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Pleuropulmonary manifestations of amyloidosis

Pleuropulmonary manifestations of amyloidosis
Literature review current through: Jan 2024.
This topic last updated: Dec 08, 2021.

INTRODUCTION — Amyloidosis results from the misfolding and orderly aggregation of proteins into fibrils that are deposited in tissues resulting in disruption of function of major organs. Over 30 proteins have been described to be amyloidogenic in humans, but only a portion of them clinically affect the lungs. Clinical reviews of the most prevalent forms of systemic amyloidosis, immunoglobulin (Ig) light chain and transthyretin amyloidosis (ATTR), rarely mention clinically apparent thoracic manifestations of disease [1]; however, autopsy series consistently document widespread amyloid deposits in the lung [2,3].

Respiratory tract involvement by amyloidosis will be reviewed here. Related topics include the following:

An overview of amyloidosis (see "Overview of amyloidosis")

Cardiac amyloidosis (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis" and "Cardiac amyloidosis: Treatment and prognosis")

Gastrointestinal amyloidosis (see "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management")

Renal amyloidosis (see "Renal amyloidosis")

Immunoglobulin light chain (AL) amyloidosis (see "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis")

AA (secondary) amyloidosis (see "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases" and "Treatment of AA (secondary) amyloidosis")

OVERVIEW — Amyloidosis is the general term for a clinical condition that develops when one of more than 30 different precursor proteins with an unstable tertiary structure misfolds and aggregates as insoluble amyloid fibrils that deposit in the extracellular space of organs and soft tissue (table 1). The pathognomonic feature of amyloid deposits is apple-green birefringence when stained with Congo red dye viewed under polarized light. (See "Overview of amyloidosis".)

Types of amyloid proteins — The types of amyloidogenic protein that affect the respiratory system include the following:

AL amyloid – The fibrils in AL (immunoglobulin light chain) amyloidosis can be derived from either lambda or kappa immunoglobulin light chains. Lambda immunoglobulin light chains predominate in systemic AL amyloidosis, including that causing lung disease, accounting for about two-thirds of cases. In contrast, kappa-derived AL amyloid deposits are over-represented in localized AL amyloidosis affecting the respiratory tract.

Transthyretin amyloid – Wild-type (age-related) and variant (hereditary) transthyretin amyloidosis (ATTRwt and ATTRm, respectively), a liver-derived transport protein, are less common causes of clinical lung disease [4,5].

AA (secondary) amyloid – AA amyloidosis due to deposition of serum amyloid A protein (SAA), and variant apolipoprotein (AApoAI and AApoAII) amyloid, rarely exhibit clinical signs of lung disease.

Distribution of pulmonary amyloidosis — Most clinically evident pulmonary amyloidosis results from plasma cell production of monoclonal free Ig light chains (AL amyloid), which are either produced in the bone marrow and subsequently deposited in the lungs or pleura (systemic AL disease), or generated in the lungs and deposited locally (localized AL disease) [6] (see "Overview of amyloidosis", section on 'Types of amyloidosis'):

Systemic amyloidosis – Precursor protein is produced remotely (outside the chest) and deposited preferentially in the lungs and potentially other organs. Sites of deposition in the chest include the lung interstitium, vasculature (pulmonary and bronchial arteries), lymph nodes, pleura, phrenic nerves, and diaphragm. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Localized amyloidosis – Precursor amyloidogenic protein produced and deposited in the thorax. Chest sites of deposition most frequently include lung parenchyma (nodules and cysts) and airways (larynx, tracheobronchial tree). (See "Overview of amyloidosis", section on 'Pathogenesis'.)

Autopsy findings — An autopsy study spanning 17 years at a single referral center for amyloidosis identified 76 cases of pulmonary amyloidosis: 76 percent Ig light chain (AL); 22 percent transthyretin amyloidosis (ATTR; 14 patients with ATTRwt and 3 patients with ATTRm); and 1 percent apolipoprotein IV (ApoAIV; AApoAIV) (table 1) [7]. (See "Overview of amyloidosis".)

Important autopsy findings include the following:

Heart and pulmonary vasculature were most frequently involved (99 percent and 97 percent, respectively).

Alveolar septal lung infiltration occurred in 59 patients (78 percent). Of these, 44 (75 percent) had AL amyloidosis, 11 (19 percent) had ATTRwt, 3 (5 percent) had ATTRm, and 1 had AApoAIV.

Although pulmonary amyloid deposition was clinically diagnosed in the majority of AL patients with lung involvement (76 percent), only 23 percent of ATTR lung cases were recognized before autopsy.

An earlier autopsy study at a different referral center of 22 patients with systemic amyloidosis (15 AL; 7 AA) revealed:

Extensive amyloid infiltrating the alveolar septa, supporting tissues surrounding airways, and pulmonary vessels in 14/15 (93 percent) of the AL patients [2]. Despite the nearly ubiquitous presence of histologic amyloid in autopsied lungs, only 33 percent of these AL patients expressed respiratory symptoms.

In contrast, AA amyloidosis (caused by deposition of serum amyloid A [SAA] protein, an acute phase reactant) did not exhibit alveolar-septal amyloid clinically nor at autopsy.

WHEN TO REFER — For patients with suspected or newly diagnosed amyloidosis, referral to a center that specializes in the evaluation and management of amyloidosis is advised, whenever feasible, to access experts in the interpretation and further processing of pathologic specimens, identification of the type of amyloid, detailed characterization of the distribution and extent of disease, and determination of optimal management approaches.

DIFFUSE PARENCHYMAL LUNG AMYLOIDOSIS — Diffuse parenchymal lung amyloid is synonymous with alveolar septal amyloid histology and most often occurs in patients with systemic AL amyloidosis (derived from lambda light chains in two-thirds of cases and kappa light chains in the remainder). Rarely, patients present with diffuse parenchymal opacities due to localized AL amyloid (predominantly kappa light chain deposition), with no evidence of a systemic plasma cell dyscrasia or involvement of other major organs [6,8]. Diffuse parenchymal lung involvement with systemic AA amyloidosis is rare, and it is infrequent (22 percent of amyloid lung cases at autopsy) with transthyretin amyloidosis (ATTR; wild-type or hereditary) [6,7]. (See 'Types of amyloid proteins' above.)

