Epidemiology and Etiology

Sarcoidosis primarily affects young and middle-aged adults, with peaks for men at ages 25 to 35 years and for women between 45 and 65 years old. There is a 2:1 male-to-female ratio. Incidence of the disease varies greatly. In the United States, incidence ranges from 5 to 40 cases per 100,000 population.1 The age-adjusted incidence for whites is 11 cases per 100,000 population, whereas the incidence is considerably higher for African Americans, at 34 cases per 100,000 population. The prevalence is 10 times greater for African Americans than for whites. African Americans have an affected family member 20% of the time, whereas only 5% of whites in the United States have an affected relative. Internationally, rates are varied, with 20 cases per 100,000 population in Sweden and 1.3 cases per 100,000 population in Japan.1 Although sarcoidosis is recognized in many other countries, exact rates are unknown, primarily due to misdiagnosis as tuberculosis. Sinonasal involvement occurs in 1% of patients with sarcoidosis and rarely presents independent of systemic sarcoidosis.

The etiology of sarcoidosis remains unknown despite extensive efforts to identify the cause. Many correlations have been made, examples ranging from tree pollen exposure to firefighters to recovery of mycobacterial DNA in tissues.1 There is a wide variety of possible associated exposure points to sarcoidosis as a multifactorial end point disease. Genetic factors clearly play a role in this disease process. As noted above, certain racial groups have much higher rates. Additionally, in A Case-Control Etiologic Sarcoidosis Study (ACCESS), patients with sarcoidosis stated five times as often as control subjects that they had siblings or parents with sarcoidosis.2 In regard to specific genes, no genes to date have been identified. Specific human leukocyte antigen (HLA) subtypes have been implicated in addition to linkage to certain genes in specific ethnic groups. There is an ongoing U.S. National Institutes of Health study investigating environmental and genetic factors. Because susceptibility to sarcoidosis depends on both genetic and environmental exposures, identification of interactions between specific sarcoidosis-susceptibility loci and environmental modifiers will probably be important in delineating the cause (or causes) of sarcoidosis.3

The pathophysiology of sarcoidosis is understood on a basic level. There is development and accumulation of granulomas throughout the body. Granulomas are formed secondary to macrophage aggregation, which then differentiate into epithelioid cells. These cells lose some phagocytic capacity and subsequently fuse to form multinucleated giant cells. T cells will then form a rim around these cells; thus the granuloma seen in Fig. 35.1 . If this process continues unchecked, fibroblasts and collagen encase the clusters of cells, and fibrosis will eventually occur. This fibrosis and sclerosis alter the function of the affected tissue and thus the associated morbidity of the disease.

Clinical Features

The most important feature of sarcoidosis is its extreme heterogeneity. Multiple systems/organs will be involved at different points in each patient′s disease course. The severity will vary, with some patients having severe pulmonary disease, whereas others will have severe dermatologic manifestations.

The presentation will depend on the organ involved and the severity of its involvement. Pulmonary symptoms are the most common, with 50% of patients presenting with dyspnea, cough, or chest pain. Pulmonary involvement most commonly shows bilateral hilar lymphadenopathy on chest radiograph but can show infiltration and fibrosis in more advanced cases. Forty-five percent of patients will have systemic symptoms, such as fever, anorexia, and arthralgias. Up to 5% of cases are detected incidentally on chest radiographs.

Other organ systems can be involved, including skin, ocular, cardiac, and neurologic. Skin lesions include erythema nodosum, lupus pernio, violaceous rash, or maculopapular plaques. The ocular manifestation most commonly seen is granulomatous uveitis, but conjunctival or scleral plaques can also be seen. Eye involvement warrants more aggressive treatment secondary to possible blindness in untreated persons. Cardiac involvement can be manifested as heart block or heart failure secondary to cardiomyopathy. However, cardiac involvement rarely shows itself as clinical disease. Neurologic sequelae are also rare but can be seen as nerve palsies, pituitary dysfunction, or lymphocytic meningitis.

