Cytologic and histologic features of COVID-19 post-vaccination lymphadenopathy.

In this study, we present six cases of axillary or supraclavicular lymphadenopathies in the days following to the Pfizer-BioNTech vaccine's first dose and its study for fine-needle aspiration cytology (two patients), biopsy with a gross needle (two patients), and the evolution of two other patients. Cytological smears and histological sections reveal reactive nodes, predominantly T, CD8, and the presence of atypia with striking mitosis. Differential diagnosis with viral lymphadenopathies and lymphoma is important, so the clinical correlation, in a vaccination context, sudden appearance, and progressive decrease in days of the adenopathy, is essential. In this article, we have studied the cytohistological manifestations of post-Pfizer-BioNTech vaccination lymphadenopathy and discussed its differential diagnosis.

INTRODUCTION

One of the most frequent secondary effects of a COVID-19 vaccine is the appearance of multiple lymphadenopathies. In the Pfizer BioNTech COVID-19 vaccine trial, the rate of ipsilateral axillary and supraclavicular lymphadenopathy was reported to be 0.3 % for the vaccine group versus <0.1 % for the placebo group.[ In Moderna’s case, 1.1% of the study’s patients were reported[ whose ultrasound and pathological morphology must be known in order not to incur in diagnostic errors, especially taking into account that these postvaccinal lymphadenopathies are detected by the PET/CT. Postvaccinal lymphadenopathies have been reported after the administration of other vaccines.[ The main differential diagnosis is with other benign lymphadenopathy and lymphoma.[ The six patients presented here had a history of recent ipsilateral vaccination of the upper limb with the first dose of Pfizer-BioNTech. They were in group 1 due to their front-line status.

CASE REPORTS

The age of the patients ranged from 27 to 62-years-old, all of them showed mobile and painful lymphadenopathy, with no other clinical history of interest than the administration of the vaccine’s first dose approximately 5 days before the appearance of the adenopathy. The most striking case was that of a 34-year-old patient with multiple supraclavicular nodes, one of them palpable [Figure 1a]. Another 27-year-old patient had non-palpable axillary lymphadenopathy. Both underwent a FNAC with ultrasound control. Two other female patients, aged 42 and 56, who also had axillary lymphadenopathy, underwent a core needle biopsy. A TCR rearrangement was done to the representative sample in paraffin with a Molecular Analysis Kit (MAD-03993TP-2/5) and Kit (MAD-003994TP-2/5). The last two patients were 40 and 62 years of age, female and male respectively, also with axillary lymphadenopathy. It was decided they would be clinically observed.

Figure 1:

Patient with supraclavicular major lymphadenopathy not adhered to deep planes (first case). (a) Clinical image. (b) Enlarged lymph nodes, with persistent ovoid morphology with homogeneous cortical echogenicity with a significant increase in vascularization with color Doppler.

Ultrasonographically, the lymph nodes were enlarged, with persistent ovoid morphology and smooth edges, with preserved echogenic thread and homogeneous cortical echogenicity with a significant increase in vascularization with color Doppler [Figure 1b].

FNAC was made using a 22-gage needle attached to a 10 ml syringe driven by ultrasound and the obtained cells were smeared on two slides. One of them was air-dried and stained with Diff-Quick [Figure 2a] and the other one fixed in alcohol and stained with Papanicolaou stain [Figure 2b]. In none of the two punctures was there enough material for more extensions or to make cellular blocks. There was no control of the in situ material. The cytological smears showed a great polymorphous cellularity, where numerous large cells with ovoid nuclei stood out, occupying almost the entire cytoplasm. Reduced to one of the cell’s poles, the nuclei were sometimes bilobed or hyperchromatic. All of them with nuclear hyperchromatism or large nucleoli. Among them there were numerous histiocytes with dense cytoplasm, sometimes polylobulated and also with prominent nucleoli and a few histiocytes with granular bodies in their cytoplasm. Occasional apoptotic cells could be observed. All of this on a lymphocytic background with lymphocytes with some atypia and irregular morphology, with nuclear notches and few plasma cells. Occasional neutrophil polymorphonuclear leukocytes and very scarce eosinophils could also be seen [Figure 2a and b]. The cytological diagnosis was nonspecific chronic adenitis.

Figure 2:

FNAC of the first case. (a) Diff-Quick stained cytology. (b) Papanicolaou smear stained cytology. The cytological smears showed a great polymorphous cellularity, some nuclei were bilobed or hyperchromatic. All of them with large nucleoli. Were numerous histiocytes sometimes polylobulated. Occasional apoptotic cells, background with lymphocytes with atypia. Occasional neutrophil polymorphonuclear leukocytes. Absence of eosinophils with presence of mitosis.

