Mucormycosis presenting with dental pain and palatal ulcer in a patient with chronic myelomonocytic leukaemia: case report and literature review

IP: 54.70.40.11 On: Fri, 07 Dec 2018 11:34:36 Case Report Mucormycosis presenting with dental pain and palatal ulcer in a patient with chronic myelomonocytic leukaemia: case report and literature review Ourania Nicolatou-Galitis, Sotirios Sachanas, Maria Drogari-Apiranthitou, Maria Moschogiannis, Dimitra Galiti, Xanthi Yiakoumis, Demetra Rontogianni, Ioannis Yiotakis, George Petrikkos and Gerassimos Pangalis

We present a case of mucormycosis that first manifested with dental pain and a palatal ulcer, in a patient with chronic myelomonocytic leukaemia-2 (CMML-2), now classified as myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (Vardiman et al., 2002).We also performed a literature review to highlight the importance of this oral sign and alert clinicians to include mucormycosis in the differential diagnosis for the early management of this life-threatening fungal infection.

Case report
A 72-year-old female Caucasian was diagnosed with CMML-2 in April 2012 and received erythropoietin from April to June 2012.She was not diabetic and had no other underlying diseases.Haemolysis led to discontinuation of erythropoietin, followed by a 10-day course of corticosteroids and folic acid.On 24 October 2012, the patient presented to our clinic with severe pain on the first left maxillary molar, tooth mobility, numbness and a deep ulcer with a dark-brown necrotic granular surface and a white well-defined irregular border on the hard palate and gingivae adjacent to the painful molar (Fig. 1a).Two weeks earlier, she had received endodontic therapy of that painful molar by a primary care dentist, with partial remission of pain.Two days before presentation to our clinic, she was started on her first chemotherapy cycle with azacitidine (Vidaza-Celgene) due to refractory anaemia and severe thrombocytopenia.The invasive 'downgrowth' type and the dark colour of the ulcer raised suspicion of an invasive fungal infection in this highrisk MDS/MPN patient.Necrotizing ulcerative gingivitis and stomatitis, chronic granulomatous infection, malignant melanoma, squamous-cell carcinoma, lymphoma, plasmacytoma, salivary gland adenocarcinoma, necrotizing sialometaplasia and giant-cell granuloma were also included in the differential diagnosis, as shown in Table 1.The next day (25 October 2012) she developed fever.The laboratory results were as follows: white cell count 37610 9 , 21 , neutrophils 48 %, lymphocytes 25 %, eosinophils 1 %, basophils 1 %, monocytes 25 %, platelets 26610 9 l 21 , haemoglobin 6.8 g dl 21 , erythrocyte sedimentation rate 133 mm and Creactive protein 24.4 mg dl 21 .During the course of her disease, the patient had never previously developed fever or showed absolute neutrophil counts of ,10 9 l 21 .On the same day, the patient was admitted to the hospital in order to receive blood transfusions.The presence of severe thrombocytopenia and fever, both having a dismal effect on her performance status, did not allow the performance of a biopsy upon her hospital admission.Microbiological culture of swabs taken from the ulcer and the nasal cavity resulted in growth of Klebsiella ozaenae and Staphylococcus aureus, respectively.She was started on intravenous (IV) piperacillin-tazobactam and metronidazole.Voriconazole While the white cell count returned to normal and platelet number improved after whole blood and platelet transfusions, on 14 November 2012 she was transferred to the ENT department of an academic hospital for evaluation and possibly a wider surgical debridement of the progressive lesion.The next day, an extensive maxillectomy was performed and the tissue specimen was sent for microbiological and histopathological examination.On direct microscopy of tissue preparations with Blankophor (0.025 %, w/v, in 20 % KOH), fungal hyphae characteristic for mucormycetes were observed (Fig. 2).Two days later (17 November 2012), a mucoralean fungus was isolated from the culture, morphologically identified as Rhizopus arrhizus.Examination of histopathology cuts stained with periodic acid-Schiff and Grocott-Gomori methenamine silver stains again showed L-AmB (IV, 7 mg kg 21 ) was continued for 1 month, followed by posaconazole (Noxafil-MSD; 400 mg twice daily), while the scheduled second azacitidine cycle was withheld.On 20 November 2012, the mucormycosis appeared to be controlled, as both direct examination and culture of a new biopsy specimen were negative.The patient died on 22 January 2013 due to progression of her disease to acute myeloid leukaemia (AML) with severe cytopenia, and multiple bacteraemias with Enterococcus and Acinetobacter.
