Analysis of the clinical parameters and management aspects of rhino-maxillary mucormycosis, Part I: challenges in diagnosis

Abstract

Background

Rhinomaxillary mucormycosis (RMM) is frequently missed by clinicians, especially when laboratory testing fails to identify fungi in tissue samples. This challenge results in delayed diagnosis and poor prognosis. Therefore, this study was conducted to clarify challenges in the diagnosis of RMM and its characteristics by developing a protocol-driven multidisciplinary workflow.

Methods

A retrospective case series study was conducted from June 2022 to January 2024. The study participants were those who had undergone initial RMM screening at Beni-Suef University's oral/maxillofacial or ENT departments. A careful history was obtained, and clinical and endoscopic examinations were performed on each patient. The following investigations were performed: CT scans, contrast-enhanced MRIs, blood analyses, and histological examinations. The RMM diagnosis was categorized into possible, probable, and proven. Descriptive statistics (percentages and means ± SDs) and chi-square tests were used to analyze the results, with p values < 0.05 indicating statistical significance.

Results

The study included 30 patients, with an average age of 56.53 ± 11.52 years. Males accounted for 60% of patients. The most common symptoms included facial pain (63.33%), swelling (56.67%), and dental pain (53.33%). The palate was predominantly affected, with the majority showing palatal necrosis. Black eschar was observed in only 10 patients (33.33%), with nasal turbinates being the most frequently affected (5 patients, 16.67%), followed by palatal and facial eschars (2 patients, 6.67% each) and periorbital eschar (1 patient, 3.33%). Three patients (10%) had normal CT and MRI scans, and in the majority of our patients, both scans showed non-specific signs, such as bone erosion, sinus opacifications, and soft tissue thickening. The histopathological examination failed to detect fungi in 40% of the patients. Ten percent had a possible RMM, 30% had a probable RMM, and 60% had a proven RMM.

Conclusion

Atypical clinical presentations and/or negative imaging or laboratory test results are present in significant numbers of RMM patients. Therefore, mucormycosis should not be ruled out on the basis of the negative results of standard examinations. Successful diagnosis and prognosis require a high index of clinical suspicion, a detailed history, rigorous examination, and timely multidisciplinary examination.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12903-025-05842-5.

Background

Mucormycosis (black fungus) is an uncommon fungal infection induced by exposure to a group of molds termed mucoromycetes, which are found in soil, manure, plants, decaying fruits and vegetables, air, and even healthy individuals’ mucus [1, 2]. Although fungal infections are rarer than bacterial infections are, they are more invasive and lethal. Rhinomaxillary mucormycosis (RMM) is the most common type of mucormycosis that affects the oral and maxillofacial region and accounts for 70% of cases [3]. RMM is an uncommon disorder that can be difficult for clinicians to detect, even if they commonly see cases of maxillary necrosis [4].

Clinicians also frequently ignore fungal infections, particularly when diagnostic investigations yield negative results [5]. Furthermore, fungal infection exhibits a vicious nature and varied symptomatology [6, 7]. This results in delayed diagnosis and a subsequent decline in surgical outcomes, which reduces the patient's quality of life [8, 9]. Therefore, this study was conducted to clarify the characteristics of RMM and diagnostic challenges by developing a protocol-driven multidisciplinary workflow to aid physicians, especially oral and maxillofacial surgeons as well as general dentists, in confirming the diagnosis and determining staging.

Materials and methods

Study design

A retrospective case series study was conducted between June 2022 and January 2024 in accordance with the Helsinki Declaration. The study was approved by the Assiut Dental Research Ethics Committee of the Faculty of Dentistry, Assiut University, Egypt, with approval number"17–2024-00012."Patients with RMM warning signs (Supplementary 1) were selected from the ENT or oral/maxillofacial outpatient clinics at Beni-Suef University and treated between November 2019 and December 2021. Only adult patients with midface involvement, with or without cerebral involvement, who received multidisciplinary treatment were included in the study. Patients with mandibular involvement; those with RMM associated with fungal infections in other body parts, such as the gastrointestinal tract, lungs, or urinary tract; and pregnant women were excluded from the study. Due to the retrospective nature of the study, patients'consent is not required; nevertheless, all patients completed a written consent form in accordance with our institutional norms before starting management.

