Abstract
Objective: Both rhino-orbital-cerebral mycosis and lethal midline granuloma (LMG) may result in midline destruction. LMG has now been generally considered as a natural killer/T cell lymphoma, nasal type (ENKTL-NT) with an association of EBV. Fungi have been detected from the diseased tissues now and then but are often considered as lymphoma-associated infections. We previously reported an ENKTL-NT case with Mucor irregularis, which played a causal role in the disease and was involved in the overexpression of Ki67 and CD56 in the mouse experiment. The present study describes a chronic Rhizopus arrhizus infection with immunological parameters that are closely similar to LMG. We aim to explore the relationship of another Mucorales fungus, R. arrhizus, and LMG in a patient and in mice.Methods: Case study and mouse infection modules were designed for our observation. A 35-year-old man with midline face ulcers which was clinically suspected as LMG was selected. Biopsy specimens were sent for lymphoma diagnosis and microbiological detection. The isolated fungus was tested in an ICR mouse model for mycological and histological analyses.Results: Five tissue samples yielded Rhizopus arrhizus. In the pathology, characteristic inflammation, necrosis, and granulation with thin-walled hyphae are observed. Immunohistochemistry showed NK/T cell infiltration (CD3+, CD8+, TIA1+, GZMB+, PRF+, individual CD56+) with hyperplasia (Ki67+) and angioinvasion. The patient recovered completely with amphotericin B. In the murine experiment, R. arrhizus caused angioinvasion with NK/T cell infiltration (CD3+, CD56+, TIA1+, GZMB +, PRF+) with proliferation (Ki67+) and was re-isolated from the infected host.Conclusions: We here describe a mid-face destruction patient, which was diagnosed by the top pathologists in China according to the current criteria of NK/T cell lymphoma, with a negative result for EBV and positive result for R. arrhizus. With a then developed mouse experiment, the R. arrhizus in the diseased lesions was responsible for the NK/T cell infiltration (CD3+, CD8+, CD56+, TIA1+, GZMB+, PRF+), proliferation (Ki67+), and angioinvasion, suggesting another fungal etiological agent for LMG, which could be eradicated with amphotericin B.Limitations: The sample size is not sufficient for statistical analysis. However, our findings are suggestive for the role fungus plays in LMG.
Highlights
Lethal midline granuloma (LMG) is a clinical-pathological entity characterized by progressive midline face ulceration, granulation, and destruction, with a high mortality rate [1, 2]
We previously identified a chronic infection by Mucor irregularis as the fungal cause of a case resembling LMG [28, 29]
Comparing multiple biopsy specimens sampled from the edge of the newly infected tissues with those in necrotic tissues, we found that typical hyphae could be observed in the newly affected tissues only, whereas atypical dysplasia were seen with positive T cell markers in the granulomatous tissue, with thin-walled hyphal elements and spores that were broken or endocytosed by the nucleate or giant cells, some of which were atypical with a high index of Ki67 expression (Figure 2)
Summary
Lethal midline granuloma (LMG) is a clinical-pathological entity characterized by progressive midline face ulceration, granulation, and destruction, with a high mortality rate [1, 2]. Diagnosis for one patient was changed from ENKTL-NT to ROCM as fungal mycelium was seen in the tissue, while the diagnosis for the other was from ROCM to NK/T cell lymphoma because the NK/T cells were seen in the tissue [27]. These cases suggest the ambiguity in understanding the role of fungi in the development of midline ulcers [27, 28]
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