DIAGNOSIS IN ONCOLOGY

DIAGNOSIS IN ONCOLOGY

Lethal Midline Granuloma Revisited: Nasal T/Natural-Killer Cell Lymphoma

Arthur Skarin, MD, Consultant Editor

C. S. Chim, G. C. Ooi, T. W.H. Shek, R. Liang, Y. L. Kwong Queen Mary Hospital, University of Hong Kong, Hong Kong A 43-year-old man presented with a 3-month history of recurrent fever, nasal obstruction, blood-stained nasal discharge, and weight loss of 8 kg. Physical examination revealed erythema and swelling of midline facial features (Fig 1A) and bilateral submandibular lymphadenopathy. Nasal endoscopy showed a 2.5-cm ulcer in the middle of the anterior palate with foul-smelling discharge (Fig 1B). Repeated superficial biopsies of the ulcer showed necrotic tissue only without infective organisms or neoplasia. An open biopsy revealed an ulcerated (Fig 2A, arrow) palatal specimen with infiltration by a mixture of small-, medium-, and large-size lymphoid cells, along with tissue necrosis (Fig 2A and 2B). Immunohistochemical study showed that these abnormal lymphoid cells were CD2+, CD3 (Leu 4)-, CD3+, CD4-, CD5-, CD15-, CD56+, and CD79a-. The diagnosis of natural-killer (NK) cell lymphoma was established. A bilateral bone marrow biopsy did not reveal evidence of lymphoma infiltration. In situ hybridization for Epstein-Barr-encoded RNA showed nuclear staining in most of the medium- to large-size lymphoid cells (Fig 2C). A complete blood picture showed a hemoglobin level of 11.4 g/L, platelet count of 287 x 109/L, and leukocyte count of 4.8 x 109/L with normal differential count. Blood urea, creatinine, bilirubin, and transaminase levels were within normal limits. The lactate dehydrogenase level was 1006 U/L (normal range, 200 to 400 U/L). The albumin level was 26 g/L (normal range, 42 to 54 g/L). Axial (Fig 3A) T1-weighted gadolinium-enhanced magnetic resonance scans of the sinuses showed an enhancing soft tissue mass destroying the nasal septum and medial wall of the left maxillary sinus, and polypoid-enhancing lesions in both maxillary antra (arrow A). There was abnormal infiltration of the subcutaneous tissues of the nose, cheeks, and upper lip (arrow B, Fig 3A and 3B). There was also involvement of the right superior alveolar ridge (arrow A, Fig 3B) and adjacent hard palate (arrow, coronal view, Fig 3C), with total erosion of the anterior hard palate. An abdominal computed tomography scan revealed no intra-abdominal lymphadenopathy or organomegaly. Treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy as well as local irradiation was initiated.

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Clinically, our patient was diagnosed as having aggressive CD56+ nasal NK cell lymphoma (angiocentric lymphoma in the Revised European-American Lymphoma classification1) with extensive tissue necrosis.2-5 In the past, this entity has been referred to by various names, such as polymorphic reticulosis, lethal midline granuloma, and midline malignant reticulosis, which describe a group of destructive and clinically malignant lesions involving the midline facial structures.3 Despite the malignant clinical course, histologic diagnosis can be difficult because of extensive tissue necrosis, and often multiple biopsies may be required. The CD56+ lymphoma cells exhibit a broad morphologic spectrum with frequent angiocentricity, angioinvasion, and zonal tumor necrosis. The nasal CD56+ NK lymphoma has a characteristic immunophenotypic profile, ie, CD2+, surface CD3 (Leu4)-, cytoplasmic CD3+, cytoplasmic CD56+, and negative for other T-cell markers.2-5 The T-cell receptor genes are characteristically in germline configuration. Interestingly, the clonal Epstein-Barr viral genome is present in almost all cases.5,6 Although most NK cell lymphomas present in the nasal or upper aerodigestive tract, they may also involve other extranodal sites (such as skin, testis, soft tissue, and gastrointestinal tract) and may rarely present with a leukemic picture.2-4 In addition, although most cases of nasal lymphoma belong to the NK cell category, true nasal T-cell lymphomas with rearranged T-cell receptor genes have also been described.2,3 CD56+ NK cell lymphoma (both the nasal and the nonnasal type) is an aggressive disease. Despite intensive combination chemotherapy, patients with localized disease have a median disease-free and overall survival time of only 9 and 12 months, respectively, and virtually none of the patients with disseminated disease survive beyond a few years.2-4,7 Recently, high-dose chemotherapy with autologous stem-cell rescue has been shown to be beneficial in patients with nasal NK cell lymphoma.8 Rhinoscleroma