Diagnostic procedures and workflow

All patients were managed by a multidisciplinary team that included the study’s investigators. Every member of the study team was an expert in their respective field, with each specialty including two specialists. The study team included diagnostic experts (radiologists, microbiologists, pathologists, and molecular biologists), medical staff (infectious disease specialists, neurologists, and critical care specialists), surgical team (oral/maxillofacial surgeon, ENT specialists, ophthalmologists, and neurosurgeon), and oral specialists (periodontists, oral/maxillofacial prosthodontists, and dental hygienists). Each participant underwent the following diagnostic procedures: 1) a comprehensive case history and clinical examinations to document the clinical symptoms, severity, and staging of RMM; 2) imaging procedures, endoscopic examinations, CT scans, and contrast-enhanced MRI scans to systematically investigate the involved area, as presented in Fig. 1; 3) blood tests, including complete blood analysis, glucose profile, serum iron level, and magnesium level, as well as liver and kidney function tests to determine the baseline function of these organs; and 4) laboratory tests, which included: a) direct microscopic examinations, the use of potassium hydroxide solution (KOH) with calcofluor white stain (CFW) as a rapid test, culture tests, polymerase chain reaction (PCR), and antimicrobial susceptibility tests; and b) histopathological examinations using hematoxylin and eosin staining. The study's investigators, who were either oral/maxillofacial surgeons or ENT specialists, examined patients and collected tissue samples and swabs from oral (by performing incisional biopsies) and nasal (through punch biopsies) lesions. Then, they consulted the study’s ophthalmologists and neurosurgeon to exclude or evaluate orbital and cerebral involvement. Until all investigations were accomplished, all patients underwent functional endoscopic sinus surgery (FESS) under local anesthesia by the study's ENT specialists to improve sinus ventilation and remove obstructions in the ostium with the same setting as the endoscopic examination.

Fig. 1.

An image demonstrating the checklist for image analysis

The study team met to analyze the collected data and divided patients into three groups on the basis of the results of the diagnostic procedures: 1) possible RMM if patients had clinical symptoms but the results of the imaging modalities and laboratory tests were negative; 2) probable RMM if patients had supportive clinical and imaging diagnostic evidence of RMM but their laboratory tests failed to detect the fungus; and 3) proven RMM if the laboratory tests identified the fungus in tissue swabs and samples [10]. The probable and proven cases were then staged on the basis of the severity and extent of the disease with respect to CT and MRI scans. Finally, at the same meeting, the roles of each specialist and treatment plans for each patient were determined, as presented in Supplementary 2. The study workflow is summarized in the flowchart presented in Fig. 2.

Fig. 2.

A flowchart summarizing the study workflow for patient management

Statistical analysis

The data collected were entered into an Excel sheet and analyzed via the IBM Statistical Package for Social Sciences for Windows, version 28.0 (Armonk, NY: IBM Corp.). Descriptive continuous data are presented as the means ± SDs, whereas categorical variables are presented as percentages. The relationship between the type of microscopic examination and the fungal detection was examined using the chi-square test, with p values < 0.05 indicating significance.

Results

Demographics

The demographic data of the 30 patients who participated in the study are shown in Table 1. Males dominated females at a ratio of 1.5:1. The patients'average age was 56.53 ± 11.52 years, and most of them were between the ages of 51 and 60 years, followed by 61 and 70 years. While 23.33% of patients experienced bilateral symptoms, 76.67% of patients (23 individuals) experienced unilateral symptoms, with a left-sided predominance. RMM occurred in four healthy patients (13.33%); one of these patients had RMM after receiving COVID-19 vaccination for the second time.

Table 1.

