---------------------------------------------------------------------------- TITLE: DEGENERATIVE AND IDIOPATHIC DISEASES SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: 31 January 1991 RESIDENT PHYSICIAN: Todd Samuelson, M.D. FACULTY: Byron J. Bailey, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ---------------------------------------------------------------------------- "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." DEGENERATIVE AND IDIOPATHIC DISEASES CASES 1 AND 2: While practicing as an otolaryngologist in Pennsylvania, two patients come to your office with the similar skull films (Figures 1 and 2). CASE 1: Phil is a 17 year old Flyer fan from Philadelphia, with no previous medical complaints. On routine physical evaluation his doctor took this Caldwell film. Seeing this, his physician drew levels for: alkaline phosphatase, calcium, and sed rate, which were normal. Your evaluation including a thorough history and physical, as well as, a review of systems were negative. A biopsy was taken (Figure 3). CASE 2: Paul a 55 year old painter from Pittsburgh, had noted a steady increase in his painter hat size, for the past two years. He had also noted dorsal kyphosis and bowing of his legs during this time. Paul had noted no other symptoms. His local doctor took this film. Your work up included lumbar and tibia films, which showed similar lesions. Laboratory evaluation included normal calcium and parathormone levels. However, alkaline phosphatase and urinary hydroxyproline levels were elevated. LESIONS OF THE SKULL: These cases are illustrative of how lesions with similar radiographic appearance can be differentiated by a thorough history and physical as well as appropriate laboratory evaluation. The following is a collection of some of the more common idiopathic bone lesions of the head and neck. Fibrous dysplasia (Table 1) Fibrous dysplasia is a skeletal disorder where medullary bone is replaced by fibro-osseous tissue. It manifests itself in three clinical forms; 1) monostotic fibrous dysplasia (MFD), 2) polyostotic fibrous dysplasia (PFD), and 3) Albright's syndrome (AS).(1,2) MFD, the term applied when the disease is confined to one bone, accounts for 75-80% of all cases. PFD, which accounts for 20-25% of the patients, is seen when two or more bones are involved. When PFD is associated with abnormal skin pigmentation, precocious puberty and other nonskeletal diseases it is termed Albright's syndrome. This accounts for 20-25% of all PFD patients.(1,2) Fibrous dysplasia occurs almost exclusively before age 30. PFD and AS tend to occur in the first decade, whereas MFD usually manifests in the second or third decade. Usually the disease is quiescent after puberty. PFD has a 3:1 female preponderance. MFD occurs with equal frequency in both sexes.(1,2) The majority (90%) of the patient with fibrous dysplasia are asymptomatic.(2) When symptomatic, common symptoms include local swelling, pain, displaced teeth and occasionally nerve compression symptoms. The most commonly affected bones are the ribs and femur for MFD and the femur and tibia for PFD.(1,2) Approximately 25% of the patients with FD have head and neck involvement. The maxilla is the most commonly affected bone followed by the mandible. In the head and neck FD typically produces a painless asymmetrical swelling.(1,2) The typical radiographic finding is an expanded osseous lesion having a poorly defined margin covered by a thin eggshell cortex.(1) However, FD may also present radiographically as a pagetoid lesion or even a sclerotic lesion.(2) Histologically, the FD lesion reveals marrow replaced by whorled spindle cells. A differentiating feature is that the FD lesion lacks "osteoblastic rimming", where osteoblasts rim the fibroosseous tissue.(1) The differential for FD often depends upon the location and radiographic characteristic of the lesion. As stated previously, FD may have a pagetoid appearance on x-ray, but clinically the difference is easy to establish. When it occurs along the sphenoid ridge, it may look radiographically like a meningioma. FD may also be difficult to differentiate from osteomyelitis, which may coexist with it. Finally, osteosarcoma most always be considered in the differential of such lesions. Indeed, 1 in 200 cases undergo malignant degeneration.(1) Management of the FD patient begins with establishment of the proper diagnosis. Biopsy of these lesions should occur when the diagnosis is in doubt or when malignant degeneration is suspected. Treatment includes excision or curretage when there is; 1) interference in function, 2) progression in deformity or 3) sarcomatous transformation.(1,2) Often, the primary goal is contouring to minimize deformity. Recurrence rates reach 20-30% with curretage.(1) Ossifying fibroma: The ossifying fibroma is similar to FD. Onset is on average 10 years after FD. Clinically it appears usually as a homogeneous dense mass on x-ray, with similar head and neck locations as FD. Usually, however, the ossifying fibroma is more discreet. Histologically, its appearance is similar to FD but "osteoblastic rimming" is present. Treatment is excision and recurrence is rare.