Exploring cutaneous lymphoproliferative disorders in the wake of COVID‐19 vaccination

Abstract Background Individual reports have described lymphoproliferative disorders (LPDs) and cutaneous lymphomas emerging after administration of the COVID‐19 vaccine; however, the relationship between reactions and vaccine types has not yet been examined. Objective Determine if there are cases of cutaneous LPDs associated with certain COVID‐19 vaccines and their outcomes. Methods We analysed PubMed, the Vaccine Adverse Events Reporting System (VAERS), and our database for instances of biopsy‐proven LPDs following COVID‐19 vaccines. Results Fifty cases of biopsy‐proven LPDs arising after COVID‐19 vaccination were found: 37 from medical literature, 11 from VAERS and two from our institution. Geographical distribution revealed the most cases in the United States, Italy, and Greece, with single cases in Spain, Colombia, Canada, Japan, and Romania. The average age of patients was 53; with a slight male predominance (male‐to‐female ratio of 1.5:1). The Pfizer‐BioNTech vaccine was associated with LPDs in 36/50 (72%) cases, aligning with its 70% share of the global vaccine market. Histopathology revealed CD30+ in 80% of cases. The most prevalent form of LPD was lymphomatoid papulosis (LyP, 30%). All reported cases produced favourable outcomes (either complete or near‐complete remission). Therapeutic approaches ranged from observation to treatment with steroids, methotrexate, or excision. Conclusion LPDs after COVID‐19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self‐limited character.

hypersensitivity to non-vaccine antigens. 1Primary cutaneous lymphoproliferative disorders (LPDs) after vaccination are reported but uncommon.
We provided an in-depth analysis of 50 LPDs after COVID-19 vaccination. 2While it is important to consider the reactions, it is also essential to investigate the vaccines themselves, elucidating their similarities and differences.Here, we analyse the nature of these vaccines, exploring the types of reactions associated with vaccine subtypes, their demographic distribution, and their mechanisms.

| METHODS
We searched PubMed, reviewed the Vaccine Adverse Events Reporting System (VAERS), and queried our institutional database, for LPDs following COVID-19 vaccination.We searched PubMed from December 2020 through September 2023 for " COVID-19 vaccination" and "lymphoproliferative disorder" or "cutaneous lymphoma" followed by specific searches for subtypes such as "lymphomatoid papulosis" or "anaplastic large cell lymphoma" along with others.All COVID-19 vaccine types were included.We similarly searched VAERS for reactions, starting broadly with lymphoproliferative disorders and narrowing to specific subtypes. 3We reviewed the reported cases for clinical and histopathologic descriptions and cross-referenced between the medical literature and VAERS to ensure cases were not counted twice.Cases lacking biopsy proven LPDs were excluded.We used Our World in Data, an epidemiological tool for tracking COVID-19 vaccination rates, to assess relative distributions of vaccines by country. 4For each vaccine (e.g., Pfizer-BioNTech), we investigated rates and types of reactions, gender, mean age, country, and histopathology.

| RESULTS
In our updated review of the literature through September 2023, 55 cases of LPDs after COVID-19 vaccination were identified: 42 from the medical literature, 11 from VAERS, and two from our institution.We included 50 of 55 cases in our analysis, excluding five due to incomplete demographic and histologic data.

What does this study add?
� We analyse world literature to report on remarkable consistencies such as reactions to the same vaccines and shared clinical and pathological findings.COVID-19 vaccination may be associated with reactive and indolent lymphoproliferative disorders, thus unusual reactions merit diagnostic biopsies.Reactions occur based on vaccine type proportionally to global market share.

| Moderna (mRNA vaccine)
The Moderna vaccine was associated with seven LPD reactions (7/50, 14%).Six of 7 (86%) reactions occurred in men, with only one reaction reported in a woman.The average age was 53 years (range 22-79 years).Five reactions were reported from the US, one from Japan and one from Spain.Two patients developed PLEVA, one LyP, one ALCL, one non-specific lymphomatoid reaction, one primary cutaneous gamma/delta T-cell lymphoma, and one SPTCL.Two 7 reactions occurred after the first dose, with the rest presenting after the second or third doses of the vaccine.Reactions occurred on average 6 days (range 3-10 days) after Moderna vaccination.Three of five cases (60%) with reported staining detected CD30 positivity.

