Mucormycosis in immunocompetent patients: a case-series of patients with maxillary sinus involvement and a critical review of the literature.

Summary Objectives To review the current literature on mucormycosis in immunocompentent/otherwise healthy individuals, to which five new cases with maxillary sinus involvement have been added. Methods We searched in the PudMed database all articles in the English language related to human infections caused by fungi of the order Mucorales , in immunocompetent/otherwise healthy patients, starting from January 1978 to June 2009. In addition, we updated the literature by reporting five new cases diagnosed and treated at the oral medicine unit of our institution. Results The literature review showed at least 126 articles published from 35 different countries in the world, to a total of 212 patients described. The most affected country was India with 94 (44.3%) patients and the most representative clinical form was the cutaneous/subcutaneous with 90 (42.5%) patients. Our five immunocompetent patients with a diagnosed infection of Mucorales localized at the maxillary sinus completely healed with lyposomial amphotericin B. Conclusions The literature analysis revealed that even in immunocompetent/otherwise healthy individuals mucormycosis infection has a worldwide distribution. What might be the real predisposing factors involved in its pathogenesis in such patients and the real causes of this peculiar geographic distribution still remains unknown. It is likely that, in our cases, a chronic insult of a well-defined and localized body area might have resulted in a local immunocompromission, thus fostering the development of an invasive fungal infection

Sleep Disturbance in Patients with Burning Mouth Syndrome: A Case-Control Study

AIM: To examine sleep complaints in patients with burning mouth syndrome (BMS) and the relationships between these disturbances, negative mood, and pain. METHODS: Fifty BMS patients were compared with an equal number of healthy controls matched for age, sex, and educational level. The Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) were administered. Descriptive statistics, including the Mann-Whitney U test and hierarchical multiple linear regression analyses were used. RESULTS: BMS patients had higher scores in all items of the PSQI and ESS than the healthy controls (P < .001). In the BMS patients, a depressed mood and anxiety correlated positively with sleep disturbances. The Pearson correlations were 0.68 for PSQI vs HAM-D (P < .001) and 0.63 for PSQI vs HAM-A (P < .001). CONCLUSION: BMS patients reported a greater degree of sleep disorders, anxiety, and depression as compared with controls. Sleep disorders could influence quality of life of BMS patients and could be a possible treatment target

Delayed immunologic evidence in pemphigus vulgaris

Any proper diagnosis of pemphigus vulgaris is supported by the combination of clinical aspects, a histological examination via biopsy, an assay of serum antibody titres by indirect immunofluorescence (IIF) and an enzyme-linked immunosorbent assay (ELISA) to detect antibodies against desmoglein 1 and 3 (Dsg 1/3). 1 Controversial is the diagnostic value of the direct immunofluorescence (DIF) performed on fresh specimens. DIF might be a more reliable tool for reaching a sure diagnosis in pemphigus vulgaris cases 2 and, perhaps, any other autoimmune muco-cutaneous blistering diseases (AMBDs), where there has been a lengthy period of negative IIF and ELISA testing. In July 2005, a 24 year-old woman was referred to our Oral Medicine Unit for desquamative gingivitis at the gingiva of the anterior lower teeth. The lesions were painful and persistent and, in September 2005, started spreading to the tongue (Fig. 1a) and upper gingival fornix (Fig. 1b), showing a positive Nikolsky’s sign. She was skin lesion-free. An oral biopsy for histology, DIF, IIF using monkey oesophagus as the preferred substrate and ELISA testing for Dsg 1/3 were performed. Histology with haematoxylin/ eosin revealed acantholysis and a prominent eosino-neutrophilic infiltrate, suggesting possible pemphigus vulgaris. Unfortunately, DIF did not show any immunoglobulins, and complement staining, IIF and ELISA testing were also negative. Throughout 2006, we performed IIF and ELISA tests three times and DIF twice, but the results were still negative. Since no inducing or triggering risk factors were found, and since the histological aspect appeared similar to a dilapidated brick wall (clumped acantholytic cells with a few intact intercellular bridges holding the keratinocytes together; Fig. 1c), our differential diagnosis included a Hailey–Hailey Syndrome. We performed a genetic analysis for the ATP2C1 gene, but no mutation was detected. We therefore decided to give her topical steroids, obtaining a partial clinical remission. In January 2007, we performed a new biopsy for histology and DIF. Even though the IIF and ELISA tests were still negative, conversely DIF showed a positive fluorescence for intercellular cement substance, with the classic ‘net-like’ aspect (Fig. 1d). IgG was positive, while IgA, IgM and C 3C were negative. Thus, we made a diagnosis of pemphigus vulgaris and treated the patient with conventional immunosuppressive therapy (75 mg/day of prednisone and 100 mg/day of azathioprine) for 3 months, thereby gaining complete clinical remission. The diagnostic protocol of AMBDs envisages the use of histopathology, DIF, IIF and Dsg 3 – ELISA testing, which was found to be a highly specific and useful diagnostic tool for pemphigus vulgaris. 3 Different studies have emphasized that IIF and ELISA tests are indispensable for a correct sero-diagnosis of pemphigus vulgaris, underlining that ELISA tests proved to be slightly more sensitive than IIF, 4 which is in turn more sensitive than immunoblotting. 5 Our case highlights the likelihood that pemphigus vulgaris may flare up in a ‘silent’ immunological pattern, confirming previous observations 6 and be sero-negative over an indeterminate period of time, thus making a correct diagnosis very difficult. We therefore recommend performing DIF and serologic analysis several times, since an immunological response might be unmasked later on. Indeed, in our case, DIF became positive after 1 year, whereas the IIF and ELISA test still remained negative, so that the combination of clinical, histological and DIF findings were sufficient to support the diagnosis of pemphigus vulgaris. It’s likely that a prolonged negative immunological response was due to a titre so low as to be undetectable by our tests, but capable of inducing clinical manifestations of pemphigus vulgaris, or that an unknown non-immunological acantholytic mechanism might have revealed pathogenic epitopes of Dsg 3, triggering an autoimmune humoral response later on. Nonetheless, since no evidence is present in the literature to support this hypothesis, further investigations need to be performed