(2,16) Paget's disease: The demographics and clinical manifestations of Paget's disease are different from FD (Table 1). It is bone disease which rarely occurs before age 40; most commonly occuring between the ages of 55 and 70. The male to female ratio is 4:3.(1) Clinically, 90% of Paget's patients have polyostotic disease. Paget's most commonly occurs in the lumbosacral region. Like FD Paget's is often incidentaly discovered on x-ray.(3) However, it is more commonly symptomatic. The classic symptoms are; 1) enlarging skull, 2) dorsal kyphosis, and 3) bowing of the legs.(2) The most common symptom, however, is bone pain.(2) Other symptoms occur as a complication of the disease, including spinal root compression, normal pressure hydrocephalus, and repeated fractures with nonunion.(2) The classic x-ray findings of Paget's usually follow the underlying histological process. Initially, there is a lytic phase associated with increased osteoclastic activity with replacement with vascular stroma. This phase is followed by a mixed phase, in which one sees increased osteoblastic activity in addition to the osteoclastic activity, resulting in a mosaic pattern of bone. This gives rise to the typical"cotton wool" appearance on x-ray. During the final phase the osteoblastic activity is preeminent. The x-ray picture becomes one of sclerosis.(1) Isotope scanning is better than plain x-ray at detecting the early stage of disease. It is often used as a screen to detect early disease; for example, in elderly with elevated alkaline phosphatase levels.(3) Although calcium and PTH levels may be elevated secondary to the increased bone turnover, usually they are normal. However, Paget's patients often have an abnormal alkaline phosphatase with the increased osteoblastic activity and increased urinary hydroxyproline with the increased osteoclastic activity.(1,2) Paget's of the head and neck occurs more commonly in the skull than in the face, as seen in FD. The skull is the third most commonly involved bone. (1) Lesions seen in the skull are typically lytic (osteoporosis circumscripta) and only slowly progress to the mixed phase.(1-3) Occasionally, late in the disease one sees the "Tam-O-Shanter" skull with a large overriding skull and involution of the skull base.(1) Paget's of the jaw rarely occurs before age 40 and is usually bilateral. In contrast, FD is usually unilateral and is rare after 30.(1) The differential for Paget's in addition to FD is again osteomyelitis, which can also coexist with it. Osteitis fibrosa from primary hyperparathyroidism is another bone disease which may difficult to distinguish from Paget's.(2) Appropriate laboratory studies are essential to differentiate the two. Finally, osteosarcoma must be ruled out in these patients. Like FD, Paget's can undergo malignant transformation.(1-3) One to five percent of the cases degenerate to osteosarcoma with a lower 5 yr. survival than other osteosarcomas.(2) More rarely it degenerates to giant cell tumor, which typically involves the skull and is less aggressive than other giant cell tumors which rarely involve the skull and is seen almost exclusively in the long bones.(1) Management of Paget's begins with establishment of the diagnosis. Usually the clinical picture is classic, but a biopsy is essential if the diagnosis is in doubt. The Paget's patient is also at risk for the development of serious sequellae including; hypercalcemia, polycythemia, neurologic compression, malignant transformation, and congestive heart failure.(2) As a result, these patients need to be followed closely. Medical treatment becomes necessary when there is; 1) impending hypercalcemia, 2) repeated fractures and nonunion, 3) compression of nerves and 4) intractable bone pain.(1-3) Calcitonin is the drug of choice. It decreases bone turnover and thus alkaline phosphatase, urinary hydroxyproline. It also has been shown to decrease the risk for heart failure. Disodium etidronate, which interferes with bone resorption and formation is especially useful in treating intractable bone pain. Mithramycin is a drug that is reserved for resistant cases, because it is associated with severe side effects.(3) Reparative granuloma vs. Giant cell tumor: Two other bone lesions which deserve mention here are the reparative granuloma and the giant cell tumor. Both lesions are similar in radiographically to FD and Paget's. Histologically they are difficult to differentiate from each other. Both have peripheral areas of bone destruction and multinucleated giant cells. Clinically, however, they are very different (Table 2).(2) The reparative granuloma occurs in the first two decades, whereas the giant cell tumor is rare before age 18. The reparative granuloma occurs almost exclusively in the mandible and less commonly in the maxilla. The giant cell tumor is most commonly seen in the long bones and is only rarely seen in the head and neck, usually in the skull. Finally, the reparative granuloma is benign with local aggression and responds to excision or XRT, whereas the giant cell tumor is very aggressive and XRT has no effect on it.