Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Otolaryngologic Manifestations of Sarcoidosis Ludwig van Beethoven is known not only for his astonishing musical compositions but also for perplexing and complicated medical condition that plagued him throughout most of adult life. Beethoven suffered from an accelerating, systemic disease. This condition caused a fluctuating hearing loss that ultimately ended in complete deafness. Traditionally, his deafness has been attributed to otosclerosis with his many other symptoms explained through alcoholism or syphilis or both. As knowledge of sarcoidosis has grown over the past 100 years, so has evidence that Beethoven was probably the first recorded case of sarcoidosis. Sarcoidosis literally means "a form of flesh" and it was named so because of its peculiar skin manifestations. It is a systemic, granulomatous disease of unknown etiology. It can be self-limited or it can be progressive, relentless process. Overall, the incidence of sarcoidosis is six to ten cases per 100,000 people in the United States, with a higher proportion of cases in the Southeast. The disease first manifests between the ages of 20 and 40. African-Americans are affected 20 times more often than Caucasians. Women are more commonly affected than men and some authors report a familial tendency especially in brother-sister combinations. Historically, Hutchinson is credited with first describing the disease and he named it "Mortimers malady" after the patient, Mrs. Mortimer, who had the unique skin findings. In 1899, Boeck described the skin manifestations in more detail and called the disease Boeck's sarcoidosis. He used sarcoid in the name because he thought it was cutaneous form of a sarcoma. The Danish ophthalmologist, Heerfordt, described the triad of uveitis, parotid enlargement, and cranial nerve paresis in 1909. Schaumann described the pathologic findings in 1916 and then, in 1940, Poe was the first to pathologically document sarcoid involvement in the larynx. Finally, Kvein and Siltzbach refined a skin test for sarcoidosis using a heat killed suspension from the lymph nodes of known sarcoid patients. While the cause or "trigger" of sarcoidosis remains unknown, the pathogenesis of its many manifestations are becoming more fully understood. A specific agent or trigger stimulates local macrophage. The stimulated macrophage secretes chemotactic factors such as lymphokines that then attract T-helper (T4) lymphocytes. The T4 cells, in turn, stimulate antibody production by B-lymphocytes. Together, the activated macrophage, B-lymphocytes, and antibodies form granulomas within the effect tissue. This over active local immune response depletes the systemic immune system creating an immunologically compromised state. Thus, sarcoid patients appear immunocompromised because of a very intense local immune response. Most theories have been used to explain the "trigger" or cause of this immune response. The theory of a transmissible agent, such as tuberculosis, has received the most attention. Studies by Bowman and coworkers in 1972, and later Mitchell and Rees in 1983, failed to isolate or identify bacterial, fungal, or mycobacterial agents in human sarcoid granulomas. Others have argued that sarcoidosis represents a unique form of tuberculosis that is very difficult to culture. Two recent studies by Michell and Saboor in 1992 have renewed interest in this possibility. Michell's group detected ribosomal RNA specific to mycobacterium tuberculosis in splenic tissue of sarcoid patients. Saboor's group used polymerase chain reaction, PCR, technology to demonstrate either tuberculosis or nontuberculosis mycobacterium DNA in 70% of the bronchopulmonary lavage fluid of sarcoid patients. The DNA was found in only 9% of the controls. By definition, sarcoidosis is a systemic disease. Pulmonary findings are present in 90% of the cases and head and neck manifestations are found in 10 to 15% of the cases. Often pulmonary symptoms go unnoticed for years and it is the head and neck manifestations that prompt the patient to seek medical attention. The chest roentgenogram findings are still used today for staging criteria irrespective of extrapulmonary involvement. The frequency or severity of head and neck manifestations does not correlate with the pulmonary findings. Stage 0 are those with normal chest X-ray findings but extrapulmonary findings. Stage I are those patients with evidence of Hilar adenopathy. These patients have an excellent prognosis with a 90% chance of spontaneous resolution. Stage II indicates peripheral lung involvement without Hilar adenopathy. Only 10% of these patients will resolve without treatment. Otolaryngologic manifestations of sarcoidosis can be varied. The most common finding is posterior cervical chain lymphadenopathy. There is usually discrete nodal involvement that is symmetrical and nontender. Skin lesions are the second most common finding and a variety of conditions have been described including Lupus pernio, Hutchinson's plaque and papular sarcoid. The latter are the most common appearing as a translucent lesion often involving the eyelid. Nasal involvement is present in 13% of the cases. Obstructive symptoms with discharge are common complaints. Mucosal lesions, when present in the nose, appear as firm submucosal, yellow nodules and are almost diagnostic of sarcoidosis. Oral cavity manifestations of sarcoid are extremely rare. Parotid gland involvement is usually bilateral, nontender and occurs in approximately 6% of the cases. Parotid enlargement, however, may be much more common than originally thought, with as many as 70% of sarcoid patients having asymptomatic parotid lesions. Neurologic symptoms occur in only 5% of the cases, but they are the most common reason for otolaryngologic consultation. Facial nerve palsies are the most common cranial nerve deficit but any cranial nerve can be affected. The paresis can either be fluctuating