Amyloidosis is a heterogeneous group of disorders that involve formation of an abnormal protein misfolded into β-pleated sheets causing its precipitation into the extracellular space, forming a substance called amyloid.1,2 The lung is commonly involved with the condition. Pulmonary amyloidosis in primary Sjogren syndrome is, however, quite rare.2 It most commonly presents as multinodular disease, with or without cysts formation; yet the cases of diffuse interlobular septal amyloidosis have also been reported.2 To our knowledge, our case is the first reported case of tracheobronchial amyloidosis (TBA) in a patient with Sjogren syndrome. We highlight the importance of endoscopic management among other therapies for such a condition.
A 57-year-old man with a history of Sjogren syndrome and associated biopsy proven pulmonary amyloidosis, presented to the hospital with 4 weeks history of fevers, night sweats, cough, left-sided pleuritic chest pain, and unintentional weight loss. Workup was pertinent for elevated inflammatory markers (CRP 38, normal <1) and polyclonal hypergammaglobulinemia of IgG and IgA, with absence of leukocytosis. Computer tomography scan of the chest (Fig. 1) revealed an obstructed apical posterior left upper lobe (LUL) segment with associated bronchiectasis. Diffuse parenchymal calcifications with multiple pulmonary cysts were seen suggestive of underlying pulmonary amyloidosis.
Flexible bronchoscopy revealed multifocal yellowish plaques diffusely infiltrating the tracheobronchial tree with focal areas of cobble-stoning. Endobronchial polypoid lesions were seen in the bronchus intermedius and right basilar segments without causing significant luminal obstruction. A large submucosal deposit was seen at the level of left main stem bronchus causing significant endoluminal narrowing and almost complete obstruction of the LUL bronchus, with evidence of recent bleeding. Airway patency was achieved using a flexible forceps, followed by electrocautery using the blunt probe to control the bleeding (Fig. 2). Multiple endobronchial biopsy specimens were obtained. Pathology revealed submucosal aggregates of amorphous eosinophilic material, which stained positive with Congo red, and showed apple-green birefringence under polarizing light microscopy, suggestive of amyloid deposits (Fig. 3). Repeat computer tomography scan of the chest and airways revealed resolution of LUL bronchus obstruction and consolidation, with severe underlying residual bronchiectasis (Fig. 4).
Sjogren syndrome is an autoimmune disease in which the immune cells attack glands that produce tears and saliva leading to dry eyes or mouth. Extraglandular tissues may also be involved and the lungs are a common site.2–9 Interstitial pulmonary fibrosis, lymphocytic interstitial pneumonitis, bronchitis, and pulmonary lymphoma are common presentations.
Pulmonary amyloidosis in Sjogren syndrome is a rare association.7,8 Amyloidosis can be of varying forms depending on the histologic nature of misfolded protein. The most common types are the light chain amyloidosis (AL) and the reactive amyloidosis (AA). AL amyloidosis involves deposition of misfolded light chains of either κ or λ type, secreted in the tissues by clonal infiltration of plasma cells and are often associated with plasma cell dyscrasias such as multiple myeloma.8–10 Serum amyloid A is the fibril type deposited in AA amyloidosis. It is a form of acute phase reactant produced in response to chronic inflammation. AA amyloidosis is the most common form in chronic inflammatory conditions such as rheumatoid arthritis, lupus, or tuberculosis.10,11 The disease can be systemic or localized.10 The lungs are commonly involved in systemic amyloidosis however localized pulmonary amyloidosis is rare. It is most commonly localized to the lungs in the setting of Sjogren syndrome and can be of AL or AA types.8 Literature search by Gupta and colleagues found 37 cases describing pulmonary amyloidosis in patient with established diagnosis of Sjogren syndrome. They found that females are more likely to be affected than males with 1:27 ratio, with median age of diagnosis of 59 years (range, 29 to 79 y). The most common presenting symptoms include cough and dyspnea.2
Pulmonary amyloidosis is classified into 4 different categories: Nodular (mostly in the forms of multiple nodules but solitary amyloid lung nodules have been described), diffuse parenchymal (septal and interstitial), tracheobronchial, mediastinal, and hilar adenopathy.5,8,10
