------------------------------------------------------------------------------- TITLE: GRANULOMATOUS DISEASE OF THE HEAD AND NECK SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: October 4, 1995 RESIDENT PHYSICIAN: James Grant, M.D. FACULTY: Francis B. Quinn, Jr., M.D. SERIES EDITOR: Francis B. Quinn, Jr., M.D. ------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I. INTRODUCTION A granuloma is the result of a basic inflammatory reaction which is essentially dictated by two major factors, a persistent, indigestible irritant, and an agent that is capable of initiating a cell mediated immune response. Histopathologically, the granuloma is characterized by the epithelioid cell, which is a modified macrophage derived from blood circulating monocytes. These "modified macrophages" are distinctly different in that they contain greater amounts of Golgi apparatus, endoplasmic reticulum, vacuoles, and vesicles. These give the cells a pale- pink, plump appearance on microscopic examination. Lymphocytes are also found in the periphery of the centrally situated epithelioid cells. Langerhan's cells (foreign body-type cells) are formed from the fusion of several epithelioid cells, and are seen in the granuloma. Fibroblasts, plasma cells, and neutrophils are also seen in the area of the granuloma. A fibroplastic proliferative process occurs, consolidating the granuloma. Thus, the histological picture is one of acute and chronic inflammation. While granulomatous disease may be isolated in the head and neck region, it is common for involvement in the head and neck area to represent only a small portion of an overall systemic disease. Whether the manifestation of disease is in the form of a lesion (non-healing, ulcerative, or erosive) or simply a constellation of vague complaints, it is important to be thorough in investigation. An exhaustive history (include travel) and complete physical examination are the cornerstone to the work-up. Also, an evaluation of a mass or lesion in the head and neck region often entails obtaining a sample of that tissue, whether by biopsy or fine needle aspiration, to examine for a neoplastic process as well as to determine the basic histological components. Pathology reports of chronic and acute inflammation may represent granulomatous disease. Laboratory studies, radiographic studies, and microbiological studies will also have a role in the work-up. The granulomatous reaction is common in several disease entities which can be classified as neoplastic disorders, systemic inflammatory disorders (including autoimmune and vasculitic processes), foreign body related, trauma related, and infectious. II. INFECTION AND GRANULOMATOUS DISEASE A. FUNGAL Histoplasmata capsulatum a relatively common fungal infection in the United States. It is endemic to the central portion of the United States, more specifically the Mississippi and Ohio River Valleys. Typically, inoculation with the spores do not cause any clinical consequences; however, symptomatic infections can occur. The usual course of a symptomatic acute infection following inhalation of the fungal spores involves fever, headache, chills, myalgia, fatigue, chest pain on deep inspiration, coryza, sore throat, and occasionally gastrointestinal symptoms. Physical examination is usually unremarkable, but a routine chest x-ray will often show small scattered infiltrates and hilar lymphadenopathy. The infection may progress into a disseminated disease or may resolve. Additionally, it may become a chronic, indolent infection. In the acute and chronic disseminated forms of histopolasmosis, constitutional symptoms of weight loss, fever, fatigue, and fever predominate. Regarding head and neck involvement, oropharyngeal ulcerations may be identified on physical exam. These ulcers are painful, indurated, and slowly enlarging-- typically found on the gingiva, mouth, tongue, pharynx, and larynx. Approximately 40-75% of adults with disseminated disease present with oropharyngeal involvement, in comparison to only 18% in children. Diagnosis requires taking swab specimen from the center of an ulcerative lesion and growing on Sabourad's medium. Amphotericin B is used to treat the disseminated forms of histoplasmosis. Blastomycosis dermatitidis is found mainly in the southeast, central and mid-atlantic regions of the United States, with the prevalence of reported infection far less than that of Histoplasmata capsulatum. The typical patient is male (10:1 male/female) in the age group of 20 to 69 years of age. The clinical presentation ranges from asymptomatic to acute pulmonary infection to disseminated disease. Constitutional symptoms predominate with disseminated disease. Physical examination may reveal skin lesions as well as oropharyngeal lesions, although not as commonly. Grossly, these lesions appear as proliferative verrucous growth with significant scarring. The larynx may also be involved, showing areas of erythematous hyperplasia on examination. Fibrosis of the cords may occur as the disease progresses, with pharyngeocutaneous fistula formation as a late clinical feature. The genitourinary system as well as the skeletal system may also be involved. In general, however, a triad of cutaneous disease, pulmonary involvement, and constitutional symptoms is the rule, rather than head an neck, genitourinary, or bony involvement. During