An English literature search using the key words: 'rhinoorbital-cerebral-maxillary mucormycosis and palatal lesion/ ulcer', 'immunocompromised host' and 'leukaemia' identified 109 more cases of sinus/rhinocerebral mucormycosis with palatal lesion or ulcer in immunocompromised hosts, as shown in Table 2. Palatal/maxillary lesions at presentation were described in 42 patients (38.5 %).Articles on rhinocerebral mucormycosis without a report of a case with palatal involvement at the time of diagnosis were not included.In eight patients (7.3 %), palatal involvement was the first presenting sign that led to the diagnosis of mucormycosis.In these eight patients, palatal lesions were described as ulcers (four cases), necrosis (two cases), and perforation and necrotic bone (two cases), while dental pain and tooth mobility were reported in two patients and preceding dental extractions in three.Of the 110 patients, the present case included, 49 (44.5 %) survived the infection: six of the nine patients (66.6 %, our case included) with palatal involvement as the first presenting sign and 43 of the remaining 101 (42.6 %) with or without palatal involvement among other signs at presentation (Table 2).

Discussion
We report a case of sinus mucormycosis in a patient with CMML-2, who presented with severe dental pain and palatal ulcer.CMML has been assigned by the World Health Organization to a new category of myeloid neoplasms, MDS/MPN disorder (Vardiman et al., 2002).CMML is defined as a clonal haematopoietic stem-cell disorder that is characterized by the presence of an absolute monocytosis (.1610 9 cells l 21 ) in the peripheral blood and the presence of myelodysplastic and myeloproliferative features in the bone marrow (Vardiman et al., 2009).The most common symptoms of CMML are a reflection of the underlying cytopenia including fatigue and dyspnoea due to anaemia, susceptibility to infections and, rarely, bleeding.The CMML-2 type is particularly associated with a high rate of progression to acute leukaemia (Vardiman et al., 2009).   of the infection in only 16 of 114 cases (14 %) (Yohai et al., 1994).It is possible that increased awareness of the clinicians, combined with active involvement of dental healthcare professionals, has contributed to the above increased report of palatal involvement at the time of onset of infection.In the present case, palatal involvement was the first presenting sign that led to the diagnosis of mucormycosis.
Our patient complained of severe dental pain.Although not specifically asked, she did not report any complaints from the sinuses and no such symptoms were obvious.Eight patients were also diagnosed from the palatal lesion in the present literature review (Auluck, 2007;Doni et al., 2011;Jayachandran & Krithika, 2006;Islam et al., 2007;Leithauser et al., 2009;Metzen et al., 2012;Viterbo et al., 2011).Of the eight cases, six presented with palatal perforation, palatal necrosis and/or mobility or falling off of the maxillary bone, and with palatal ulcer combined with facial swelling and discharge from the nostril.We believe that all these findings at presentation implicate a more advanced stage of the infection (Auluck, 2007;Doni et al., 2011;Islam et al., 2007;Jayachandran & Krithika, 2006;Metzen et al., 2012).Of the two remaining cases, one was reported as a necrotic lesion on the palate, but it was not shown or further clinically described, in a patient with chronic graft-versus-host disease after allogeneic stem-cell transplantation.Ulcers on the palate and the dorsum of the tongue were reported in the second case in a recent liver transplantation patient (Leithauser et al., 2009;Viterbo et al., 2011).To the best of our knowledge, and also to our surprise, our case is the first described case of sinus mucormycosis with palatal ulceration in a patient with MDS/ MPN disorder.As palatal involvement is considered a 'common' sign in rhinocerebral mucormycosis, it is possible that more cases exist but that this specific sign has been just under-reported.
