A Fatal Case of Disseminated Mucormycosis in a Patient Shortly after Starting Treatment against Malignant Lymphoma

Abstract

Disseminated mucormycosis is a fatal infection commonly observed in patients with prolonged neutropenia, such as those undergoing treatment for hematological malignancies or post-transplantation. This report describes a case of malignant lymphoma in a patient with no history of cytotoxic chemotherapy. The patient died early, and disseminated mucormycosis was identified during an autopsy. Notably, no imaging findings were suggestive of mucormycosis, which complicated the diagnosis. Given that both mucormycosis and malignant lymphoma were suspected from the initial presentation, it is important to consider mucormycosis as a potential differential diagnosis in patients with altered consciousness.

Introduction

Mucormycosis is a life-threatening infection caused by fungi of the order Mucorales (1). It manifests in various forms, including rhino-orbito-cerebral, pulmonary, cutaneous, gastrointestinal, arterial, and disseminated infections (2,3). The disseminated form is rare and typically occurs in severely immunocompromised patients such as those undergoing bone marrow transplantation (4-6). Due to its nonspecific presentation and lack of serological tests, disseminated mucormycosis is often difficult to diagnose ante mortem and is frequently confirmed only by autopsy. This form is associated with a poor prognosis (7), making early recognition and intervention critical for improving outcomes (8). We herein report the case of a patient who presented with fever and altered consciousness. Initially suspected to have malignant lymphoma and treated with chemotherapy, he rapidly deteriorated and died. Autopsy revealed disseminated mucormycosis.

Case Report

The patient was a 56-year-old man with a 5-year history of diabetes mellitus and Graves' disease who was managed with metformin and thiamazole. He had no prior surgeries, known allergies, or significant family medical history. The patient was employed as a system engineer and primarily performed office-based duties.

The patient presented with fever and sore throat persisting for approximately 2 weeks, which was initially suspected to be due to a peritonsillar abscess, and was admitted to another hospital. He was able to work normally. However, after admission, he showed signs of impaired consciousness, which was initially believed to be due to delirium. The patient also experienced difficulties in communication and ambulation. Imaging studies revealed a mass in the pharyngeal region, and a cytological evaluation indicated malignant lymphoma. The cerebral spinal fluid (CSF) cytology results were negative. As his consciousness gradually declined, he was referred to our hospital for further evaluation.

On admission, his vital signs were as follows: body temperature, 38.8°C; blood pressure, 118/73 mmHg; and heart rate, 74 beats/min. The Glasgow Coma Scale score was 9 (2 for spontaneous eye opening, 3 for incomprehensible sounds, and 4 for pain response). Peripheral blood counts on the day of admission were as follows: white blood cells, 7,930/μL (neutrophils 75%, eosinophils 2.0%, basophils 1.0%, monocytes 11%, lymphocytes 11%); hemoglobin, 12.1 g/dL; and platelets, 102,000/μL. The biochemical tests were lactate dehydrogenase 1,666 U/L, aspartate aminotransferase 86 U/L, alanine aminotransferase 48 U/L, albumin 2.9 g/dL, C-reactive protein at 9.2 mg/dL, ferritin 1,279.1 ng/mL, and soluble interleukin-2 receptor level 4,698 U/mL. His blood glucose level was 188 mg/dL, HbA1c level was 7.7%, and blood culture results were repeatedly negative. His β-D-glucan level was within the normal range, and a cytomegalovirus antigenemia analysis was negative. Serological tests for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) were negative. All the blood test results are shown in Table.

Table.

Blood Test Results on Admission.

Complete blood count			Biochemistry
White blood cell	7,930	/uL	Albumin	2.9	g/dL	Iron (Fe)	18	ug/dL
Stab	1	%	Lactate dydrogenase	1,666	U/L	Total iron biding capacity	264	ug/dL
Segmented	74	%	Aspartate aminotransferase	86	U/L	Ferritin	1,279.1	ng/mL
Eosinophil	2	%	Alanin aminotransferase	48	U/L	Total Cholesterol	87	mg/dL
Basophil	1	%	Total bilirubin	1.2	mg/dL	Triglyceride	278	mg/dL
Monocytes	11	%	Uric acid	6.8	mg/dL
Lymphocyte	11	%	Blood Urea Nitrogen	12	mg/dL	Immunologic test
Red blood cell	3.99×108	/uL	Creatinine	1.03	mg/dL	Immunoglobulin G (IgG)	1,156.2	mg/dL
Hemoglobin	12.1	g/dL	C-reactive protein	9.2	mg/dL	Immunoglobulin A (IgA)	286.1	mg/dL
Hematocrit	34.3	%	Natrium	128	mEq/L	Immunoglobulin M (IgM)	30.5	mg/dL
MCV	86	fL	Potassium	3.8	mEq/L	Soluble IL-2 receptor	4,698	U/mL
Platelet	10.2×104	/uL	Chloride	97	mEq/L	Antinuclear antibody	(-)
			Calcium	8.3	mg/dL	Infectious test
Coagulation test			Glucose	188	mg/dL	Beta-D-Glucan	<4.0	pg/mL
Prothrombin time	14	s	HbA1c	7.7	%	Cytomegalovirus antigen	(-)
APTT	51	s	Free T3	1.43	pg/mL	Hepatitis B surface antigen	(-)
FDP	6	ug/mL	Free T4	0.73	mg/dL	Hepatitis C antibody	(-)
Fibrinogen	474	mg/dL	Thyroid stimulating hormone	<0.01	μU/mL	Human immunodeficiency virus antibody	(-)