Last Updated: August 15, 2002 Rate this Article Email to a Colleague Get CME/CE for article

Synonyms and related keywords: respiratory scleroma, scleroma, Mikulich disease, rhinosclerosis, Klebsiella rhinoscleromatis, K rhinoscleromatis, scleroma respiratorium, nasal polyposis, scleroma respiratorium

AUTHOR INFORMATION Section 1 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyAuthor: Egle Goriniene, MD, Staff Physician, Department of Infectious Diseases, New Jersey Medical School

Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Editor(s): Jacek C Szepietowski, MD, PhD, Professor and Vice-Head, Department of Dermatology, Venereology and Allergology, University of Medicine at Wroclaw, Poland; David F Butler, MD, Professor, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Jeffrey P Callen, MD, Chief, Professor, Department of Internal Medicine, Division of Dermatology, University of Louisville School of Medicine; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; and Dirk M Elston, MD, Teaching Faculty, Department of Dermatology, Geisinger Medical Center

Disclosure

INTRODUCTION Section 2 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyBackground: Rhinoscleroma is a chronic granulomatous condition of the nose and other structures of the upper respiratory tract. Rhinoscleroma is a result of infection by the bacterium Klebsiella rhinoscleromatis. After the polish surgeon Johann von Mikulich described the histologic features in 1877, von Frisch identified the organism in 1882. In 1932, Belinov proposed the use of the term scleroma respiratorium because the pathologic process in rhinosclerosis may involve not only the upper airways but also the lower airways. In 1961, Steffen and Smith demonstrated that K rhinoscleromatis conformed to Koch's postulates and that it was an etiologic factor in the inflammatory changes typical of scleroma. Pathophysiology: Rhinoscleroma is contracted by means of the direct inhalation of droplets or contaminated material. The disease probably begins in areas of epithelial transition such as the vestibule of the nose, the subglottic area of the larynx, or the area between the nasopharynx and oropharynx. Cellular immunity is impaired in patients with rhinoscleroma; however, their humoral immunity is preserved.

The CD4/CD8 cell ratio in the lesion is altered with decreased levels of CD4 lymphocytes; this change possibly induces a diminished T-cell response. Macrophages are not fully activated. Mucopolysaccharides in the bacterial capsule probably contribute to the inhibition of phagocytosis. Otherwise, patients are immunocompetent in every regard except for the ineffective phagocytosis of the organism by the Mikulicz cells.

Rhinoscleroma usually affects the nasal cavity, but lesions associated with rhinoscleroma may also affect the larynx; nasopharynx; oral cavity; paranasal sinuses; or soft tissues of the lips, nose, trachea, and bronchi.

Frequency: In the US: The incidence of rhinoscleroma appears to be increasing in the United States. Rare sporadic cases occur in the United States, usually in immigrant populations arriving from the countries in which the disease is endemic.

Internationally: Rhinoscleroma is considered endemic in Central America, Egypt, tropical Africa, India, and Indonesia. Worldwide, 5% of all cases occur in Africa.

Mortality/Morbidity: Rhinoscleroma is rarely lethal, unless it causes airway obstruction.

The diagnosis may elude the clinician for years, and this delay can substantially increase the rate or severity of resultant morbidity.

Race: Patients of all races can be affected. Sex: Rhinoscleroma tends to affect females somewhat more often than it does males.

Age: Typically, rhinoscleroma appears in patients aged 10-30 years.

CLINICAL Section 3 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyHistory: Rhinoscleroma should be considered in patients from countries in which the disease is endemic if they have nasal polyps that significantly adher to the nasal septum with relative sparing of the sinuses. Most often, the presentation is nonspecific.

