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.

Lethal Epstein-Barr virus associated NK/T-cell lymphoma with primary manifestation in the conjunctiva.

BACKGROUND: Lethal midline granulomas (LMG) are very rare angiocentric NK/T-cell lymphomas in association with Epstein-Barr virus. LMG are reported mainly in East Asia occurring in immune compromised patients. HISTORY AND SIGNS: A 41-year old male patient presented with a conjunctival swelling of his upper left eyelid. The lesion had increased over a period of 2 months despite topical corticosteroid treatment. Conjunctival biopsy revealed a highly malignant, CD3 + and BCL2 + extranodal T-cell lymphoma with features of an NK/T-cell origin (CD56 +, TIA + TCR-rearrangement: germline). All lymphoma cells were positive for Epstein-Barr virus RNA. The proliferation rate was highly elevated at 100 %. THERAPY AND OUTCOME: Systemic 1 (st) cycle chemotherapy with cyclophosphamide, doxorubicin, vincristin and prednisone resulted in a complete remission of the swelling within 4 days. However, one week later a massive conjunctival tumour reappeared with only partial regression after combined chemo- and radiotherapy. The patient died within a month because of untreatable pancytopenia due to malignant bone marrow infiltration. CONCLUSIONS: LMG is a rare but highly malignant Epstein-Barr virus associated NK/T-cell lymphoma that can occur in healthy, immune competent Caucasians. This is the first reported case of an LMG in an immune-competent Caucasian patient with primary ocular manifestation. The LMG has a high mortality rate despite systemic treatment and can be lethal within a few months or even weeks.

Midfacial granuloma syndrome or an inflammatory non-specific disease? A case report.

We report a case of idiopathic midline destructive disease in a 57-year-old man. The patient had a non-specific histological pattern in biopsies obtained from the nose and upper lip, characterized by a granulomatous reaction with progressive destruction of the tissues. The patient's general medical history was non-contributory. Clinical and laboratory data did not support any feasible etiology for this destructive process. The patient was treated with prednisone until the discovery of type II diabetes mellitus (never diagnosed before) and was then in turn treated only with oral antidiabetic therapy. Follow-up controls revealed progressive reduction of the symptoms and of the nasal and lip lesions and total remission of symptoms up to 2 years after the onset of the disease. We discuss the diagnostic and subsequent therapeutic problems in the management of the midline necrotizing lesions.

Linfoma centrofacial: un análisis retrospectivo, clínico, patologíco y terapeutico de 10 casos / Centrofacial linfoma: a therapeutic pathological clinical retrospective analysis of ten cases

Se comunican 10 casos de linfoma centrofacial estudiados de manera retrospectiva entre 1995 y 1999, que correspondieron a 6.6 por ciento de todos los linfomas diagnosticasos durante este periodo; cuatro de los 10 pacientes fueron del sexo masculino, con mediana de edad de 59 años 89 a 87 años). En dos pacientes se localizó en el paladar, en dos se afectaron antro nasal y senos paranasales, En otros dos casos se afectaron paladar y nariz, y en dos más al maxilar; uno se localizó en el párpado y el tabique nasal y otro en el paladar y la amígdala derecha. Todos se mostraron como lesiones expansivas, mayores de 4 cm de diámetro (4.5 a 7 cm). Histopatológicamente, tres fueron de alto grado de malignidad (angiocéntricos) y siete de grado intermedio. En un caso se relacionó con infección por VIH. Según su estadio clínico al momento del diagnóstico, siete fueron estadio I; dos estadio II y uno estadio IV por infiltración asintomática de médula ósea. Todos recibieron quimioterapia combinada con ciclofosfamida, doxorrubicina, vincristina y prednisona cada 21 a 28 días, durante seis ciclos. Se logró respuesta completa en cuatro de los pacientes, respuesta parcial en dos y no hubo respuesta en cuatro enfermos. Fallecieron cuatro pacientes: dos por infección grave uno por actividad tumoral y uno por toxicidad a quimioterapia. La supervivencia libre de enfermedad es de 39 por ciento y la supervivencia total de 56 por ciento a 36 meses. Nuestros resultados terapéuticos son similares a lo informado en la literatura; consideramos que ante un linforma centrofacial es obligado realizar fenotipo inmunológico de las células linfomatosas y análisis exhaustivos para detectar genoma de virus linfotrópicos en el tejido tumoral, en virtud de sus implicaciones pronósticas, y un mayor número de estudios prospectivos y controlados que permitan conocer las características clínicas, inmunofenotípicas y de asociación con infecciones virales en pacientes mestizos mexicanos y establecer el mejor esquema terapéutico para las particularidades de nuestro país

Wegener's granulomatosis of the head and neck.