Contrast-enhanced computed tomography revealed an enlarged left pharyngeal region, mediastinal lymphadenopathy, and mild hepatomegaly (Fig. 1A-C). No findings suggestive of chronic obstructive pulmonary disease or sinusitis were observed. Contrast-enhanced magnetic resonance imaging (MRI) revealed an enlarged ventricular cavity (Fig. 1D). A CSF examination revealed a normal cell count of 2 cells/μL and normal cytology, with protein and glucose levels of 32 mg/dL and 64 mg/dL, respectively. Bacterial and fungal cultures were negative.

Figure 1.

Contrast-enhanced computed tomography images (A-C). Enlarged masses in the left pharynx (yellow circle) (A) and left mediastinal lymph node (red circle) (B). Slight hepatomegaly (C). T1 weighted magnetic resonance imaging with contrast demonstrating hydrocephalus (D).

Microscopic examination of the left tonsillar mass revealed diffuse infiltration of large lymphoid cells with a starry sky appearance. Immunohistochemical staining showed large lymphoid cells positive for CD20, BCL2, BCL6, MUM1, and C-MYC (50%) but negative for CD3, CD10, and Epstein-Barr virus [in situ hybridization to Epstein-Barr virus -encoded RNA (ISH-EBER)], with a Ki-67 proliferation index ＞95%. G-banding and fluorescence ISH (FISH) analyses were not performed because of the low sample volumes. These results are consistent with those of non-germinal center B-cell-like diffuse large B-cell lymphoma (Fig. 2).

Figure 2.

Histological and immunohistochemical features of left pharynx samples. (A) Diffuse and polymorphous infiltration of medium- to large-sized lymphocytes. (B) Immunohistochemical analysis. The tumor cells were positive for CD20.

The patient initially presented impaired consciousness and systemic inflammation. Based on these findings, malignant lymphoma was considered the most likely explanation for the patient's condition. Shortly after hospital admission, his level of consciousness declined further, and dexamethasone was administered. Although his condition improved temporarily, it soon worsened. On hospital day 4, rituximab combined with methotrexate (MTX), cytarabine (Ara-C), and rituximab (RTX) was initiated (Fig. 3).

Figure 3.

Clinical course of the patient. WBC: white blood cell, Plt: platelet, LDH: lactate dehydrogenase, CRP: C-reactive protein, DEX: dexamethasone, MTX: methotrexate, Ara-C: cytarabine, RTX: rituximab, CFPM: cefepime, VCM: vancomycin, MCFG: micafungin, CPFG: caspofungin

Following chemotherapy, the patient's ability to communicate improved briefly; however, by day 9, during the neutropenic phase, his consciousness deteriorated. Empiric antibiotic therapy with vancomycin (VCM) and meropenem (MEPM) was administered for febrile neutropenia. The patient received prophylactic micafungin (MCFG) at a dose of 50 mg to prevent Aspergillus infection. Due to persistent fever despite MEPM and VCM, antifungal therapy was escalated to caspofungin (CPFG).

On day 11, the patient developed ST-segment elevation in leads II, III, and aVF (Fig. 4) along with decreased cardiac contractility on echocardiography. The patient was diagnosed with myocardial infarction. Given his poor overall condition, cardiac catheterization was not performed and the patient died on the same day.

Figure 4.

Electrocardiogram (ECG) showed ST elevation in leads II, III, aVf.

An autopsy revealed widespread fungal infiltration involving multiple organs, including the liver, heart, lungs, kidneys, spleen, and brain (Fig. 5, 6). Histopathology revealed broad, ribbon-like, non-septate hyphae with irregular, wide-angle branching, characteristic of Mucorales. Paraffin-embedded tissue samples were subjected to polymerase chain reaction amplification and sequencing of the fungal 18S ribosomal DNA region, identifying a sequence identical to Cunninghamella spp. and confirming a diagnosis of disseminated mucormycosis (9). Fungal infiltration was not observed in the left tonsillar biopsy specimen.

Figure 5.

Autopsy findings of the liver (A-D) and heart (E, F). Gross findings of the liver with hemorrhagic infarction (A). A thrombus filled with fungal hyphae (B, C) stained by Grocott (D) is detected. Gross findings of the heart (E) and mycotic thrombosis in vessel lumen (F). Invasive nonseptate branching hyphae penetrated the myocardium.