(2) CASES 3 AND 4: Due to an excessive number of bizarre idiopathic bone lesions that come to your office, after solving the above cases, you decide to move to Washington, to find more normal patients. One day, two patients come to your office with the following sialograms (Figures 4 and 5). Case 3: Sally is a 45 year old from Seattle. Sally had noted recurrent nontender parotid gland enlargement. Sally stated that she had a dry mouth and was unable to eat crackers. She also stated that she frequently had to use an eye drop to keep her eyes moist. Sally noted no other symptoms. Laboratory studies including Rheumatoid factor and ANA antibody tests were negative. However, she did have an elevated Westergren ESR. SS-A, and SS-B antibodies were present. A lip biopsy showed infiltration of the minor salivary gland with lymphocytes and histiocytes. Her "focus score" was greater than 1. Case 4: Cy, also from Seattle, was referred with repeated episodes of painful parotid swelling. Examination revealed a swollen, tender gland with purulent discharge. RECCURENT PAROTID SWELLING: The differential for recurrent parotid gland swelling includes autoimmune "pseudosialectasis" and Mikulicz syndrome. (Table 3) The former when localized to the parotid gland is termed Mikulicz disease and has an adult and a childhood form.(4) When the autoimmune parotitis is associated with xeropthalmia and/or xerostomia it is termed "Sicca-syndrome" or primary Sjogren's. When primary sjogren's is associated with a connective tissue disorder it is called secondary sjogren's.(4,6) Mikulicz syndrome is essentially a term used for all cases of recurrent parotid swelling which are not autoimmune. It includes three major categories; chronic recurrent sialadenitis, sialosis, and multinodular gland.(5) Autoimmune parotid swelling: The autoimmune diseases of the parotid gland have a unifying histologic pattern. This consists of an early lymphocytic infiltrate, followed by thinning and fragmentation of the connective tissue reticulum of the terminal or intercalated duct walls. Later the acini are destroyed. Usually the ducts are relatively uninvolved , unless there is superimposing infection.(4) Like the histologic pattern, the sialographic appearance is similar for all diseases in this category.(Table 4) It consists of a diffuse pattern of globular collections of contrast material. Originally, this characteristic sialography was termed sialectasis. It was thought that there was actual dilitation of the acini, which collected the contrast material. However, what really happens is that the destroyed and weakened acini actually allow extravasation of contrast material, which form globular collections outside the acini. These globular collections remain after the contrast material is allowed to drain.(4) There are four progressive radiographic features of autoimmune parotid swelling: 1) punctate, when the spherical collections are 1 mm or less; 2) globular, when the collections are 1 to 2 mm; 3) cavitary, when there are large irregular collections with eneven distribution; and 4) destructive, when there is no recognizable branching. The latter two stages represent superimposing infection.(4) Autoimmune parotitis usually presents as recurrent swelling that affects one side at a time. The swelling is painless and is unpredictable in duration. Rarely is there associated edema. Most childhood forms resolve at puberty and never progress to the latter two radiographic stages. The adult for is 10 times more common.(4,6) The classic disease with autoimmune parotitis is Sjogren's syndrome. Sjogren's is the second most common connective tissue disorder behind rheumatoid arthritis. It may occur at almost any age but typically occurs between ages 40 and 60. This disease is more common in women and occurs with a 9:1 ratio.(6) In addition to parotid swelling, the symptoms of Sjogren's include; xerostomia, and xeropthalmia. Filamentary keratitis, which is diagnostic of keratoconjunctivits sicca, is a common finding. Although any connective tissue disorder may be associated with secondary Sjogren's, RA is the most commonly associated connective tissue disorder in secondary sjogren's.(6) Extraglandular symptoms in secondary Sjogren's include; dry skin, vaginal pruritis, arthralgia, and myalgia. Patients with suspected Sjogren's should have a laboratory test battery to better define the disease process. Certain humoral antibodies are characteristic of the disease. (Table 5) SS-A and SS-B are are autoantibodies found exclusively in primary Sjogren's. Determination of antibodies to specific HLA antigens can also help differentiate primary from secondary sjogren's. Primary Sjogren's has a high correlation with HLA-B8 and HLA-DW3 antibodies. Secondary Sjogren's is associated with HLA-DW4 antibody. Rheumatoid factor and antinuclear antibodies may be present in both disease forms. The erythrocyte sedimentation rate is often elevated in either disease. Quantitative immunoglobulins often show polyclonal hypergammaglobulinemia.