Mucor irregularis infection and lethal midline granuloma: a case report and review of published literature.

Mucor irregularis (Rhizomucor variabilis) infection and lethal midline granuloma (LMG) are characterized by progressive swelling, ulceration, and destruction of the central face that is usually fatal. Pathological features are inflammation, necrosis, and granulation. LMG has been called by various names, and in recent years, it has been known as NK/T cell lymphoma. However, diagnosis still relies on the progressive necrosis course rather than malignancy in histology. The disease has long challenged physicians, particularly when it worsens with radiotherapy or chemotherapy but sometimes achieves total remission without anti-malignancy therapies. We describe a 35-year-old man who had typical clinical-pathological symptoms of LMG, which turned out to be primary M. irregularis infection; that was diagnosed by positive tissue culture and fungal elements in histology. The patient was successfully treated with antifungal therapy (liposomal amphotericin B, total 4,600 mg and amphotericin B total 277 mg, over a duration of 70 days). We hereby review current knowledge about the epidemiology, clinical manifestations, radiographic characteristics, and pathologic features of LMG with those of M. irregularis infection and their associations. We conclude that primary M. irregulars infection can mimic the clinico-pathological symptoms of LMG and the condition responds favorably to aggressive antifungal therapy.

The dilemma of midline destructive lesions: a case series and diagnostic review.

BACKGROUND: Midline destructive lesions (MDLs) of the nose are a diagnostic dilemma due to an extensive differential diagnosis and vague presenting signs and symptoms. Etiologies may be neoplastic, autoimmune, traumatic, infectious, or unknown. STUDY DESIGN: Case series and review of the literature were done. METHODS: Medical records of 8 patients presenting with an MDL were reviewed. RESULTS: Each patient received nasal endoscopy, computed tomography scan of the sinuses, laboratory workup, culture (aerobes, anaerobes, fungus, and acid-fast bacilli), and biopsy with flow cytometry. Laboratory tests included complete blood count, basic metabolic panel, erythrocyte sedimentation rate, angiotensin-converting enzyme, antineutrophil antibodies, rheumatoid factor, anti-Ro and anti-La antibodies, Epstein-Barr virus antibodies, coccidiomycosis serology, HIV antibodies, fluorescent treponemal antibody absorption, classic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibody, proteinase 3, and myeloperoxidase. Choice of diagnostic study was individualized for each patient. Two patients were diagnosed with natural killer/T-cell lymphoma, 2 were diagnosed with Wegener's granulomatosis, and 4 remained idiopathic, despite the extensive workup. A diagnostic algorithm to aid in the approach to MDLs is presented. CONCLUSIONS: The diagnosis of MDLs remains difficult but is aided by a systematic approach and familiarity with multiple diagnostic techniques. It is imperative to take multiple tissue specimens from various sites, send them fresh, and communicate suspicion of lymphoma. Despite diagnostic advances and improved understanding of the diseases underlying MDLs, an etiology is often not identified.

Cocaïne et lésions destructrices centro-faciales : à propos d'un cas.

INTRODUCTION: Cocaine use is associated with multiple complications, some of which can mimic systemic diseases, especially Antineutrophil Cytoplasmic Antibody (ANCA) associated vasculitis. We report a case of Cocaine Induced Midline Destructive Lesions (CIMDL) for which a diagnosis of granulomatosis with polyangiitis (GPA) was discussed. CASE REPORT: A 42-year-old male, cocaine consumer, was admitted in our department for a centrofacial destructive process. He had no extra ear, nose and throat (ENT) involvement. ANCA were positive with a perinuclear fluorescence pattern and an anti-Proteinase 3 specificity. Regarding this unusual immunologic pattern and in the absence of histological argument for a GPA, a diagnosis of CIMDL was made. CONCLUSION: CIMDL is a centrofacial destructive process due to intranasal cocaine use. It is frequently associated with the presence of p-ANCA with both anti-HNE and anti-PR3 specificity.

Cocaine-induced midline destructive lesions mimicking ENT-limited Wegener's granulomatosis.