Metastatic prostate cancer presenting as paraneoplastic pemphigus: a favourable clinical response to combined androgen blockade and conventional immunosuppressive therapy

Paraneoplastic pemphigus (PNP), first described in 1990, is an autoimmune mucocutaneous blistering disease which is associated with an underlying malignancy and is characterized by polymorphic clinical signs. Pathogenesis is due to an aberrant autoimmune response against the proteins of the plakin family such as plectin, envoplakin, periplakin, desmoplakin I and II, and bullous pemphigoid antigen I (BP230), although several cases of PNP with antibodies to desmoglein (Dsg) 1 and 3 have been described. A 77-year-old man was admitted to our Oral Medicine Unit because of recalcitrant severe oral bullous ⁄erosive mucositis with crusting lesions of the lips, accompanied by marked conjunctivitis of both eyes, with cutaneous bullous lesions of the abdomen and bilaterally of the hip and inguinal area. Nikolsky’s sign, performed on the oral mucosa and skin, was positive. Oral biopsy revealed suprabasal epithelial detachment with an eosinophilic and neutrophilic infiltrate. Direct immunofluorescence showed positive fluorescence in the intercellular cement substance (ICS) of IgG and complement 3c, while IgA and IgM were negative. Indirect immunofluorescence, using normal human skin as substrate, showed an intercellular signal confined to the ICS with a titre of 1 : 360. Enzyme-linked immunosorbent assay gave a value of 54 U mL)1 for Dsg1 (normal 0–14) and a value of 162 U mL)1 for Dsg3 (normal 0–14), confirming a diagnosis of pemphigus vulgaris. PNP was suspected due to the severe and polymorphic mucocutaneous involvement, in particular of the conjunctiva and labial mucosa, which resembled erythema multiforme-like lesions. Routine haematological tests, serum tumour markers [b2-microglobulin, prostate-specific antigen (PSA), alpha-fetoprotein, carcinoembryonic antigen, Ca 19-9, Ca 72-4, Ca 125, acid phosphatase, Bence-Jones proteinuria], chest X-ray, echocardiogram, colonoscopy and oesophagogastroduodenoscopy were negative except for microhaematuria and an elevated level of PSA (49Æ1 ng mL)1; normal 0–4). A total body computed tomography (CT) scan revealed enlargement of the prostate, while bone scintigraphy revealed multiple foci of increased uptake (L2–L3, D8–D10). An ultrasound-guided needle biopsy of the prostate revealed a diffuse infiltration of adenocarcinoma. The prostate cancer grading (Gleason scale) was 8 (4 + 4). Immunoblotting analysis revealed the presence of antibodies to 250-, 210-, 190-, 160- and 130-kDa proteins (Fig. 2). So, in line with the criteria previously proposed,2 a diagnosis of PNP was confirmed. Our patient was diagnosed with a diffuse infiltration of prostate adenocarcinoma and bone metastasis. Over time, he developed mucocutaneous manifestations of PNP with a high positive titre of anti-Dsg1 and Dsg3. To our knowledge, despite the wide variety of haematological (Hodgkin and non- Hodgkin lymphoma, Castleman disease, thymoma)4 and nonhaematological malignancies (pancreas, colon, breast)2 related to PNP, it appears that this is the first case of PNP with metastatic prostate cancer. The only previous patient with PNP and prostate cancer also had chronic lymphoid leukaemia,10 so in that case the role of prostate cancer appears to be unlikely, although it might have contributed, as the most common malignancies related to PNP are nonhaematological. Another paraneoplastic case with prostate cancer has been described, but this was paraneoplastic bullous pemphigoid, associated with breast cancer