Clinical features — Patients with diffuse parenchymal lung (interstitial/alveolar septal) amyloidosis most often experience exertional dyspnea and fatigue [4]. In those with concurrent amyloid cardiomyopathy, shortness of breath and diminished exercise capacity may be misattributed to heart failure and not amyloid lung involvement. Consequently, amyloid interstitial lung disease may go unrecognized in patients with multiorgan disease. Persistent dyspnea and interstitial prominence on imaging studies, despite aggressive diuresis, raises the possibility of amyloid lung involvement.

Imaging — Standard- and high-resolution computed tomography (HRCT) features of diffuse parenchymal amyloidosis vary and include reticular, reticulonodular, and ground glass opacities, and also subpleural honeycombing patterns. The interstitial lung findings on chest imaging do not differ between specific amyloidogenic proteins, ranging from nonspecific reticular lung opacities to a classic reticulonodular pattern mimicking granulomatous lung disease. Additionally, there are no imaging findings that distinguish amyloidosis from other causes of interstitial changes. The appearance of interstitial lung disease in the absence of ongoing heart failure in a patient with known amyloidosis should raise the possibility of lung involvement.

Systemic AL (immunoglobulin [Ig] light chain) amyloidosis – HRCT features associated with systemic Ig light chain deposition include interlobular septal thickening, 2 to 4 mm micronodules, and linear, reticulonodular, and patchy ground glass opacities [9,10]. The opacities are predominantly in the middle and basilar lung fields, extending from hilum to subpleural space.

Localized AL amyloidosis – Localized AL amyloidosis most commonly presents as nodular or cystic pulmonary amyloidosis, as described below (see 'Nodular pulmonary amyloidosis' below and 'Cystic pulmonary amyloidosis' below). However, patients with localized AL amyloidosis can have HRCT features of interlobular septal thickening and patchy or ground glass opacities [9,10]. The radiographic appearance of the interstitial lung amyloidosis does not differentiate systemic from localized disease.

ATTR wild-type and variant – Typically, ATTR amyloidosis in the lungs is associated with an HRCT pattern of interlobular septal thickening; however, unilateral disease can occur, both with and without accompanying transthyretin amyloid (ATTR) cardiomyopathy. Rarely, ATTR can present as isolated lung nodules [11]. (See 'Nodular pulmonary amyloidosis' below.)

Pulmonary function tests — Patients with diffuse lung parenchymal amyloidosis typically exhibit restrictive lung physiology, reduced diffusing capacity for carbon monoxide (DLCO), and exertional hypoxemia, regardless of the amyloid type. DLCO is most sensitive to the presence of alveolar septal lung infiltration. (See "Overview of pulmonary function testing in adults".)

Diagnosis — The approach to the diagnosis of diffuse parenchymal lung amyloidosis depends on whether the patient has known systemic AL or transthyretin amyloidosis. The diagnosis requires histopathologic demonstration of green birefringence on Congo red staining or other techniques such as mass spectroscopy or electron microscopic demonstration of amyloid fibrils and identification of the amyloidogenic protein. In some cases, systemic amyloidosis is demonstrated by biopsy of extrapulmonary tissue, and a clinical diagnosis of lung parenchymal amyloidosis is based on the CT appearance in the absence of preexisting lung disease or coincident pulmonary edema. (See 'Imaging' above.)

Known systemic AL amyloidosis – For most patients, the diagnosis of systemic AL amyloidosis is established prior to recognition of diffuse lung parenchymal amyloidosis. If histologic diagnosis of lung amyloid will not alter treatment plans, lung biopsy may not be necessary. In such patients, pulmonary edema due to amyloid cardiomyopathy must be excluded. Progressive interstitial lung disease in the absence of heart failure may warrant biopsy confirmation if treatment is predicated on advancing amyloidosis in the lung.

Amyloidosis not previously diagnosed – If systemic AL amyloidosis is suspected as the cause of lung disease (eg, based on proteinuria, macroglossia, periorbital ecchymoses, or infiltrative cardiomyopathy), tissue biopsy is required to establish the presence of amyloid deposits. Sampling options from least to most invasive include abdominal fat pad aspirates, minor salivary glands, stomach or rectal biopsies, and lung biopsies. (See "Overview of amyloidosis", section on 'Diagnosis'.)

When a diagnosis cannot be achieved with less invasive methods, diffuse alveolar-septal amyloid can often be diagnosed by transbronchial biopsy, with risks commensurate with the procedure in patients with nonamyloid-related interstitial lung disease (ILD) [12]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Indications and contraindications", section on 'Contraindications' and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Endobronchial biopsy'.)

Surgical lung biopsy is a more invasive, definitive alternative, if transbronchial biopsy is not possible or proves nondiagnostic.

On hematoxylin-eosin stained biopsy sections, amyloid (and light chain deposition disease) appears as pink, amorphous deposits in the extracellular or vascular space. Congo red staining is needed to confirm green birefringence under cross polarized light, which is diagnostic of amyloidosis. The presence of giant cell granulomata surrounding amyloid deposits favors a diagnosis of localized amyloid disease, whether in the lung or other organs [13]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Identifying amyloid' and 'Differential diagnosis' below.)

The next and perhaps most critical step is to determine the type of amyloid by immunohistochemical staining with appropriate antibodies, immunogold electron microscopy, or laser capture tandem mass spectrometry [14]. These tests often require that tissue samples be sent to a referral center, as described separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Determining the type of amyloid'.)

