Pleuropulmonary manifestations of

amyloidosis
Author: John L Berk, MD
Section Editors: Joyce S Lee, MD, David J Feller-Kopman, MD, Helen J Lachmann, MA, MB,
BChir, MD, FRCP, FRCPath
Deputy Editors: Paul Dieffenbach, MD, Paul L Romain, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Apr 2022. | 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 "Amyloid cardiomyopathy: 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 and light and
heavy chain deposition diseases".)

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 and light and heavy chain deposition diseases", 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
syndrome. (See "Interstitial lung disease associated with Sjögren
syndrome: 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
syndrome, 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 syndrome (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 syndrome 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 in adults", 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 computed
tomography'.)

● 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 and light and heavy chain
deposition diseases".)

● 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 light and heavy chain deposition diseases" 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 and light and
heavy chain deposition diseases".)
● 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 and light and heavy chain
deposition diseases".)

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