| 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 Some take-home points initially are: We still do not know the etiology of sarcoidosis, the manifestations are protean, the disease is very heterogeneous, the treatments are pretty much the same for each site presentation, and the prognosis is variable. As always, we start off with a bit of a historical perspective. Dr. Hutchinson, pictured here, in 1875 was first to really recognize the commonality of the skin lesions and the cutaneous aspects, but he originally thought that it was probably due to some form of gout. And then Dr. Beck, in 1899, coined the term "sarcoid" because he thought the lesions resembled sarcomas. Then he also began to recognize that this was not just a disease that affected the skin, but had systemic aspects as well In 1909, Heerfordt's syndrome, or uveoparotid fever, which is also well recognized and well described in the medical literature, which consists of fever, uveitis and parotid enlargement was first recognized as a clinical entity. He also began to recognize that there were neurologic symptoms that could be a part of the disease. The first large case series was reported in about 1948, and again mapped out the dermatologic manifestations and also began to look at the pulmonary manifestations, the neurologic manifestations, and really began to see sarcoidosis as a common clinical entity. Sarcoidosis occurs worldwide. It affects all races, and in the United States the prevalence is about 1 to 40 per 100,000. The incidence in the U.S.A. is about 10.9 per 100,000 for Whites and about 35.5 per 100,000 for Blacks. The lifetime risk is about 2.4 percent for U.S. Blacks and about 0.85 percent for U.S. Whites. As I mentioned, there is a wide variation. The disease is very heterogeneous. You will see multiple systems and multiple organs involved in different patients at different times. The severity of the disease may be different. One patient may have very severe dermatological manifestations with only minor pulmonary disease, while one patient may have severe pulmonary disease and no other manifestations. African-Americans tend to present more acutely and more severely, which may explain why the prevalence is higher in African-Americans in the sense that they tend to present to the physician so they tend to get counted and their disease tends to get recognized. It is thought that other populations may have a more indolent form of the disease and also may be mistaken as having some other disease. Whites in the United States tend to present more asymptomatically, as I was mentioning, and those that do form the manifestations of the disease tend to have a more chronic disease, a more indolent disease. Twenty-five percent with chronic pulmonary disease die from respiratory failure. The extrathoracic manifestations like erythema nodosum is much more common in U.S. Blacks, Puerto Ricans, as well as Scandinavians. These also happen to be individuals who have the more severe forms of the disease and have the higher mortality/morbidity rates. The real etiology of the disease is elusive; it is unclear. The disease is heterogeneous, there is no precise definition, there is significant overlap with other diseases, particularly if you look at mycobacterium infections like tuberculosis, syphilis, and other diseases that cause granulomatous changes. Often you will see a patient with sarcoidosis come in and they will have classic features of the disease, and then they will have a positive PPD. So, is this tuberculosis with sarcoidosis on top of it, or is it just sarcoidosis? Is sarcoidosis due to a mycobacterium like TB? It is very unclear. And what makes it even more difficult is there is no definitive diagnostic test to make the diagnosis. If you look at the environmental factors and why some people think this is a key part of the disease aspect, there are numerous case reports that look at clustering the disease, and they find that among nurses working at the same hospital, a lot of them will have sarcoidosis. Close contacts. You have a patient who has sarcoidosis, people who live in the same house, people who live in the same neighborhood, there is often clustering of the disease. People who live near hospitals. There also tends to be a clustering of the disease. The work environments. There is a report of firefighters who were sharing the same house, and if you looked at them over 10 years, a lot of them began to develop sarcoidosis. And then we also know that if you get exposed to certain dust and metals, they will produce diseases histologically indistinguishable from sarcoidosis. So, again, the environment, whether or not there is some dust in the atmosphere, whether or not there is some antigen that people are exposed to causing the disease is under intense investigation. If you look at the microbes, as I mentioned earlier, there