Differential diagnosis

Light chain deposition disease (LCDD) can mimic alveolar septal amyloid clinically, radiographically, and on hematoxylin-eosin stains. Congo red staining does not exhibit green birefringence in LCDD, and electron microscopy distinctively reveals granular deposits without fibrils, and immunofluorescence microscopy is strongly positive for monoclonal light chain. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Collagen deposition in chronic fibrosing interstitial pneumonia can appear similar to diffuse amyloid deposits on hematoxylin and eosin stains, but should appear white (collagen) as opposed to green (amyloid) when stained with Congo red dye and viewed under polarized light [4]. Notably, overstaining with Congo red dye can make any connective tissue appear congophilic.

Management — The management of diffuse parenchymal (alveolar septal) amyloidosis is based on the specific amyloid type defined by the amyloidogenic protein. The objective of treating the underlying amyloid process in patients with interstitial lung amyloidosis is primarily to limit or prevent progression of the lung process. Although resorption of existing amyloid can follow successful treatment of the plasma cell dyscrasia or elimination of TTR or non-TTR protein aggregation in the kidneys, heart, or liver, the lung rarely remodels in a clinically meaningful fashion [15]. In our experience, patients with symptomatic lung amyloidosis tolerate AL amyloid chemotherapy protocols poorly and without clinical benefit. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

In patients with cardiomyopathy due to AL amyloidosis, progressive cardiomyopathy dictates survival far more than alveolar septal lung involvement. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Impact of organ involvement'.)

Lung transplantation is generally not an option due to the underlying plasma cell dyscrasia, despite rare case reports of successful lung transplantation in patients with limited disease [16,17].

NODULAR PULMONARY AMYLOIDOSIS — Nodular and nodular-cystic amyloidosis, likely reflecting a spectrum of the same disease biology, are the most frequent forms of pulmonary amyloidosis and are almost uniformly due to localized immunoglobulin (Ig) light chain (AL) amyloid.

Pathogenesis and type of amyloid protein

Association with extranodal marginal zone lymphoma – Accumulating evidence suggests that nodular pulmonary amyloidosis (NPA) often arises as a complication of a low-grade B cell lymphoma such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type tissue [18,19]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Immunoglobulin light chain type – In a 25-year autopsy study with 18 cases of NPA, immunohistochemical staining revealed lymphoproliferative cells (clonal plasma cells) surrounding amyloid deposits in 78 percent [18]. Laser capture tandem mass spectrometry of amyloid detected uniform (100 percent) light chain Ig (AL) expression with kappa chain predominance over lambda light chain (3:1). In contrast, systemic AL amyloidosis has a predominance of lambda light chain. (See 'Distribution of pulmonary amyloidosis' above.)

An unusual coexpression of heavy chain Ig (AL/heavy chain amyloidosis [AH]) was noted in 72 percent of NPA. In contrast, systemic AL amyloid lung involvement is predominantly characterized by clonal lambda light chain in the absence of AH.

Other forms of amyloidosis – Biopsy of lung nodules can result in finding of other types of systemic amyloid. Wild-type transthyretin amyloidosis (ATTRwt), hereditary transthyretin amyloidosis (ATTRm), and AA (secondary) amyloidosis have been reported in isolated cases, although the low prevalence of AA amyloidosis in the United States makes it a very rare finding on lung biopsy. In most patients with inflammatory conditions, nodular cystic amyloidosis is due to localized AL amyloid formation, not AA amyloid, despite an association with Sjögren's disease. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Pulmonary nodular amyloidosis'.)

Clinical features — The median age at presentation of NPA is 67 years (range 36 to 80) [20,21]. NPA may present as an isolated lesion or, more often, as multiple bilateral nodules.

In one series, 5 of 14 autopsy cases (36 percent), 3 of whom had Sjögren's disease, exhibited autoimmune disease, and three cases (17 percent) were diagnosed with extranodal MALT lymphomas [18].  

Imaging — Pulmonary nodules noted on chest radiograph are further evaluated with computed tomography.

The nodules in NPA typically have a smooth or sometimes lobular contour, but spiculated nodules have been described, generally reflecting preexisting emphysematous lung architecture [9,10]. Nodules may be singular or multiple [6]. The nodules range in diameter from 8 mm to 3 cm (rarely larger) and are predominantly found in the mid and lower lung zones, extending from the subpleural space to the hilum but without associated lymphadenopathy [10].

Initial growth of the nodules is often followed by quiescence, but the nodules do not regress. As a rule, multiple NPA opacities exhibit synchronous growth.

Nodule calcification occurs over time [8]. When present, it indicates the lesion has been present for >5 years.

Nodular amyloid cavitation occurs but is a relatively rare event (<10 percent of cases), mimicking squamous cell carcinoma, lung infarction, or abscess formation [6].  

Positron emission tomography (PET) and computed tomography (CT) can help differentiate NPA from lung cancers, generally yielding low fluorodeoxyglucose (FDG) uptake (standard uptake value [SUV] <5) in NPA due to the acellular protein composition, unless surrounding MALT lymphoma complicates the presentation, producing a higher SUV [22]. However, negative FDG update does not exclude lymphoma or adenocarcinoma with lepidic growth (formerly bronchioloalveolar cancer) [23].

Pulmonary function tests — Pulmonary function tests are often obtained prior to lung biopsy to assess respiratory compromise, but spirometry and lung volumes are generally not affected by the presence of amyloid nodules. However, if nodular opacities are extensive, the diffusing capacity for carbon monoxide (DLCO) can be reduced.

Diagnosis/histopathology — The diagnosis of NPA is typically made on histopathology of a biopsy sample or resected nodule, often obtained by CT-guided transthoracic needle biopsy or video-assisted thoracoscopic surgery (VATS) [24]. While nodular lung disease occurs in systemic AL, it is sufficiently rare to warrant biopsy identification. When multiple nodules are present and accessible, we obtain CT-guided transthoracic biopsy.

On histopathology, NPA nodules are well-circumscribed and hematoxylin-eosin staining reveals deposits of eosinophilic material with typical apple-green birefringence on Congo red staining [21]. Giant cell granulomas may surround the amyloid deposits, and aggregates of lymphocytes and plasma cells can be seen around the amyloid deposits.