the course of evaluating the patient, a chest x-ray should be taken which is abnormal in 75% of the cases. Nodular infiltrates are usually discernable. Additional diagnostic tests is obtaining a sputum specimen for Sabourd's medium culture and culture from skin scrapings. Treatment is amphotericin B. Mucormycosis is an opportunistic fungal infection affecting immunocompromised patients (poorly controlled diabetic, hematologic malignancy, transplant patient, etc.). Mucor sp., Rhizopus sp., and Absidia sp. comprise the group of fungi causing disease. They are ubiquitous in the environment. When the mucormycosis originates in the nose or paranasal sinuses, the patient presents with early complaints of low grade fever, dull sinus pain, nasal congestion and/or bloody discharge, while the later clinical picture consists of diplopia, obtundation, and increasing fever. Physical examination may reveal facial edema, tenderness to palpation of the face, cranial nerve dysfunction, proptosis, reduced ocular motion, and chemosis. In addition, examination of the mucous membranes may show a black eschar overlying areas of frank necrosis. Diagnosis entails microscopic examination of tissue taken from craniofacial lesions. The fungal hyphae will be observed and are described as sparsely septate, with broad hyphae. Computerized tomography is used to determine the overall extent of disease. Treatment is demands aggressive craniofacial debridement of necrotic tissue with orbital exenteration as needed. Amphotericin B pharmacotherapy is also indicated. Aspergillus fumigatus is also ubiquitous in the environment. Transmission is by inhalation of the spores. Generally, it causes a self-limited acute pneumonitis in an otherwise healthy patient following a relatively large exposure to the spores. Those individuals with an underlying pulmonary disease such as chronic obstructive pulmonary disease may harbor a chronic infection with long standing cough and often hemoptysis as a complaint Pulmonary cavitation containing a ball composed of hyphae (coined aspergilloma) may occur. There is an invasive form of aspergillosis, but it is generally contained within an immunocompromised patient population. Regarding head and neck manifestations, the non-invasive form of the disease usually involves a single sinus cavity with symptoms of thick, dark nasal secretions, facial hypesthesia, and fullness as presenting complaints. This may progress to form a fibrosing, granulomatous inflammatory reaction in involved sinus. In the invasive form of the disease (immunocompromised), the paranasal sinus structures may be destroyed with possible extension into the orbit. Diagnosis is microscopic examination of the secretions in addition to a culture. The hyphae may be differentiated from other fungi (especially mucormycosis group) by their morphology-- septate, bifurcating hyphae. Computerized tomography will demonstrate sinus pathology, frequently with calcifications. Treatment is surgical excision of the involved tissue, with amphotericin B reserved for the invasive forms of the disease. Rhinosporidium seeberi is prominent in Southern India and Sri Lanka, but is extremely uncommon in North America. Travel history is of obvious importance. The mucous membranes of the nose, conjunctiva, and palate are the most common sites of involvement. The lesions are painless, but polypid, friable, and erythematous ("strawberry lesions"). Treatment consists of excision of the lesion. Coccidioides immitis and Cryptococcus neoformans may cause granulomatous type inflammatory reactions; however, they rarely affect the head and neck regions. B. PARASITIC Leishmaniasis (caused by Leishamania sp.) presents as four distinct clinical pictures-- (1) visceral leshmaniasis a.k.a. kala azar, (2) cutaneous leshmaniasis (new world vs. old), (3) mucocutaneous leshmaniasis a.k.a. espundia, and (4) diffuse cutaneous leshmaniasis. These parasites are transmitted from an animal reservoir to humans via an insect vector, the sandfly. Of the clinical forms, the new world cutaneous and mucocutaneous tend to have more involvement in the head and neck regions. The new world cutaneous form is caused by Leishmania mexicana. Following a bite from the infected fly, 1-3 cm well- demarcated papules are found at the inoculum sites. Ulceration of the lesions occurs later. These generally resolve spontaneously without treatment or adverse sequelae within 6 months. As an exception, however, primary lesions of the ear may, for unknown reasons, persist for years, causing extensive destruction of the pinna and surrounding structures. Biopsy of the lesion is required for diagnosis. Treatment of the more persistent infection requires Pentosam (sodium antimony gluconate) parenterally for at least 20 days. Leishmania braziliensis causes the mucocutaneous form of leshmaniasis, primarily found in Central and South America (except Chile and Argentina). Following the sandfly bite on an extremity (usually lower), several lesions appear that undergo extensive ulceration. Hematogenous spread may occur, typically involving the mucous membranes of the oral cavity and nasopharynx. Progressive inflammation and destruction of tissue occurs over a long time course. Examination reveals the mutilating lesions in the oral and nasal cavity. Diagnosis is based on biopsy, while treatment consists of