Palatal ulcer is easily accessible and may facilitate the establishment of an early working diagnosis by a clinician, provided there is a high index of suspicion.Early diagnosis of mucormycosis is critical, as treatment should start as soon as possible in order to decrease mortality (Chamilos et al., 2008;Gamaletsou et al., 2012;Petrikkos et al., 2014;Skiada et al., 2013;Yohai et al., 1994).The rapid progression of the infection and the lack of serology tests for the diagnosis of mucormycosis, combined with the fact that it is not always possible to perform surgical biopsies, particularly in patients with thrombocytopenia, highlight the importance of early clinical suspicion.Early diagnosis, before fungal invasion of critical tissue mass, can also facilitate the surgical removal of the necrotic tissues, which has been associated with higher survival (Lanternier et al., 2012).
The outcome of mucormycosis in a patient with progressive haematological malignancy is hard to predict and the expected case fatality rate is high (Petrikkos et al., 2014).However, there are three critical points in the management of this patient, in which a different approach could have saved considerable morbidity.The first is the time elapsed between the first visit to the dentist and the second one to the oral medicine specialist.Although the observation of the palatal ulcer by the oral medicine specialist initiated the diagnostic procedure at an early stage, before the development of other clinical signs from the maxilla or the sinus area, increased awareness by the dentist could have critically contributed to the initiation of the diagnostic procedure 2 weeks earlier.This time is critical for such a rapidly developing infection.The second point is the timing of the first biopsy.Had the first biopsy taken place upon recognition of the palatal ulcer and direct microscopy was performed, an additional week could have been saved.The diagnostic value of direct microscopy of the bioptic tissue with KOH (10-20 %), preferably with a fluorescent brightener such as Blancophor or calco-fluor-white, is very high, as it allows rapid presumptive diagnosis, much earlier than histology and culture and is strongly recommended (Cornely et al., 2014).Unfortunately, severe thrombocytopenia and fever did not allow the immediate performance of the biopsy upon the patient's admission to the hospital.The third point is the initiation of antifungal therapy with L-AmB instead of voriconazole.Voriconazole has been considered as a risk factor for breakthrough mucormycosis (Lewis et al., 2011).
R. arrhizus was the infecting agent in the present case, a species more frequently involved in mucormycosis in Europe (Petrikkos et al., 2014).Antifungal susceptibility testing was not considered necessary and was not performed.The recommendation for guiding treatment based on MICs is only marginally supported with strength of recommendation C and quality of evidence II, based on uncontrolled trials (CIIu).(CIIu) as the clinical relevance is uncertain; no data are available to correlate MIC and outcome (Cornely et al., 2014) and the antifungal therapy of choice is L-AmB with a minimum dose of 5 mg kg 21 day 21 .
Posaconazole is also an option, with a lower strength of recommendation (BIIu) (Cornely et al., 2014).A combination of these two drugs in this patient was not considered, as the infection appeared controlled after 20 days of treatment.
Six of the nine patients (66.6 %; present case included) with palatal involvement as the only presenting sign of the infection survived compared with 43 of 101 patients (42.6 %) with signs of sinusitis and/or facial/orbital cellulitis, with or without palatal involvement at presentation.Palatal involvement as the first presenting symptom may be associated with dental pain and tooth mobility, as in our case, leading the patient to the dentist, who can be the first clinician to suspect an infection (Auluck, 2007;Doni et al., 2011;Jayachandran & Krithika, 2006;Islam et al., 2007;Metzen et al., 2012;Viterbo et al., 2011).The lesion does not have to be the typical necrotic eschar as described for mucormycosis in order to include this infection in the differential diagnosis, as necrosis occurs at a later stage.However, our patient received endodontic treatment upon the first visit to the dentist.with no activity against mucormycosis such as voriconazole, uncontrolled diabetes and iron overload with or without desferoxamine treatment (Ibrahim et al., 2008;Lanternier et al., 2012;Petrikkos et al., 2012Petrikkos et al., , 2014;;Sun & Singh, 2011).Our patient developed haemolysis, which led to discontinuation of her initial therapy with erythropoietin.The availability of free iron as a sequela of haemolysis may also have contributed to the development of the infection in addition to her underlying haematological disease.The short corticosteroid use was administered 4 months earlier and it is highly unlikely to be related to the development of the infection.Voriconazole, which can predispose to breakthrough mucormycoses, could not be related to the mucormycosis of our patient either, as the infection was already clinically present when this drug was administered but delayed the more appropriate treatment with L-AmB.Voriconazole was administered initially based on the possible diagnosis of aspergillosis, as the lesions of palatal aspergillosis and mucormycosis are usually described as similar or even identical and aspergillosis is considered more frequent (Bonifaz et al., 2008;Karabulut et al., 2005;Skiada et al., 2013).