The possibility of underlying MALT lymphoma should be assessed with morphologic, immunophenotypic, and genetic analysis of the histopathology to identify monoclonal B lymphocytes. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)", section on 'Diagnosis'.)

Management — NPA generally does not affect lung function or impact survival; thus, patients with NPA do not need specific therapy [24]. Sometimes a nodule is resected at the time of diagnosis, and NPA may not recur. For patients with NPA and multiple nodules, surveillance is needed over time (approximately annually) to determine the rate of disease progression and to identify any individual nodules that demonstrate differential growth that would indicate a different process. In general, amyloid nodules exhibit synchronous growth, so enlargement of a single nodule out of proportion to the other nodules should prompt investigation for possible lung cancer or MALT lymphoma. The evaluation and management of MALT lymphoma are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)" and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

CYSTIC PULMONARY AMYLOIDOSIS — Cystic pulmonary amyloidosis (CPA) is a rare form of localized amyloidosis in which the formation and progressive growth of lung cysts is attributed to a ball-valve mechanism imparted by amyloid deposits partially obstructing distal airways [25].

Clinical features — CPA predominantly affects females (62 percent) with a median age of 61 years. It is frequently associated with Sjögren's disease (48 percent) and mucosa-associated lymphoid tissue (MALT) lymphoma (33 percent) [25].

CPA typically arises due to local expression of kappa Ig light chain amyloid (83 percent), similar to nodular pulmonary amyloidosis (NPA) [25]. (See 'Nodular pulmonary amyloidosis' above.)

Patients are often asymptomatic with incidental radiographic abnormalities. Cough and/or dyspnea are rarely reported [26].

Imaging — On high resolution computed tomography (HRCT), multiple thin-walled cysts (often >10) with or without heterogeneously calcified small peripheral nodules and/or vascular septae typically populate the mid and lower lung zones (81 percent) [25]. The diameter of the cysts is typically <1 to 2 cm [25,26]. Cysts are round or lobulated and, over time, tend to enlarge more prominently than nodular opacities. (See "Diagnostic approach to the adult with cystic lung disease", section on 'Radiographic features'.)

Pulmonary function tests — Pulmonary function tests are usually obtained to assess the presence and severity of respiratory impairment.

Up to 42 percent of patients with CPA have normal pulmonary function tests [25], similar to NPA. (See 'Nodular pulmonary amyloidosis' above.)

Over time, the cysts may enlarge or proliferate (71 percent of cases), potentially leading to restrictive spirometry (reduced forced vital capacity) with air trapping demonstrated on lung volumes.

Diagnosis and differential diagnosis — The diagnosis of CPA is typically suspected based on the presence on CT of lung cysts in association with small nodules, particularly when one or more nodules is calcified. Underlying Sjögren's disease is another clue to the diagnosis.

The need for lung biopsy to rule out associated MALT lymphoma or lymphocytic interstitial pneumonia (LIP) depends on the rate of growth of the lung nodules [25]. We reserve video-assisted lung biopsy for faster-growing nodules (eg, >3 mm in a year); nodules with little growth over time are generally observed.

Cystic lung disease has an extensive differential diagnosis. (See "Diagnostic approach to the adult with cystic lung disease", section on 'Causes of cystic lung disease'.)

Certain HRCT features help distinguish CPA from other cystic lung diseases (table 2):

Lymphoid interstitial pneumonia (LIP) – Ground glass opacities, which are often present in LIP, are not typically seen with CPA (image 1). The cysts in LIP tend to be few in number, discrete, and peribronchovascular in distribution. (See "Lymphoid interstitial pneumonia", section on 'Chest imaging'.)

Lymphangioleiomyomatosis (LAM) – Rarely exhibits nodules that are characteristic of CPA. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Chest CT'.)

Pulmonary Langerhans cell histiocytosis (PLCH) – The upper lobe predominance, thick-walled appearance, and irregular shape of lung cysts seen in PLCH (image 2 and image 3) contrast with the diffuse distribution and thin-walled appearance of cysts in CPA. (See "Pulmonary Langerhans cell histiocytosis", section on 'Imaging'.)

Light chain deposition disease (LCDD) – LCDD is a multisystem disease that can cause multiple lung cysts and one or more nodules, similar to CPA (see 'Cystic pulmonary amyloidosis' above) [27,28]. However, the light chain fragments in LCDD (usually kappa) do not have the necessary biochemical characteristics to form amyloid fibrils and thus deposits are granular rather than fibrillar and do not exhibit apple green birefringence when stained with Congo red. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Management — Observation for metachronous growth of a nodule (approximately annually) is the most important management objective, as metachronous growth may indicate the presence of another disease process (eg, lung cancer, MALT lymphoma). As the initial proliferative phase of nodular disease (approximately one to four years) is typically followed by disease quiescence, surgical resection offers little benefit and does not alter survival. However, surgical biopsy of rapidly enlarging nodules, those with surrounding ground glass opacities, or PET positive (5 to 6 standard update value [SUV]) scans is prudent if treatment for MALT/marginal zone lymphoma is considered. Notably, isolated MALT lymphoma of the lung may not impact patient survival. The management of MALT lymphoma is discussed separately. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)  

TRACHEOBRONCHIAL AMYLOIDOSIS — Tracheobronchial amyloidosis (TBA) is an under-recognized form of lung amyloid involvement that constitutes approximately 1.1 percent of referrals to an amyloid center [29], but 23 percent of symptomatic benign airway lesions referred for laser resection [30].

TBA is almost exclusively due to localized Ig light chain (AL) amyloid deposition, reflecting the presence of clonal plasma cells residing deep to the airway and secreting amyloidogenic AL [6].  

Rarely, apolipoprotein AI (AApoAI) amyloid, associated with germline mutations in the APOA1 gene, can involve the larynx, including the subglottic space [31-33].

