Systemic ATTR amyloidosis involving the lung. Eosinophilic amorphous material consistent with vascular amyloid deposition in the lung (a, H&E, arrow) stained with Congo red (b, arrow). Congo red stain viewed under polarized light (c, Congo red, arrow)
Radiologically, the amyloid deposits appear as nonspecific diffuse interstitial or alveolar opacities, with or without calcification . The differential diagnosis may include idiopathic pulmonary fibrosis, scleroderma, and rheumatoid lung disease.
In the Mayo Clinic study , only 1 of 55 cases of pulmonary amyloidosis was found to be of systemic familial ATTR type. In another study over 90-year period, three cases of familial amyloidosis were identified, two of which had pulmonary involvement . In an autopsy study of 19 patients with heterozygotic familial amyloidotic polyneuropathy, all lung samples showed involvement of bronchial/bronchiolar walls, pulmonary artery, and vein walls at various degrees .
In contrast, a Swedish autopsy study on 33 individuals with senile ATTR amyloidosis reported the lung as the second most involved site after the heart. The pulmonary amyloid deposits were described as interstitial distribution in a “drop-like” manner . In a similar study, 2 of 21 patients had a diffuse parenchymal involvement of the lung by senile amyloidosis as an incidental finding at the time of autopsy . In a single autopsy case of senile amyloidosis reported by Ueda et al. , the lung tissue revealed scattered patchy amyloid deposits in the pulmonary parenchyma and pulmonary vein. A unique case of confluent nodular senile amyloidosis of the lung associated with scattered lymphoplasmacytic infiltrates composed of polytypic plasma cells and a mixture of small B- and T-lymphocytes has been documented. The radiologic aspect suggested a localized nodular amyloidosis, but immunohistochemistry (IHC), mass spectrometry, and genetic analysis (i.e., to exclude a TTR gene mutation) confirmed the senile ATTR type . Patients with pulmonary involvement by senile ATTR amyloidosis are usually asymptomatic and follow a benign course .
The autopsy study of Bergstrom et al.  revealed codeposition of AApoAIV and TTR in senile systemic ATTR amyloidosis involving the heart. Moreover, in one case was further shown by IHC that the two proteins presented anatomically distinct patterns of distribution within the heart and other organs. For example, in the heart, ApoAIV amyloid deposits presented as small patchy intracellular, interstitial, or larger nodular deposits with bright birefringence on Congo red stain, whereas TTR-positive deposits occurred as interstitial or larger deposits with weak birefringence on Congo red stain. In contrast, in the lung, ApoAIV amyloid was identified in vessel walls, whereas TTR-derived amyloid appeared as small deposits in the alveolar septa .
As in other organs, proteomic analysis of lung specimens involved by systemic AL amyloidosis using laser microdissection and liquid chromatography/tandem mass spectrometry (LMD/MS) reveals a fairly pure composition of Ig light chain peptides, without admixed Ig heavy chains . The systemic amyloid distribution should be confirmed with clinical studies and assessment of other organs, in particular the heart and kidney. It is also important to perform serum protein studies and bone marrow biopsy in order to evaluate the presence of an underlying plasma cell neoplasm or systemic B-cell lymphoma.
Clinicopathological Classification of Localized Pulmonary Amyloidosis
Nodular Pulmonary Amyloidosis
Nodular pulmonary amyloidosis (NPA) is often asymptomatic representing an incidental finding on imaging studies (Fig. 33.2a). Patients with autoimmune diseases, in particular Sjogren syndrome, have an increased incidence of NPA [17–21]. The nodules are often multifocal and found in peripheral and subpleural areas. The radiologic appearance of the nodules shows discrete borders with frequent calcification, often central or in an irregular pattern within the nodule which may raise concern for a metastatic disease [8, 22, 23].
Nodular pulmonary amyloidosis. Nodular amyloid deposition presenting as an isolated nodule in the left lung parenchyma (a, CT image, arrow). The biopsy shows eosinophilic extracellular deposit (b, H&E) stained with Congo red (c) and showing appropriate color change under polarized light (d, Congo red)
Histologically, extensive amyloid involvement dominates the lesions of NPA (Fig. 33.2b–d), with aggregates of lymphocytes and plasma cells present within and at the periphery of the nodules (Fig. 33.3a, b). The degree of lymphoplasmacytic infiltrate is quite variable, but generally is scant and may include reactive lymphoid follicles as well as monocytoid small lymphocytes and plasma cells with occasional atypical cytology (Dutcher bodies, Mott cells). The infiltrate may extend beyond the nodule following a lymphangitic distribution. There is often a foreign body giant cell reaction to the amyloid deposits . The chronicity of the process may be reflected by the presence of calcification within the nodule, or even metaplastic ossification [8, 23].