(6-8) Approximately 5% of the patients with Sjogren's develop a lymphoprliferative neoplasm. The greatest risk for degeneration is seen in patients with 1) primary Sjogren's, 2) constant parotid swelling and 3) lymphadenopathy. A decrease in the serum IgM levels heralds the progression to malignancy.(6-8) A prominent diagnostic tool is the lip biopsy. The usual biopsy site is just lateral to the midline on the mucosal surface of the lower lip. The biopsy is formalin fixed. From the biopsy a focus score is obtained. A focus is 50 or more lymphocytes, histiocytes , or plasma cells. The score is determined by counting the number of foci in 4 square millimeters. A score of greater than 1 is characteristic of Sjogren's. There exists a "sicca-like" syndrome which is similar to Sjogren's but with a negative biopsy.(6-8) Treatment of Sjogren's is usually supportive. Oral steroids or steroid eye drops are usually reserved for severe disability.(9) Mikulicz syndrome: Mikulicz syndrome represents a several clinical entities in three major groups; 1) recurrent sialadenitis, 2) sialosis, and 3) multinodular gland.(5) Recurrent sialadenitis usually presents as a unilateral swollen, red, tender gland with purulent discharge. Often the patient complains of pain in the gland while chewing. In contrast to sjogren's, sialography reveals dilation and focal narrowing of Stensen's duct.(Table 4) The peripheral ducts are usually normal. Sialectasis if present is usually focal and nonuniform. Because of the clearly different clinical picture sialography is rarely performed on these patients. The major indications are: to demonstrate a stone or stricture, to differentiate from autoimmune disease, and to evaluate the extent of irreversible ductal disease. Treatment of recurrent sialadenitis begins with demonstration and removal of any stones. The patient is further treated with antibiotics, warm compresses and sialogogues. In severe cases excision may be necessary.(5,10) Sialosis is a term that applies to recurrent bilateral nontender parotid swelling that occurs almost exclusively secondarily to some underlying pathology.(Table 6) These include; cirrhosis, diabetes, alcoholism, malnutrition, or ovarian, thyroid, or pancreatic insufficiency. Sialosis can also result from using the following drugs; sulfisoxazole, phenalbutazone, catecholamines, or iodide containing compounds. Sialography reveals an enlarged gland with normal peripheral ducts that are merely more spread apart.(Table 4)(5) "Multinodular gland" is a term that actually represents a group of diseases with just that, a lumpy parotid gland. Although rare, autoimmune sialadenitis can present in this fashion. The remainder of causes include; 1) granulomatous diseases, 2) lymphoproliferative neoplasms, and 3) other tumors.(Table 7) Granulomatous diseases that involve the parotid include tuberculosis and sarcoid. Approximately 10-30% of patients with sarcoid involve the parotid. Heerfordt's syndrome is disease where sarcoid involves the facial nerve, producing facial swelling, uveitis, and facial paralysis. Lymphoma often presents like this in the parotid. A CT-sialogram is helpful in differentiation this from other causes of parotid swelling. Warthin's tumor is the most common tumor of parotid origin that presents as a multinodular gland.(5) CASES 5 AND 6: Your reputation as a diagnostician of recurrent parotid swelling secure, every lumpy faced lumberjack in Washington comes to see you. You decide to move to the other Washington, Washington D.C., to rid yourself of this scourge. One day, two patients with epistaxis come to see you. Case 5: Walter is a 35 year old weatherman who complains of recurrent nosebleeds. Originally he thought this was due to getting out in the weather so often. However, recently he has noted severe sinusitis. He has also noted occasional episodes of hemoptysis. On physical exam Walter is found to have a large ulcer on his septum, with several others on his turbinates. A chest x-ray reveals several small nodules bilaterally in his lower lobes. His urinalysis is normal, but he is slightly anemic. A generous biopsy is taken from his right turbinate (Figure 6). Case 6: Paul is a 50 year old politician with a long history of cough, and hemoptysis. He thought that this was due to frequenting "smoke filled rooms" of D.C. However, he had recently developed recurrent sinusitis with bloody discharge. When his illness kept him from an important meeting with a lobbyist he decided to come to see you. On exam, he too had several nasal ulcers. His chest x-ray also revealed several nodular densities in his lower lobes. His blood count and his urinalysis were normal. A biopsy was also taken of his turbinate (Figure 7). MIDLINE DESTRUCTIVE DISEASES: The differential for midline destructive diseases include; Wegener's granulomatosis, lymphomatoid granulomatosis, lymphoma, idiopathic midline destructive disease, polyarteritis nodosa, allergic granulomatosis and vasculitis, and foreign body granulomas. Midline destructive diseases are difficult to differentiate on a clinical basis alone. The key to diagnosis and thus treatment is the biopsy. Due to the necrosis and tissue destruction that occurs with these diseases, an adequate biopsy is difficult to obtain. Best results are achieved when the superficial scab is removed and a generous biopsy is performed including some normal appearing tissue.