{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:43:08Z","timestamp":1792608188120,"version":"4.5.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> 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 <jats:italic>Mucor irregularis<\/jats:italic>, 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 <jats:italic>Rhizopus arrhizus<\/jats:italic> infection with immunological parameters that are closely similar to LMG. We aim to explore the relationship of another Mucorales fungus, <jats:italic>R. arrhizus<\/jats:italic>, and LMG in a patient and in mice.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Five tissue samples yielded <jats:italic>Rhizopus arrhizus<\/jats:italic>. 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, <jats:italic>R. arrhizus<\/jats:italic> caused angioinvasion with NK\/T cell infiltration (CD3+, CD56+, TIA1+, GZMB +, PRF+) with proliferation (Ki67+) and was re-isolated from the infected host.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> 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 <jats:italic>R. arrhizus<\/jats:italic>. With a then developed mouse experiment, the <jats:italic>R. arrhizus<\/jats:italic> 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.<\/jats:p><jats:p><jats:bold>Limitations:<\/jats:bold> The sample size is not sufficient for statistical analysis. However, our findings are suggestive for the role fungus plays in LMG.<\/jats:p>","DOI":"10.3389\/fmed.2021.578684","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T15:47:43Z","timestamp":1622648863000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Case Report: Rhizopus arrhizus Rhino-Orbital-Cerebral Mycosis and Lethal Midline Granuloma: Another Fungal Etiological Agent"],"prefix":"10.3389","volume":"8","author":[{"given":"Dong Ming","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li De","family":"Lun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Lun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Sybren","family":"de Hoog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.anorl.2016.08.006","article-title":"Nasal NK\/T-cell lymphoma: a tragic case","volume":"134","author":"Taali","year":"2017","journal-title":"Eur Ann Otorhinolaryngol Head Neck Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1177\/0049475516684088","article-title":"Deceptive nasal NK\/T-cell lymphoma","volume":"47","author":"Thakur","year":"2017","journal-title":"Trop Doctor."},{"key":"B3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1136\/bmj.2.3159.65","article-title":"Observations on malignant granuloma of the nose","volume":"2","author":"Woods","year":"1921","journal-title":"Br Med J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1017\/S0022215100118407","article-title":"Photographs of a case of rapid destruction of the nose and face","volume":"105","author":"McBride","year":"1991","journal-title":"J Laryngol Otol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1136\/bmj.3.5668.471-b","article-title":"Malignant granuloma","volume":"3","author":"Brown","year":"1969","journal-title":"Br Med J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1136\/bmj.4.5680.431-a","article-title":"Malignant granuloma","volume":"4","author":"Friedmann","year":"1969","journal-title":"Br Med J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1136\/bmj.4.5938.205","article-title":"Non-healing granulomata of the upper respiratory tract","volume":"4","author":"Harrison","year":"1974","journal-title":"Br Med J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1017\/S0022215100085819","article-title":"Idiopathic pleomorphic midfacial granuloma (Stewart's type)","volume":"92","author":"Friedmann","year":"1978","journal-title":"J Laryngol Otol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s12308-009-0034-z","article-title":"Commentary on the 2008. WHO classification of mature T- and NK-cell neoplasms","volume":"2","author":"Lim","year":"2009","journal-title":"J Hematopathol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1007\/s11899-016-0355-9","article-title":"Extranodal NK\/T cell lymphoma, nasal type (ENKTL-NT): an update on epidemiology, clinical presentation, and natural history in North American and European cases","volume":"11","author":"Haverkos","year":"2016","journal-title":"Curr Hematol Malig Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.beha.2013.04.003","article-title":"International analysis of the frequency and outcomes of NK\/T-cell lymphomas","volume":"26","author":"William","year":"2013","journal-title":"Best Pract Res Clin Haematol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.3109\/10428190903186502","article-title":"Extranodal natural killer\/T-cell lymphoma: current concepts in biology and treatment","volume":"50","author":"Kohrt","year":"2009","journal-title":"Leuk Lymphoma."},{"key":"B13","first-page":"215","article-title":"Angiocentric nasal T-cell lymphoma in a patient withidiopathic CD4+ lymphocytopenia","volume":"8","author":"Moradi","year":"2009","journal-title":"Iran J Allergy Asthma Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1746-160X-9-4","article-title":"Extranodal natural killer\/T-cell lymphoma, nasal type: \u2018midline lethal granuloma.