Outlines of patients’ demographic data, risk factors, and clinical features of rhino-maxillary mucormycosis

Variables	Description
Total Number	30
Sex (n, %):
▪ Female	12 (40%)
▪ Male	18 (60%)
▪ Female: Male	1: 1.5
Age (In Years):
▪ Mean ± SD	56.53 ± 11.52
Age Group (In Years):
▪ 30- 50	7 (23.33%)
▪ 51- 60	10 (33.33%)
▪ 61- 70	9 (30%)
▪ 71- 76	4 (13.33%)
Side (n, %):
▪ Right	11 (36.67%)
▪ Left	12 (40%)
▪ Bilateral	7 (23.33%)
Risk Factors (n, %):
▪ Healthy Patients	4 (13.33%)
▪ Chronic Sinusitis	2 (6.67%)
▪ Diabetes Mellitus	4 (13.33%)
▪ Diabetes + Cardiovascular Problems	2 (6.67%)
▪ Diabetes + Thyroid Dysfunction:	2 (6.67%)
▪ Diabetes + COVID-19	6 (20%)
▪ COVID-19	4 (13.33%)
▪ Immunosuppression Drugs:	3 (10%)
Corticosteroids	2 (6.67%)
Chemotherapy	1 (3.33%)
▪ Post Covid-19 Vaccination:	3 (10%)
Healthy Patient	1 (3.33%)
Diabetic Patient	2 (6.67%)
COVID-19 Management:
Treated with Corticosteroids	6 (20%)
No Corticosteroids	4 (13.33%)
Ventilated	6 (20%)
Total number of:a
Diabetic Patients	16 (53.33%)
Diabetic Patients with Ketoacidosis	10 (33.33%)
COVID-19 Patients	10 (33.33%)
Corticosteroid Patients	8 (26.67%)
Social History (n, %):
▪ Smoker	3 (10%)
▪ Waterpipe	5 (16.67%)
▪ Farmers	4 (13.33%)
Duration of Signs and Symptoms (In Days)
▪ Mean ± SD	13.53 ± 6.38
Involved Anatomical Areas (n, %):
▪ Nasal	3 (10%)
▪ Sinonasal	5 (16.67%)
▪ Sinonasal and Orofacial	12 (40%)
▪ Sinonasal and Orbital	3 (10%)
▪ Sinonasal Orofacial, and Orbital	4 (13.33%)
▪ Sinonasal Orofacial, Orbital, and CNS	3 (10%)
Sites of Clinical Signs and Symptoms (n, %)a
▪ Nasal and Paranasal Sinuses	30 (100%)
▪ Orofacial	19 (63.33%)
▪ Orbitalb	10 (33.33%)
▪ CNS	3 (10%)
Systemic Manifestations:	5 (16.67%)
▪ Headache	4 (13.33%)
▪ Fever	1 (3.33%)
Signs and Symptoms of CNS Involvement:	3 (10%)
▪ Altered Consciousness	3 (10%)
▪ Focal Seizures	2 (6.67%)
▪ Bilateral cavernous sinus thrombosis	1 (3.33%)
▪ Cavernous Sinus Thrombosis	2 (6.67%)
▪ Left Side Generalized Muscle Weakness	1 (3.33%)

^aThe overall count exceeds 30 patients because several patients had more than one risk factors and clinical presentation; and ^bOne patient (3.33%) had a bilateral orbital involvement due to bilateral cavernous sinuses thrombosis

Risk factors

Diabetes (53.33%) was the most common risk factor in the present study, followed by COVID-19 (33.33%) and corticosteroid therapy (26.67%). The average duration of diabetes was 90.95 ± 13.47 months. Diabetic ketoacidosis accounted for 33.33% of the cases. The average time between the diagnosis of RMM and COVID-19 was 19.45 ± 0.36 days. The average duration of corticosteroid use was 18.92 ± 4.66 days for managing COVID-19 sequelae and 3.58 ± 0.74 years for immunosuppressive purposes. RMM developed following COVID-19 vaccination in 10% of patients and following chemotherapy in 3.33% of patients.

Clinical signs and symptoms

The sinonasal region was the most common affected area, followed by the orofacial region (63.33%), orbital area (33.33%), and CNS (10%), as shown in Table 1. For each anatomical region, the frequencies of the clinical manifestations are shown in Fig. 3. The RMM patients presented several clinical symptoms, and the most prevalent complaints were facial pain (63.33%), facial swelling (56.67%), and dental pain (53.33%). Palatal necrosis (Fig. 4a & b) developed in 10% of the patients. The most frequent site of black eschar, which was observed in 33.33% of the patients (10 patients), was the nasal turbinates (16.67%) (Fig. 4c & d). Three patients with black eschar also had cutaneous eschar; two cases involved the cheek and ala of the nose, and one case involved the periorbital region. Patients also reported nerve involvement, ulcerations, and discoloration of the affected sites. Seven patients exhibited motor nerve involvement, and seven patients experienced left infraorbital nerve paresthesia. Patients with atypical symptoms, including fever, headache, seizures, disturbed consciousness, loss of vision, diplopia, nasal discharge/obstruction, dental pain, looseness of teeth, and walking abnormalities, were also recorded.