(1,11) Wegener's granulomatosis: Probably the most common midline destructive disease is Wegener's granulomatosis. Wegener's occurs in all age groups, with a peak incidence from ages 30 to 40. The male to female ratio is 3:2. Classically Wegener's is thought to include the diagnostic triad of; 1) necrotizing granulomas of the upper respiratory tract and lungs, 2) focal glomerulitis, and 3) disseminating vasculitis.(1,11,14) When the disease doesn't involve the kidneys it is termed limited Wegener's granulomatosis. As a result of the diversity of organ involvement, there is plethora of symptomatology. Nasal symptoms include; sinusitis, epistaxis and nasal obstruction. Serous otitis media and sensorineural hearing loss have been reported. When Wegener's involves the larynx the ulcerating lesions can cause subglottic stenosis. Pulmonary symptoms include chest pain, cough, and hemoptysis. Wegener's can also present as skin petechiae or ulcers. Renal symptoms are usually late in the disease. Proteinuria and hematuria herald the onset of glomerulitis.(1) Diagnosis is made by biopsy of the offending lesion. Wegener's is characterized by coagulation necrosis from the vasculitis, multinucleated giant cells and pallisading histiocytes. The most important differentiating features compared with other midline destructive lesions are the presence of granulomas and typical polymorphonuclear cells.(Table 8)(1) Management begins with establishing the diagnosis. Subsequently, the extent of disease is determined, using appropriate laboratory studies including, chest x-ray, and sinus films. A urinalysis is important to look for proteinuria and hematuria. Cyclophosphamide and steroids are the drugs of choice for treatment of Classic Wegener's. In the pre-cyclophosphamide era long term survival averaged 5 months. Now long term remissions and even cures can be achieved.(1,14) The drug should be continued for one year after disappearance of symptoms.(1) For limited Wegener's, trimethoprim/ sulfamethoxazole is often used for treatment.(12,14) Lymphomatoid granulomatosis: It is now apparent that lymphomatoid granulomatosis (LYG), polymorphic reticulosis, and lethal midline granuloma are synonyms of the same disease. It is thought that lymphomatoid granulomatosis is really a type of T-cell lymphoma.(1,13,14) LYG differs from conventional lymphoma by being composed of a polymorphic infiltrate rather than a monomorphic infiltrate.(1,14) Further, LYG occurs primarily in extranodal tissues like the lungs, skin, CNS, and kidneys. Although commonly involved in typical lymphomas, the lymph nodes, bone marrow , and the spleen are rarely involved in lymphomatoid granulomatosis.(Table 9)(1) LYG may occur in all age groups with the peak incidence from age 40 to 50. The male to female ratio for all patients with LYG is 1.7:1. When the head and neck is involved the ratio is 3-5:1.(1,14) Patients with LYG most commonly present with pulmonary symptoms including cough, shortness of breath, and hemoptysis. Constitutional symptoms are also common in these patients and may include fever, malaise or weight loss. A systemic lupus erythematosis type of skin lesion is present in 40% of the patients. This contrasts Wegener's patients which typically have ulcerating skin lesions. Many patients with LYG have CNS symptoms including; ataxia, mental confusion, and seizures. Splenomegaly, hepatomegaly, and lymphadenopathy usually only occur if there is a complicating conventional lymphoma associated with the LYG.(1) The typical presentation for the otolaryngologist is ulcerating lesions of the upper respiratory tract, usually confined to the nose and sinuses. Without biopsy these are essentially impossible to differentiate from Wegener's ulcerations.(1,14) Again, management includes establishing the diagnosis and evaluating the extent of disease. The chest x-ray is essential to rule out pulmonary involvement, as LYG tends to involve the lungs more commonly than Wegener's. A complete blood count is necessary to determine if the patient is anemic or if there is a superimposing infection.(1) Histologically, (See Table 8) LYG reveals sheets of atypical polymorphonuclear cells. It has no granulomas, and no pallisading histiocytes. This is in contrast to Wegener's which has typical polymorphs, granulomas, and pallisading histiocytes.(1,13,14) Treatment of LYG consists of radiation therapy for localized disease. Cyclophosphamide and prednisone are used for multiregional disease. The overall mortality rate is high 50-70%. Pulmonary involvement, leukopenia, fever, and anergy imply a poor prognosis for LYG patients.(1,13,14) Malignant lymphoma: Although 12% of those with LYG degenerate to lymphoma, lymphoma may involve the upper respiratory tract in the absence of LYG.