Among the more puzzling non-neoplastic necrotizing lesions of the head and neck area is Wegener's granulomatosis. This is a condition of unknown cause that may present (in the head and neck area) with ulceration of the nasal septum, sinus mucosa, oral mucosa, or external ear canal, or even destruction of the vocal cord. Diagnosis depends on the pathologic finding of a characteristic inflammatory reaction pattern (which, in its best-developed form, includes necrosis, granulomatous inflammation, and vasculitis) and the serum finding of an elevated antinuclear cytoplasmic antigen. Treatment is principally medical, with the use of powerful immunosuppressive agents. Distinction from other conditions that may mimic Wegener's granulomatosis (such as malignant lymphoma and infections) is of critical importance in constructing an appropriate treatment strategy.

Combined therapy for angioimmunoproliferative lesions.

43 patients with a diagnosis of angioimmunoproliferative lesions (AIL) entered onto a prospective clinical trial to evaluate the use of combined therapy as a primary therapeutic approach. Patients were treated initially with involved field radiotherapy 40-55 Gy (40 patients received 45 Gy) followed by six cycles of chemotherapy which consisted of CEOP-Bleo (cyclophosphamide, epirubin, vincristine, prednisone and bleomycin). Complete response was achieved in 41 cases (95%). At a median follow-up of 40 months, 40 patients (91%) remain in first complete remission. 2 patients died during radiotherapy secondary to sepsis and tumour progression. Treatment was well tolerated. The treatment of AIL remains controversial. Our results show that combined therapy appears to be the best therapeutic approach in patients with this type of malignant lymphoma. More studies are necessary to define the role of combined therapy in patients with AIL.

[Difficulties in recognition and treatment of lethal midline granuloma and otolaryngologic and radiotherapeutic practice]. / Uber die Schwierigkeiten bei der Erkennung und Behandlung des "Lethal midline granuloma" in der otolaryngologischen und strahlentherapeutischen Praxis.

The authors report on two cases of a "lethal midline granuloma". The first patient was treated by irradiation and chemotherapy. He lives for the last three and a half years in complete remission. The established diabetes did not affect the healing process. In the second case only a palliative irradiation was practicable because of the extreme tumour propagation, but the result was nevertheless good.

[Idiopathic form of lethal midline granuloma. Case report]. / Idiopatyczna postac ziarniniaka srodkowej czesci twarzy (midline lethal granuloma). Opis przypadku.

A case of the idiopathic form of facial midline granuloma is described in a man aged 35 years. Good result was obtained after radiotherapy, cobalt radiotherapy and chemotherapy. After 4 years no relapse or generalization of changes were noted.

Current concepts of the lethal midline granuloma syndrome.

"Lethal midline granuloma" is an unusual but devastating spectrum of lymphoproliferative disorders that is now thought to include four entities: idiopathic midline destructive disease, Wegener's granulomatosis, polymorphic reticulosis, and nasal lymphoma. These disorders must be considered in the differential diagnosis of any patient with chronic, nonspecific complaints localized to the upper airway. An aggressive diagnostic and therapeutic approach may significantly decrease morbidity and death resulting from these lesions.

[Is Stewart's malignant midline granuloma a peripheral T-cell lymphoma? Apropos of 5 cases]. / Le granulome malin centro-facial de Stewart est-il un lymphome T périphérique? A propos de 5 observations.