Fig. 3.

A picture illustrating frequencies of each clinical signs and symptoms for every anatomical region

Fig. 4.

Photographs demonstrating the following: a & b Clinical photographs showing palatal bone necrosis with unhealed extraction sockets in “b”; lesions appear clinically similar to osteomyelitis. c Yellow arrow pointing to pus accumulation on black eschar at the midpalate. d The dark eschar of the middle turbinates is visible in the endoscopic image. The blue arrows indicate pus collection, whereas the black arrows indicate nasal mucosal ulcerations. e Coronal CT scans showing a thicker maxillary sinus mucosa, involvement of the ethmoidal sinus, and bone erosion of the maxillary anterior wall, orbital floor, and medial orbital wall with thickened right inferior and medial rectus muscles. f The red arrow represents RMM extension into the orbital medial wall and floor, along with destruction of zygomatic complex structures. g Histological section showing extensive fungal invasion into tissues, with the violet arrow pointing toward fungal hyphal branches at a 90-degree angle

Results of imaging modalities

Nasal ulcerations were the most prevalent endoscopic finding (Table 2), constituting 36.67% of all patients, and nasal mucosal discolorations composed 30% of cases. Among the nasal turbinates (16.67%), the middle turbinate was the most often impacted in 10% of the cases. Nasal polyps were responsible for 16.67% of nasal blockages. Approximately ten percent of the patients had a normal radiographic appearance on CT and contrast-enhanced MR images, whereas 27 patients (90%) experienced symptoms during their scans, with thickened mucosal tissues being the most frequently observed sign. Twenty patients had paranasal sinus opacifications, and 13.33% of patients had bilateral paranasal sinus involvement. In addition to the maxillary sinus, seven patients had ethmoidal sinus involvement, five had sphenoidal sinus involvement, and two patients had involvement of all three sinuses. Seven patients had proptosis, and their MRI findings revealed a guitar pick sign due to orbital distortion. Cavernous sinus thrombosis was found on MRI in all three of the patients with CNS involvement; in one of them, a medial temporal lobe abscess developed on the ipsilateral side, and it extended contralaterally to the other cavernous sinus, resulting in bilateral orbital chemosis.

Table 2.

Endoscopic Findings of the study’s patients

Parameter	Description
Nasal Endoscopic Findings (n, %):	30 (100%)
Nasal Laterality:
Unilateral	23 (76.67%)
Bilateral	7 (23.33%)
Nasal Discharge	7 (23.33%)
Nasal Mucosal Discoloration	9 (30%)
Nasal Ulceration	11 (36.67%)
Nasal Black Eschar	5 (16.67%)
Nasal Obstruction	9 (30%)
Paranasal Sinuses Endoscopic Finding: (n, %):
No Involvement	3 (10%)
Involved:	27 (90%)
Only Maxillary Sinus:	17 (56.67%)
Unilateral	13 (43.33%)
Bilateral	4 (13.33%)
Maxillary + Other Sinuses:	10 (33.33%)
Ethmoid + Maxillary	5 (16.67%)
Sphenoid + Maxillary	3 (10%)
Sphenoidal + Ethmoid + Maxillary	2 (6.67%)
Endoscopic Findings of Involved Sinuses:
Mucosal Thickening	27 (90%)
Sinus Polyps	8 (26.67%)
Sinus Opacifications:	20 (66.67%)
Complete	12 (40%)
Partial	8 (26.67%)

Twenty patients had a destroyed maxilla on their CT scans, with its palatine process predominating in 50% of cases. In four patients, bone destruction was observed in the lateral nasal wall and anterior maxilla. Two patients exhibited bone deterioration in the anterior maxilla, and one patient had zygomatic involvement in addition to anterior maxilla and lateral nasal bone destruction. The orbital medial wall had the highest rate of bone destruction, followed by the superior and inferior orbital walls (Fig. 4e & f). Fat stranding was also more evident on MRI and was observed in 22 patients; 12 patients had fat stranding in the soft tissues surrounding their maxillary sinuses, and 10 patients had fat stranding in the orbits. Postcontrast MRI revealed nonenhanced or hypoenhanced"black signs", which were found in the nose, paranasal sinuses, and perisinus soft tissues, in 10 (33.33%) individuals.