Patients may present with the following:

Nasal obstruction (most common complaint)

Rhinorrhea

Epistaxis

Dysphagia

Nasal deformity

Anesthesia of the soft palate

Difficulty breathing that progresses to stridor

Dysphonia

Anosmia

Physical: The disease commonly affects the nasal cavity (95-100% of patients), but it can also affect the nasopharynx (18-43%), larynx (15-40%), trachea (12%), and bronchi (2-7%). The oral cavity, paranasal sinuses, and soft tissues of the lips and nose can be affected as well. In rare cases, rhinoscleroma spreads to the orbit. Most often, the presentation is nonspecific.

Rhinoscleroma is divided into 3 stages: (1) the catarrhal, or atrophic, stage; (2) the granulomatous stage; and (3) the sclerotic stage.

Catarrhal, or atrophic, stage

This first stage begins with a nonspecific rhinitis that evolves into purulent fetid rhinorrhea and crusting.

This stage can last for weeks or months.

Granulomatous, or hypertrophic, stage

The nasal mucosa becomes bluish red and granular, with the formation of rubbery nodules or polyps in the nose.

Epistaxis occurs with nasal enlargement, deformity, and destruction of the nasal cartilage (Hebra nose).

The damage may progress to anosmia, anesthesia of the soft palate, enlargement of the uvula, dysphonia, and various degrees of airway obstruction.

Lesions occur in the form of atrophic changes and granulomas, and in the fibrotic, thick, healed stage.

The anterior-inferior part of the antrum and its medial wall are more commonly affected than other structures.

Involvement of the maxillary antrum is suggested in scleroma, and the maxillary antrum may act as a reservoir of infection.

The soft palate is markedly thickened at its attachment to the hard palate, which tapers off toward its free edge. This sign can help in the early diagnosis of the condition.

Physical examination frequently reveals erythematous granular or nodular swellings covered with crusts.

The tumorlike appearance and local spread are suggestive of malignancy.

Sclerotic stage

The sclerotic stage is characterized by sclerosis and fibrosis.

The sclerotic stage develops where the nodules are replaced by fibrous tissue leading to extensive scarring and possible stenosis.

Causes: Rhinoscleroma is caused by the gram-negative coccobacillus K rhinoscleromatis.

Although crowded conditions, poor hygiene, and poor nutrition appear to be necessary for transmission of the infectious agent, the actual pathogenesis of infection remains elusive.

DIFFERENTIALS Section 4 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyActinomycosis Basal Cell Carcinoma Leishmaniasis Leprosy Nasopalatine Duct Cyst Sarcoidosis Sporotrichosis Syphilis Verrucous Carcinoma Wegener Granulomatosis

Other Problems to be Considered: VasculitisNeoplastic disease (eg, lymphoma)Extranodal Rosai-Dorfman disease

Infectious granulomatous processes may include those caused by bacteria (tuberculosis, actinomycosis, syphilis, leprosy), fungi (histoplasmosis, blastomycosis, paracoccidioidomycosis, sporotrichosis), and parasites (mucocutaneous leishmaniasis).

Rhinoscleroma can mimic various inflammatory and neoplastic processes, including leprosy, paracoccidioidomycosis, sarcoidosis, basal cell carcinoma, and Wegener granulomatosis. Rhinoscleroma should be added to the list of opportunistic infections that can occur in patients infected with the human immunodeficiency virus.

Granulomatous lesions of the craniofacial area are common. These lesions vary in nature. They can be lymphohistiocytic with or without eosinophils; they can be tuberculoid with epithelioid cells and giant cells; or, occasionally, they are composed of essentially giant cells. The etiology of these lesions may be known or easy to find; their causes include foreign body granulomas, sarcoidosis, leprosy, rhinoscleroma, fungal diseases (especially zygomycosis and rhinosporidiosis), and parasitic diseases.

Lethal midline granuloma is a clinical entity characterized by a necrotic and relentlessly progressive destructive presentation. After a malignant process (especially lymphoid) and Wegener granulomatosis are eliminated from the differentials, the diagnosis is idiopathic midline nonhealing granuloma. Some lesions remain in the facial area, whereas others disseminate as a malignant disease.