Multinodular amyloidosis with or without cyst formation is the most common form of pulmonary amyloidosis associated with Sjogren syndrome. It is mostly of the AL type that is light chain amyloidosis that occurs without systemic disease.1,2 The mechanism is poorly understood, but it has been speculated that localized monoclonal or polyclonal inflammatory cells in the lungs secrete immunoglobulins in the form of κ or λ light chains that are misfolded and deposit in the lung tissues in the form of amyloid nodules. Nodules are typically large, vary in size, have smooth margins, and often calcify.7,8 They are typically subpleural or peripheral in location with a lower lobe predominance.5 Accompanying cysts form when small distal airways become compressed by surrounding cellular inflammatory infiltrates, leading to check valve mechanism. Cysts are usually large, not numerous and are randomly distributed.5,7
Diffuse septal amyloidosis mimics interstitial lung diseases and involves diffuse infiltration of inflammatory cells with amyloid deposition in the interstitium. It can be of AA, or AL type, localized or diffuse. It is known to carry a worse prognosis compared with the nodular type.5
TBA is rare, and involves submucosal deposition of amyloid plaques in the airways. Clinically, it usually manifests itself with recurrent cough, wheezing, shortness of breath, postobstructive pneumonia, and bronchiectasis.11 Endoscopically, TBA can present as submucosal plaques, nodules (single or multiple), polypoid lesions protruding into the lumen of the airway, or rarely circumferential wall thickening. Different endoscopic forms may exist in the same patient. Piazza et al12 speculate that TBA is a spectrum of the disease that starts as submucosal plaques which become confluent leading to circumferential narrowing or formation of endoluminal polypoid lesions.
Amyloid plaques are superficial, yellow in color and thus sometimes difficult to discern from surrounding mucosa.13 Keukeleire and colleagues described the endoscopic use of autofluorescence light which gives a bright bluish discoloration to the amyloid deposit, highlighting it from surrounding normal mucosa.
Asymptomatic patients usually do not require therapy and can be followed with serial PFTs, bronchoscopies, and imaging.11,12
If symptomatic, the most commonly used approach is bronchoscopic intervention with mechanical debridement using a flexible forceps, laser therapy (CO2 vs. Nd:YAG), or combination of both.11,14 Alternative therapies that have been used include cryodebridement in combination with argon plasma coagulation, or electrocautery but experience is limited. Amyloid plaques are friable and can easily bleed. The advantage of using laser therapy is to decrease the incidence of bleeding during the debulking process. Combination of forceps and Nd:YAG laser (low-power high-energy density) is preferred method for circumferential or polypoid lesions. It has been speculated that energy delivered to the mucosa damages plasma cells that infiltrate the airway wall and play major role in amyloid formation. Laser therapy also creates a scar that limits the growth of subsequent amyloid plaques.12 CO2 laser is generally preferred for submucosal plaques located in the glottic or supraglottic areas as this technique spares the mucosa and is less likely to be complicated by scar formation which would be intolerable at those levels.12 In cases were lesions are not easily accessible through the bronchoscope, systemic chemotherapy has been used but failed to show any clinical benefit in TBA.12,15
Systemic chemotherapy (melphalan, prednisone, and colchicines) with autologous hematopoetic stem cell transplantation has shown to improve survival in patients with systemic AL amyloidosis in some clinical trials. Steroids may improve symptoms in TBA, but likely due to its effect on concomitant pneumonitis.15,16
Recently, external beam radiation therapy has been shown to be promising in TBA. A recent study from Mayo clinic published in 2007 followed 7 patients with TBA treated with external beam radiation.15 Follow-up ranged from 10 to 69 months, with monitoring of symptoms, serial FEV1, bronchoscopies, and imaging. They found that EBRT provided symptomatic as well as objective improvement compared with systemic therapy with side effect limited to grade 1 and 2 esophagitis.15
Pulmonary amyloidosis is a rare complication of Sjogren syndrome and should be suspected in patients with persistent respiratory symptoms.6 Although it can present in multiple forms, multiple nodules with or without associated cysts is the most common, and TBA is rare. In patients with symptomatic TBA, bronchoscopy with mechanical debridement alone or in combination with an ablative technique is safe and effective.14 To our knowledge, our case is the first describing TBA in the setting of Sjogren syndrome.
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