Results of blood analyses

All patients had mild anemia, with hematocrit values ranging from 32 to 40%. Ninety percent of patients had neutrophilia and lymphocytopenia. Increased serum iron levels were also recorded in 26 patients (86.67%), ranging from 193.56 to 508.69 ng/mL, with an average of 395.48 ± 64.56 ng/mL. All patients also had increased serum C-dimer levels, with a mean of 789 ± 91.25 ng/mL, ranging between 555 and 1560.34 ng/mL.

Results of fungal identification

The fungus was identified in only 60% of the tissue swabs and samples. The rapid test using KOH + CFW identified the fungus in 20% of the patients. Fungi were detected in 46.67% of the patients by culture and in 60% of the patients by histological examination (Fig. 4g). The PCR test identified the fungus in 53.33% of the patients (Fig. 5a), and it was the most sensitive test for detecting mixed fungal infections. The histology analysis was superior to other tests in identifying the fungus, with a p value of 0.01. The most common Mucoraceae type was Rhizopus arrhizus, which was found in 30% of patients. Rhizopus arrhizus and Aspergillus flavus accounted for 13.33% of the cases, followed by Rhizopus arrhizus and Candida albicans at 6.67%. In one patient, Rhizopus homothallicus was discovered (Table 3).

Fig. 5.

Photographs demonstrating the diagnostic criteria of RMM in the study patients: a Bar chart representing the sensitivity of laboratory tests for fungal identification, with the KOH + CFW test having the lowest sensitivity and histopathological investigations having the greatest sensitivity. b Bar chart demonstrating that only 60% of cases had investigations confirming RMM diagnosis and that 30% of those cases had imaging modalities supporting diagnosis with no fungal detection in laboratory tests, whereas 10% of cases had neither imaging scans nor laboratory tests producing any diagnostically significant evidence. c Graph with bars depicting the frequency of RMM stages, with stage"2c"being the most common, indicating sinonasal and oral involvement. d A graph depicting the percentage of patients with respect to RMM severity, with the majority having the mild form

Table 3.

Frequency of fungus identification in tissue swabs and samples

Variables	Descriptive Data
Fungus Identification
Detected	18 (60%)
Undetected	12 (40%)
KOH + CFW Rapid Test
Positive:	6 (20%)
Aseptate Hyphae	2 (6.67%)
Septate Hyphae	3 (10%)
Aseptate and Septate	1 (3.33%)
Negative	24 (80%)
Culture
Positive:	14 (46.67%)
Rhizopus Arrhizus	11 (36.67%)
Rhizopus Homothallicus	1 (3.33%)
Rhizopus Arrhizus + Aspergillus Flavus	2 (6.67%)
Negative	16 (53.33%)
PCR
Positive:	16 (53.33%)
One species:	10 (33.33%)
Rhizopus Arrhizus	9 (30%)
Rhizopus Homothallicus	1 (10%)
Mixed Infection	6 (20%)
Rhizopus Arrhizus + Aspergillus Flavus	4 (13.33%)
Rhizopus Arrhizus + Candida Albicans	2 (6.67%)
Negative	14 (46.67%)
Histopathologic Examination
Positive	18 (60%)
Diagnostic Hyphae	18 (60%)
Inflammatory Cells Infiltration	18 (60%)
Angioinvasion	12 (40%)
Bony Invasion	6 (20%)
Perineural Invasion	2 (6.67%)
Tissue Necrosis	4 (13.33%)
Negative	12 (40%)
Chi- square Test
Chi^	11.19
P- value	0.01

KOH Potassium hydroxide solution, CFW Calcofluor-white stain, and PCR Polymerization chain reaction

Diagnostic results

On the basis of the results of the diagnostic tests, three patients were classified with possible RMM (10%), nine with probable RMM (30%), and 18 with proven RMM (60%) (Fig. 5b). The most common RMM appearance was stage “2” (17 participants), with subdivision “c” accounting for 8 occurrences (Fig. 5c). RMM severity was determined as follows: 43.33% of RMM patients had mild RMM, 40% had moderate RMM, and 16.67% had severe RMM (Table 4, Fig. 5d).