Pentosam for at least 30 days. Amphotericin B is used for those cased that fail to respond to antimonial therapy. Serological tests exist which allow the early diagnosis of relapse by detecting a rising antibody titre on direct agglutination test. Myiasis refers to an infection with the larvae (maggots) of the common screw-worm fly. Infection occurs when the fly deposits the larvae in an open wound or when the itself may invades normal tissue or else enters through the mouth, ears, or nose. In the U.S., the most common form of myiasis is furuncular. A pruritic furuncular type lesion forms in the area that the larva has penetrated the skin, later a non-healing papule is found. From this papule, larva may be found to emerge. In a second clinical variant of myiasis, a nonfuruncular lesion is typically found in the nasopharynx. Geographically, this type is generally found in the orient. Diagnosis is made by microscopic examination. Treatment is surgical opening of the lesions and removal of the larvae. C. BACTERIAL Disease caused by Mycobacterium tuberculosis is well studied and provides an excellent example of the granulomatous inflammatory process. The disease is spread from person to person by inhalation of an airborne droplet containing the organism. In the overwhelming majority of patients, the primay infection is asymptomatic; however, inoculation initiates an inflammatory response with a cell mediated hypersensitivity component developing over time. It is this immune response that sequesters the tubercle bacilli and prevents further multiplication or spread. The healing process then occurs, often leaving a calcified granuloma. A ghon complex, seen radiographically, refers to the peripheral lung granuloma which has become calcified in conjunction with a calcified hilar lymph node. Most patients undergo complete resolution of the initial infection; however, in approximately 5% of those exposed, a symptomatic, clinical state occurs when there is inadequate containment of the organism. Some may develop symptoms shortly after the initial infection, while others develop disease years later, where the bacilli have been in a dormant state. The clinical manifestations of tuberculosis are extensive, but pulmonary disease is usually an integral component. Regarding head and neck involvement, cervical lymphadenopathy (referred to as scrofula) is the most common. The lymph nodes are multiple, matted, and non-tender, with usual bilateral involvement of the posterior triangles. The larynx is involved in approximately 1% of patients who have active pulmonary tuberculosis, with bronchogenic spread as the most likely mechanism for infection. Specifically, the arytenoids are involved with greatest frequency, followed by the true vocal cord, epiglottis, false cord, and subglottic area. The lesions may be edematous, granulomatous, or ulcerated; however, on biopsy sections, a tuberculoma is usually found. In a patient with laryngeal involvement, the symptoms include cough, hoarseness, and weakened voice. Oral cavity lesions are found in .05 to 1.5 % of the patients with evidence of pulmonary disease. The lesions may present in several forms, either painful or painless, single or multiple, and as fissures, nodules, plaques, vesicles, or ulcers. The tongue has the greatest incidence of involvement (approx 50%) in those with oral involvement. The gingiva, buccal folds, and dental sockets may also be sites for lesions. Salivary glands may also be involved, usually secondary to oral cavity infection.. Typically, the patient presents with diffuse enlargement of the parotid gland. Although far less common than other head and neck sites, otologic involvement may be found, usually in the clinical form of multiple tympanic membrane perforations. A thin, watery otorrhea may be present. In addition, a mastoiditis may ensue as the disease progresses. Diagnosis requires asking about constitutional symptoms, a positive PPD, an abnormal chest X-ray, and sputum showing acid fast bacilli. An excisional biopsy of a lymph node may also be warranted for diagnostic purposes. Treatment requires the use of anti-tuberculosis agents, isoniazid and rifampin, for a period of 9 months. A tympanomastoidectomy may be required for otologic complications and lymph node excision may be indicated for chronically draining, fluctuant nodes. Nontuberculosis mycobacterial infections may also present as granulomatous lesions in the head and neck region. Included in the group of non-TB mycobacterium M. kansaii, M scrofulaceum, M intracellularis, and M. fortuitum. Transmission appears to be from soil to mouth or eye. Children are more frequently infected with corneal ulceration as the most common involvement of the head and neck region. Followed by ocular involvement is cervical lymphadenopathy (scrofula), typically unilateral within the anterior cervical, preauricular, and submandibular regions. The lymph nodes are discrete, separate, and may progress into an abscess. Diagnosis is made by excisional biopsy of the involved lymph node with acid fast bacilli culture. Staining of the sample for acid fast bacilli will give the presumptive diagnosis. Treatment consists of antibiotics (i.e. isoniazid, rifampin, ethambutol, sulfonamide, fluroquinolones) that are sensitive for the particular organism Mycobacterium leprea is the organism that causes