(1) The demographics are similar for both diseases. However, there are many differences, discussed above. Lymphomas also have a worse prognosis than LYG. Treatment consists of XRT, which is usually unsuccesful. As a result, chemotherapy is now frequently being used.(1,14) Idiopathic midline destructive disease (IMDD) is a rare idiopathic disease which remains localized to the head and neck. It can be differentiated histologically from Wegener's and LYG. The IMDD lesion is composed of sheets of typical polymorphs. There are no granulomas and no vasculitis. The treatment of choice is radiation therapy. Polyarteritis nodosa (PAN) is another vasculitis that may affect the upper respiratory tract. In contrast to the other vasculitidies, PAN affects the small to medium size arteries only. The veins are spared. PAN also rarely affects the lungs. Allergic granulomatosis and vasculitis of Churg-strauss (AGV) is characterized by the diagnostic triad of: 1) asthma, 2) systemic vasculitis, and 3) tissue and peripheral eosinophilia. The systemic vasculitis is indistinguishable from PAN. Approximately 70% of these patients present with nasal symptoms including; polyps, rhinorhea, obstruction, crusting and septal perforation. Histologically, these lesions are similar to Wegener's ith pallisading histiocytes, granulomas, vasculitis, and typical polymorphs. The major difference is the presence of a tremendous amount of eosinophilia.(1) Foreign body granulomas must always be considered in patients with intranasal ulcers or granulomas. These lesions often occur in patients who use cocaine. They also may occur in patients who have had intramucosal steroid injections for allergies. Biopsies of these patients reveal multinucleated giant cells. The presence of foreign material (demonstratable by polarized light) and the abscence of vasculitis distinguishes this from Wegener's. CASES 7, 8 AND 9: Fed up with these idiopathic diseases, you decide to take your show on the road and set up your office in a trailer. This maneuver doesn't seem to help as you again run into unusual idiopathic diseases. Case 7: Amy a 45 year old from Amarillo began having recurrent "colds" and exertional dyspnea about one year ago. Clinical exam was negative. However, laryngeal tomograms revealed some subglottic narrowing. Bronchoscopy revealed a soft tissue mass. The biopsy is seen in figure 8. The rest of the exam was normal. Further, sampling of fat from the anterior wall of the abdomen was negative for similar material. Case 8: Sal a 40 year old from Salt Lake City also began having exertional dyspnea, as well as, fever, and weight loss. He further noted general lymphadenopathy as well as several skin nodules. Laryngeal tomograms again revealed some subglottic stenosis. A biopsy of one of the subcutaneous foci is seen in figure 9. Case 9: Ralph Pugilisto, although a 40 year old pacifist, looked like a boxer. He presented with a saddle deformity of the nose, and cauliflower ears. He too complained of exertional dyspnea, fatigue and malaise. Again he was found to have a subglottic mass. Biopsy revealed chronic subepithelial inflammation and fibrosis. Ralph was treated and improved but had recurrent episodes of inflammation and stenosis. NON-NEOPLASTIC, NONTRAUMATIC SUBGLOTTIC STENOSIS: The differential for non-neoplastic, nontraumatic subglottic stenosis includes; 1) Wegener's granulomatosis, 2) amyloidosis, 3) sarcoidosis, and 4) relapsing polychondritis.(15) Clinically these diseases are usually very different. As a result, the diagnosis is often made by a thorough history and physical. Biopsy is often only confirmatory. However, occasionally these patients present with subglottic stenosis alone, especially with sarcoidosis and amyloidosis. Since special stains may be required to confirm the diagnosis in theses cases, one must remember these entities and alert the pathologist when there is any suspicion. Wegener's Granulomatosis (Discussed above) Amyloidosis Amyloidosis is a rare disease that is characterized by the deposition of extracellular fibrillar proteins in various tissues. Typically occurring between the ages of 40 and 60. It manifests in several different forms; 1) primary systemic, 2) secondary systemic, 3) localized, 4) myeloma associated, and 5) hereditary- familial amyloidosis.(Table 11)(1,17) The above categories account respectively for 56, 8, 9, 26, and 1% of the cases.(1) The primary systemic form effects primarily mesenchymal tissues such as the heart, tongue, and GI tract. Secondary systemic amyloidosis is so named because it is associated with chronic destructive diseases such as tuberculosis, rheumatoid arthritis, and osteomyelitis. This form of amyloid primarily effects the kidneys, adrenals, liver, or spleen. Although only 12% of the patients with myeloma develop amyloid, myeloma associated amyloidosis is the second most common form of amyloid. This form also is primarily deposited in mesynchymal tissues. Localized amyloid may be either primary or secondary but is limited to one sight of the body.(1) By light microscopy all forms of amyloid are identical. Chemical analysis, however, reveals that primary amyloid, and myeloma associated amyloid are composed of light chain immunoglobulins (AL). Secondary amyloid is composed of amyloid protein A (AA). Localized amyloid may be composed of several different types of protein.