Table 4.

Diagnosis of Rhino-maxillary mucormycosis according to data analysis of the clinical examination and diagnostic modalities

Parameters	Data
Diagnosis
-Possible RMM	3 (10%)
-Probable RMM	9 (30%)
-Proven RMM	18 (60%)
Staging^:
-Stage 1	3 (10%)
-Stage 2	17 (56.67%)
-Stage 3	7 (23.33%)
-Stage 4	3 (10%)
Severitya
-Mild:	13 (43.33%)
M1:	8(26.67%)
E-	3 (10%)
E +	5 (16.67%)
M2	4 (13.33%)
M3	1 (3.33%)
-Moderate	12 (40%)
MO1	8 (26.67%)
MO2	2 (6.67%)
MO3	2 (6.67%)
-Severe	5 (16.67%)
S1	2 (6.67%)
S2	2 (6.67%)
S3	1 (3.33%)

^{^}Stage 1: Nasal mucosal involvements; Stage 2: Involvement of nose and paranasal sinuses with or without orofacial extension; Stage 3: Orbital involvement; Stage 4: CNS involvements

^aThe Severity of the RMM is determined according to the number of involved areas; Mild: Indicates involvement of two anatomical areas:M1: Nasal and paranasal sinuses; E-: No black eschar; E + : A presence of black eschar:M2: Sinonasal Area + Oral Cavity; M3: Sinonasal Area + Orbit with normal vision; Moderate: Indicates involvements of three anatomical areas or two anatomical areas with vision loss; MO1: Sinonasal Area + Oral Cavity + Fascial Spaces/Fossae; MO2: Sinonasal Area + Oral Cavity + Orbit with Normal Vision; MO3: Sinonasal Area + Orbit with Vision loss; Severe: Indicates involvements of three anatomical areas with loss of vision; S1: Sinonasal Area + Oral Cavity + Orbit with vision loss; S2: Cavernous sinus involvement; S3: CNS involvement beyond cavernous sinus

Discussion

Clinicians frequently ignore fungal infections since they are uncommon illnesses, particularly when test results are negative. RMM and other fungal infections are aggressive and present with a range of symptoms. The patient's quality of life and treatment results are negatively impacted by a delayed or an inaccurate diagnosis [5–8]. Through the development of a protocol-driven multidisciplinary workflow, this study aimed to clarify the characteristics of RMM and diagnostic challenges in order to assist medical professionals, particularly general dentists and oral and maxillofacial surgeons, in confirming the diagnosis and determining the stages and severity of RMM.

The demographic data of the study patients were in line with earlier research, which also revealed a male preponderance [10–12]. The cause of the male predominance is uncertain, but others have suggested that estrogen protects females from fungal infections. However, this is unsubstantiated and does not explain how fungal infections arise in children [13, 14]. We hypothesize that the male predominance arises from the fact that males engage in more outdoor activities than women do, increasing their susceptibility to infection. This finding corroborates Egger et al.'s findings. [15] On the other hand, some authors reported that there is no significant sex predilection [16, 17]. Our study revealed an average age of 56.53 ± 11.52 years, which is similar to that reported by Tomar et al. [18] but differs from that reported by Rudagi et al. [16], who reported an average age of 62.5 ± 7.7 years. With respect to the effect of patient age on the development of fungal infection, studies have reported contradictory results [19–21]. Some argue that aging decreases immunity and increases the risk of infection, whereas Vaezi et al. [22] reported that age is not a crucial component.

Regarding risk factors for the occurrence of RMM, the study results indicate that not only medically compromised patients but also healthy individuals are likely to develop RMM, which has also been reported by many authors [23]. All of the healthy patients included in our study were smokers or waterpipe users, and all of them were farmers who used organic manures. Our findings support earlier research showing that the environment, personal hygiene, and tobacco use all play a role in the development of RMM [24]. Diabetes was the most common risk factor in our study, followed by COVID-19 and corticosteroid administration, which is similar to the findings of prior investigations [11, 13]. On the other hand, the results of this study differ from those of other studies reporting that COVID-19 is the most common risk factor [25, 26]. The mechanisms by which these risk factors predispose humans to fungal infection are unknown. Some studies have suggested that these diseases induce elevated serum iron levels, hyperglycemia, and ketoacidosis, all of which reduce immunity and increase the risk of opportunistic infections [3, 27–29].