leprosy (Hansen's disease), a chronic granulomatous infection which involves superficial tissues such as skin and peripheral nerves. Epidemiologically, the disease is far more prevalent in tropical climates and is transmitted from human to human through open, weeping ulcers, nasal secretions, and breast milk. There appears to be a spectrum of disease, ranging from a tuberculoid form and a lepromatous form.. The tuberculoid form is characterized not so much by the skin lesions (a hypopigmented, concave macule), but by the massive involvement of peripheral nerves resulting in severe pain and muscle atrophy. Involvement of the facial nerve may occur, albeit rarely, that may result in exposure keratitis and corneal ulceration. In contrast, the lepromatous form of leprosy has widespread skin lesions, typically hypopigmented maculas with ill defined borders. Centrally, the lesion is indurated and convex. There may also be neurologic involvement, but cutaneous disease is more pronounced. Early symptoms with lepromatous leprosy include nasal stuffiness, epistaxis, and hoarseness, which relate to mucosal nodules in the nose (especially anterior inferior turbinate) and laryngeal ulcerations. The mucosal lesions may progress to septal perforation with subsequent nasal collapse and saddle nose deformity. The skin lesions of leprosy show a predilection for cheeks, nose, brow, and ear. Lateral loss of the eyebrow is a common finding. The involved skin in the face and forehead regions may become corrugated and thickened late in the course of disease, resulting in a leonine facies. Diagnosis is by skin scrapings, which on culture and staining demonstrate the organism. Biopsy of skin lesions is also indicated. Dapsone is the usual course of therapy; however, resistance to this medication has become an increasing problem. Other agents used in treatment includes rifampin, clofazimine, ethionamide, and quinolones. Vaccination with bacillus Clamette-Guerin (BCG) in endemic areas continues despite conflicting clinical results and modest efficacy. Cat-Scratch Disease is caused by an intracellular, gram negative bacilli which requires special staining (Warthin- Starry) for detection. Cat exposure, with scratch or bite, is identified in a large number of cases. The disease is found mainly in children --90% under the age of 18. Clinically, a primary lesion, vesicular or papular or pustular, is seen at the site of inoculation. Regional lymphadenitis then occur. Additionally, in 38-73% of studied cases, cervical lymphadenopathy is also seen. Systemic complaints of fatigue, malaise, and low grade fever may co-exist. Diagnosis is based on history of exposure, no other causes for lymphadenopathy, positive skin test, and histological findings on biopsied lymph node. This disease is self-limited and has not been shown to be responsive to any form of anti-microbial therapy as of yet. Treatment is generally supportive, with incision and drainage of necrotic lymph nodes only in cases of severe abscess formation. Aspiration of the necrotic lymph nodes may be a better solution. In general, lymphadenopathy resolves within 2-6 months. Actinomycosis is an indolent suppurative infection caused by an anaerobic organism. Infection follows after aspiration of the Actinomyces organism into the lung or contact of the organism on damaged mucosa (i.e. poor dental hygiene, dental abscess). Pathologically, the agent grows in characteristic grains. The infectious process is walled off by the granulomatous inflammatory process with extensive fibrosis demonstrated on histological studies. Sinus tract formation may occur. Cervicofacial actinomycosis typically presents as a red, indurated, non tender subcutaneous mass in the anterior cervical triangle or submandibular region. The overlying skin may have a purplish discoloration. There may be several draining sinuses present (61% of patients). In addition, 57-89% of patients report fever, while other symptoms include weight loss, malaise, nausea, vomiting, and sweating. Demonstration of the granules on microscopic examination provides the diagnosis as well as confirmation by culture on thioglycollate broth with CO2 atmosphere. Treatment consists of oral penicillin or tetracycline for 2-4 months (mild cases) or 6 weeks of parenteral penicillin g (severe cases). Surgical debridement of necrotic tissue may be necessary to facilitate recovery. Syphilis, caused by the spirochete Treponema pallidum, may present with several manifestations in the head and neck area, each correlating with a specific stage of the disease. In the primary stage, a painless ulcer (chancre) exists at the site of inoculum. Although this is generally found in the genital area, it may manifest in the head and neck region, more specifically, involving the lips, tonsils, or tongue. Reactive lymphadenopathy is also found. This generally resolves spontaneously and is followed by a secondary stage where widespread muco-cutaneous lesions predominate. These lesions may appear as white maculas or papules and, histologically, are found to contain the organism admixed with dense infiltrates of plasma cells and lymphocytes. These lesions are extremely contagious. Other symptoms include acute rhinitis, pharyngitis, laryngitis, otitis media. In addition, there may be loss of eyelashes and localized alopecia. As in the primary stage, the