As soon as the diagnosis of mucormycosis was established, our patient was treated with L-AmB, which is the drug of choice, combined with haematological support, surgical debridements and maxillectomy.The mucormycosis was successfully controlled 1 month later, but the associated interruption of the antineoplastic therapy did not allow the control of the progressive AML.The patient died of progressive leukaemia and multiple bacteremias.
In conclusion, increased awareness of dentists and maxillofacial surgeons may initiate the early diagnosis of a sinus mucormycosis in high-risk patients who present with dental pain and palatal ulcer.Early diagnosis and prompt treatment is critical for prognosis.This is important in view of the increasing numbers of cases of mucormycosis being reported worldwide (Bitar et al., 2009;Kurosawa et al., 2012;Llata et al., 2011;Petrikkos et al., 2014;Skiada et al., 2013;Sun & Singh, 2011).
(6 mg kg 21 IV every 12 h for 1 day, followed by 4 mg kg 21 IV every 12 h) was added because of the suspicion of aspergillosis, considered the most probable mycosis.Despite the antimicrobial treatment, her clinical condition worsened and she developed left facial swelling and cellulitis.Computerized tomography (CT) of the paranasal sinuses disclosed an air-fluid level in the left maxillary sinus and inflammatory lesions in the left nasal cavity, the left ethmoid sinus and the base of the left frontal sinus (Fig.1b).Magnetic resonance imaging did not show ocular or brain extension.On 31 October 2012, a tissue specimen for biopsy was taken from the palatal ulcer, while liposomal amphotericin B (L-AmB; Ambisome-Gilead) at 5 mg (kg body weight) 21 day 21 was introduced.L-AmB was increased to 7 mg (kg body weight) 21 day 21 on 4 November 2012, combined with limited (due to the poor haematological profile of the patient) surgical debridement for removal of the necrotic tissues.The histological examination revealed broad, irregularly shaped non-septate fungal hyphae with right-angle branching, elements compatible with those observed in infections with zygomycetes of the order Mucorales (mucormycetes) invading the tissue.The cellulitis improved, but after 2 days (6 November 2012), the palatal/ gingival ulcer had worsened and increased in size.The same night, the patient developed supraventricular tachycardia and pulmonary oedema, and was treated with amiodarone (Angoron), diuretics and oxygen.On 13 November 2012, she developed acute dyspnoea [tissue oxygen saturation (StO 2 ) 88 %, partial pressure of O 2 (pO 2 ) 80 mmHg, partial pressure of CO 2 (pCO 2 ) 30 mmHg, under mechanical ventilation (50 % oxygen)].A CT scan of the thoracic area showed bilateral diffuse infiltrations of the interstitial tissues, while an echocardiography disclosed an ejection fraction of 45 %, reduction of intraventricular septum mobility and pulmonary hypertension.The patient received diuretics with improvement of her clinical condition (StO 2 98 % with nasal O 2 at 2 l min 21 ).

Fig. 1 .
Fig. 1.(a) Dark-brown ulcer with granular surface and a whitish elevated periphery on the palate adjacent to the left maxillary molar.(b) CT scan of the paranasal sinuses.An air-fluid level in the left maxillary sinus and inflammatory lesions in the left nasal cavity and ethmoid sinus can be seen.

Table 1 .
Neville et al., 1997)s and main clinical characteristics of palatal lesions relevant to the present case (based onNeville et al., 1997)