| Oxford-AstraZeneca (adenovirus- vectored vaccine)
Oxford-AstraZeneca was associated with six reactions (6/50, 12%).Three reactions occurred in men and three in women.The average age was 65 years (range of 56-79 years).Three reactions were documented in Greece, with two from Italy and one from Colombia.Two reactions of LyP were reported, one ALCL, one PLEVA, 1 MF, and one pcPTCL.Five of 6 (83%) reactions occurred after the first dose of the vaccine.Reactions occurred on average 12 days (range 7-28 days) after Oxford-AstraZeneca vaccination.Five of 6 (83%) cases demonstrated CD30 positivity.

| Johnson & Johnson (adenovirus- vectored vaccine)
Johnson & Johnson was associated with only one reaction, SPTCL, in a 28-year-old woman, after her first dose of the vaccine.The reaction occurred 3 days after vaccination.This case was documented in the US and did not demonstrate CD30 positivity.

| Combined analysis
The average age of patients was 53 years, with a slight male predominance (male-to-female ratio 1.5:1).Geographical distribution revealed the most reported cases in the United States (24), Italy (17), and Greece (4), with single cases in Spain, Colombia, Canada, Japan, and Romania.Reactions occurred on average 13 days (range 2-42 days) after vaccination Histopathology revealed CD30þ in 80% of cases.The most common LPD was lymphomatoid papulosis (30%) (Figure 1).We did not find a pattern in the anatomic location of lesions or association with vaccine site.All cases resulted in complete or near-complete remission of the LPD, regardless of therapy which ranged from observation to steroids, methotrexate, or excision.