secondary stage resolves spontaneously and a latent stage is entered. The tertiary stage of syphilis is found in 1/3 of these patients, whereas, 1/3 undergo spontaneous remission after the second stage and the remaining 1/3 have latent disease for life. The characteristic lesion of tertiary syphilis is the gumma which is a lesion containing nodules of plasma cells, lymphocytes, epithelioid cells, and fibroblasts. Nasoseptal perforation (resulting in saddle nose deformity) and hard palate perforations occurs commonly. Laryngeal involvement includes a diffuse, gummatous nodular infiltrate. Ulcerations of the larynx may also occur with chondritis or perichondritis occurring when there is secondary bacterial invasion. The temporal bone may also be affected in syphilis, particularity when the gummatous lesion causes an obliterative endarteritis. By the reduced blood supply, the bony labyrinth becomes destroyed, followed by gradual loss of the membranous labyrinth. The patient may present with hearing loss (sensorineural --sudden, bilateral , fluctuating, with poor speech discrimination scores) and/or vertigo. In addition, there may be a frank osteomyelitis of the temporal bone. Congenitally acquired syphilis has its own set of clinical manifestations. This may include a saddle nose deformity, frontal bossing, short maxilla, Hutchinson's incisors, mulberry molars, mental retardation, and a sensorineural hearing loss. Approximately 40-50% of these children also present with meningitic disease. Diagnosis consists of darkfield microscopy on non-oral lesions (oral flora may resemble T. pallidum) and the use of serological testing, namely VDRL and FTA-ABS. The VDRL is used as a screening test but is not specific for syphilis. There are numerous reasons for a false-positive finding. A positive VDRL is confirmed with the FTA-ABS, which is more specific. A patient remains positive for FTA-ABS regardless of their treatment status. Treatment consists of penicillin or tetracycline (allergic patients) ,while steroids may be used to reduce otological type symptoms. Klebsiella rhinoscleromatis causes rhinoscleroma which has three distinct phases: (1) catarrhal stage--prolonged purulent rhinorrhea (honeycombed color), (2) granulomatous stage- -characterized by small, nodular masses in the upper airway which later coalesce, and (3) sclerotic stage--dense fibrosis that causes stenosis of the nose, larynx, and tracheobronchial tree. Epidemiologically, this organism is found in Central America and Eastern Europe. Demonstrating the existence of the organism in vacuolated histiocytes can be useful for diagnosis. Treatment is with streptomycin or tetracycline. Patients with significant stenosis may require dilatation procedures. III. TRAUMA AND GRANULOMATOUS DISEASE Post-intubation granulomas of the larynx are relatively uncommon, with several studies showing widely disparate rates of occurrence. It occurs almost exclusively in the adult population and for unknown reasons women are involved more frequently (75% of documented cases). In the majority of cases, the lesion is situated on the vocal process of the arytenoid cartilage. Mucosal abrasion form the tube initiates the sequence of events including subsequent perichondritis followed by secondary infection. A contact ulcer may form with ensuing granuloma formation. The lesion may be sessile or pedunculated. The patient may complain of voice alteration (hoarseness, breathy voice) or even dyspnea with the larger lesions. Indirect laryngoscopy supplemented with an flexible endoscopic examination is needed for diagnosis. Treatment may be observational, instructing the patient on voice rest and the use of antibiotics for secondary infections, or may warrant surgical excision for the pedunculated lesions. Pyogenic granuloma is typically seen as a response to minor trauma with a secondary bacterial invasion. It is a misnomer in that it is not a true granulomatous infection, rather granulation tissue that forms following the inciting traumatic event. Generally, these are painless, soft lesions that are found along the gingiva. Grossly, they may appear to be elevated, pedunculated, or sessile and tend to bleed easily if traumatized. Treatment is surgical excision for those lesions that are particularity symptomatic. IV. FOREIGN BODY REACTION AND GRANULOMATOUS DISEASE The urate crystals in gout incite granulomatous lesions as they are deposited in the tissues. Histologically, the crystals are surrounded by a fibroblasts, plasma cells, macrophages, and foreign body giant cells. The resulting lesion is referred to as a tophi. The tophaceous deposits occur throughout the body, but classically involve the helix or antihelix of the ear. Tophi may ulcerate and extrude a material that is rich in monosodium urate crystals. Examination under polarizing microscopy for urate crystals aids in distinguishing this from other causes of subcutaneous nodules. Gout also produces an arthritis type picture since the crystals are capable of inciting a significant inflammatory response within the joint space. Usually the joints of the lower extremities are affected, but there have been reports of involvement of the cricoarytenoid joint. Symptoms from this involvement include throat pain, hoarseness, and dysphonia. Chronic inflammation of the joint space may result in fixation of the arytenoid