The specimen obtained with a core needle biopsy was fixated in formaldehyde and processed in paraffin. (The reason for doing the bag and not the removal of the lymph node is simply to follow the radiologist’s criterion, many of whom do the bag first, and the lymph node removal is performed only when the former is found insufficient to diagnose.) It showed a partial lymph node with preservation of their structure with expansion of the T zone, numerous globular endothelial vessels, with the presence of atypical immunoblasts and lymphocytes. The marginal sinuses are occupied by histiocytes with the presence of cellular debris and apoptotic cells [Figure 3a]. Immunohistochemical staining is predominantly T (CD3 over CD20) and predominantly CD8 over CD4 [CD8-Figure 3b]. The TCRbeta and TCRgamma genes show polyclonal rearrangements with expression for the genes TCRbeta or TCRgamma.

Figure 3:

Lymph node core needle biopsy. (a) (H & E) Lymphoid tissue with numerous lymphocytes in marginal sinuses. Among the lymphoid cells, polymorphonuclear cells with immunoblasts, plasma cells, and lymphocytes are observed. Presence of great atypia. Absence of neoplastic cells. (b) Immunohistochemical staining with anti-CD8. High CD8 positivity that predominates over CD4.

Histologic features confirmed the diagnosis of a nonspecific chronic adenitis.

After a conservative treatment with anti-inflammatory drugs, the size of the lymphadenopathy decreased in all patients practically until their resolution.

DISCUSSION

Adenopathy related to recent vaccination status is not an uncommon benign aetiology resulting in unilateral axillary adenopathy and has been well-documented following smallpox, Bacille Calmette-Guerin and anthrax vaccination.[ More recently, unilateral adenopathy has been reported in adults receiving the Human Papilloma Virus vaccine in the ipsilateral deltoid muscle and with the influenza vaccine.[

The benign lymphadenopathies have been divided into several groups according to their morphological pattern.[ The cellular polymorphism with the presence of atypia in various components (immunoblasts, lymphocytes, plasma cells, and histiocytes) should lead to suspicion of this type of lymphadenitis, which is completed by observing the preservation of the architecture with zone T expansion and especially the clinical history post-vaccination.

The major and most important differential diagnosis is Hodgkin’s lymphoma and peripheral T-cell lymphoma.[ In the postvaccinal lymphadenitis there is a preserved architecture of the lymph node and a mixed cellular response. The absence of Reed-Sternberg cells is important to differentiate postvaccinal lymphadenitis from Hodgkin’s disease too. It is important not to misinterpret reticular lymphoblasts as Reed-Sternberg cells. The diagnostic Reed-Sternberg cell has a moderate to abundant amount of cytoplasm with two or more distinct nuclei, each of which contains a nucleolus. The reticular lymphoblast has a single nucleus with one or more nucleoli and scant cytoplasm.[ Although the cytological atypia with the presence of mitosis is true and striking, [Figures 2a, b and 3a] we believe that it is a post-vaccinal lymphadenitis, where in order to identify it as such, it is very important to know the clinical context of having received the COVID vaccine in previous days. We do not know of agents that are capable of developing lymphomagenesis processes in such a short time - appearing suddenly and diminishing in size within days. In addition, as mentioned before, similar reactions have been described with other vaccines. The combined analysis of the TCR beta and TCR gamma genes facilitates the detection of up to 99% of the lymphoproliferative processes of T cells.[ In our case, said analysis has shown a polyclonal expression.

Hence, while hyperplastic axillary adenopathy can occur shortly after receiving any vaccination, it is more common after a vaccine that evokes a very strong immune response, including the Pfizer-BioNTech COVID-19 Vaccine.[

These findings, although subject to increasing the sample size, were decisive for adopting a wait-and-see approach in the last two cases, which were solved practically spontaneously. An attitude that was already adopted by Studdiford et al. in 2008[ and Pereira et al. in 2019[ with supraclavicular and cervical lymphadenopathies after Human Papilloma Virus vaccination, as long as there is a temporal relationship and there is no other possible aetiology.

CONCLUSION

All of this highlights the importance of clinical data that is essential when interpreting cytological smears or core needle biopsies, as well as tests such as the PET/CT. Our data confirms cytohistologically - to our knowledge, for the 1st time - the atypical and self-limiting, though reactive, nature of COVID-19 postvaccinal lymphadenopathies. If they are punctured, a wrong interpretation as lymphoma is risked.