\u2019","volume":"9","author":"Tlholoe","year":"2013","journal-title":"Head Face Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1097\/01.coc.0000198738.61238.eb","article-title":"Lethal midline granuloma-nasal natural killer\/T-cell lymphoma","volume":"29","author":"Mendenhall","year":"2006","journal-title":"Am J Clin Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1186\/s12885-017-3612-y","article-title":"Extranodal natural killer\/T-cell lymphoma in Malawi: a report of three cases","volume":"17","author":"Tomoka","year":"2017","journal-title":"BMC Cancer."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1136\/annrheumdis-2014-205187","article-title":"IgG4-related midline destructive lesion","volume":"73","author":"Della-Torre","year":"2014","journal-title":"Ann Rheum Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1002\/phar.1172","article-title":"Posaconazole pharmacokinetics in a 2-year-old boy with rhino-cerebral-orbital zygomycosis","volume":"33","author":"Egelund","year":"2013","journal-title":"Pharmacotherapy."},{"key":"B19","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1034\/j.1600-0714.2001.300310.x","article-title":"Midfacial granuloma syndrome or an inflammatory non-specific disease? A case report","volume":"30","author":"Torre","year":"2001","journal-title":"J Oral Pathol Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1177\/014556130408300815","article-title":"Rhinoorbital mucormycosis secondary to Rhizopus oryzae: a case report and literature review","volume":"83","author":"Hilal","year":"2004","journal-title":"Ear Nose Throat J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1136\/jcp.2008.062976","article-title":"Spontaneous regression of natural killer cell lymphoma","volume":"62","author":"Isobe","year":"2009","journal-title":"J Clin Pathol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/1721727X1401200101","article-title":"Rhino-orbital-cerebral mycosis and cavernous thromboses","volume":"12","author":"Li","year":"2014","journal-title":"Eur J Inflamm."},{"key":"B23","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.amjoto.2014.07.012","article-title":"One case of nasal tye NK\/T - cell lymphoma","volume":"34","author":"Zhang","year":"2015","journal-title":"J Clin Dermatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1046\/j.1439-0507.2001.00615.x","article-title":"Case report. Rhinocerebral zygomycosis","volume":"44","author":"Aydogdu","year":"2001","journal-title":"Mycoses."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1097\/00007611-199711000-00015","article-title":"Fatal rhino-orbital-cerebral zygomycosis","volume":"90","author":"Kameh","year":"1997","journal-title":"South Med J."},{"key":"B26","doi-asserted-by":"publisher","first-page":"250","DOI":"10.3109\/01676830.2013.788665","article-title":"NK\/T-cell lymphoma of the nasal cavity causing contralateral dacryoadenitis","volume":"32","author":"Luemsamran","year":"2013","journal-title":"Orbit."},{"key":"B27","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.mycmed.2016.04.005","article-title":"Mucormycosis or extranodal natural killer\/T cell lymphoma, similar symptoms but different diagnosis","volume":"26","author":"Zhang","year":"2016","journal-title":"J Mycol Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s11046-012-9559-2","article-title":"Mucor irregularis infection and lethal midline granuloma: a case report and review of published literature","volume":"174","author":"Li","year":"2012","journal-title":"Mycopathologia."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.13346\/j.mycosystema.190166","article-title":"Studies of atypical hyperplasia in mice caused by Mucor irregularis and Rhizopus oryzae isolated from lethal midline granuloma","volume":"38","author":"Ge","year":"2019","journal-title":"Mycosystema."},{"key":"B30","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0966-3274(96)80007-4","article-title":"15-Deoxyspergualin inhibits interleukin 6 production in in vitro stimulated human lymphocytes","volume":"4","author":"Borg","year":"1996","journal-title":"Transpl Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"4195","DOI":"10.1128\/IAI.00741-12","article-title":"Nocardia farcinica activates human dendritic cells and induces secretion of interleukin-23 (IL-23) rather than IL-12p70","volume":"80","author":"Eisenblatter","year":"2012","journal-title":"Infect Immun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1111\/j.1365-2249.1995.tb03863.x","article-title":"Serological distinction of integral plasma membrane proteins as a class of mycobacterial antigens and their relevance for human T cell activation","volume":"102","author":"Mehrotra","year":"1995","journal-title":"Clin Exp Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1177\/1535370215614658","article-title":"Does Leishmaniasis disease alter the parenchyma and protein expression in salivary glands?","volume":"241","author":"Junior","year":"2016","journal-title":"Exp Biol Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/0140-6736(90)90002-M","article-title":"Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma","volume":"335","author":"Harabuchi","year":"1990","journal-title":"Lancet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1534\/g3.118.200235","article-title":"Phylogenetic and phylogenomic definition of rhizopus species","volume":"8","author":"Gryganskyi","year":"2018","journal-title":"G3."