Central giant cell granuloma and histiocytosis X (especially eosinophilic granuloma) are 2 other varieties of granuloma that differ from the aforementioned granulomatous infiltrates in their clinical presentation and evolution. Quick Find Author InformationIntroductionClinicalDifferentialsWorkupTreatmentMedicationFollow-upBibliography

Click for related images. Related ArticlesActinomycosis

Basal Cell Carcinoma

Leishmaniasis

Leprosy

Nasopalatine Duct Cyst

Sarcoidosis

Sporotrichosis

Syphilis

Verrucous Carcinoma

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WORKUP Section 5 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyLab Studies: Laboratory markers

A positive result with culturing in MacConkey agar is diagnostic of rhinoscleroma.

However, culture results are positive in only 50-60% of patients.

Bacterial identification

Bacteria can be seen by using periodic acid-Schiff, Giemsa, Gram, and silver stains.

A highly sensitive and specific method for identifying K rhinoscleromatis organisms is the analysis of a biopsy specimen with the immunoperoxidase technique.

Imaging Studies: CT findings in primary nasal and nasopharyngeal rhinoscleroma include soft-tissue masses of variable sizes.

The lesions are characteristically homogeneous and nonenhancing, and they have distinct edge definition.

Adjacent fascial planes are not invaded.

The subglottic area is involved in laryngeal and tracheal scleroma.

The lesions primarily cause concentric irregular narrowing of the airway.

In the trachea, cryptlike irregularities are diagnostic of scleroma.

MRI should be performed in patients with rhinoscleroma.

Nasal masses can obstruct the ostiomeatal units, and secretions may be retained in the related sinuses.

In the hypertrophic stage of rhinoscleroma, both T1- and T2-weighted images show characteristic mild-to-marked high signal intensity.

Procedures: Diagnosis is facilitated by the use of cytologic methods that are easy to perform and do not cause pain in the patient (see Further Outpatient Care).

Cytologic analysis is performed on brushing specimens of a lesion.

The characteristic cells of the Mikulicz type may be observed in the smear.

This chronic infectious disease of the upper respiratory tract is routinely diagnosed by means of tissue biopsy of the lesions.

Nasal endoscopy reveals signs of all 3 stages of scleroma: catarrhal, granulomatous, and sclerotic.

Bronchoscopy has a role in the early diagnosis of rhinoscleroma.

Histologic Findings: Histopathologic analysis has a definite role in the diagnosis of rhinoscleroma. Classic histopathologic findings include large vacuolated Mikulicz cells and transformed plasma cells with Russell bodies. The Mikulicz cell is a large macrophage with clear cytoplasm that contains the bacilli; this cell is specific to the lesions in rhinoscleroma. The disease is most commonly diagnosed during the proliferative phase, in which the clinical and histologic presentations are most easily recognized.

The histologic findings correspond to the 3 clinical stages. In the catarrhal (or atrophic) stage, squamous metaplasia and a nonspecific subepithelial infiltrate of polymorphonuclear leukocytes with granulation tissue are observed. In the granulomatous stage, the diagnostic features include chronic inflammatory cells, Russell bodies, pseudoepitheliomatous hyperplasia, and groups of large vacuolated histiocytes that contain K rhinoscleromatis organisms (Mikulicz cells). If numerous, these bacteria can be seen with hematoxylin and eosin staining, but periodic acid-Schiff, silver impregnation, or immunohistochemical staining may be required to confirm their presence and identity. In the sclerotic stage, extensive fibrosis may lead to stenosis and disfiguration. Microscopically, the connective tissue is highly vascular, with an inflammatory infiltrate consisting primarily of plasma cells and lymphocytes and a possible sprinkling of eosinophils. Russell bodies in the plasma cells are common. However, the groups, clusters, or sheets of large (100- to 200-mm) vacuolated histiocytes (ie, Mikulicz cells) that contain the causative agent are most striking. Although the organisms are occasionally visible on standard hematoxylin and eosin stains, they are more readily demonstrated by using silver impregnation Warthin-Starry stains. The exudative stage results in a dense nonspecific fibrosis. In the exudative and cicatricial stages, Mikulicz cells may be difficult to detect.

Electron microscopy reveals large phagosomes filled with bacilli and surrounded by a finely granular or fibrillar material that is arranged in a radial pattern. This finding represents the accumulation of antibodies on the bacterial surface (type A granules), as well as the aggregation of bacterial mucopolysaccharides surrounded by antibodies (type B granules).