The prevalence of cocaine use is rising worldwide, with a resultant rise in associated pathology. Regular nasal use can cause cocaine-induced midline destructive lesions (CIMDL), which can be difficult to distinguish from ear, nose, and throat (ENT)-limited Wegener's granulomatosis (WG). Two cocaine users presented with mid-facial pain, epistaxis, and systemic symptoms. Both had nasal septal perforation, necrosis of sinus mucosa, and positive anti-neutrophil cytoplasmic antibodies (ANCA). Histology was inconclusive and treatment with immunosuppressive drugs was commenced. The first patient continued to use cocaine initially, with improvement in her symptoms only on high doses of steroid. Later she stopped cocaine and this plus a switch from cyclophosphamide to mycophenolate mofetil resulted in successful symptom resolution and steroid withdrawal. The second patient denied cocaine use but having only partially responded to high-dose prednisolone and methotrexate, she admitted continued cocaine use and was lost to follow-up. Evaluation of a patient with destructive lesions of the mid-face should include enquiry about intranasal use of cocaine. Localized ENT involvement, inconsistent ANCA pattern, and atypical biopsy findings for WG should be recognized as features of CIMDL. Although cessation of cocaine use is crucial, there may be a role for immunosuppression.

Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients.

BACKGROUND/AIMS: The substitution of valine by methionine in the brain-derived neurotrophic factor (BDNF Val/Met) gene alters the intracellular trafficking and regulated secretion of BDNF. This study tested whether the BDNF Val/Met polymorphism is associated with bipolar disorder in Korean subjects, and whether clinical features vary according to genotype. METHODS: The allelic and genotypic distributions of BDNF Val/Met were determined in a population of 169 bipolar patients and 251 normal controls. Between-genotype comparisons of clinical features were performed without a priori knowledge of the genotype of individual patients. RESULTS: Allelic distributions did not differ significantly between bipolar patients and controls (chi(2) = 0.400, p = 0.821). However, the rate of suicide attempts among the Val/Val (11.3%), Val/Met (28.8%) and Met/Met (38.9%) genotype groups were significantly different (chi(2) = 9.879, p = 0.007). Relative to patients with the Val/Val genotype, those with the Met/Met genotype had a 4.9-fold higher risk of suicide attempts (95% CI, 1.7-14.7). CONCLUSIONS: These findings suggest that BDNF Val/Met is related to the suicidal behavior of bipolar patients, and may have clinical relevance as a biological indicator of bipolar patients at risk of suicide.

[Brownish plaques on both sides of the nose]. / Bräunliche Plaques an beiden Nasenseiten.

Granuloma fissuratum (Gf) is painful granular tissue caused by constant pressure exerted by glasses. The differential diagnosis includes further granulomatous dermatoses such as cutaneous sarcoidosis, mycobacterioses and autoimmune diseases. It is also important to rule out a basal cell carcinoma. The simplest and most effective treatment of Gf is to correct the glasses frame or, even better, to avoid wearing glasses to correct eyesight. Topical antiseptic/antibiotic treatment is recommended for superinfected lesions. The Gf usually heals within 1-6 months after correction of the glasses. If the lesion does not heal on its own, complete excision is recommended.

Erythematous indurated swelling on nose and upper lip. Cutaneous T cell lymphoma.

A 40-year-old man presented for diagnosis with nodules and plaques of the nose and upper lip, progessive over 1(1/2) years.

Extranodal NK/T-cell lymphoma, nasal type.

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL), previously known as lethal midline granuloma is a distinct clinico-pathological entity associated with Epstein-Barr virus that typically causes destruction of the midface, palatal and orbital walls. In addition, ENKTCL can involve the skin, soft tissue, testes, gastrointestinal and upper respiratory tract. ENKTCL neoplastic cells express some T-cell associated antigens, most commonly CD2 and cytoplasmic CD3epsilon and, in favour of an NK-cell origin, CD56. Early stage disease may respond to radiotherapy alone, however late stage disease does not respond well to any available therapies. Overall, patients with ENKTCL have a cumulative probability of survival at 5 years ranging from 37.9% to 45.3%.

Frequent mutations of Fas gene in nasal NK/T cell lymphoma.