The study revealed that the most prevalent clinical manifestations of RMM included facial pain and swelling, along with nasal and palatal necrosis. The clinical presentations of the study subjects were similar to those of prior studies [7, 10, 30]. Rudagi et al. [16] reported that RMM more frequently affects the palate and sinonasal region, which is consistent with our findings. This is attributed to the fact that the most prevalent route of infection is inhalation of fungal spores from the surrounding environment. The fungus then spreads by direct extension or vascular extension into adjacent areas such as the oral, orbital, and cerebral cavities [16]. RMM usually manifests as black necrotic eschar with edema of the surrounding tissues; the symptoms range from increasing fulminant to localized disease. However, many authors have reported that the clinical manifestations of RMM are vague and misleading, making early diagnosis challenging [4]. These vague clinical manifestations, including nasal obstruction, bloody nasal discharge, facial pain and headache, visual disturbance, and facial paralysis, were reported in 10% of the patients. Furthermore, others reported that even the common clinical presentations of RMM (palatal ulcers and palatal bone exposure) also occur with other diseases, such as osteomyelitis, Wegener’s granulomatosis, midline lethal granuloma, necrotizing sialometaplasia, and squamous cell carcinoma [31]. Furthermore, the black eschar itself may appear in various conditions, including malignancy, trauma, and bacterial infections, or it might be mistaken for hematomas or dried crusted blood. Many studies have reported that black eschar only indicates tissue gangrene, which is caused by vascular thrombosis, so its occurrence is not limited to mucormycosis [32–34]. Our results support these findings, where the characteristic black eschar was recorded in only 10 (33.33%) of the study patients, and the remaining patients (20 patients, 66.67%) had nonspecific clinical manifestations.

Many authors have reported that periodontitis is another unusual oral symptom to consider, as it may be a risk factor for mucormycosis [11]. In our study, 14 (46.67%) patients mentioned that their condition started with periodontitis with looseness of teeth and dental pain, which did not respond to standard dental treatment. Deshpande et al. [35] also reported an infrequent case where mucormycosis simulated severe periodontitis, causing delayed diagnosis and a worse prognosis. This finding indicates that not only do oral and maxillofacial surgeons have to increase their clinical suspicion index and expand their knowledge of RMM, but also general dentists should avoid delayed diagnosis and poor prognosis after treatment.

The results of the CT and MRI scans assisted in determining the staging of RMM by determining the involved anatomical areas. This improved the communication between radiologists and surgeons and standardized the reporting of mucormycosis cases. MRI images were superior to CT scans with respect to detecting soft tissue involvement, particularly orbital and brain involvement, whereas CT scans (bony windows) were much better at detecting bony erosions and destruction. Contrast-enhanced MR scans aid in detecting the black sign, which indicates loss of vascularity and necrosis of the involved tissues. This aligns with the findings of other authors [36]. However, in the majority of our patients, both scans revealed nonspecific signs such as bone erosion, sinus opacifications, and soft tissue thickening. Even the black sign on MR images indicates that the disease is invasive and invades the vascularity of the area. Imaging data do not indicate the underlying cause of tissue damage, and all diagnostic images reflect only the impact of the lesion on the involved tissues [23]. Additionally, patient scans yielded normal results in 10% of cases, which indicates that CT and MRI scans could provide misleading negative results during the early stages of the disease. Our observations are also reported by others, who mentioned that mucormycosis has no diagnostic clinical or radiologic characteristics and that the diagnosis is based on histopathology [37, 38].

The precise diagnosis of mucormycosis mainly depends on histological examination and culture [8]. The laboratory findings in our study are comparable to those of previous studies [39], with the results showing that the KOH + CFW test has the lowest sensitivity for detecting fungi, that the PCR test is more effective in detecting mixed fungal infections, and that histopathological investigation is the most accurate test. Furthermore, 40% of the participants experienced false-negative results, which is consistent with previous findings [27]. The false-negative results from microscopic examinations could be attributed to the following reasons: 1) regarding rapid and culture tests, tissue swabs are obtained from the outermost layers of tissue surfaces, while fungi usually infiltrate the deeper layers; and 2) in terms of histological examinations, failures may be attributed to poor biopsy methods, incorrect sample preparation processes, and a lack of knowledge about hyphal fragility, which results in fungal fragmentation and low fungal loads, as stated by others. Therefore, some authors have stated that clinicians and microbiologists must collaborate to establish effective diagnostic methods [40].