Sinonasal involvement can include nonspecific symptoms, such as nasal obstruction, postnasal drip, crusting, congestion, epistaxis, chronic rhinosinusitis (CRS), and headache. These findings are the usual initial sinonasal manifestations. The most consistent finding in the nose and sinuses is an erythematous, edematous, friable, hypertrophied mucosa. When subcutaneous granulomatous infiltration occurs, yellowish nodules are seen on the septum and inferior turbinate, as seen in Fig. 35.2 . If the lacrimal system or olfactory cleft is involved, epiphora or anosmia will occur. Nasal polyposis and rhinophyma can coexist in sarcoidosis. Septal perforations can also be associated with sarcoidosis and thus when seen with no known cause necessitate inclusion of sarcoidosis in the differential diagnosis.

Aggressive forms can cause hard and/or soft palate erosions, creating an oronasal fistula in addition to possibly causing a saddle nose deformity.4 Other head and neck manifestations can occur in the larynx, oral cavity, salivary gland, and facial skin (as seen in Fig. 35.3 ), along with otologic involvement and cranial nerve palsies.

Diagnostic Work-up

In patients with lesions of the nose that appear granulomatous, the differential diagnosis is extensive. Included in this are sarcoidosis and all lesions listed in Table 35.1 . Diagnosis of sinonasal lesions can be performed on pathologic examination of nasal biopsy taken in the office or the operating room. Other sites of biopsy can be transbronchial lung and skin lesions, minor salivary glands, and lymph nodes.

Regarding examination for systemic involvement, there are multiple studies to be performed. Although routine laboratory evaluation is often normal, hypercalcemia/hypercalciuria can occur. Alkaline phosphatase levels can be elevated in hepatic involvement. The most commonly disturbed laboratory marker is angiotensin-converting enzyme (ACE). ACE is secreted by noncaseating granulomas and is elevated in ~60% of patients. Unfortunately, sensitivity is only 60%, whereas specificity is 70%.

Chest radiography is of key importance in both diagnosis and staging. High-resolution computed tomography (CT) scans can be helpful in evaluating the lungs, and some experts advocate gallium scans. Pulmonary function testing should also be performed to evaluate lung function. It is important to involve rheumatologic and pulmonary specialists in the diagnosis and care of these patients.

Treatment

It is important to note that many patients with sarcoidosis are not severely affected by the disease. However, sinonasal involvement is an indication of more severe systemic disease, thus often requiring more aggressive therapy. In regards to sarcoidosis as a whole, systemic corticosteroids are the mainstay of therapy. Steroids are initiated only when symptoms become onerous enough to warrant the associated side effects with long-term oral steroid therapy. An international expert panel has suggested initiating treatment with oral prednisone at a dose of 20 to 40 mg per day.5 The panel recommends evaluating the response to treatment after 1 to 3 months. If there has been a response, the prednisone dose should be tapered to 5 to 15 mg per day, with treatment planned for an additional 9 to 12 months. If there is no response at 3 months, there is likely irreversible fibrotic disease, nonadherence to therapy, or an inadequate dose of prednisone. Once treatment with prednisone has been initiated, limiting it to short courses is unlikely to be helpful. Other medications to consider in those who fail steroid therapy are methotrexate (and other immunosuppressants), hydroxychloroquine, and tetracyclines. Methotrexate has been shown to be effective as a steroid-sparing medication. In those patients with severe lung, heart, or liver involvement, transplantation has been used with similar efficacy as with patients undergoing transplants for other reasons.

Treatment for sinonasal involvement includes other specific treatment modalities in addition to the use of oral corticosteroids. Patients will often present with the clinical picture of chronic sinusitis and meet the criteria for endoscopic sinus surgery (ESS). Though not proven to provide long-term relief of sinonasal symptoms, ESS has been shown to improve symptoms in the short term.4 It also allows for irrigation of the nasal cavities to relieve secretory stasis, improve access for office débridement, and enhance the ability to deliver topical steroids. However, even with these improvements, after sinus surgery one should inform patients with sarcoidosis that it is common to have crusting, secretory stasis, and more frequent infections.

Outcomes and Prognosis

Overall, the prognosis in patients with sarcoidosis is good. Fifty percent will have a mild form of the disease for most of their life. Patients who have a poorer prognosis tend to be African American and tend to have onset later than 40 years of age. Any patient who has persistent pulmonary symptoms for longer than 6 months has a worse prognosis, as do those patients who present with extra-thoracic disease, particularly in those with neurologic or cardiac involvement. In regards to those patients with sinonasal symptoms in addition to systemic sarcoidosis, a more difficult clinical picture and course can be expected in comparison to those with solely CRS.