| DISCUSSION
We describe LPDs by vaccine manufacturer for 50 cases of LPDs after COVID-19 vaccination.
We found that 72% of LPDs involved Pfizer-BioNTech (mRNA), the most administered vaccine (~70% of market share) internationally.Moderna (mRNA) makes up ~20% of worldwide vaccinations and 14% of LPDs in our dataset.Oxford-AstraZeneca (adenovirus-vectored) comprises ~7% of global vaccines and 12% of LPDs in our dataset.Its administration was limited due to health concerns such as blood clots.
Johnson & Johnson (adenovirus-vectored) comprises less than 2% of global vaccines and makes up 2% of LPDs in our analysis.
Pfizer-BioNTech reactions were most documented in the US and Italy; Moderna reactions in the US, Japan, and Spain; Oxford-AstraZeneca from Greece, Italy, and Colombia; and Johnson & Johnson from the US.Analysis of LPDs by country demonstrated predominance of Pfizer-BioNTech reactions in the US, Italy, Canada, and Romania, Oxford-AstraZeneca in Greece and Colombia, and Moderna in Spain and Japan.Pfizer-BioNTech-associated LPDs were not reported in Greece (aside from one case), Spain, Colombia, or Japan possibly due to higher rates of other vaccines in these countries or limited cases.Of note, vaccine reactions were predominantly reported from Western countries which used similar vaccine types.Reporting bias likely explains the lack of reports from other countries, although it is possible that the different vaccines used in those countries may be less associated with LPDs.Pfizer-BioNTech, Moderna, and Oxford-AstraZeneca comprised similar proportions of reactions in our dataset to their global distribution rates.Thus, LPDs may arise with different vaccine types rather than mRNA vaccines exclusively and appear proportional to global market shares. 4fizer-BioNTech has been used in at least 146 countries, Oxford-AstraZeneca in 141, Johnson & Johnson in 111, and Moderna in 87.The initial efficacy for preventing infection based on pre-authorisation clinical trials was highest with Moderna and Pfizer-BioNTech at over 90%.Oxford-AstraZeneca has an efficacy rate of 74% and Johnson & Johnson of 52%. 15ne study of cutaneous reactions to COVID-19 vaccines in Turkey found elevated rates of both local injection site and systemic reactions after the Pfizer-BioNTech vaccine compared to Sinovac/CoronaVac (inactivated SARS-CoV-2).These investigators suggested that the Pfizer-BioNTech vaccine triggers an inflammatory pathway through polyethylene glycol (PEG), activating the innate immune system, leading to skin-resident memory T-cell activation and a Th17/ Th22-predominant environment, causing neutrophil flow and triggering cutaneous reactions. 16Thus, not only are vaccines generally proportional to global market shares, but their rates of reaction may also reflect their efficacy in generating robust immune responses.For example, Johnson & Johnson may provoke the lowest rates of LPDs in part because of its low distribution but also due to its low efficacy at stimulating the immune system to produce antibodies.
[19] The Pfizer-BioNTech vaccine is a lipid nanoparticle-formulated, N1-methylpseudouridine (m1Ψ)-modified mRNA that encodes full-length transmembrane spike protein with two proline substitutions at residues K986 and V987 to stabilise the protein in perfusion conformation (S-2P). [20,21]Similarly, Moderna contains lipid nanoparticle-formulated m1Ψ-modified mRNA encoding the S-2P antigen. 18These mRNA vaccines provide cells with genetic material in the form of nucleoside-modified mRNA delivered in lipid nanoparticles to encode the SARS-CoV-2 spike glycoprotein in order to produce antibodies to fight a COVID-19 infection.
Oxford-AstraZeneca is a viral vector vaccine. 22pecifically, the vaccine is composed of a recombinant, replication-deficient chimpanzee adenovirus (ChA-dOx1) vector encoding the full-length wild-type SARS-CoV-2 spike protein with N-terminal tissue plasminogen activator signal sequence that moves the protein to the cell surface, ultimately making spike protein. 23ohnson & Johnson is also a viral vector vaccine which is made of a recombinant, replication-deficient human adenovirus type 26 vector encoding full-length spike protein with the wild-type signal sequence, 2P, and furin cleavage site mutations.24 Viral vector vaccines deliver antigen-coding genes to host cells to produce an immune response, mimicking a natural infection.While they have different mechanisms, both mRNA and viral vector vaccines produce antibodies based on the spike protein to prepare the body for COVID-19, which may account for their similar rates of reactions.
Moderna showed the greatest rate of male predominant vaccine reactions (86%) followed by Pfizer-BioNTech (58%).Oxford-AstraZeneca had an equal male to female ratio, and Johnson & Johnson was only associated with a single reaction in a woman.Overall, most reactions occurred in men, which could be a result of random chance from a small sample size, though some LPDs are more common in men. 25 Cutaneous lymphomas are uncommon in the general population.For instance, the estimated incidence of CTCL is 8.55 per million. 26LPDs after COVID-19 vaccination are even less common and associated with distinct age and gender distributions.However, clinical presentation in terms of lesion type and anatomic location are similar for LPDs following and not following vaccination.Most (82%) cases were new LPDs in healthy patients, however, 9 cases (18%) were recurrences of LPDs previously in complete remission.Both new and relapsed LPDs demonstrated Pfizer-BioNTech and male predominance, however, new LPDs had a younger average age on average.Reactions to Oxford-AstraZeneca were more common in older patients (average 65 years), while with Pfizer-BioNTech reactions were identified in a much younger average age (47 years).The average age at presentation of cutaneous LPDs is 65 compared to 53 for LPDs after COVID-19 vaccination. 27Since vaccine administration to children was delayed, the true mean age may be lower.The difference in average age for new versus recurrent LPDs and for different vaccine types may speak to the immunogenicity of the vaccine.Since older patients are more likely to already have LPDs, it is more likely that older patients would have recurrences compared to younger patients.For example, there may be higher rates of reaction to Oxford-AstraZeneca in older patients because this vaccine stimulates a less rigorous immune response, thus producing reactions in patients who tend to be older and more susceptible to antigenic reactions.