Anemia, neutrophilia, lymphocytopenia, hyperferritinemia, and elevated D-dimer levels were documented in our patients. Many authors have reported that these signs are good predictors of the presence of fungal infections, particularly in their chronic form [27, 39, 41, 42]. However, they are also not specific to fungal infection [41]. All the aforementioned observations revealed that RMM lacks pathognomonic clinical or radiologic characteristics and that fungus identification in tissue samples should not serve as the only basis for a diagnosis.

Many authors have reported that fungal diseases are more likely to be misdiagnosed [43–45]. We hypothesize that late diagnosis or misdiagnosis of mucormycosis could be due to the following reasons: 1) most physicians do not consider it in the differential diagnosis of patients'disease due to its rarity, even in high-risk patients; 2) its clinical manifestations are similar to those of other infections and allergic sinusitis; 3) most clinicians insist on identifying black eschar and/or fungi during clinical or microscopic exams to verify the diagnosis; and 4) negative laboratory tests delay the decision. Therefore, for the timely diagnosis of RMM, it is imperative that physicians have a high clinical index of fungal suspicion. Moreover, clinicians must recognize that not all RMM patients have a proven diagnosis, but probable or possible cases may also be diagnosed. Furthermore, a correlation between a detailed medical history, a meticulous clinical examination, and hematologic, biochemical, and radiologic findings is essential to reach a diagnosis. Additionally, if swelling, ulceration, bone necrosis, osteomyelitis, or symptoms that do not improve after 48 to 72 h of standard treatment are observed, fungal infection must be added to the differential diagnosis. Furthermore, it should also be considered that RMM has a high probability. This conclusion is in line with those of previous studies [4, 10, 27, 41].

The clinical importance of this study lies in its focus on the necessity of diagnosing mucormycosis on the basis of physicians’ clinical suspicion rather than the identification of fungi in tissue samples. Therefore, we recommend that health-care authorities initiate educational programs for the general public, physicians, and pathologists to increase patient awareness of the disease, motivate clinicians to heighten their clinical suspicion of mucormycosis, and teach pathologists how to prepare samples and identify fungi. The study has some limitations, including the following: 1) inclusion of only a single center, which may not represent the entire population; and 2) no inquiry into the association between risk factor severity and RMM.

Conclusion

On the basis of the results of the present study, a significant number of RMM patients presented with nonspecific clinical symptoms along with negative laboratory or imaging findings. Therefore, negative laboratory results should not rule out mucormycosis if other clinical conditions are suspected. Physicians must maintain a high clinical index of fungal suspicion, even in healthy patients. Moreover, fungal infection must be added to the differential diagnosis of oral and maxillofacial lesions.

Abbreviations

RMM

Rhinomaxillary mucormycosis

KOH

Potassium hydroxide solution

CFW

Calcofluor white stain

PCR

Polymerase chain reaction

Authors’ contributions

S.A.ElB: design and conception, creation of figure and table, and final approval of the manuscript. G.A.KH: design and conception, search of literature, manuscript writing, creation of figure and table, and final approval of the manuscript. K. E.: design and conception, collecting data, and final approval of the manuscript. H.M.: collect data and final approval of the manuscript. M.N.A.M: collect data and final approval of the manuscript. M.Y.A: collect data and final approval of the manuscript. M.M.ElS: design and conception, and final approval of the manuscript.

Funding

The authors state that no funding was obtained for this study.

Data availability

Data is provided with in the manuscript and supplementary files.

Declarations

Ethics approval and consent to participate

A retrospective case series study was conducted between June 2022 and January 2024 in accordance with the Helsinki Declaration. The study was approved by the Assiut Dental Research Ethics Committee, Faculty of Dentistry, Assiut University, Egypt, with approval number"17–2024-00012."The consent that was obtained from all of the participants was informed.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.