are numerous germs that can cause granulomatous infections: tuberculosis, histoplasmosis, Chlamydia, syphilis, toxoplasmosis, parasites, bacteria, and fungi. Every spectrum of microbes in the universe can cause symptoms and diseases and signs very similar to sarcoidosis. So, is there some unknown pathogen that is producing this disease in individuals remains unclear. Additionally if you take homogenates of sarcoid tissue and you inject it into the skin, some patients will develop this dissimulated granulomas, which suggests that perhaps there is a pathogen at work. There are numerous case reports of sarcoidosis being transmitted by these transplants. However, to date, there are no microorganisms that have been identified as the exact cause of sarcoidosis. When you look at the genetic factors, genetics also seems to play a big role in all of this. There are probably multiple genes involved. One theory, or one aspect is that monozygotic twins tend to show higher rates, so perhaps there is some genetic defect or some genetic predisposition. Also, the disease tends to develop in susceptible hosts after antigen exposures. And there is also familiar clustering. So if you take U.S. Blacks and U.S. Whites, if a family member has sarcoidosis, there is a risk that another family member will have sarcoidosis as well. Again, genetic factors continued: tuberculosis and leprosy, there have been well-defined studies that show that the disease severity as well as the prognosis of these diseases is directly linked to genetic predisposition. And of course, we both know that these cause granulomatous infections as well. Vermillion disease, which can cause a granulomatous infection of the lungs, has been linked to susceptibility of HLA molecules. They are also serologic studies in patients with sarcoidosis, especially in Whites, that show that there are HLA-primary associations that tends to put people at higher risk for developing the disorder. Current research is looking at genetic polymorphism and genes controlling growth factor regulation. The pathological features of sarcoidosis: The hallmark is noncaseating granuloma. Again, you have monocyte aggregation which differentiates into epithelioid and giant cells and T-cells will then form a rim forming the granuloma, and then you will have multiple effector cells like mast cells, other monocytes, platelets, fibroblasts, they will begin to create the well-defined granuloma. And at this stage, if this process goes unchecked, the end result is always fibrosis, which is what causes most of the morbidity related to the disorder. Here is a picture if the progression in the lungs. You have a normal lung, normal alveoli, then you have formation of the granuloma. This is the granuloma at higher magnification. You see the well-defined rim and noncaseation in the center. And then at end-stage, you get fibrosis and replacement of the normal architecture by this fibrotic disease and, of course, that leads to the significant pathology and morbidity. The immune system certainly plays a role in sarcoidosis; T-cells in particular seem to have a key role in all of this. It has been shown that there are increased monoclonal populations of T-cells in sarcoidosis. There is also evidence that there is a single antigen, single T-cell type in certain individuals, and as well as the T-cells help propagate the cascade which eventually produce the granulomas and the fibrosis So, how do you make the diagnosis? Really the history is probably the most important part. The diagnosis of sarcoidosis is really a diagnosis of exclusion. You want to make sure that they do not have another potentially treatable granulomatous infection. And eventually obtain a biopsy. Now, where do you do the biopsy? There have been numerous studies about doing minor salivary gland biopsies, doing mediastinoscopy in order to get lymph nodes out of the mediastinum. The basic thing is to find the most accessible site where you think the pathology exists and biopsy that. And again, you want to see the noncaseating granuloma to help make the definitive diagnosis. You also want to be mindful that there are many other causes and we have many other tests now to help us differentiate those causes. As I mentioned, there is no definitive laboratory test. The ACE level, which is elevated in some patients with sarcoidosis, lacks specificity because it is also elevated in liver disease, diabetes, and infection, but it is a useful adjuvant test as part of your work-up. The Gallium 67 scan pictured here is also a useful test. It shows increased uptake and sarcoidosis lesions. This is called the Panda sign, the idea is that is sort of looks like a giant panda. You have the lacrimal glands, the parotid and the nasopharynx and sub-mandibulary gland forming areas of increased uptake and that is suggestive of sarcoidosis. You get lots of false