Epidemiology and Etiology

The incidence of LCH is estimated to be 4 to 5.4 per 1 million people.6 Because of the difficulty of diagnosis, this rate is likely underestimated. It is slightly more common in men, with a 1.5:1 ratio. Although it can occur at any age, incidence peaks between 1 and 3 years.6

The understanding of the etiology of the development of LCH continues to progress. Normal histiocyte development occurs in the bone marrow from pluripotent stem cells. Cytokines cause the differentiation of these cells into tissue macrophages, monocytes, dendritic cells, interdigitating reticulum cells, and Langerhans cells. All histiocytoses are secondary to inappropriate production of one of these cell lines. LCH is thought to be secondary to “neoplastic” proliferation of Langerhans cells. The cause of this proliferation is unknown but could be a genetic defect, abnormal response to infection, autoimmune misreponse, or a combination of factors.7

Clinical Features

Overall, some observations on histiocytoses can be made. Systemic involvement can be seen by weight loss, fever, chills, and fatigue. Seborrheic, erythematous rash is the most common skin presentation and thus is usually noted in patients. The most common presentation in the head and neck is otitis media. Nasal involvement can include a nasal mass, epistaxis, or septal perforation. Histologic examination reveals sheets of polygonal histiocytes with a variable number of eosinophils, plasma cells, and lymphocytes. The nucleus of the Langerhans cells is characteristically pale and deeply grooved. Birbeck granules may be seen in the cytoplasm of the Langerhans cells on electron microscopy ( Fig. 35.4 ).

Specifics can be seen in the separate groups of histiocytosis. Eosinophilic granuloma is the localized form of LCH and occurs most frequently in children and young adults. The disease may be monostotic or polyostotic and in the head and neck usually affects the temporal or frontal bones. The head and neck presentation can vary but is most commonly otologic, such as acute mastoiditis, middle ear granulation tissue, tympanic membrane perforations, or facial nerve paralysis. Sinonasal involvement can be seen with nasal mass or proptosis secondary to sphenoid involvement.

Hand-Schüller-Christian disease is the chronic disseminated form of LCH. It also occurs in children and young adults. This form of LCH is polyostotic; thus head and neck manifestation usually includes skull lesions. These lesions cause exophthalmos secondary to periorbital and paranasal mass effect. Erosion into the sella turcica leads to diabetes insipidus. Cranial nerve involvement also can be seen.

Letterer-Siwe disease is the acute disseminated form of LCH. This disease is usually seen at a younger age than LCH, mainly in infants and young children. Multiple organ systems are affected; thus, the patient may present with fever, proptosis, splenomegaly, hepatomegaly, or dermatitis. Head and neck manifestations are similar to other forms of LCH.

Diagnostic Work-up

To diagnose LCH, fresh-tissue biopsy is required. Diagnostic criteria established by the Histiocyte Society include either Birbeck granules on electron microscopy or CD1a-positive cells.8 Birbeck granules are cytoplasmic inclusion bodies that sometimes have a “tennis racquet” appearance. In LCH, the Langerhans histiocytes lose their healthy dendritic morphology and become rounder. They take on a macrophage like appearance and as the disease progresses fibrosis replaces the Langerhans cells.7

Further diagnosis/evaluation depends on the systems involved. Evaluation should be tailored to identify systems (e.g., liver function tests for hepatic involvement). Testing of specific systems can be continued both for initial evaluation and for following disease course. Radiographic examination of the head and neck includes plain radiograph of the skull. Typically seen is a lytic lesion with a punched out pattern.

Treatment

Treatment depends on the systemic involvement and must be tailored to the patient′s age, disease extent, and complications associated with each treatment. Type 1 disease (eosinophilic granuloma) is traditionally treated with surgical curettage. Resection with margins is not required. Also acceptable is watchful waiting, with steroids administered topically or via injection. Radiation therapy is used for lesions inaccessible to curettage. Type 2 disease (Hand-Schüller-Christian disease) includes lesions at multiple sites. Treatment typically includes surgical excision, chemotherapy, and/or radiation therapy. Oral steroids also have a role in treatment of type 2 disease. The side effects of chemotherapy must be considered and weighed. Type 3 disease (Letterer-Siwe disease) usually includes bone marrow involvement as part of its dissemination. Treatment is a combination of radiation and chemotherapy. Surgery may have a role in palliation. Consultation with a hematologist and radiation oncologist is a must in the treatment of these patients.