TREATMENT Section 6 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyMedical Care: Bronchoscopy has a role in the initial treatment of symptoms. Treatment should also include long-term antimicrobial therapy and surgical intervention in patients with symptoms of obstruction.

Bacterial overinfection responds to treatment with third-generation cephalosporins and clindamycin.

Sclerotic lesions respond well to treatment with ciprofloxacin.

Surgical Care: Surgery combined with antibiotic therapy is beneficial in patients with granulomatous disease and nasal or pharyngeal obstruction or nasal sinus involvement due to the proliferation of lesions. Tracheotomy should be considered in patients with laryngeal obstruction of the second degree (granulomatous stage) and above (sclerotic stage).

Plastic surgery is necessary in patients with cicatricial stenosis or when imperforation remains in the nasal cavity, pharynx, larynx, or trachea (Sun, 1998).

Extensive granulomatous lesions are treated by means of open excision by using the laryngofissure approach, which is the best method for a quick recovery in patients without evidence of subglottic stenosis.

Surgery and laser therapy are required to treat airway compromise and tissue deformity. Fiberoptic intubation allows assessment of the pathology and subsequent passage of a cuffed tracheal tube to secure the airway. To overcome respiratory obstruction as the fiberscope passes through the opening in the membrane, either rapid intubation or a technique of preoxygenation and voluntary hyperventilation followed by breath holding during bronchoscopy is used. The thin caliber and maneuverability of the flexible fiberoptic bronchoscope makes fiberoptic intubation an excellent technique for airway management in cicatricial membranes of the pharynx.

Treatment of the advanced cicatrix with carbon dioxide laser vaporization yields excellent results.

Obstructive lesions of the larynx and subglottic space are always a challenging problem for the endoscopist and anesthetist. At this level of the obstruction, the effectiveness and innocuous nature of carbon dioxide laser treatment are related to the degree of endoscopic exposure. Because of the transtracheal high-frequency jet ventilator, ensuring a free laryngeal endoscopic operative field is now possible. The transtracheal catheter is introduced percutaneously through the cricothyroid membrane into the trachea under endoscopic control and connected to a high-frequency jet ventilator.

Among many advantages of this technique, the most convincing include a clear operating field for the surgeon, complete relaxation of the patient, good respiratory gas exchange, elimination of the risk of igniting an endotracheal tube with the laser, decrease in the risk of aspiration of blood and debris, and the ability to provide oxygen and/or mechanical ventilation in the postoperative period.

Palatal symptoms may be relieved by means of uvulopalatopharyngoplasty.

Consultations: Consultation with a plastic surgeon may be helpful in patients with cicatricial stenosis or in those with imperforation of the nasal cavity, pharynx, larynx, or trachea.

An endoscopist and an anesthetist may be required to perform vaporization with a carbon dioxide laser.

MEDICATION Section 7 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyThe goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.Drug Category: Antibiotic agents -- Tetracycline is the drug of choice. Other antibiotics include ciprofloxacin and rifampin. Bacterial overinfection responds to treatment with clindamycin and third-generation cephalosporins. Sclerotic lesions respond well to treatment with ciprofloxacin. Ciprofloxacin has the following advantages: Its oral administration is convenient, it achieves good tissue penetration, it is concentrated in macrophages, and it may prove useful in the treatment of patients with rhinoscleroma.