(1,17) The diagnosis of amyloid is established by the biopsy. Histiologically this disease is characterized by deposition of extracellular proteins, which are green birefringent under polarized light after staining with Congo red. Reversibility of the birefringence with potassium permanganate implies secondary amyloid. Crystal violet is also used to stain for amyloid.(1,17,18) Generalized amyloid has a much worse prognosis than localized amyloid. As a result, once amyloidosis has been identified in one sight, the patient must be evaluated for generalized amyloid. This is done by either rectal biopsy or fine needle aspiration of the anterior abdominal wall fat. Approximately 80-90% of patients with generalized amyloid show positive results for these tests.(17,18) Amyloid may deposit in several sights in the head and neck. Amyloid deposits in the larynx are typically localized. The true vocal cord is the most common site of deposition in the larynx. Thus, the most common symptom is hoarseness. Typically, amyloid presents as firm grey, red or yellow nodules with intact mucosa. Subglottically these nodules tend to be diffuse in nature. The orbit is the most common site of deposition for localized amyloid in the head and neck. It typically presents as a painless mass in the superior orbit.(17,18) The tongue in contrast is the most commonly involved area for generalized amyloid in the head and neck. Indeed, 50% of those with primary amyloid have lingual involvement. Twelve percent have macroglossia. Treatment for localized amyloid is excision.(1) Sarcoidosis: Sarcoid is an idiopathic disease that is characterized by noncaseating granulomas. Typically this disease occurs in the third and fourth decade. Rarely it occurs before age 15. It is relatively prevalent in US blacks and Puerto Ricans.(19-22) The sarcoid patient typically presents with deposition of granulomas in the lungs and intrathoracic nodes. Generalized adenopathy occur in 25-50%. Splenomegaly occurs in 10%. Sarcoidosis may also be associated with constitutional symptoms of fever, weight loss, and arthralgia. Immunologically, sarcoid is associated with impaired T-cell function, delayed hypersensitivity, and even anergy. Four to six percent of sarcoid patients have neural involvement, and 15-25% may involve the eyes. Sarcoid may deposit in the subcutaneous area of the skin, "Darrier Rousey" nodules.(19,21,22) Head and neck manifestations occur in 10-15% patients. The most common presentation is cervical adenopathy. The nares is involved in 1% of the patients. The typical lesions of yellow subcutaneous nodules and polypoid changes may deposit anywhere in the upper respiratory tract. In the larynx sarcoid usually deposits in the subglottis. Pathognomonic of laryngeal sarcoid is a pale pink turbin like epiglottis, that is diffusely enlarged. The orbit also may be involved. Lesions here include; orbital masses, lacrimal swelling, and uveitis. Parotid swelling may also occur, with or without facial nerve involvement.(22) Laboratory evaluation of these patients include: a chest film to look for intrathoracic granulomas, and a skin test to rule out anergy. A PPD is often placed to rule out TB. Angiotensin converting enzyme levels are elevated in 80-90% of sarcoid patients. Although a nonspecific test, ACE levels may be used to follow the course of the disease. Treatment of sarcoid is oral steroids.(19-22) Relapsing polychondritis: Relapsing polycondritis is a rare disorder characterized by inflammation of cartilage and other tissues with a high concentration of glycosaminoglycans. The cause of this disease is unknown. Although, an immunological mechanism is theorized.(23,24) The diagnosis of RP is mainly clinical. It is an episodic progressive disease, in which the following may be involved: 1) recurrent chondritis of both auricles, 2) nonerosive inflammatory polyarthritis, 3) chondritis of nasal cartilages, 4) inflammation of ocular cartilages, 5) chondritis of the respiratory tract, and/or 6) cochlear and vestibular damage.(Table 14) Auricular chondritis and arthritis occur in approximately 50% of the patients. Nasal, ocular, and respiratory tract involvement each occur approximately 15% of the time. Cochlear and vestibular involvement comprise the rest of the cases.(23) Whatever the sight, the chondritis usually develops rapidly and resolves in 5 to 10 days. Occasionally the chondritis is associated with lymphadenopathy. The arthritis associated with RP is often migratory, especially early in the disease process. Any joint may be involved. Frequently it mimics rhuematoid arthritis. After several episodes chondritis, the involved structures often become deformed. Recurrent nasal chondritis may produce a saddle deformity. Auricular chondritis often produces a cauliflower deformity.