or a relentless, progressive course. Although Heerfordt's disease most often includes facial nerve paresis, any cranial nerve can be affected in association with uveitis and parotid enlargement. Fever is also commonly associated with this constellation of findings. Laryngeal sarcoid is present in 1 - 5% of all individuals. Interestingly, it is commonly found in those patients with no pulmonary manifestations. The supraglottic area is most commonly affected but the subglottic region can also be involved. True vocal cords are rarely affected. Localized, pale edema or punctuate submucosal nodules or even a mass lesion have been described on laryngoscopy. Pale edema is the most common presentation. The differential diagnosis for sarcoidosis can be exhaustive and depends to a certain extent on the sites affected and the clinical presentation. Diagnosis depends on a thorough physical examination, chest X-ray, serologic testing, and tissue evaluation. Sarcoidosis is a diagnosis of exclusion and when the larynx is involved, a variety of chronic granulomatous diseases must be ruled out. The diagnosis requires a tissue evaluation to rule out other granulomatous diseases. It is, therefore, very important that biopsies in cases of potential sarcoidosis be analyzed for routine, fungal, and mycobacterial cultures and stains. Noncaseating granulomas are the hallmark of sarcoidosis. Various intracytoplasmic inclusion bodies have been associated with sarcoidosis; however, none is pathognomonic. Tissue is best taken from a superficial lymph node, but other described sites include lung and mediastinal biopsies when lymph nodes are not available. Studies by Marx and coworkers have shown that random biopsies of salivary gland tissue are very useful. Traditionally, labial biopsies have been used but a more effective site is the tail of parotid region. This is 93% effective irrespective of the presence of parotid enlargement. The incision is hidden behind the lobule and the procedure can be performed in the office setting using local anesthesia. Serologic testing can support the diagnosis of sarcoidosis. Again, no single test is diagnostic. Tests such as the Erythrocyte Sedimentation Rate (ESR) and the Angiotensin Converting Enzyme level (ACE). The ACE level is the most useful test. It converts angiotensin I to angiotensin II. The enzyme is concentrated within the pulmonary vasculature and is also found in bronchopulmonary lavage fluid, serum and cerebral spinal fluid. ACE levels are elevated in 60% of patients with sarcoidosis. Its greatest use is not so much in the diagnosis of this disease, but as a measure of the "granuloma load" or as a marker of patients response to therapy. Another useful test is the gallium-67 scan. It is a more sensitive measure of pulmonary involvement than plain chest X-rays and can also detect subclinical disease in the parotid gland. The combination of an elevated ACE level and a positive gallium-67 scan is 85% specific for sarcoidosis. When considering treatment options for sarcoidosis, it should be remembered that many patients will show spontaneous resolution without intervention. When pulmonary manifestations are present, treatment is generally required. Extrapulmonary manifestations require treatment when major organs, neurologic, ocular, deforming skin lesions, or aerodigestive tract involvement are present. Oral steroids remain the cornerstone of treatment, but there is no set protocol. Patients are usually treated for at least six months initially. ACE or the ESR levels can be used to monitor response to the medical regimen. Local steroids either as topical ointment or as nasal sprays can be of benefit when skin or nasal involvement is present. The prognosis for patients requiring treatment is good, with over 70% of the patients either improving or experiencing no further progression of disease. Those with progressive disease can have a relentless course that can end in death due to either respiratory or cardiac failure. Those patients with laryngeal involvement also require oral steroids and it remains the treatment of choice. Some authors, such as Krespi, have advocated intralesional steroids for supraglottic sites, but this requires a general anesthetic with each treatment. There have been five reported cases of glottic sarcoidosis treated with external beam radiation therapy. Four of the five patients failed therapy and one patient later developed laryngeal carcinoma. Case Presentation A 41-year-old black female presented with an approximately 4 month history of progressive hoarseness, severe nasal obstruction with constant rhinorrhea, a nontender facial rash, and dyspnea on exertion. There was no associated weight loss, fever, cough, night sweats or hemoptysis. Her past history was significant for right breast cancer treated in 1985 and recurrent dacryocystitis treated by dacryocystorhinostomy with partial resection of the inferior turbinates in January 1994. Her examination was significant for a 10cm x 9cm elevated, plaque-like lesion involving the left cheek, copious nasal secretions, but no cervical lymphadenopathy. Endoscopy revealed complete obstruction of the velopharyngeal inlet with mature scar tissue and pale supraglottic edema obscuring the glottis. She then underwent awake tracheotomy and direct laryngoscopy, which confirmed an edematous, pale epiglottis nearly obstructing the glottis. Biopsies of the skin and epiglottis revealed noncaseating granulomas. Further evaluation included serologic testing, chest x-ray, PPD, and Gallium-67 imaging. S.B. has been receiving oral steroids for the treatment of sarcoidosis. All cultures for the skin, epiglottis and sputum were negative at last follow-up (5 weeks). Bibliography Babin RW, Liu C, Aschenbrener C. Histopathology of neurosensory deafness in sarcoidosis. Ann Otol Rhinol Laryngol 1984;93:389-393. Bower JS, Belen JE, Weg JG, Dantzker DR. 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