Other than for Moderna, most vaccines were associated with reactions occurring after the first dose of the vaccine.Given that many patients developed LPDs after their initial dose, a question is raised about previous exposure to the antigen.It is possible that these patients had a previous asymptomatic COVID- 19   Eighty percent of cases demonstrated CD30 positivity.In the case of Pfizer-BioNTech, 88% of cases demonstrated CD30 positivity, with only 60% in Moderna, 83% in Oxford-AstraZeneca, and none in Johnson & Johnson.CD30 is a tumour necrosis factor (TNF) superfamily receptor expressed on activated T-cells, which can exhibit acquisition of cytotoxic proteins, granzyme or TIA, contributing to a strong immune response.CD30 can be expressed in various conditions, induced by antigens, mitogens, arthropod bites, or viruses. 28In the event of CD30 antigenic activation, signal mediation takes place, preventing apoptosis and promoting abnormal cell proliferation.The vaccine spike glycoprotein leads to a powerful adaptive T-cell and B-cell immune response including neutralising antibody production.The COVID-19 vaccine may induce hypersensitivity to components of the vaccine vehicle, adaptive cellular immune responses to human-manufactured spike glycoprotein, or inherently immune-enhancing effects. 29The COVID-19 vaccine's spike protein may serve as an antigenic trigger resulting in clonal expansion of antigenically responsive T-cells and subsequent oncogenic hits eventuating in CD30þ LPDs. 30The different rates of CD30 positivity by vaccine type may reflect limited sample or it may indicate the increased immunogenicity of certain vaccines such as Pfizer-BioNTech, which may have an especially reactive vaccine component.Of note, there are few reports of LPDs after COVID-19 infection, further suggesting that a component of the vaccine may be related to these indolent disorders.
The combination of CD30þ LyP, PLEVA (only 1/7 PLEVA cases was CD30 negative), and ALCL comprised 25 cases, with MF, SS, and SPTCL comprising 10, and CLH and CD4þ PC-SMPTCL comprising 8 (with 7 other LPDs).While PLEVA may not classically be grouped with these other LPDs, intraepithelial atypical lymphocytes, phenotypic abnormalities, and TCR-gamma rearrangements have led to its consideration as a T-cell dyscrasia and highlight their similarity, thus we have included it in our analysis. 31LyP and ALCL were especially common after the Pfizer-BioNTech and Oxford-AstraZeneca vaccine, with PLEVA being most common after Moderna and SPTCL after Johnson & Johnson.While the predominance of CD30þ LPDs following closely after COVID-19 vaccination, is striking, the connection is not proven.The few cases without CD30 positivity may have occurred through another pathway of T-cell activation through antigenic stimulation, clonal expansion, and LPD development.
Limitations of this study include limited sample size, reporting bias, publication bias based on language or country of origin, and inability to prove causation.We counted a reaction as CD30 positive if the report labelled it as "CD30 positive" or mentioned significant degree of CD30 positivity, however, we recognise that there is variability in degree of CD30 positivity, which could not be determined by this study.
Importantly, all patients had complete or nearcomplete remission of LPDs with treatment ranging from observation to steroids, methotrexate, or excision, showing that LPDs after COVID-19 vaccination have favourable outcomes.This is consistent with other cutaneous COVID-19 vaccine reactions, which are also self-limited and generally short-lived. 32We demonstrate a potential association, not causation, for selflimited disorders following COVID vaccination.The COVID-19 vaccine should be administered according to national and international guidelines.Vaccination is recommended to decrease the risk of developing severe COVID-19 infection, and potential complications.
We investigate different cutaneous LPDs after COVID-19 vaccination and their association with various vaccine types.Reactions occur proportionally to global distribution, with most LPDs linked to Pfizer-BioNTech, followed by Moderna and Oxford-AstraZeneca.These LPDs overall affected younger patients and had male predominance.Most cases had CD30þ positivity, suggestive of antigenic activation in these cases.COVID-19 vaccination remains safe and important to prevent severe COVID-19 and complications.LPDs that occurred following vaccination appear to be rare, reactive, selflimited disorders.
infection, resulting in development of memory T-cells before vaccination.Reactions occurred at a mean of 13 days after vaccination, with fastest onset for Johnson & Johnson followed by Moderna, Oxford-AstraZeneca, and Pfizer-BioNTech.Johnson & Johnson and Moderna may have relatively faster LPD onset due to small sample size or possible underlying predisposition in those individuals.Conversely, Pfizer-BioNTech may be associated with more insidious onset of LPDs.The temporal relationship between vaccination and LPDs development may suggest a potential relationship.