AUTHOR=Li Dong Ming , Lun Li De , Ge Jie , Zhang Gong Jie , Li Xin Lun , de Hoog G. Sybren 

TITLE=Case Report: Rhizopus arrhizus Rhino-Orbital-Cerebral Mycosis and Lethal Midline Granuloma: Another Fungal Etiological Agent

JOURNAL=Frontiers in Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.578684

DOI=10.3389/fmed.2021.578684

ISSN=2296-858X

ABSTRACT=Objective: Both rhino-orbital-cerebral mycosis and lethal midline granuloma (LMG) may result in midline destruction. LMG has now been generally considered as 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 overexpressions of Ki67 and CD56 in mouse experiment. The present study describes a chronic Rhizopus arrhizus infection with immunological parameters closely similar to LMG. We aim to explore the relationship of another Mucorales fungus, R. arrhizus, and LMG in patient and in mice.
Methods: Case study and mouse infection modules were design for our observation. A 35-year-old man with midline face ulcers clinically suspected as LMG was selected. Biopsy specimens were sent for lymphoma diagnosis and for 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 pathology, characteristic inflammation, necrosis and granulation with thin-walled hyphae is observed. Immnohistochemistry 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 angioinvaion 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 negative result of EBV and positive for R. arrhizus. With a then developed mouse experiment, The R. arrhizus in the diseased lesions was responsible for NK/T cell infiltration (CD3+, CD8+, CD56+, TIA1+, GZMB+, PRF+), proliferation (Ki67+) and angioinvasion, suggesting another fungal aetiological agent for LMG, which could be eradicated with amphotericin B.
Limitations: Sample size is not sufficient for statistical analysis. However, our findings are suggestive for the role fungus plays in LMG.