Sunitinib adverse event: oral bullous and lichenoid mucositis

Sunitinib is an oral, multi-targeted tyrosine kinase inhibitor that inhibits the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), the stem cell factor receptor (SCF or c-Kit), and the colony-stimulating factor-1 receptor.1 It was approved for the treatment of renal and gastrointestinal stromal tumors2 and also recently showed anti-tumor activity in patients with metastatic breast cancer.1 This case is the first to describe the oral clinical aspects of sunitinib-suspected oral mucositis toxicity in a breast cancer patient. Although the frequency of grade 3/4 toxicities occurring with Sunitinib is relatively low (< 10%), mostly reported in renal cell cancer rather than metastatic breast cancer studies, the oral adverse event, always described as stomatitis or mucositis, occurred with varying frequency nonetheless (10-30%).3 This case is unique because for the first time it describes the oral clinical aspects of sunitinib-induced stomatitis, characterized by bullous and erosive lesions with widespread lichenoid and necrotizing areas which appeared 12 hours after the second day of the third cycle. She discontinued sunitinib and received prednisone (25 mg PO qd) for three days, followed by topical corticosteroids such as mouthwash bid for seven days. The patient was counseled to modify her diet regimen, eat soft foods, drink non-alcoholic liquids with a straw, and to maintain meticulous oral hygiene by using a toothbrush with soft bristles and a diluted solution of chlorexidine 0.12% as a mouthwash in case of bleeding gums.3 Ten days later she was in complete clinical remission. The patient was not re-challenge, because she refused to take the medication again. Although the first target of sunitinib is the capillary endothelium which blocks VEGFR 1/2/3, PDGFR, c-Kit and Flt-3 (FMS-like tyrosine kinase 3), the presence of these receptors has also been detected in other tissue, e.g., c-Kit in the acini and ducts of salivary glands,4 in human keratinocytes,5 and VEGFR-1 in the epidermal layer of unwounded skin. It is likely that the initial damage induced by suninib in the oral cavity may affect not only vascular tissue, but even salivary glands and keratinocytes. Once the damage is established, these lesions might self-maintain, due to an impairment of wound healing mechanisms. In fact, the wound repair mechanisms are regulated via VEGF which is both expressed by epithelial cells of salivary glands7 and keratinocytes.6 These are the main sources of VEGF during wound healing, acting in a paracrine and autocrine manner,6 and promoting wound healing via stimulation of endothelial cell-mediated angiogenesis. Thus, clinicians should consider sunitinib as a trigger to oral mucositis

Analysis of thromboembolic risk related to high-dose intravenous immunoglobulin treatment: a preliminary clinical study of 10 patients with autoimmune mucocutaneous blistering diseases

BACKGROUND: Intravenous immunoglobulin (IVIg) treatment is a well-known treatment that has been used successfully in a broad spectrum of autoimmune diseases. Currently no data are available in the literature about the role of IVIg in the pathogenesis of thromboembolic events in patients with autoimmune blistering diseases refractory to conventional immunosuppressive treatment. AIM: To determine the relationship between IVIg and thromboembolism in patients with autoimmune blistering diseases and to establish a protocol to deal with the thromboembolic risk. METHODS: In our preliminary clinical study, 10 patients with autoimmune blistering diseases underwent IVIg cycles to a total of 133 cycles in all (total number of infusions in the patient group: 399), at a standard dose of 2 g/kg/infusion accompanied by an accurate and a complete clinical and laboratory screening for thromboembolism. Preventive measures, such as hydration before and after IVIg, and administration of 100 mg of acetyl salicylic acid (aspirin) or 1000 IU of subcutaneous heparin calcium per day for 3 weeks, were introduced to reduce the thromboembolic risk. RESULTS: Throughout the 2 years of IVIg treatment, no patient developed a superficial and/or deep venous or arterial thrombosis, even though some of the patients had underlying thromboembolic risk factors and had tested positive for some congenital and acquired thrombophilia markers. CONCLUSIONS: Our results indicate that thromboembolic events are uncommon, despite the presence of risk factors. However, as these disorders are very rare and the percentage of nonresponder patients is very low, further investigations are needed to better understand whether IVIg alone is able to trigger these fatal events in blistering disorders