positives, as you can imagine, and it is a very non-specific test. The sensitivities range from about 50 to 86 percent for ACE levels and from 86 to about 99 percent for the Gallium scans. But again, these tests do not have great specificity. The Kveim Silk Spot test has been well described in the past. You inject homogenates of sarcoid spleen or lymph nodes into the skin site of patients who you suspect of having sarcoid. The test is really obsolete at this point because it is not standardized. It takes almost 2 months in most patients to get a good result, and FDA has not approved this test for use. So, it is more of historical interest. Other tests that can help, nonspecific tests that can help with the diagnosis are hypercalcemia, anemia, thrombocytopenia, and elevated LFTs. Again, when making the diagnosis of sarcoidosis, you are looking for the classic history, hopefully a pathology specimen that shows noncaseating granulomas, and then some of these diagnostic tests which will also help with the diagnosis. The pulmonary manifestations should be talked about a little bit because these cause probably the most morbidity in patients. It occurs in almost every patient. How active it is depends on the patient individually. Typically it is an interstitial lung disease. You have dry rales, restrictive lung volumes, it affects the alveoli of the blood vessels as well as the bronchioles, and it is divided classically into three stages. The first stage is where you just have hilar lymphadenopathy, second stage you have hilar lymphadenopathy with infiltrates, and the third stage is infiltrates without lymphadenopathy. Just some x-rays showing the different stages: Stage 1, which is the hilar lymphadenopathy—these are not the best x-rays—Stage 2, you do see hilar lymphadenopathy and then you also see the infiltrates, and here you really do not see hilar lymphadenopathy, but you do begin to see infiltrates. Overall, if a patient has sarcoidosis the prognosis is pretty good. Fifty percent will exist with mild disease for most of their life. Patients who have poor prognosis tend to be African-American, tend to have onset later than 40 years of age. Any patient who has persistent pulmonary symptoms greater than 6 months has a worse prognosis, and patients who present with extrathoracic disease also have a poor prognosis, particularly if it presents in the nervous system or in the cardiac system. Prednisone is by far the most studied, most commonly used, and it is the mainstay; it is first-line therapy for anyone who has severe disease. You dose it at about 30 to 40 mg a day, you give it at least for several months, and then you try to taper it depending on the symptoms, depending on the patient. There are no real standardized or duration studies done in the literature and the effects on long-term outcomes are not known, but it tends, the belief is that it does not affect long-term outcomes. You only treat the acute symptoms with this medication. These other medications are used if patients are not tolerating steroids, they have side effects, or if the disease continues to progress despite steroids. Methotrexate is the most common used adjuvant. It has been pretty well studied. It has good efficaciousness, and again, it is used in refractory cases. It also can be a steroid-sparing medication. So, you have a patient who is on steroids, the dose seems to be too high for them, you add Methotrexate, you are able to reduce the dose of the steroid. Cyclosporine, as well as anti-malarial agents and other agents that tend to be treated for other granulomatous infections, have also been tried. For the most part, these are only case reports or small case series. There are not any large studies looking at any of these agents, but any of them can be tried if the patient is failing use of steroids. Since we dealt with the pulmonary system, kind of go from the neck on up to the brain in terms of what we are likely to see in our practice. Laryngeal sarcoidosis. There was a large study by the Mayo Clinic that looked at 3,000 patients with sarcoidosis and they basically did chart review and said, "Who has head and neck manifestations?" And most of the numbers listed here are from that study. Laryngeal sarcoidosis is about one percent; it may be higher because a lot of patients may be asymptomatic, and if they are asymptomatic, no one is looking at their larynx to see if there are changes, which there could be. But in patients who present, about one percent, isolated disease has been described, although it is very rare. And this is a diagnosis of exclusion. Do not assume because someone has sarcoidosis and presents with laryngeal involvement that it is sarcoidosis. It may not be, although it most certainly could. Typical symptoms for any laryngeal involvement: hoarseness, dysphasia, dyspnea, etc. This is a CT scan just showing thickening