For the vast majority of TBA due to localized clonal plasma cell expansion, the inciting event activating a plasma cell clone remains unclear.

Clinical features — The age of disease onset is broad, ranging from childhood to older age and varies with gender; women tend to present at a younger age (25 to 45 years) than men (50 to 70 years) [29]. In one study, the range was 27 to 63 years [29]. One patient presented at two years of age with disease localized to the trachea [34]. Females are affected more commonly than males (60 percent and 40 percent, respectively) and tend to have more extensive airway involvement and faster disease progression.

Symptoms include cough, wheezing, dyspnea, hoarseness, and hemoptysis; exertional dyspnea is most predictive of significant airway narrowing [6,35-37].

The distribution of TBA lesions can follow one or more of the following patterns:

Proximal airway – Subglottic tracheal disease extending to the main carina

Mid airways – Distal trachea and main bronchial involvement extending to secondary carinae

Distal airways – Disease distal to secondary carinae (bronchial)

Pulmonary function tests — PFT findings tend to follow the disease distribution [29].  

Proximal disease – Patients with mild airway narrowing may have (deceptively) normal spirometry, lung volumes, and diffusing capacity for carbon monoxide (DLCO). However, severe airway wall thickening induces airflow obstruction and air trapping. Importantly, blunted inspiratory and expiratory limbs of the flow volume loop may be the only abnormal PFT finding. (See "Flow-volume loops".)

Mid disease – Spirometry may be normal or demonstrate obstructed airflow.

Distal disease – Nonspecific airflow reductions with air trapping and diminished DLCO.

CT imaging — CT features also depend on the distribution pattern [29].

Proximal disease (larynx and trachea) – Airway wall thickening is generally associated with a degree of airway lumen narrowing, which can be unilateral, circumferential (including posterior tracheal membrane), or project into the airway lumen.

Mid airway – Airway wall thickening tends to be circumferential distal to the main carina. The right main bronchus is more likely to be affected than the left, but disease is often bilateral.

Distal airway – The distribution can be unilateral and localized, diffuse and unilateral, or diffuse and bilateral.

Airway wall calcifications – Airway wall calcifications occur after approximately five years of amyloid deposition. As it is the amyloid deposits that calcify, airway wall thickening must precede calcification of amyloid deposits, unlike calcification of airway cartilage (with age or kidney failure), which occurs in a regular pattern in otherwise normal airway architecture.

Flexible bronchoscopy — Endobronchial TBA can be focal or diffuse and has four main appearances on endoscopic inspection [29,35]:

Focal, raised, hard-edged, yellow deposits

Concentric, infiltrating, submucosal disease with an inflamed surface

Nodular disease (single or multiple)

Capillary prominence on an erythematous base

Diagnosis — The diagnosis of TBA can be challenging as symptoms of dyspnea and dysphonia are nonspecific. Often patients are misdiagnosed as refractory asthma, delaying recognition of TBA by a median 11 months (range 4 to 42 months) [29]. Upper airway obstruction should be suspected in patients with unexplained exertional dyspnea (normal PFTs, chest radiograph, echocardiogram, hemoglobin). At times, blunting of one or both limbs of the flow volume loop may be the only signal of upper airway obstruction. Neck CT (noncontrast) imaging and upper airway visualization (laryngoscopy) should be obtained for diagnosis.

Imaging – Neck CT is the most sensitive diagnostic test, identifying airway wall thickening, mural and intraluminal nodules, submucosal calcification, and length of airway involvement. Contrast administration at the time of imaging obscures recognition of amyloid deposit calcification, particularly in the soft tissues of the head and neck. Consequently, noncontrast studies prove more informative. Image slice thickness of 2.5 mm is sufficient; high-resolution imaging is not required, but may enhance disease depiction. Amyloid involvement of the trachea can calcify and resemble tracheobronchopathia osteochondroplastica (TPO), although amyloidosis involves the posterior tracheal wall, whereas TPO spares the posterior wall [10].

Biopsy – In patients with subglottic airway narrowing, laryngoscopy can help characterize the abnormality, but targeted biopsy is needed to confirm the diagnosis. It should be noted that airway amyloid lesions can be quite friable and techniques to control airway bleeding such as the use of argon plasma coagulation may be required.

Differential diagnosis — The differential diagnosis considerations for proximal tracheal narrowing include sarcoidosis, relapsing polychondritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

Management — The biology of airway amyloidosis appears to involve an active phase of amyloid deposition followed by a period of quiescence and frequently complete clinical arrest [6,38]. Thus, systemic treatment is not indicated.

Local treatment of airway amyloid is based on one of two circumstances: altered voice production (laryngeal/subglottic disease) or shortness of breath (airway narrowing). Management decisions are based on the degree of voice and respiratory impairment coupled with evidence of progression:

Asymptomatic, mild physiologic impairment – Asymptomatic patients with mild physiologic impairment due to TBA can be monitored with clinical assessment and periodic direct visualization, CT, and PFTs, deferring specific therapy until symptoms develop.

Hoarseness – Hoarseness often reflects direct infiltration of the true vocal cords, stiffening the cords and diminishing mucosal wave movement. Alternatively, hoarseness may result from subglottic amyloid deposition that disrupts normal laminar flow through the larynx. Either of these mechanisms can independently induce hoarseness, although both mechanisms often contribute simultaneously.

For vocal fold involvement with amyloid, endoscopic laser is typically used to remove or reduce nodular deposits while preserving vocal fold function [37]. However, infiltrative deposits of amyloid affecting the true vocal folds are not amenable to laser. In rare cases, external beam radiation therapy has improved voice production, but further study is needed [39]. When hoarseness is due to airway narrowing below the glottis, treatment is the same as described for shortness of breath.

Shortness of breath and hemoptysis – Shortness of breath correlates directly with the location and degree of airway obstruction, with symptoms initially limited to exertion and ultimately occurring at rest [40]. Acute bronchitis with airway mucus accumulation and bleeding from friable mucosa may accelerate the symptoms of a narrowed airway.

