Clinicopathologic Features of Human Monkeypox Lymphadenitis.

To the Editor: In July 2022, an outbreak of human monkeypox was reported in several nonendemic countries. Even though enlarged lymph nodes and tonsils are commonly identified in patients diagnosed with monkeypox,1, 2 descriptions of lymph node pathology in human monkeypox infection are lacking. Herein, we present the first pathologic description of monkeypox lymphadenitis in humans. A 46-year-old man presented with progressive throat pain, dysphagia, and dyspnea for 2 weeks, with subsequent development of a vesiculopustular rash on his trunk and upper extremities. His medical history was notable for HIV-1 infection with a CD4 count of 816 cells/μl and undetectable HIV-1 RNA in plasma. He had an enlarged right tonsil for several months and recent unprotected receptive oral sex with another man. Nasolaryngoscopic examination revealed a profoundly enlarged right tonsil covered in yellow exudate and bilateral cervical lymphadenopathy, which were confirmed on computed tomography (Figure 1A,B). The patient was admitted to intensive care for airway observation and further diagnostic workup. A skin lesion swab screened positive for monkeypox virus DNA using a nonvariola Orthopoxvirus quantitative polymerase chain reaction (qPCR), and infection was confirmed with a separate clade 2/3 (West African) monkeypox virus qPCR.3, 4 At the time, malignancy was suspected clinically, as the patient's throat pain and dysphagia preceded any skin manifestations and in part due to the lack of institutional experience with monkeypox infection. Fine-needle aspiration (FNA) of the dominant right level 2A lymph node was performed, revealing a predominance of small to intermediate-sized mature lymphocytes, scattered plasma cells, and foci of necrosis (Figure 1C–E). By immunohistochemistry, scattered CD30+ immunoblasts were present (Figure 1F). TdT and HHV-8 stains and in situ hybridization for EBV-encoded RNA (EBER) were negative. Flow cytometry detected, of all CD45+ events, 44% CD3+ T-cells, 36% CD19+ B-cells, and fewer granulocytes, NK-cells, plasma cells, and monocytes. B-cells and plasma cells showed a skewed kappa:lambda ratio of approximately 1:1. Plasma cells uniformly expressed CD117 and demonstrated downregulation of CD27 and CD81. T- and NK-cells showed no immunophenotypic abnormalities. Representative flow cytometry plots are shown in Figure 2A. The lymph node aspirate was monkeypox DNA-positive via nonvariola Orthopoxvirus qPCR and clade 2/3 monkeypox virus qPCR (Figure 2B), supporting a diagnosis of necrotizing lymphadenitis secondary to monkeypox infection. Given the initial uncertainty of the diagnosis and prognosis, intubation and tracheostomy were considered, but neither was ultimately necessary. The patient was treated with dexamethasone and tecovirimat while inpatient and was provided an additional 9-day course of tecovirimat at discharge (to complete 14 days total). While the tonsillar hypertrophy persisted, the dysphonia and odynophagia improved after dexamethasone treatment. The patient was offered follow-up with Otolaryngology and Infectious Diseases, but did not return following discharge. The variola (smallpox) and monkeypox viruses are related viruses in the Orthopoxvirus genus and have similar cutaneous disease presentation and progression. While mucosal involvement of smallpox is typically described as an enanthem of the oral cavity, monkeypox has been associated with oropharyngotonsillitis.1, 5 Additionally, prominent peripheral lymphadenopathy (particularly cervical and inguinal) has been cited as the singular clinical feature that may distinguish monkeypox from smallpox.6 To our knowledge, this is the first description of lymph node pathology in human monkeypox infection and contributes to the list of possible causes of necrotizing lymphadenitis. This case also illustrates that monkeypox lymphadenitis can be associated with abnormal flow cytometry findings, including lambda-skewed B-cells and plasma cells and aberrant expression of CD117 on plasma cells. However, light chain-skewing without monotypia and CD117 expression on plasma cells are not considered specific markers of malignancy and, in this setting, are consistent with the reactive etiology. Overall, it is important for both the treating clinician and pathologist to recognize necrotizing lymphadenitis as a manifestation of human monkeypox infection, especially if lymphadenopathy precedes the rash or if the rash is not disseminated. Furthermore, this case supports FNA as a suitable diagnostic modality for confirming monkeypox lymphadenitis and excluding other diagnostic possibilities, such as malignancy. ZJQ, RG, and HDL conceived, drafted, critically revised, and approved the final version of the report. DSM, KW, and SK critically revised the clinical portions of the report and approved the final version. TM and OS critically revised the hematopathology portions of the report and approved the final version. VN and BAP provided substantial contributions to the acquisition of qPCR data, critically revised the virology portions of the report, and approved the final version. The authors have no conflicts of interest to declare. Institutional Review Board approval is not required for this case report, as it is not considered research. Informed consent is not required for this case report, as no identifiable information is included. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.