and in man (1, 2). Malignant TFH cells, the hallmark of AITH, might be especially sensitive to mRNA vaccines when they harbor the RHOA G17V mutation which was present in our case. Indeed, this mutation facilitates proliferation and activation of several signaling pathways in TFH cells (16). Furthermore, mice genetically engineered to reproduce the RHOA G17V and TET2 mutations—both were present in our case—develop lymphoma upon immunization with sheep red blood cells (16). This experimental observation is relevant to RNA vaccines as RNA of sheep red blood cells was shown to be responsible for their ability to stimulate TFH and induce germinal center reaction (17).
Our case first raises the question of the COVID-19 prevention strategy to be used in this patient which is currently poorly protected against COVID-19. On the short term, the only option is to recommend strict masking and social distancing, and to offer him anti-SARS-CoV-2 antibody therapy in case of high-risk contact (16). On the longer term, the use of mRNA vaccines should clearly be avoided while other types of vaccines might be considered.
At this time, extrapolation of the findings of this case to other patients with AITL or other peripheral T cell lymphoma involving TFH cells is premature. AITL patients are rare and their mutation profile is heterogeneous. Furthermore, their immune reactions might be affected by their treatment. It is therefore unlikely that existing pharmacovigilance systems will be efficient to identify extremely rare cases like ours. Prospective studies involving systematic PET/CT imaging after SARS-CoV-2 vaccination in AITL patients with specified mutation profiles might eventually be needed. Whatever the result of such studies, it should not affect the overall favorable benefit-risk ratio of these much-needed vaccines.
This observation, which has been posted as a pre-print on the SSRN platform (18), suggests that vaccination with the BNT162b2 mRNA vaccine might induce rapid progression of AITL. Dedicated studies are needed to determine whether this case can be extrapolated to populations of patients with AITL or other peripheral T cell lymphoma involving TFH cells.