Drug NameCiprofloxacin (Cipro) -- Fluoroquinolone with activity against Pseudomonas species, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared. Adult Dose250-500 mg PO bid for 7-14 d Pediatric Dose18 years: Administer as in adults ContraindicationsDocumented hypersensitivity InteractionsAntacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after fluoroquinolone dose; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT) PregnancyC - Safety for use during pregnancy has not been established. PrecautionsIn prolonged therapy, periodically evaluate organ system (eg, renal, hepatic, hematopoietic) function; adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapyDrug NameCefixime (Suprax) -- Third-generation cephalosporin. Arrests bacterial cell wall synthesis and inhibits bacterial growth by binding to one or more penicillin-binding proteins. Adult Dose200 mg PO q12h or 400 mg/d PO qd or divided q12h Pediatric Dose50 kg or >12 years: Administer as in adults ContraindicationsDocumented hypersensitivity InteractionsCoadministration with aminoglycosides increases nephrotoxicity; probenecid may increase effects PregnancyB - Usually safe but benefits must outweigh the risks. PrecautionsAdjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged or repeated use may cause superinfections and promote growth of nonsusceptible organismsDrug NameRifampin (Rifadin, Rimactane) -- Inhibits DNA-dependent bacteria by binding to beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription. Adult Dose600 mg/d PO/IV single daily dose Pediatric Dose10-20 mg/kg PO/IV; not to exceed 600 mg/d ContraindicationsDocumented hypersensitivity InteractionsInduces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; coadministration with enalapril may increase BP; coadministration with isoniazid may increase rate of hepatotoxicity more than with either agent alone (discontinue 1 or both if LFT results change) PregnancyC - Safety for use during pregnancy has not been established. PrecautionsObtain CBCs and baseline clinical chemical values prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy associated with thrombocytopenia (reversible if therapy discontinued as soon as purpura appears); if treatment continued or resumed after purpura appears, cerebral hemorrhage or death may occurDrug NameClindamycin (Cleocin) -- Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes and causing arrest of RNA-dependent protein synthesis. Adult Dose150-450 mg/dose PO q6-8h; not to exceed 1.8 g/d600-1200 mg/d IV/IM divided q6-8h depending on degree of infection Pediatric Dose8-20 mg/kg/d (hydrochloride) PO divided tid/qid8-25 mg/kg/d (palmitate) PO divided tid/qid20-40 mg/kg/d (phosphate) IV/IM divided tid/qid ContraindicationsDocumented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis InteractionsIncreases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption PregnancyB - Usually safe but benefits must outweigh the risks. PrecautionsAdjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficileDrug Category: Corticosteroid agents -- These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug NamePrednisone (Deltasone, Meticorten, Orasone) -- May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Adult Dose5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve Pediatric Dose4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve ContraindicationsDocumented hypersensitivity; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI tract disease InteractionsCoadministration with estrogens may decrease clearance; concurrent digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics PregnancyB - Usually safe but benefits must outweigh the risks. PrecautionsAbrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid useFOLLOW-UP Section 8 of 9

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Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up BibliographyFurther Inpatient Care: Bronchoscopy plays a role in the follow-up care of patients.

Further Outpatient Care: Owing to the high rate of recurrence, prolonged antibiotic therapy (months to years) is necessary.

Nasal cytology is an easy and noninvasive investigation.

This method can be performed on an outpatient basis as an adjuvant to clinical and histopathologic studies, along with nasal endoscopy.

Nasal cytology is a simple, reliable, and timesaving procedure that can be used with further therapy.

Relapses occur, and close observation is the key to the long-term follow-up care of the patient.

In/Out Patient Meds: The choice of long-term antibiotic therapy should be guided by the patient's age and sex.

Repeat biopsy can be performed to help determine the appropriate duration of the antibiotic therapy.

Complications: Rhinoscleroma is a rare cause of upper airway obstruction. Only isolated studies in the literature report isolated tracheal obstruction.

Scleroma is known to cause slowly progressive asphyxia.

Prognosis: The course is usually chronic.

Relapses can occur.

Lethal midline granuloma in Okinawa with special emphasis on polymorphic reticulosis.

Jpn J Cancer Res. 1994 Apr;85(4):384-8. Unique Identifier : AIDSLINE MED/94259652 Kojya S; Itokazu T; Maeshiro N; Esu H; Noda Y; Mishima K; Ohsawa M; Aozasa K; Department of Otorhinolaryngology, University of the Ryukyus; Faculty of Medicine, Okinawa.