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of Fas gene in lymphoid cells results in accumulation of these cells, which might thus contribute to lymphomagenesis. We examined the open reading frame of Fas cDNA in 14 cases of nasal NK/T-cell lymphoma. Mutations of Fas gene were detected in seven (50%) of 14 cases which comprised four frameshift, two missense, and one silent mutations. Frameshift mutations were caused by insertion of 1 bp (A) at nucleotide 1095 in two cases and by deletion of 1 bp at nucleotide 597 and at 704, respectively, in one each. Mouse T-cell lymphoma cells transfected with two missense mutated genes and frameshift mutations caused by insertion of 1 bp (A) at nucleotide 1095 were resistant to apoptosis induced by the anti-Fas antibody. These findings suggested that accumulation of lymphoid cells with Fas mutations provides a basis for the development of nasal NK/T-cell lymphoma.

p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan.

Mutations of p53, K-ras, c-kit, and beta-catenin gene were examined in 100 cases of sinonasal NK/T-cell lymphoma (NKTCL) from Korea and Japan. Age of patients ranged from 12 to 72 (median 41.0) in Korea and 27 to 82 (median 61.0) years in Japan. Gene mutations were analyzed on paraffin-embedded specimens by PCR-SSCP followed by direct sequencing. p53 is a well-known tumor suppressor gene. c-kit gene encodes a receptor tyrosine kinase, which plays a crucial role in proliferation and differentiation of hematopoietic stem cells. Mutations of K-ras and beta-catenin are frequently observed in cancers. Thirteen of 42 (31.0%) cases from Korea and 36 of 58 (62.1%) from Japan had p53 mutations, showing significant differences in the incidence of p53 mutation between two countries. Of the Japanese cases 18 (31.0%) had mutations in exon 4, while only 3 cases (7.1%) were found in Korea cases (p<0.01 by chi2 test). K-ras, c-kit and beta-catenin mutations were also found in higher incidence in Japanese cases. In conclusion, different frequency of p53 mutations with different pattern of exon involvement and difference in age of disease onset is evident between sinonasal NKTCL in Korea and Japan.

Idiopathic midline destructive disease: fact or fiction.

The differential diagnosis of a progressive destructive lesion of the midface and upper airway region includes both neoplastic and non-neoplastic entities; of these, the majority of cases prove to be either Wegener's granulomatosis or lymphoma. Historically, these sorts of necrotizing midfacial lesions were diagnosed clinically, and as a consequence a variety of overlapping categories of disease sprang up. As pathologic examination of biopsy material became both more widespread and (particularly in the last several years) more sophisticated, many lesions previously thought to be of mysterious origins have proven to be examples of lymphoma (in particular, sinonasal natural killer cell or T cell [NK/T] lymphomas). At present, the evaluation of a patient with a progressive destructive process involving the midface region should include imaging studies (to delineate the extent of disease) as well as biopsy (with sampling of lesional tissue for application of sophisticated testing--including immunohistochemical studies, flow cytometry, or molecular studies as necessary--to exclude the possibility of a NK/T cell lymphoma). There remain occasional patients whose necrotizing midfacial lesions continue to be difficult to classify despite the application of extensive testing; such patients are sometimes described as suffering from the nebulous entity of "idiopathic midline destructive disease". While it remains to be seen whether such patients will ultimately be assigned to other diagnostic groups (as, for example, occult toxic injuries--as in the case of cocaine abusers who are not forthcoming with regard to their drug usage), it seems likely that "idiopathic midline destructive disease" is a diagnostic term of questionable validity which should be used only with extreme reticence in modern practice.

Adenocarcinoma developing in a patient with midline granuloma.

A 51-year-old man with midline granuloma was treated successfully with a combination of local radiation and oral cyclophosphamide. Six years after therapy, adenocarcinoma of the lung developed. Possible relationships between these two diseases are discussed.

Nasal NK/T-cell lymphoma causing diagnostic difficulties.