(23) Laryngeal involvement is rare. The typical presenting symptoms include hoarseness, dyspnea, and rarely hemoptysis. The laryngeal structures may be severely involved in the inflammatory response. Ultimately laryngeal collapse may occur. Most believe that tracheostomy is essential early in the disease process before this can occur. The indications for tracheostomy are severe edema of the glottis and subglottic regions of the larynx, as well as, laryngeal collapse.(23,24) Evaluation of these patients includes biopsy, which often reveals; 1) lack of basophilic staining of the cartilage, 2) perichondrial inflammation, and 3) eventual cartilage destruction and replacement with fibrous tissue. The erythrocyte sedimentation rate is often increased with active disease. On the blood count the patient may have anemia, or leukocytosis. The former occurs especially when nasal involvement leads to recurrent bouts of epistaxis.(23) The course of disease is variably, ranging from mild disease to severe fulminating attacks. Mortality is generally related to respiratory involvement (e.g., laryngeal collapse) or cardiovascular disease (e.g., aneurysms or valvular insufficiency).The cause of RP is unknown, thus treatment is often symptomatic. Steroids have been used, but mainly in life threatening situations. However, because of the relapsing nature of the disease it is uncertain whether any therapy changes the course of disease.(24) QUESTIONS?: 1. What bone disorder does Phil the Flyer fan from Philadelphia have? 2. What bone disorder does Paul the painter from Pittsburgh have? 3. What is the cause of parotid swelling in Sally from Seattle? 4. What is the cause of parotid swelling in Cy from Seattle? 5. What disease is causing Walter the weatherman from Washington D.C. to have recurrent nose bleeds? 6. What disease is causing Paul the politician to have nosebleeds? 7. What is that green birefringent material found in the subglottis of Amy from Amarillo? 8. What is causing Sal from Salt Lake to have all of those granulomatous lesions in his skin and in his subglottis? 9. Why, if Ralph Pugilisto is a pacifist, does he have the face of a boxer, with a saddle nose deformity and cauliflower ears? --------------------------------------------------------------------------- BIBLIOGRAPHY: 1. Batsakis JG. Surgical pathology of the head and neck: Course Syllabus. Nov 13-17 1989. 2. English GM. Otolaryngology.J.B. Lippincott Co. Phila., 1989, Chap. 29,1-29. 3. Frame B, Marel GM: Paget's Disease: A review of the current knowledge. Rad 1981: 141(1):21-24. 4. Som PF et al: Manifestations of Parotid gland enlargement: Radiographic, Pathologic, and clinical correlations. PartI The autoimmune pseudosialectasis. Rad 1981: 141(2):415-419. 5. Som PF et al: Manifestations of Parotid gland enlargement: Radiographic, Pathologic, and clinical correlations. PartII: The diseases of the Mikulicz syndrome. Rad 1981: 141(2):421-426. 6. Lyons GD et al: Sicca Syndrome - diagnostic perplexities. Laryng 1983: 93(7):880-883. 7. Batsakis JG: The pathology of head and neck tumors: The lymphoepithelial lesion and Sjogren's syndrome, part 16. Head Neck Surg 1982: 5:150-163. 8. Lindstrom FD, et al. Evaluation of lip salivary gland biopsy in 21 patients with primary Sjogren,s syndrome. Clin Immunol Immunopathol 1987: 45:156-165. 9. Fox RI et al. Primary Sjogren syndrome: Clinical and immunopathologic features. Semin Arthritis Rheum 1984: 14:77-105. 10. Petersdorf RG et al. Staphylococcal Parotitis. N Eng J Med. 1958: 259:1250-54. 11. McDonald TJ, DeRemee RA, Weiland LH. Wegener,s granulomatosis and polymorphic reticulosis: Two diseases or one? Arch Otol 1981: 107:141-144. 12. DeRemee RA. The treatment of Wegener,s granulomatosis with trimethoprim/sulfamethoxazole: Illusion or vision? Arth Rheum 1988:31:1068-1072. 13. Gaulard P et al. Lethal midline granuloma (polymorphic reticulosis) and Lymphomatoid granulomatosis. Cancer 1988: 62:705- 710. 14. Pickens JP, Modica L. Current concepts of the lethal midline granuloma syndrome. Otol H N Surg 1989:100:623-630. 15. Djalilian M et al. Nontraumatic, nonneoplastic subglottic stenosis. Presented at meeting of the American Laryngological Association, Atlanta, Georgia, Apr.6-7, 1975. 16. Fu YS, Perzin KH. Non-epithelial tumors of the nasal cavity, paranasal sinuses, and nasopharynx: A clinicopathologic study. Cancer 1974: 33:1289-1305. 17. SimpsonII GT et al. Localized Amyloidosis of the head and neck and upper aerodigestive adn lower respiratory tracts. Ann Otol Rhinol Laryngol 1984: 93: 374-379. 18. Finn DF, Farmer JC. Management of Amyloidosis of the Larynx and Trachea. Arch Otol 1982: 108:54-56. 19. Milton CM: Sarcoidosis in ENT practice. Clin Otol 1985:10:351- 355. 20. McCaffrey TV, McDonald TJ: Sarcoidosis of the nose and paranasal sinuses. Laryng 1983:93:1281-1284 21. Dash GI, Kimmelman CP. Head and Neck manifestations of Sarcoidosis. Laryng 1988:98:50-53. 22. Lazarus AA. Sarcoidosis. Otol Clin N Am 1982: 15(3): 621-633 23. Standfer JA Jr, Mattox DE. Head and neck manifestations of collagen vascular diseases. Otol Clin N Am 1986: 19:181-210. 24. Campbell SM, et al. Head and neck manifestations of autoimmune disease. Am J Otol 1983:4:187-216. -------------------------------END----------------------------------------