Oral lichen planus in childhood: a case series

BACKGROUND: Although the exact incidence of pediatric oral lichen planus (OLP) is unknown, the oral mucosa seems to be less commonly involved, and the clinical presentation is often atypical. The aim of the study is to present a case series of OLP in childhood. METHODS: From our database, we retrospectively selected and analyzed the clinical data of OLP patients under the age of 18 where the diagnosis had been confirmed by histopathological analysis. RESULTS: The case series from our database shows eight patients, four males and four females. The mean (±SD) age at the time of diagnosis of the disease was 13.5 (±2.73) years, ranging in age from 9 to 17. Clinically, a reticular pattern was present in six patients (75%), and the tongue was the most commonly involved oral site (six cases, 75%). We also report the first case of OLP in a 9-year-old girl affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. CONCLUSIONS: We report the largest case series of pediatric OLP published in literature thus far. Differences in the disease between adults and pediatric patients have been detected, but further investigation and a larger case series are needed to establish any detailed differences in clinical outcome

Oral lichen planus in childhood: a case series

BACKGROUND: Although the exact incidence of pediatric oral lichen planus (OLP) is unknown, the oral mucosa seems to be less commonly involved, and the clinical presentation is often atypical. The aim of the study is to present a case series of OLP in childhood. METHODS: From our database, we retrospectively selected and analyzed the clinical data of OLP patients under the age of 18 where the diagnosis had been confirmed by histopathological analysis. RESULTS: The case series from our database shows eight patients, four males and four females. The mean (±SD) age at the time of diagnosis of the disease was 13.5 (±2.73) years, ranging in age from 9 to 17. Clinically, a reticular pattern was present in six patients (75%), and the tongue was the most commonly involved oral site (six cases, 75%). We also report the first case of OLP in a 9-year-old girl affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. CONCLUSIONS: We report the largest case series of pediatric OLP published in literature thus far. Differences in the disease between adults and pediatric patients have been detected, but further investigation and a larger case series are needed to establish any detailed differences in clinical outcome

Socio-demographic characteristics and pain in 75 Burning Mouth Syndrome patients

To examine socio-demographic and clinical characteristics in a subset of patients with Burning mouth Syndrome (BMS) and to analyze the relationships between these variables and pain. Methods: 75 subjects enrolled during the period from May 2012 to November 2012. Demographic characteristics and clinical information including age, sex, educational level, marital status, job status, age at disease onset, oral symptoms and triggers were collected. To assess pain, the Visual Analogue Scale (VAS) was performed (fig 1). Results: Descriptive statistics, the Pearson Chi square tests, the Kruskal Wallis non-parametric tests and the Spearman bivariate correlation were used.The patient age ranged from 18-83 with a mean age of 61.17 (+/-11.75) and a female predominance of 3:1. The age at disease onset was 56.75 (+/-12.01). A lower educational level (8.57+/-4.95), and a high percentage of unemployment (80%) were found (table 1). There were no statistically significant differences in the VAS scale between males and females (p value 0.597) and in marital status (p value 0.495) but only in job status (the median and inter-quartile were 7-4 and 5-3 for unemployed and employed respectively; p value 0.019*) and in age at disease onset (Spearman correlation was 0.279; p value 0.015*). Table 2 and table 3 show the symptoms and triggers reported by the patients . Table 4 and table 5 show the dependence analysis of symptoms and triggers versus gender, marital status, job status, age, educational level and age at disease onset. Conclusions: The prevalence of BMS is higher in women, with a lower educational level, who are married and unemployed. Pain is higher in the unemployed. In addition, there was a diagnostic delay of about four years which modified the perception of pain. Clinical Relevance: A lower educational level, unemployment and diagnostic delay could influence clinical outcomes in BMS

Oral Cancer in HSCT Pediatric Patients Arising on GVHD: A Comprehensive Review

After haematopoietic stem cell transplantation and a history of GVHD, the risk of developing secondary malignancies, including oral cancer, is higher. This risk increases with time post-transplantation; therefore, pediatric patients undergoing HSCT, who have long-term survival chances, are in a high-risk category. The aim of this review is to provide data on HSCT, GVHD, clinical manifestations, histological features and treatment of oral cancer, and outcomes in HSCT pediatric patients, affected by oral GVHD, who have been developed OSCC. Descriptive statistics were used to validate data. Fifteen studies on a total of 33 patients were selected. Data on oral cancer showed that the tongue was the most frequently involved site (13 pts; 39.39%), followed by the floor of the mouth (4 pts; 12.12%), and buccal mucosa (4 pts; 12.12%). Oral squamous cell carcinoma was the histological feature reported. There were 19 (57.58%) deaths occurring between 2 and 46.5 months after OC diagnosis. Eleven patients survived with a median follow-up of 34 months. Considering the high risk of developing oral cancer, a conventional oral examination every 6 months is recommended for HSCT pediatric patients who have developed GVHD