cartilages. Gout is treated medically, using colchicine or indomethacin for acute attacks, and allopurinol for prophylaxis. Cholesterol granulomas are usually found in the pneumatized area of the temporal bone or the paranasal sinuses. For these granulomas to form, there is a predisposing lack of aeration to the site. Cholesterol precipitates in the areas of cell breakdown (erythrocytes, mucosa) with a resulting foreign body reaction. Regarding temporal bone involvement, the patient may be asymptomatic or may have symptoms related to CN V-VIII dysfunction when the cerebellopontine angle is involved in the expansile lesion . Cholesteatomas may also be found in association with cholesterol granulomas, where the clinical symptoms are more likely to be related to the cholesteatoma. Paranasal sinus involvement also occurs. The patient may complain of nasal congestion, rhinorrhea, facial pain, and possibly ophthalomolgical complaints if there is ocular extension. Most lesions in the sinus, however, do not expand or cause erosion of the bony walls. Diagnosis is made by CT scan which shows a smooth walled lesion, whether in the temporal bone or sinus cavity, which is isodense to brain tissue. The cholesterol granulomas are surgically drained. V. NEOPLASM AND GRANULOMATOUS DISEASE Eosinophilic granuloma presents as a bony lesion, usually involving the flat bones of the skull (i.e. frontal, temporal, mandible). It is characterized by a localized collection of histiocytes (polygonal and in sheets) eosinophils that causes resorption of bone, producing a radiolucent lesion. The age of the patient is generally children and young adults. This disease process is considered the localized form of histiocytosis X. Treatment is surgical excision with radiation therapy used for recurrent lesions. Hand-Schuller-Christian disease is considered to be a chronic, disseminated form of histiocytosis X. The presence of sheets of polygonal histiocytes admixed with eosinophils, plasma cells, and lymphocytes is the characteristic microscopic finding in the lesions. Again, this tends to be a disease of children and young adults. Typically, there are several bony lesions present (polyostic), abdominal viscera involvement, and cutaneous lesions (poor prognostic sign). In addition, there is triad that exists in approximately 10% of the patients, consisting of bone lesions, diabetes insipidus, and exopthalamos. The diagnosis is made on biopsy. Treatment plans differ--consisting of pharmacological (vinblastine and corticosteroids) to radiation therapy. Despite treatment, the mortality rate approximates 30%. Letterer-Siwe is a disease of infants that consists of hepatosplenomegaly, lymphadenopathy, bleeding diathesis, anemia, cutaneous lesions, and generalized hyperplasia of macrophages in a variety of organs. This is the acute disseminated form of histiocytosis X. The temporal bone may be involved, with ear pain and/or otorrhea (18% - 61%) as a clinical symptom. Treatment consists of chemotherapeutic agents, but the disease is uniformly fatal in 1-2 years. Polymorphic reticulosis is the accepted terminology for what had originally been coined lethal midline granuloma. Another disease entity, lymphomatoid granulomatosis is also felt to be the same as polymorphic reticulosis.. Histopathologically, this disease involves a dense infiltration of cells consisting of atypical polymorphonuclear cells, mature lymphocytes, stimulated lymphocytes, plasma cells, histiocytes, and immunoblasts, with some cells showing moderate immaturity. A distinct vasculitis is not seen. The infiltration involves the vascular system of the involved tissue, resulting in infarction and rapid necrosis. Studies of the lymphocytes reveal that it is likely a form of T- cell lymphoma. Furthermore, the finding of EBV DNA integrated within the genome of the lymphoma suggests that there may be a viral cause. Typically, the age of patient ranges from 10 - 87 years (peak incidence 40-50) with a marked male predominance. The initial presentation may be as benign as nasal congestion with clear rhinorrhea; however, the patient's condition rapidly deteriorates as the involved structures necrose as a result of vascular compromise. Destruction of the external nose, nasal cavity, soft palate, hard palate, and nasopharynx progresses in an unrelenting fashion. High spiking fevers and sepsis frequently occurs. Death occurs form hemorrhage, secondary infection, and/or cachexia. Systemic features are also present, consisting of profound malaise, night sweats, migratory arthralgia, and weakness. The disease may become disseminated with involvement of central nervous system, gastrointestinal tract, and the lungs. Pulmonary related complaints consists of cough, chest pain, and hemoptysis. Cutaneous involvement is almost always present--seen as a maculopapular rash that progresses to an ulcerated lesion. Diagnosis of polymorphic reticulosis is made by biopsy and immunohistochemical staining and processing. It is important to differentiate the disease of polymorphic reticulosis from Wegner' granulomatosis, as the presentation and examination may have some significant similarities. Differences exist, however, that should allow accurate diagnosis. For instance, histological examination of the lesions in Wegener's disease are necrotizing granulomas with giant cells and