Outcomes and Prognosis

The prognosis varies according to age of onset and organ system involvement. Involvement of one location carries a very good prognosis. Intermediate forms and patients with chronic dissemination have variable outcomes, with mortality rates reported up to 20%.7 Type 3 disease has been found to be uniformly fatal.

Epidemiology and Etiology

LMG-NTL is associated with the Epstein-Barr virus (EBV). It is much more common in Asia than in Western countries.9 LMG as a whole is extremely rare; thus, the LMGNTL type is even rarer. Other epidemiologic factors, such as age, gender, and race, can assist in the diagnosis of a different cause for the lesion. There is a subset of patients who have a lesion that does not fit into any category of cause; these are labeled as having idiopathic midline destructive disease (IMDD). Many of these entities are discussed elsewhere in this chapter.

LMG-NTL is thought to be a form of extranodal non-Hodgkin lymphoma. A specific NK/T cell clonal line loses its genetic regulatory restriction and reproduces itself in an uncontrolled manner. Incorporation of the EBV genome likely plays a role in this process. Different subtypes are based on the β-chain of the T cell receptor. The older terminology angiocentric is secondary to the fact that the cells form perivascular infiltrates. Regarding IMDD, its cause is unknown. Sheets of polymorphonuclear cells are seen. There are no granulomas or vasculitis.

Clinical Features

Midline destructive lesions often present with symptoms of CRS that do not respond to treatment. Patients will complain of epistaxis, obstruction, nasal discharge, facial pain, and swelling, as well as dryness. The lesion usually arises in the nasal cavity. Duration of symptoms is generally less than 1 year, with median duration of 7 months.9 Although the disease is usually limited to the midface and is locally destructive, cervical lymph node or systemic involvement can occur. In those patients with systemic involvement, fever, weight loss, and malaise may be noted.

Diagnostic Work-up

To diagnose the cause of a midline destructive lesion, multiple modalities are used. As previously mentioned, the differential diagnosis is broad. Table 35.1 lists categories of specific causes of the lesion. A complete history should be taken, and a physical examination with nasal endoscopy should be done. Hematologic evaluation includes those markers for other causes listed in this chapter (e.g., ACE for sarcoidosis), as well as a complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), and EBV antibodies. Initial radiologic examination is CT of the nose and paranasal sinuses and should subsequently include chest and abdomen scans if systemic involvement is suspected. Specific findings on the history or physical exam can guide further evaluation (e.g., cultures if infection is suspected); however, the most important aspect is multiple biopsies of the primary site. The overlying crust should be removed and biopsies taken from multiple surrounding sites of normal-appearing tissue. In addition to normal pathologic evaluation, immunohistochemistry and flow cytometry should be performed. Identification of a specific cell marker will allow for the accurate diagnosis of a pathologic cell line.

Treatment

The best therapy for LMG-NTL is unknown. Surgical therapy for the primary site with reconstruction can be required if the lesion destroys facial structures. Resection of LMG-NTL can leave a large defect that is a reconstruction dilemma ( Fig. 35.5 ). Thus, the primary modality of treatment includes some combination of radiotherapy and chemotherapy. A multidisciplinary approach to these treatments is a must. Treatment of IMDD is similar to LMG-NTL. Treatment of other midline destructive lesions is listed elsewhere in this chapter.

Outcomes and Prognosis

LMG-NTL itself has a poor prognosis, especially if disease is disseminated. There is often an initial response followed by long-term failure. Lee et al11 reviewed 57 patients with LMG-NTL reported in the literature between 1966 and 1996. Patients were treated with various combinations of radiotherapy and chemotherapy. The 5-year overall survival rate was 22% and was adversely impacted by advanced stage and age.11 Other subsets of midline destructive lesions have variable outcomes, but most are better than LMG-NTL.