For patients with symptomatic airway obstruction, treatment is determined by the site and type of obstruction.

Amyloid deposits projecting into airway lumen – Laser excision is generally effective at clearing amyloid lesions that project into the lumen of the upper or central airways with little risk of inadvertent airway wall injury [41,42]. Limited experience with cryotherapy does not suggest a greater efficacy than laser therapy, and we do not use it. (See "Bronchoscopic laser in the management of airway disease in adults", section on 'Equipment and technique'.)

Circumferential airway wall thickening – While formal study is lacking, laser treatments, in our experience, can remove small quadrants of circumferential disease in a series of repeated operations to limit the potential area of injury and allow airway tissue healing before undertaking sequential surgeries. Additionally, a mucosal sparing surgical technique may minimize tissue injury in areas of amyloid resection. Aggressive debulking of circumferential submucosal amyloid deposits should be avoided as it can cause extensive airway injury, potentially triggering a fibrotic response resulting in airway stenosis. (See "Bronchoscopic laser in the management of airway disease in adults", section on 'Nonmalignant central airway obstruction'.)

Balloon dilation of a stenotic airway is generally beneficial when the amyloid deposit is not calcified, although the improvement may be transient. Airway stenting with uncovered or partially covered stents should be avoided, as continued amyloid deposition can overgrow and embed the stent. While limited case series support the use of silicone stents [43,44], they should only be used as a bridge to a tissue-removing procedure.

Steroid or mitomycin injection into the surgical bed after laser treatment can diminish exuberant fibrotic response to airway tissue removal, but this has little clinical effect on the amyloidogenic process.

Recurrent or refractory airway obstruction – For patients with recurrent airway obstruction, repeated laser treatments to remove segments of amyloid tissue can relieve stenoses while limiting injury and subsequent scarring to the involved airway. Patients with severe airway narrowing require multidisciplinary consultation and an individualized approach. It is essential to ensure maintenance of an adequate airway during any treatments that result in airway swelling. Multimodality therapy may include balloon dilation, cautious laser treatments and, rarely, subsequent external beam radiotherapy (EBRT).

EBRT is used in selected patients with TBA to eliminate surrounding clonal plasma cells producing amyloidogenic protein [39,40,45-49]. (See "Radiation therapy techniques in cancer treatment", section on 'External beam radiation therapy'.)

-EBRT is only applicable when tissue typing documents AL amyloid, indicating an underlying clonal plasma cell process. In addition, progressive disease should be a prerequisite for EBRT, as disease quiescence can occur spontaneously.

-In several case series, low-dose radiation (20 Gy) improved performance status and arrested disease progression, presumably by eliminating the radio-sensitive clonal plasma cells producing and depositing AL amyloid in the airway [39,46-48,50]. After 10 to 20 years of surveillance, recurrent amyloid growth in the treatment field has occurred in 4 percent of cases in our practice.

-After EBRT, patients should be monitored annually for thyroid cancers by physical and ultrasound examinations.

PLEURAL DISEASE — Persistent pleural effusions (PPE) develop in 1 to 2 percent of patients with systemic (AL) amyloidosis [51]. Although less common, patients with transthyretin amyloidosis (wild-type or hereditary) or secondary amyloidosis (eg, familial Mediterranean fever) can present with PPE. Amyloid infiltration of the parietal pleura induces leakage of fluid into the pleural space and impairs drainage from the pleural cavity.

Clinical features — Pleural effusions due to amyloidosis are moderate-sized and refractory to diuresis. The main symptom is dyspnea.

Fluid sampling typically reveals a median of 306 white blood cells/cm3 (20 to 6188 range) with exudative chemistries in 37 percent of cases signaling disruption of pleural membrane function [51].

Rarely, unilateral or bilateral chylous effusions complicate late-stage AL amyloidosis [52-54]. In our experience, chylous effusions associate with limited survival.

Isolated pulmonary hypertension, hypothyroidism, or low oncotic pressure due to nephrotic range proteinuria do not induce persistent pleural effusions in patients with AL amyloidosis [51].  

Imaging — Left and right unilateral pleural effusions occur equally and are moderate in size. Free-flowing pleural fluid can be identified with upright and lateral decubitus chest radiographs or ultrasound. Computed tomography may be obtained to confirm the presence of pleural fluid but does not typically identify pleural thickening.

Diagnosis — PPE should be suspected in patients with Ig light chain (AL) amyloidosis complicated by cardiomyopathy who present with pleural fluid on chest imaging [51].

Pleural fluid chemistries and cell counts are nonspecific and not diagnostic of amyloid-related PPE.

While parietal pleural biopsies often identify pleural amyloid deposits, the presence of pleural amyloid infiltration can be inferred by the refractoriness of the effusions to aggressive diuresis and/or direct fluid drainage.  

Management and prognosis — PPEs due to amyloid deposition are typically refractory to aggressive diuresis, often despite normalization of left atrial filling pressures [51]. We generally employ one or more of the following interventions in sequence, proceeding to more invasive interventions if less invasive steps are insufficient. (See "Management of malignant pleural effusions".)

Diuresis – Initial management usually involves aggressive diuresis to lower left atrial filling pressures. Diuresis diminishes the rate of pleural effusion recurrence but does not resolve the effusions.

Large volume thoracentesis – For patients who remain dyspneic despite diuresis, large volume thoracentesis under ultrasound guidance is helpful to confirm that dyspnea improves with fluid removal. Repeat large volume thoracentesis can be performed periodically in patients with slow reaccumulation of fluid (eg, once every four weeks or more) or a limited prognosis. (See "Large volume (therapeutic) thoracentesis: Procedure and complications".)

Indwelling pleural catheter – Tunneled placement of an indwelling catheter enables intermittent fluid removal in patients requiring frequent (weekly) drainage. (See "Management of nonmalignant pleural effusions in adults", section on 'Indwelling pleural catheter'.)