vasculitis, whereas the polymorphic reticulosis lesion shows angiocentric infiltration of atypical polymorphonuclear cells. In addition, the use of laboratory methods for detecting anti-neutrophil cytoplasmic antibodies (ANCA) is helpful in diagnosing Wegener's. Although recurrence of disease is possible, localized disease may be effectively treated with external beam radiation therapy with debridement of necrotic tissue as needed. Multiregional disease may be treated cyclophosphamide and prednisone, while diffuse systemic disease is treated with a larger armament of chemotherapeutic agents. The overall mortality rate is 50 - 70%. VI. INFLAMMATORY DISEASES AND GRANULOMATOUS DISEASE Wegener's Granulomatosis is a systemic disease, probably autoimmune, characterized by vasculitis and a predominantly epithelioid necrotizing granulomas in the involved tissue. Typically, the patient has a triad of necrotizing granulomas of the upper airway and lungs (cavitating lesions), renal involvement (focal necrotizing glomerulonephritis) and disseminated vasculitis. The patient may present with widely varying symptomatology, but complaints of nasal obstruction, bloody rhinorrhea, nasal crusting, and nasal pain are the most common. On examination, the mucosa of the nasal cavity is ulcerated with possible perforation of the nasal septum (especially posterior surface of the vomer). Otologic involvement occurs in 20-25% of the cases with serous otitis media and possible sensorineural hearing loss related to cochlear vasculitis, while tracheal manifestations may be stridor from subglottic involvement. Diagnosis is based on biopsy of the nasal mucosa displaying granuloma formation and vasculitic involvement of the small arteries. Laboratory evaluation should include a standard chemistry panel (BUN/Creatinine), sedimentation rate, rheumatoid factor, and anti-neutrophil cytoplasmic antibodies. ANCA is found in approximately 90% of those with Wegener's disease, more specifically, the c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies) variant. A chest X-ray is also indicated. Treatment for limited, mild forms of Wegener's has responded well to trimethoprim-sulfamethoxazole (unknown mechanism of action), while the more severe forms require immunosuppressive therapy of corticosteroids, cyclophosphamide, and imuran. Systemic lupus erythematosus is a disease in which tissues are damaged by deposition of autoantibodies and immune complexes. There is a definite gender predilection with women being affected in 90% of the studied cases. Black females in child bearing age comprise the largest group of those affected by this disease. The prevalence is approximately 15-50 per 100,000 in the United States. There is an exceedingly large number of manifestations of the disease, but malar rash (50% incidence), oral ulceration (40% incidence), polyarthritis (60% incidence), and arthralgia (95% incidence) are some of the more common. Laryngeal involvement may include a chondritis/perichondritis, diffuse thickening of the vocal cords, and arthritic involvement of the cricoarytenoid and/or cricothyroid joints. The patient may complain of hoarseness, dysphonia, pain, and possibly obstruction. In addition, the patient may have nasal cavity involvement, examination revealing anterior septal perforations. Discoid lupus erythematosus is the cutaneous form of lupus erythematosus often involving the exterior of the nose. Dull, red maculas may be found, which later heal with atrophy, scarring , dispigmentation, and telangiectasia. The diagnosis of SLE requires meeting certain number of clinical manifestations in addition to a positive findings on autoantibody studies (i.e. ANA, anti-DNA, anti Ro) . The American Rheumatism Association has set forth the criteria for diagnosis. Treatment consists of non-steroidal anti-inflammatory drugs, , glucocorticosteroids, and anti-malarials, while cytotoxic chemotherapy (azathioprine, chlorambucil, cyclophosphamide) is used for the more severe, resistant cases. Sjorgens syndrome afflicts mainly middle aged women (9:1 female to male predilection) and characterized as an immunological disorder which produces progressive destruction of the exocrine glands. The primary form of the syndrome (sicca complex) only involves the exocrine glands versus the secondary form in which there is a connective tissue disease having the sicca complex as a manifestation. The mechanism of injury is related to lymphocytic infiltration and immune-complex deposition in the tissues. The salivary and lacrimal glands are predominately involved, causing a sicca syndrome, which presents with xerostomia and xerophthalmia with secondary keratoconjunctivitis as the mucosa and conjunctiva become dry as the glandular tissue dysfunctions. Dental caries is also a common complication. Systemic involvement of the disease includes glomerulonephritis (40%), vasculitis (25%), sensory polyneuropathy, Raynoud's phenomenon, thyroid disease resembling Hashimoto's thyroiditis, and interstitial pneumonitis. Interestingly, approximately 10% of the patients develop a pseudolymphoma which presents as lymphadenopathy, splenomegaly, parotid gland enlargement, or pulmonary nodules--10% of this group later develop a non-hodgkin's lymphoma. A triad of keratoconjunctivitis sicca, xerostomia, and histopathology showing mononuclear cell infiltration into