Figure 6.

Gross findings of representative slices of the lung with hemorrhagic infarction (A). Histologic findings of alveolar embolization caused by mucor hyphae (B). Thrombosis and necrosis of the glomeruli (C), spleen (D), and brain parenchyma (E, F) with fungal hyphae.

Regarding lymphoma, the patient's pharyngeal and mediastinal lymph node lesions had regressed, and no viable lymphoma cells were detected elsewhere, suggesting a favorable therapeutic response.

Discussion

Fungal agents of mucormycosis are commonly found in soil and decaying organic matter and are transmitted by inhalation and contact (6,10). The main species involved in human mucormycosis are Rhizopus, Rhizomucor, Lichtheimia, Mucor, and to a lesser extent, Cunninghamella, Saksenaea, Actinomucor,, and Apophysomyces (11-13). Cunninghamella was identified in this case, causing severe infections in humans, affecting multiple organ systems, including the rhinocerebral, pulmonary, cutaneous, and gastrointestinal systems (14). The frequency of Cunninghamella in patients with mucormycosis is reportedly 2.5-7% (12,15). Cunninghamella is more common in patients with pulmonary or disseminated disease (12). The patient was an office worker who lived in an urban area. However, no information is available regarding activities such as gardening or soil exposure, and the route of infection remains unclear.

No serological data were found to support mucormycosis, and the diagnosis requires a biopsy, making an early diagnosis challenging. Consequently, it is often detected by autopsy (16). Disseminated mucormycosis also presents with nonspecific symptoms, which further complicates the diagnosis (5). Although no abscess was observed on imaging, hydrocephalus was a notable finding in this case, and disseminated mucormycosis could potentially lead to obstructive hydrocephalus (17). A similar mechanism is presumed to have caused the hydrocephalus in the present case; however, unlike in previous reports, no obstruction was evident on imaging, which further complicated the diagnostic process.

The histological subtype of lymphoma in this patient could not be fully determined because a FISH analysis was not performed; therefore, the diagnosis of double-hit lymphoma could not be confirmed. However, based on findings suggestive of high-grade lymphoma, such as a starry sky appearance, the patient was suspected to have central nervous system (CNS) involvement from the initial presentation. Therefore, the combination of MTX and Ara-C was selected because of its CNS penetration.

The standard treatment approach for mucormycosis includes the prompt administration of liposomal amphotericin B and surgical debridement or drainage, because echinocandins are generally ineffective against Mucorales. The overall mortality rate of mucormycosis is approximately 50%, but it can increase to 90% once the disease disseminates (8). In addition, the mortality associated with Cunninghamella infections was significantly higher than that with other Mucorales species (12). However, an improved prognosis can be achieved through an early diagnosis and treatment (7). Although his prognosis may have been poor, even if liposomal amphotericin B had been used, early intervention may have prolonged survival.

The patient experienced myocardial infarction shortly before death, which has been reported as a possible manifestation of disseminated mucormycosis (18). Cunninghamella, in particular, invades blood vessels and forms mycotic thrombi, leading to infarction with hemorrhagic necrosis (19). Although no gross infarcts were observed in the myocardium at autopsy, the possibility of hyperacute infarctogenic changes cannot be excluded as the myocardial vessels demonstrated extensive mycelial invasion and numerous fungal emboli.

Therefore, the direct cause of death requires careful consideration. Although the pre-mortem electrocardiogram changes may have reflected right coronary artery occlusion, infarction in this region is rarely fatal; therefore, cardiac involvement may not be regarded as the immediate cause of death. The widespread presence of fungal hyphae in multiple organs at autopsy suggests that multiorgan failure from disseminated mucormycosis was the most probable cause.

Diabetes mellitus is generally regarded as a risk factor for mucormycosis. It is only associated with rhino-orbital-cerebral mucormycosis. Disseminated mucormycosis generally occurs in severely immunocompromised patients or individuals who have received deferoxamine (12). In addition, most cases of mucormycosis caused by Cunninghamella spp. have been reported in organ transplant patients (20). Given his normal neutrophil count on admission and no history of autoimmune disease, HIV infection, or immunosuppressive therapy, along with the lack of prior chemotherapy for malignant lymphoma, he was not considered immunocompromised to the extent typically associated with disseminated mucormycosis. Although no direct evidence, such as imaging findings, was available, the rapid deterioration and early death following the initiation of treatment suggest that concurrent mucormycosis and malignant lymphoma were likely present since the initial presentation. There have been case reports of disseminated mucormycosis due to Cunninghamella in non-immunocompromised patients (21-23), but in small numbers. Therefore, the possibility of disseminated mucormycosis should be considered when encountering a patient with fever and impaired consciousness that are difficult to differentiate.

Informed consent was obtained from the patient for publication of this case report.

The authors state that they have no Conflict of Interest (COI).