of the epiglottis, which is classic for sarcoidosis. As I was going to mention, it has a predilection for the supraglottis, the epiglottis and the false chords in particular. It does not seem to involve the true vocal chords very much. One person theorized that perhaps it the paucity of lymphatics in the true vocal cords is the reason why there is not great involvement of those chords. However, we have seen that and it can indeed occur. Classically, you'll see an edematous, pale, and diffuse enlargement of the supraglottic structures. Ulcerations are not common, so if you see ulcerations, think that this is probably not sarcoidosis. Subglottic stenosis has been described and typically the vocal chord mobility is normal. If you see vocal chord abnormalities, it could be for two reasons. There could be thoracic disease that is causing compression of the vocal chords. Certainly it could be a peripheral neuropathy, the sarcoidosis can affect cranial nerves, or it could be that the inflammatory mass now has become full thickness and transglottic and it is causing vocal cord immobility. If you see a patient who has laryngeal sarcoidosis, asymptomatic patients can be followed. They do not have to be treated. Anyone who is symptomatic, of course, needs treatment. And as I will say over and over, high-dose steroids are first-line therapy. The overall effectiveness has never been fully studied because for the most part they are just case reports or small case series looking at this issue. But, the studies that are published say the majority should respond at least partially, and they should respond relatively quickly - within a few weeks. If a patient does not respond, you need to make sure it is the right diagnosis. You can also do adjuvant therapy by injecting intralesional steroid with Kenalog. Surgery is certainly an option in our hands, but again there are only case reports in the literature. Most patients will respond to steroid therapy, and the surgeries that have been done have been varied. XRT radiation therapy has been given in several case reports, and it is for severe cases. Most of those patients have been “trached” and now they are getting radiation therapy to attempt to regress the disease. So, moving on to the oral cavity, sarcoidosis can occur in the oral cavity. Lesions are very rare, sites can be anywhere: lips, gingiva, palate, and buccal mucosa. There have been several case reports of tongue involvement, and again, this is even more rare. These lesions tend to be painless, gelatinous nodules. It can also resemble, if the disease becomes severe enough, angular stomatitis or herpes labialis. You can see lip swelling. It can even infect the TMJ joint, so people can present with various TMJ disorders. Salivary gland involvement is well recognized. I mentioned earlier uveoparotid fever. This patient has diffuse parotid enlargement. Xerostomia tends to be a major problem with these patients—they get salivary gland involvement—and for the most part there is not a lot of literature on treating just asymptomatic enlargement. These patients tend to be watched. I did not see any major case reports of people doing parotidectomies, etc., for these diseases, or for this manifestation, but I am sure there are individual cases where that may be an option. In terms of the moving further up the sinonasal cavity, involvement again is uncommon at one percent. And there is some evidence that if you have concomitant pulmonary disease and sinonasal disease, that the sinonasal disease is a good measure of the activity in the pulmonary system. Complaints typically are chronic nasal congestion, obstruction, people have recurrent sinusitis, you can see nasal polyps, anosmia, etc. The classic appearance is dry, crusted mucosa with yellow submucosal nodules. It has a propensity to affect the septum in the inferior turbinate. Patients require systemic steroid therapy. Response is highly variable. Adjuvant therapy, nasal irrigation, topical nasal steroids, endoscopic surgery; there have been numerous case reports referring to endoscopic surgery and its role in sarcoidosis. It seems that it only provides short-term relief. It also facilitates office evaluation as well as irrigation. However, it does not have an effect on long-term prognosis If you look at the skin involvement of the face, about 35 percent will have skin involvement. There are non-specific lesions as well as specific lesions. Non-specific would be erythema nodosums pictured here, which are tender subcutaneous nodules, of sudden onset, In terms of the face, again, you will see papules, which are single or multiple. You will see plaques that are much larger lesions, flat-topped lesions. You will see the lupus pernio, which is one of the few lesions that is highly characteristic of sarcoidosis. Chronic indurated papules affecting the mid-face, particularly