We present history, clinical presentation and anatomo-pathologic findings of a 24-year-old female patient with a nasal NK/T-cell lymphoma. This rare tumor is characterized by its angiocentric and angiodestructive growth, which results in extensive tumor necrosis. At the first encounter this tumor necrosis made it difficult to identify the nature of the tumor cells. However, this necrosis is a key feature: it is the result of the capacity of neoplastic NK/T-cells to invade vessels. The T-cell character of the neoplastic lymphoid has been shown by immunohistochemitry.

Centrofacial malignant granulomas. Clinicopathologic study of 40 cases and review of the literature.

An important problem in the treatment of centrofacial ulcerations is to establish a precise diagnosis, since similar clinical and microscopic findings can result from many different causes (as in the centrofacial malignant granuloma syndrome [CFMG]). A comprehensive surgical biopsy protocol (known as SNFMI/GMCF), involving microbiology, parasitology, immunology and pathology laboratories, allowed us to evaluate and to treat 40 cases of CFMG, who form the basis of this report. In 13 of them, specific diagnoses were found and curative treatments could be given. In the remaining 27, the optical microscopy pattern met the criteria for CFMG without identifiable origin or the presence of so-called lethal midline granulomas; however, a more precise evaluation with the help of immunofluorescence studies led to the recognition of malignant lymphoma (ulcerative lymphoma of the midface [ULM]). Most of these lymphomas belonged to the T cell lineage; the others were of B lymphoid origin, or, more rarely, of histiocytic origin. Patients with ULM received radiotherapy and chemotherapy with a response rate of 70.3%; however, the toxicity was significant, with frequent occurrence of chemotherapy-induced neutropenia followed by severe infectious facial cellulitis. Six patients were enrolled in a preliminary open trial of treatment with recombinant alpha-2b interferon with little success. Three patients were treated with radiation therapy only, and survived. Thus, CFMG is a syndrome with specific causes and treatments, requiring multiple extensive biopsies to make the correct diagnosis. The recognition of ULM as the cause of the previously called "lethal midline granulomas" leads logically to the use of chemotherapy with growth factors in order to ameliorate its bad prognosis.

Imported mucocutaneous leishmaniasis in New York City. Report of a patient treated with amphotericin B.

A case of mococutaneous leishmaniasis in a patient referred to Memorial Sloan-Kettering Cancer Center, New York, with a presumptive diagnosis of lethal mid-line granuloma is described. The patient had lived in Bolivia and had been treated with antimony during and after which his mucosal lesions progressed. These lesions completely healed with 971 mg of amphotericin B. Mucocutaneous leishmaniasis is endemic in many areas of Central and South America and may occur in patients in the United States who have lived in or traveled to these areas. Organisms may be difficult to identify, and multiple biopsies and cultures may be necessary. The use of amphotericin B for the treatment of leishmaniasis is reviewed. It is an effective alternative to antimony therapy, and in some cases resistant to antimony, it may be the drug of choice.

Midline granuloma syndrome: a clinicopathologic study of 13 patients.

Thirteen patients with the clinical features of the midline granuloma syndrome are reported. Seven of the patients were determined to have Wegener's granulomatosis and had segmental necrotizing glomerulonephritis in their renal biopsies. Eighteen upper aerodigestive trace mucosal biopsies were available for review from the seven patients, and nine of these biopsies had a granulomatous angiodestructive inflammatory cell infiltrate considered "diagnostic" of Wegener's granulomatosis. The remaining nine biopsies lacked the specific histologic features of Wegener's granulomatosis but were considered consistent with mucosal involvement by the disease. Five of the remaining six patients had upper aerodigestive tract biopsies that were characterized by lymphocytic infiltrates. Three of the five patients had appreciable numbers of "atypical" cells in their biopsies and presented with radiologic evidence of lung involvement. It is our impression that patients with "significant cellular atypia" in their lymphocytic infiltrates have a disease indistinguishable from lymphomatoid granulomatosis, and these patients have a high propensity for either the presence or development of systematic disease that may require chemotherapy. Two patients had lymphocytic infiltrates with only minor degrees of cytologic atypia and no evidence of multisystem disease, and both of these patients responded to local radiation therapy. The remaining patient had a nonspecific histologic pattern in her numerous biopsies and was diagnosed as idiopathic midline destructive disease. She also had an adequate response to radiation therapy.