Pleurodesis – Pleurodesis offers the possibility of stopping fluid reaccumulation with a single procedure. However, data on the success of pleurodesis for amyloid PPE are limited. Some patients may be candidates for bedside talc pleurodesis via a chest tube, although rapidly recurring effusions predict poor surface symphysis. Patients with amyloid cardiomyopathy are generally not candidates for more invasive surgical video-assisted thoracoscopy procedures for manual pleurodesis or talc insufflation. (See "Management of nonmalignant pleural effusions in adults", section on 'Pleurodesis'.)

Prognosis – The presence of persistent pleural effusions is associated with decreased survival in patients with untreated AL amyloidosis (1.8 months) when compared with patients with untreated AL amyloid cardiomyopathy without PPE (6 months) [51].  

PULMONARY VASCULAR DISEASE

Pulmonary hypertension (PH; groups 2 and 3) – Pulmonary hypertension (PH) due to elevated left heart filling pressures frequently accompanies Ig light chain (AL) amyloid cardiomyopathy (group 2). It is a late complication of AL amyloidosis, being identified <3 months (median) before death and reflecting advanced systemic disease [55]. ATTR cardiomyopathy can also cause PH (group 2). (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Management'.)

PH (group 3) can be a manifestation of advanced lung disease due to diffuse lung parenchymal amyloidosis. (See 'Diffuse parenchymal lung amyloidosis' above and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

Pulmonary arterial hypertension (PAH group 1) and PH (group 5) – Despite the nearly ubiquitous presence (>95 percent) of amyloid in the pulmonary vessels of patients with AL disease at autopsy [2,7], only a small number of case reports document PAH (group 1) in the absence of left-sided heart disease (group 2) [55-57]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Patients with AA amyloidosis due to familial Mediterranean fever rarely express clinically recognized PH (group 5) [56,58-60]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Secondary (AA) amyloidosis'.)

LYMPHADENOPATHY — Lymphadenopathy (LAN) is a rare manifestation of amyloidosis, diagnosed in 47 of 3008 patients (1.6 percent) presenting to a single amyloid center over 19 years [61]. Common LAN sites include the mediastinum (30 percent), cervical or supraclavicular (23 percent), inguinal (17 percent), and axillary (15 percent). In patients with thoracic involvement with systemic amyloidosis, 75 percent have mediastinal or hilar LAN [62].

Clinical features – Amyloid LAN was most often associated with systemic Ig light chain (AL) amyloidosis (83 percent), with isolated cases of hereditary transthyretin amyloidosis (ATTRm), wild-type transthyretin amyloidosis (ATTRwt), and secondary AA amyloidosis (see 'Types of amyloid proteins' above). Similar proportions of systemic and localized amyloidosis were noted in a separate series of patients with amyloid LAN [20].

Among 29 patients with LAN in the setting of systemic AL amyloidosis, the majority (70 percent) had a lambda light chain gammopathy [61]. In contrast, kappa light chain was more common among those with limited amyloid LAN without demonstrable amyloid in other organs.

Imaging – Mediastinal LAN due to amyloid deposition often calcifies. This feature can also be seen in granulomatous diseases, treated lymphoma, metastatic adenocarcinoma, and Castleman disease. Hilar LAN may be unilateral or bilateral and may be calcified [20].

Diagnosis – Endobronchial ultrasound-guided transbronchial needle aspiration can be a helpful modality for diagnosis [24,63-65]. Patients diagnosed with AL amyloid limited to lymph nodes are at risk for future expression of multiorgan disease. Consequently, a full evaluation for signs of major organ dysfunction is needed at the time of LAN diagnosis.

Evaluation for systemic amyloidosis – Patients presenting with amyloid LAN should be evaluated for systemic amyloidosis (eg, serum and urine protein electrophoresis with immunofixation, serum free light chain analysis including ratio, an abdominal fat pad aspirate and bone marrow biopsy, and evaluation for other organ involvement) [61]. Amyloid LAN that is isolated at presentation may progress to involve major organs with AL amyloidosis. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Diagnosis'.)

Treatment – Patients with amyloid LAN do not usually require lymph node resection unless the nodes are impinging on other structures and causing symptoms. Surgery is often difficult as the node masses tend not to be encapsulated and often adhere to adjacent tissues. Instead, medical treatment focuses on major organ manifestations of amyloidosis, eg, systemic AL amyloidosis. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Prognosis – Among patients with apparently isolated LAN at presentation, a high proportion subsequently develop major organ involvement. In a single-center experience, 10 of 14 patients with LAN progressed to systemic disease over a median 10-month period [61]. Patients with LAN and Waldenstrom macroglobulinemia/AL amyloidosis most frequently progress to major organ disease.  

DIAPHRAGM DYSFUNCTION — Diaphragm plegia or paralysis can occur in patients with systemic immunoglobulin light chain (AL) amyloidosis due to:

Amyloid infiltration of the diaphragm muscle (eg, systemic AL amyloidosis due to multiple myeloma) [66,67]

Mononeuritis multiplex involving the phrenic nerve [68]

Phrenic nerve damage due to impingement from amyloid lymphadenopathy

Unilateral diaphragmatic weakness is usually asymptomatic at rest but may cause exertional dyspnea and decreased exercise performance. Bilateral diaphragmatic weakness typically presents with orthopnea and dyspnea on exertion and may have associated hypercapnia. Chest radiographs show unilateral or bilateral elevation of the hemidiaphragm, depending on the site(s) of amyloid deposition. The evaluation of diaphragm dysfunction is described separately. (See "Diagnosis and management of nontraumatic unilateral diaphragmatic paralysis (complete or partial) in adults" and "Diagnostic evaluation of adults with bilateral diaphragm paralysis".)

Treatment focuses on the underlying plasma cell dyscrasia. Noninvasive positive pressure ventilation when sleeping or symptomatic can be of benefit [68]. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis" and "Treatment of bilateral diaphragmatic paralysis in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunoglobulin light chain (AL) amyloidosis" and "Society guideline links: Pleural effusion".)