the nasal ala. You can also see sarcoidosis develop in scars as well as the scalp, causing alopecia And treatment, most people are using high potency steroids topically, or they are using Kenalog injections which may be the preferred way. Systemic therapy is used if they have widespread recalcitrant disease. So, otologic, most patients tend to be asymptomatic, but if you look at ABR's, you will find that a lot of patients do have abnormalities. They can present with gradual or fluctuating sensorineural hearing loss. It tends to be bilateral, although asymmetric losses tend to be common, and the etiology of hearing loss in sarcoidosis is not well understood. There are several theories. Is it mechanical pressure from lesions on the skull base? Could it be actual neural invasion of the lesions themselves? Or could it just be perivasculitis from inflammation of the blood vessels surrounding the eighth nerve? In terms of the external and auditory canal, these areas are not affected commonly. You can see the dermatological lesions. You can treat them with injections or creams. I only saw one case reported with middle ear disease that presented as chronic otitis media, and it responded well to systemic steroids. Neural, otologic, and neurologic, these are uncommon but serious manifestations. The incidence in clinical studies is about 5-16 percent; if you look at pathological specimens, it is about 15 percent. It tends to occur late in the disease. Any aspect of the nervous system can be affected. Cranial neuropathies are the most common and isolated are much greater than multiple neuropathies. Cranial Nerve No. 7 is the most commonly seen, unilateral is greater than sequential which is greater than bilateral, although all three can be seen. The site is felt to be proximal to the styloid foramen and the prognosis is excellent; 80 percent will recover with or without therapy. The other cranial nerves, Cranial Nerve 8, as I mentioned, about 10-20 percent will be affected. It usually presents as an abnormal ABR, most of them are asymmetric. The oculomotor nerves are rarely involved. Cranial Nerve 1 can be involved by direct involvement of disease at the skull base or sinonasal disease that tend to present as anosmia. And the other cranial nerves are not classically involved although it has been described. The diagnosis itself can be extremely challenging because biopsies carry risk, obviously. MRI is one of the best imaging techniques; you give it with and without contrast, and the lesions will enhance. They can mimic MS. So, if you do a spinal tap, you will see mononuclear pleocytosis, increased proteins, as well as there will be increased levels of ACE in 50 percent of the patients, and if you do see that it can be a marker of disease activity, so it is something that you can potentially follow. How do you treat it? You give steroids. And, again, high dose, long-term, tapered over many months. Most patients will do well. If they do not respond to that, you can try some of the adjuvant therapies. Cyclosporine has been the most commonly described because it has good CSF penetration and it has good steroid-sparing effect, as well as low cost and high tolerability. The rest of these agents have been looked at but only really in very small case series. Radiotherapy is reserved for diffuse encephalopathy and if patients present this way, they have a very poor prognosis and outcomes. If your patient doesn't get better on steroid therapy, strongly consider biopsy because you may have the wrong diagnosis. In conclusion, sarcoidosis is a systemic disease with protean features and unknown etiology. Head and neck manifestations are numerous. Steroids remain the most acceptable and widely used treatment options. Adjuvant therapy is reserved for patients who fail to respond to conventional therapy. Case Presentation: He complained only of the above nasal symptoms. He denied change in hearing status, otorrhea, otalgia, sinus pressure, sinus pain, oral cavity pain, dysphagia, odynophagia, hoarseness, or trismus. He did not seek ENT evaluation in the past. He is classified as Stage II pulmonary sarcoidosis. Beside his head and neck complaints, he also had chronic lower extremity rashes and joint swelling in hands. His head and neck exam was positive for pustules along the alar rims with septum and inferior turbinate crusting. His middle turbinates and OMCs appeared clear of disease. The other lesions were appreciated on examination. He was started on nasal saline irrigations, flunisolide nasal steroid, and Bactroban ointment. At one-month follow-up, he reported improvement in his symptoms. His exam showed improvement of the nasal crusting. He is currently not taking systemic corticosteroids. Bibliography: Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003;361:1111-1118.
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