Midline granuloma includes diverse clinicopathological entities, such as Wegener granulomatosis, polymorphic reticulosis, lethal midline granuloma and conventional malignant lymphoma of the nose usually of B-cell origin. The authors describe five patients with LMG clinically and pathologically typical. Using an extensive panel of monoclonal antibodies, they demonstrate an "activate" T-cell phenotype observed on the initial lesion of the face in one patient, similar to that found in two patients with LMG but studied after dissemination in peripheral T-cell lymphoma. Furthermore, many atypical cells were found in LMG, and stained with the Ki-67 monoclonal antibody, a marker of proliferating cells. These findings support the view that LMG is closely related to T-cell malignancies. Two of them were treated with recombinant Interferon alpha 2a followed by a response rapidly objective. Immunohistologic studies are very important for confirming the T-cell origin of such a disease and for selecting patients to be treated with Interferon alpha.

Immunohistochemical demonstration of insulin-like growth factor I in inflammatory lesions in Wegener's granulomatosis and idiopathic midline destructive disease.

The immunoreactivity of the trophic peptide insulin-like growth factor I (IGF-I; somatomedin C) was mapped in nasal mucosa biopsies from three patients with Wegener's granulomatosis (WG) and one with idiopathic midline destructive disease (IMDD; idiopathic midline granuloma). Strongly increased IGF-I immuno-reactivity restricted to cells bordering and in vessel walls and in granulomas (WG) was demonstrated, while necrotic and noninflammatory areas were negative. Treatment with steroids and cyclophosphamide reduced the IGF-I immunoreactivity. The abnormally increased IGF-I immunoreactivities in WG and IMDD probably reflects the reactive growth processes in diseased tissue and is not thought to be the primary cause of either disease. IGF-I may be formed locally by cells in and close to the vascular walls in areas with active disease resulting in e.g. vascular growth, granuloma formation, and finally vessel obliteration and necrosis. IGF-I is likely to form, possibly in concert with other trophic factors, a link in the chain of events resulting in the tissue abnormalities in WG and IMDD.

Dilemmas in the management of chronic nasal and sinus inflammatory diseases of unknown etiology.

The diagnostic criteria and therapeutic regimens for upper airway necrotizing diseases such as Wegener's granulomatosis, polymorphic reticulosis, and the recently described idiopathic midline destructive disease have been better defined and clarified in the past decades. Despite an improved understanding of the various disease processes, there continues to be difficulty in establishing an early diagnosis before proceeding with prompt treatment to minimize loss of function and cosmetic deformity. To achieve these goals, we have expanded the indications for the use of the cytotoxic drug, cyclophosphamide, in those patients whose clinical and histologic presentations are suggestive of Wegener's granulomatosis, but in whom a specific diagnosis has not been confirmed by biopsy specimen. We have seen ten patients with upper airway lesions of a chronic inflammatory nature over the past six years at the Medical College of Wisconsin affiliated hospitals. Only three of these have had a definitive histopathologic diagnosis of Wegener's granulomatosis made prior to the initiation of cytotoxic therapy. Six have undergone treatment under our expanded criteria without a prior definitive diagnosis. Five of these have had arrest of the disease process, and one has had no response to therapy. One patient was not treated. There have been no serious side-effects from cyclophosphamide therapy in these patients.

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.

Immunological features and corticosteroid therapy of midline granuloma.

This paper presents treatment of midline granuloma with corticosteroids and immunological features of this disease. The cellular immunity state of this patient was examined by counting T cell subpopulation and lymphocyte blastformation index (BI) by phytohemagglutinin at various time intervals during the corticosteroid therapy. Consequently, the percentage of T cells and BI became greatly increased according to the subsiding of the primary lesion, whereas non-T cell production and its function were depressed. In this communication we discuss a possible autoantibody mechanism and impared lymphocyte transformation in midline granuloma.

Some aspects of therapy in the non-healing granulomas of Wegener and Stewart.

The non-healing granulomas of Wegener and Stewart (Wegener's granuloma and lethal midline granuloma) have been recognized since 1897. A mainstay of therapy has been the empirical application of treatments based upon theoretical or pathological assumption, and we are only slightly closer to classifying these diseases. Between 1967 and 1975 eight patients with non-healing granuloma of Wegener's type, and one patient with non-healing granuloma of Stewart's type, presented to the Otolaryngology Service of the conjoined McGill University Hospitals. All received corticosteriods and all those with the Wegener type of granuloma received azathioprine (Immuran). Four patients are alive and well today from five months to eight years and 10 months after starting therapy. Some aspects of the changing historical, clinical, pathologic, and therapeutic indices of these diseases are presented, with our experiences in these areas.