SUMMARY AND RECOMMENDATIONS

Overview – Amyloidosis develops when one of more than 30 different precursor proteins with an unstable tertiary structure misfolds and aggregates as insoluble amyloid fibrils, which are deposited in the extracellular space of individual organs and soft tissue (table 1). Different types of precursor proteins tend to have different patterns of lung deposition. (See 'Overview' above.)

For patients with suspected or newly diagnosed amyloidosis, referral to a center that specializes in the evaluation and management of amyloidosis is advised, whenever feasible, for help with processing of pathologic specimens, identification of the type of amyloid, detailed characterization of the distribution and extent of disease, and determination of optimal management approaches. (See 'When to refer' above.)

Systemic versus localized AL amyloidosis – Most clinically evident pulmonary amyloidosis results from plasma cell production of monoclonal immunoglobulin (Ig) light chain (AL) amyloid, which is either produced in the bone marrow and subsequently deposited in the lungs or pleura (systemic AL disease) or generated in the lungs and deposited locally (localized AL disease). (See 'Overview' above.)

Lambda versus kappa light chain AL amyloid – Systemic amyloidosis involving the lung is most often lambda light chain AL, while localized lung disease (eg, nodular pulmonary amyloidosis or tracheobronchial amyloidosis) is more often kappa AL amyloid. (See 'Overview' above.)

Diffuse parenchymal lung amyloidosis – Diffuse parenchymal lung amyloidosis is usually associated with systemic AL amyloidosis and deposition of light chain fragments (most often lambda) in the lung; however, patients with localized lung amyloidosis can exhibit unilateral or diffuse alveolar septal amyloidosis. Diffuse lung parenchymal involvement occasionally occurs with transthyretin amyloidosis (ATTR), and rarely with AA amyloidosis. Management is based on the specific amyloid type and systemic manifestations, as discussed separately. (See 'Diffuse parenchymal lung amyloidosis' above and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Nodular pulmonary amyloidosis (NPA) and cystic pulmonary amyloidosis (CPA) – NPA and CPA generally represent localized lung AL amyloidosis and may reflect underlying mucosa-associated lymphoid tissue (MALT) lymphoma. Patients presenting with multiple nodules require surveillance over time to determine the rate of disease progression; metachronous growth of a nodule may indicate the presence of another disease process (eg, lung cancer, MALT lymphoma). NPA does not require specific therapy because it does not typically impact survival. (See 'Nodular pulmonary amyloidosis' above.)

Tracheobronchial amyloidosis – Tracheobronchial amyloidosis is almost exclusively due to Ig light chain (AL) amyloid produced by clonal plasma cells localized to the airways. Symptoms, when present, may include cough, wheezing, hoarseness, exertional dyspnea, and hemoptysis. The diagnosis is based on a combination of neck noncontrast CT and upper airway visualization with biopsy confirmation. Treatment is reserved for symptomatic patients. (See 'Tracheobronchial amyloidosis' above.)

For patients with hemoptysis or dyspnea due to amyloid deposits projecting into the airway lumen, we suggest bronchoscopic laser treatment rather than bronchoscopic cryotherapy or initial external beam radiotherapy (EBRT) (Grade 2C). (See 'Management' above.)

For patients with symptomatic circumferential airway wall thickening, we suggest a stepped approach with laser excision of small quadrants of disease in a series of repeated operations to reduce the risk of airway scarring and stricture formation (Grade 2C). Patients with severe airway narrowing require a multidisciplinary, individualized approach. It is essential to ensure maintenance of an adequate airway during any treatments that result in airway swelling. Multimodality therapy may include balloon dilation, cautious laser treatments and, rarely, subsequent EBRT. (See 'Management' above.)

Pleural disease – Persistent pleural effusions occur in systemic AL and transthyretin amyloidosis (ATTR) due to pleural amyloid deposits. Pleural fluid chemistries and cell counts are nonspecific but can help to exclude other etiologies. Pleural amyloid infiltration can often be inferred by the refractoriness of effusions to aggressive diuresis and/or direct fluid drainage in a patient with known systemic amyloidosis but can also be confirmed by pleural biopsy. (See 'Pleural disease' above.)

For patients with symptomatic pleural effusions due to amyloidosis, an initial trial of diuresis is appropriate. For patients who have refractory symptomatic pleural effusion despite a trial of diuresis, we suggest large volume thoracentesis under ultrasound guidance, repeated as needed (Grade 2C). For patients who improve symptomatically with thoracentesis but require repeated drainage, placement of an indwelling pleural catheter for intermittent home drainage is an alternative option. (See 'Management and prognosis' above.)

Pulmonary hypertension – Pulmonary hypertension (PH; group 2) frequently accompanies the cardiomyopathy of systemic AL or ATTR amyloidosis. Pulmonary arterial hypertension (PAH; group 1) occurs rarely in systemic amyloidosis, so more common causes of PH must be excluded, such as cardiomyopathy (group 2) or advanced parenchymal lung disease (group 3). Management is based on the diagnostic group and severity of PH as detailed separately. (See 'Pulmonary vascular disease' above.)

Amyloid lymphadenopathy (LAN) – Amyloid LAN that appears isolated at presentation may progress to systemic AL amyloidosis involving major organs. Lymph node resection is avoided unless the nodes are impinging on other structures. (See 'Lymphadenopathy' above.)

Diaphragm dysfunction – Unilateral diaphragm dysfunction can occur due to amyloid-related mononeuritis multiplex or phrenic nerve compression by lymphadenopathy. Amyloid myopathy can also cause diaphragm dysfunction. Treatment focuses on the underlying plasma cell dyscrasia, as described separately. Noninvasive positive pressure ventilation when sleeping or symptomatic can be of benefit. (See 'Diaphragm dysfunction' above and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

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Topic 131094 Version 10.0

References

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