the exocrine gland is basis for diagnosis. Minor salivary gland biopsy is typically used, with specificity in the 50 - 95% range. Detection of antibodies directed to the Sjorgens's syndrome antigen is also useful (SS-A nd SS-B). Of note, ANA is positive in approximately 50%-70% of the patients. Treatment is generally aimed at relieving the symptoms by lubricating tears, nasal sprays of normal saline, and proper oral hygiene. Churg-Strauss Syndrome has been described as an allergic angiitis and multi-system granulomatous vasculitis. The mean age of onset is estimated at 44 with a male to female ratio of 1.3:1. Pathologically, the granulomatous lesion occurs in small to medium size arteries, capillaries, veins, and venules with an associated infiltration of eosinophils in the tissue. The pathogenesis of the disease is uncertain, but is most likely related to an aberrant hypersensitivity phenomena. The disease has three phases: (1) a prodromal stage, allergic disease predominates consisting of allergic rhinitis, nasal polyposis, nasal stuffiness, and an element of asthma, (2) hypereosinophilia is striking in the second phase--peripheral blood eosinophilia, chronic eosinophilic pneumonia, or eosinophilic gastroenteritis, and (3) a wide spread vasculitic disease which may have fatal results. Diagnosis is based on biopsy, which shows the allergic granuloma characteristic of this disease. Treatment consists of high dose glucocorticosteroids, with a 50% 5 year survival if treated properly. Sarcoidosis is a chronic disease characterized by the accumulation of non-caseating epithelioid granulomas, affecting many organ systems. The etiology is uncertain, with the prevalence of disease in the United States ranging from 10-40 per 100,000 (17:1 black:white ration). It generally occurs during the third to fifth decade, with a gender preference for females. Manifestations of the disease become apparant when the normal architecture of the involved tissue becomes distorted by the sarcoid granulomas. The lung, lymph nodes, skin, and eye are most common organs affected, and to lesser extent, other head and neck structures. Approximately 90% of individuals with sarcoidosis have an abnormal chest x-ray, while only 50% of these patients will actually have evidence of permanent lung disease. Dyspnea and a dry couph are common complaints. Lymphadenopathy is also a common fining, affecting 75 - 90% of patients. Intrathoracic lymph node groups are predominately involved; however, cervical lymph nodes (non-tender, non-adherent, rubbery, and firm) may also be appreciated. Skin manifestations (in 25% of the patients) includes erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules, or lupus pernio. The manifestation of lupus pernio is seen as an indurated blue- purple, shiny, swollen lesion with predilection for the nose, cheeks, ears. Additionally, skin plaques and maculopapular eruptions typically involve the facial structures. Regarding ophthalmological manifestations (25% incidence), the patient may present with uveitis and episcleritis. Although cervical lymphadenopathy is the most prevalent abnormality in sarcoidosis, parotid gland involvement is present in approximately 10% of the studied case. Bilateral parotid gland involvement is the rule. The parotid glands on physical examination are non-tender, firm, and smooth. In 5% of the cases, the larynx, supraglottic, may demonstrate an erythematous, edematous, nodular, and non- ulcerated mucosa, with airway obstruction as a symptom. Diagnosis of sarcoidosis requires a combination of radiographic, clinical, and histologic positive findings. Common findings from laboratory evidence includes hypergammaglobulinemia on serum protein electrophoresis, elevated liver functions tests (transaminases), elevated serum calcium on electrolyte panel, and an elevated erythrocyte sedimentation rate. Angiotensin converting enzyme is also elevated in 80-90% of the patients and is helpful in diagnosis as well as monitoring disease status. Prednisone is used for treatment. VII. NECROTIZING SIALOMETAPLASIA Necrotizing sialometaplasia presents with a deepseated and sharply demarcated ulcer in the oral cavity, typically at the junction of the hard and soft palate. Histologically, the cells lining the ducts of the minor salivary gland has undergone metaplastic change. The architecture of the gland, however, retains it's normal architecture. This is in sharp contrast to the malignant process where there is loss of normal architecture. Diagnosis is based on biopsy. Spontaneous resolution occurs. --------------------------------------------------------------------------- BIBLIOGRAPHY Boros, D. L. and Yoshida, T. Basic and Clinical Aspects of Granulomatous Diseases. New York: Elsevier North Holland, Inc, 1980. Samuelson, T.E. and Bailey J.B. Degenerative and Idiopathic Diseases. In: Bailey B.J., ed. Head and Neck Surgery, Otolaryngology. Philadelphia: JB Lippincott, 1993. Schecter G.L. and Crawford P.A. Connective Tissue Diseases. In: Bailey B.J., ed. Head and Neck Surgery, Otolaryngology. Philadelphia: JB Lippincott, 1993. Littlejohn M.C. and Bailey B.J. Granulomatous Disease of the Head and Neck. In: Bailey B.J., ed. Head and Neck Surgery, Otolaryngology. Philadelphia: JB Lippincott, 1993. Benjamin, B. Diagnostic Laryngology. W.B. 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