},{"key":"B36","doi-asserted-by":"publisher","first-page":"bcr2016215855","DOI":"10.1136\/bcr-2016-215855","article-title":"Lethargy and vision loss: successful management of rhinocerebral mucormycosis","volume":"2016","author":"Mulki","year":"2016","journal-title":"BMJ Case Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/S1473-3099(09)70131-8","article-title":"Cerebral phaeohyphomycosis\u2013a cure at what lengths?","volume":"9","author":"Li","year":"2009","journal-title":"Lancet Infect Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.mycmed.2013.04.002","article-title":"Rhinocerebral mucormycosis due to Rhizopus oryzae in a diabetic patient: a case report","volume":"23","author":"Erami","year":"2013","journal-title":"J Mycol Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s15010-013-0552-6","article-title":"Successful isavuconazole salvage therapy in a patient with invasive mucormycosis","volume":"42","author":"Ervens","year":"2014","journal-title":"Infection."},{"key":"B40","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.mycmed.2013.06.003","article-title":"A mucormycosis case treated with a combination of caspofungin and amphotericin B","volume":"23","author":"Kazak","year":"2013","journal-title":"J Mycol Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e129","DOI":"10.1371\/journal.ppat.0020129","article-title":"Fungal invasion of normally non-phagocytic host cells","volume":"2","author":"Filler","year":"2006","journal-title":"PLoS Pathog."},{"key":"B42","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1128\/IAI.73.2.778-783.2005","article-title":"Rhizopus oryzae adheres to, is phagocytosed by, and damages endothelial cells in vitro","volume":"73","author":"Ibrahim","year":"2005","journal-title":"Infect Immun"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e34","DOI":"10.1161\/01.ATV.0000216407.89528.b0","article-title":"Rapid release of active tissue factor from human arterial smooth muscle cells under flow conditions","volume":"26","author":"Stampfuss","year":"2006","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"325","DOI":"10.4193\/Rhin11.245","article-title":"Extranodal natural killer\/T-cell lymphoma: a diagnostic dilemma","volume":"50","author":"Yanagi","year":"2012","journal-title":"Rhinology."},{"key":"B45","first-page":"189","article-title":"Emerging insights on the pathogenesis and treatment of extranodal NK\/T cell lymphomas (ENKTL)","volume":"23","author":"Haverkos","year":"2017","journal-title":"Discov Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1093\/ajcp\/77.2.162","article-title":"Idiopathic midline destructive disease (IMDD): a subgroup of patients with the midline granuloma syndrome","volume":"77","author":"Tsokos","year":"1982","journal-title":"Am J Clin Pathol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1002\/1097-0142(19821201)50:11<2336::AID-CNCR2820501120>3.0.CO;2-C","article-title":"Nasal T-cell lymphoma as a type of so-called lethal midline granuloma","volume":"50","author":"Ishii","year":"1982","journal-title":"Cancer."},{"key":"B48","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.oraloncology.2004.10.007","article-title":"Idiopathic midline destructive disease: fact or fiction","volume":"41","author":"Rodrigo","year":"2005","journal-title":"Oral Oncol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"96","DOI":"10.4103\/0973-029X.80016","article-title":"Extranodal NK\/T-cell lymphoma, nasal type (angiocentric T-cell lymphoma): a review about the terminology","volume":"15","author":"Metgud","year":"2011","journal-title":"J Oral Maxillofac Pathol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"4124","DOI":"10.1200\/JCO.2008.16.4558","article-title":"International peripheral T-cell and natural killer\/T-cell lymphoma study: pathology findings and clinical outcomes","volume":"26","author":"Vose","year":"2008","journal-title":"J Clin Oncol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"5416","DOI":"10.1182\/blood-2011-07-366526","article-title":"Mucorales-specific T cells emerge in the course of invasive mucormycosis and may be used as a surrogate diagnostic marker in high-risk patients","volume":"118","author":"Potenza","year":"2011","journal-title":"Blood."},{"key":"B52","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.imbio.2012.10.013","article-title":"Rhizopus oryzae hyphae are damaged by human natural killer (NK) cells, but suppress NK cell mediated immunity","volume":"218","author":"Schmidt","year":"2013","journal-title":"Immunobiology."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.3389\/fimmu.2017.01623","article-title":"Natural killer cells in antifungal immunity","volume":"8","author":"Schmidt","year":"2017","journal-title":"Front Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jcyt.2015.09.013","article-title":"Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells","volume":"18","author":"Deo","year":"2016","journal-title":"Cytotherapy."},{"key":"B55","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nature17949","article-title":"Unique human immune signature of Ebola virus disease in Guinea","volume":"533","author":"Ruibal","year":"2016","journal-title":"Nature."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.578684\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T15:47:49Z","timestamp":1622648869000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.578684\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,2]]},"references-count":55,"alternative-id":["10.3389\/fmed.2021.578684"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.578684","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,2]]},"article-number":"578684"}}