Abstract: Lethal midline granuloma (LMG) is a clinical term used to describe a condition which may be manifested histologically as Wegener's granulomatosis (WG), polymorphic reticulosis (PR), and malignant lymphoma (ML). WG is an inflammatory disease, and PR and ML are considered to represent a neoplastic proliferation of lymphoreticular cells. In this report, twenty-two cases of LMG in Okinawa were examined. The frequency of LMG per 100,000 outpatients of the ear, nose and throat clinic in Okinawa was 67, and the higher frequency of PR (27) and ML (34) in Okinawa than in other districts of Japan was characteristic. Polymerase chain reaction, in situ hybridization, and immunohistochemical studies showed that the proliferating cells in PR were CD43+ and simultaneously contained Epstein-Barr viral genome in their nuclei. The higher frequency of PR and ML in Okinawa is discussed in conjunction with a review of pertinent literature: multiple factors including genetic, viral environmental, and socioeconomic factors seem to affect the frequencies of these diseases.Lethal midline granuloma

progressively destructive condition of uncertain aetiology, involving the nose and paranasal sinuses. It leads to erosion of the sinonasal and adjacent structures, when left untreated eventually causing death by extension to the central nervous system, infection or haemorrhage.

Radiologically, midfacial bone destruction with relatively little associated soft tissue thickening is seen. This condition resembles the findings in Wegeners granulomatosis head and neck manifestation, although in the latter the changes are less pronounced

Wegener's granulomatosis, head and neck manifestation

(Friedrich Wegener, 20th century, German pathologist), systemic disease primarily affecting the upper respiratory tract, lungs and kidneys. It is characterized by necrotizing granuloma, vasculitis and glomerulonephritis. Patients usually present with constitutional symptoms such as fever and weight loss. They may also have nasal discharge and sinusitis; clinical examination reveals a crusted, granular mucosa, with ulceration and bone destruction. CT shows bone destruction in the nose and paranasal sinuses, without a significant soft tissue mass (Fig. 1). Similar, but more pronounced, abnormalities are seen in lethal midline granuloma .In about 20% of cases, Wegener's granulomatosis also involves the orbit. Wegener's granulomatosis limited to the orbits is very rare. The orbital symptoms are the same as those of orbital pseudotumour but patients with Wegener's granulomatosis usually have constitutional symptoms. Wegener's granulomatosis may affect the larynx; soft tissue thickening causing subglottic or glottic stenosis is seen in such cases (Fig. 2). Soft tissue masses mimicking a malignant tumour of the nasopharynx or skull base have also been described.A positive titre for c-ANCA is a diagnostic criterion for Wegener's granulomatosis. This cytoplasmic antibody directed at neutrophil cytoplasmic antigen is elevated during periods of active disease. In the absence of respiratory tract or renal lesions, the diagnosis cannot be confirmed until the elevated c-ANCA titers are identified. For a general description of the disease, see Wegener's granulomatosis .

RH

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Fig. 1aAxial CT image of nose. Septal perforations and defect in left inferior turbinate (arrowheads), without associated soft tissue thickening.

Wegener's granulomatosis, head and neck manifestation, Fig. 1aWegener's granulomatosis, head and neck manifestation, Fig. 2a

Lethal Midline Granuloma: Report of Three Cases

Shin-Yu Lu, DDS; Wei-Jen Chen1, MD; Hock-Liew Eng1, MDLethal midline granuloma (LMG) is a rare clinical entity characterized by progressive relentless ulcerations and necrosis of midfacial structures. It occurs more frequently in Oriental than in Western populations with no demonstrable etiology. Treatment and outcome for cases differ, but their pathological distinction may not always be possible from routine biopsy specimens. The histological features often seen include widespread coagulative necrosis, heavy inflammatory infiltrates, and atypical pleomorphic cells. However, the paucity of these atypical cells in biopsy specimens and the degree of necrosis can make the diagnosis of a neoplastic lesion very difficult. Because of the progress in pathology methodology including immunohistochemistry, most cases have been proven to be malignant lymphomas of T-cell lineage.We present 3 patients for whom an initial clinical diagnosis of LMG was made. From their several oral biopsies and nasal specimens, difficulties were encountered in differentiating "midline granuloma" from other possible diseases using histomorphological criteria alone. After extensive evaluations, malignant T-cell lymphoma was the specific disease entity identified in only one case by cell membrane immunostaining technique. A literature review was carried out, and recent concepts of the etiology and pathogenesis of this disease are presented.

(Chang Gung Med J 2000;23:99-106)

Key words: lethal midline granuloma, T-cell lymphoma.

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