Nodular pulmonary AL kappa amyloidosis involving the lung. Eosinophilic amyloid deposits in the lung and surrounding predominantly plasmacytic infiltrate (a, H&E, arrow). Immunohistochemistry shows plasma cells expressing CD138 (b, immunoperoxidase, arrow) and immunoglobulin kappa light chains (c, immunoperoxidase for kappa) but not immunoglobulin lambda light chains (d, immunoperoxidase for lambda)
Although NPA derives from Ig proteins, it demonstrates distinct clinicopathological features compared to systemic AL amyloidosis. A recent series of NPA cases analyzed by LMD/MS confirmed the etiology and provided further characterization of the deposits . First of all, NPA was more often related to Ig kappa (k) light chains rather than lambda (λ) Ig light chains, with a ratio of approximately 3:1, in contrast to the λ predominance in systemic AL amyloidosis. Furthermore, the majority of cases (two-thirds) incorporated a mixture of heavy and light chain Ig, designated as Ig-associated amyloidosis (AL/AH type), which is a rare finding in systemic amyloidosis. Before this study, AL/AH amyloidosis has been reported in a single case of localized pulmonary amyloid associated with a lymphoplasmacytoid lymphoma . This characteristic feature may reflect the localized source of the abnormal proteins at the site of amyloid deposition, allowing the entire mixture of proteins to be more readily incorporated into the matrix. In most cases, a clonal population of B cells and/or plasma cells can be identified in close proximity to the amyloid nodules (Fig. 33.3b–d) which differentiates NPA from the usual presentation of primary systemic amyloidosis . Moreover, CD19 expression in monotypic plasma cells has been associated with lymphoplasmacytic neoplasms, only rarely occurring in plasma cell neoplasms that are primary to the bone marrow .
Based on these findings, NPA has been considered as a form of extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type [27–31]. This concept was further supported by the association of NPA with a connective tissue disorder, in particular Sjogren syndrome [17–21], as well as by the association of Sjogren syndrome and localized amyloid deposition in other anatomic sites that are characteristically involved by MALT lymphoma such as skin, salivary gland, and breast [24, 32]. Therefore, autoimmunity may represent a risk factor for NPA .
It is worthwhile to mention that although several MALT1 gene translocations involving gene locus at 18q21 were reported in 40–60 % of pulmonary MALT lymphomas [34, 35], no translocation was found in NPA cases . Nevertheless, gene expression profiling studies have identified distinct molecular subsets of pulmonary MALT lymphoma, one of these showing increased plasma cells and a predominant plasma cell gene signature but no MALT1 translocations . Therefore, it has been suggested that NPA may correspond to this particular subset of pulmonary MALT lymphoma .
As a localized form, NPA is not associated with a clonal Ig serum protein. The coincident NPA and monoclonal gammopathy of undetermined significance (MGUS) should not be considered evidence of systemic amyloidosis, as this would incorrectly imply a very poor prognosis. In careful study of several patients reported to have both conditions, Ig proteins within the amyloid deposits were found to be unrelated to the clonal serum proteins .
In conclusion, NPA represents a lymphoplasmacytic neoplasm in the spectrum of MALT lymphoma. Because of its localized nature, organ dysfunction should not be expected. The clinical course is characterized by indolent behavior and late recurrences either in the lung or other sites. Similar lymphoma recurrence rates (i.e., 33 % and 37 %, respectively) within a median time of 48 months were reported in two series of MALT lymphoma patients [24, 37]. However, the cystic degeneration of the surrounding alveolar parenchyma may occur in a subset of cases, but the underlying pathogenesis of this condition is unknown [38–40].
Tracheobronchial amyloidosis affects the respiratory tract anywhere along the trachea, bronchi, and bronchioles. It generally presents with symptoms of airway obstruction, such as dyspnea or cough, atelectasis, hemoptysis, and recurrent pneumonia [2, 3]. There also may be vocal changes due to laryngeal involvement. Although rare, patients may present with acute respiratory failure due to subglottic stenosis . Imaging studies show nodular and irregular narrowing of the tracheal lumen, airway wall thickening (Fig. 33.4), and calcification . The amyloid is deposited just underneath the respiratory epithelium, in diffuse deposits or forming nodules, which may appear polypoid on endoscopy. Histologically, the deposits are acellular or may be associated with a very scant lymphoplasmacytic infiltrate .
Tracheobronchial amyloidosis. Amyloid deposition in the respiratory tract causing thickening of the tracheal wall and irregular narrowing of the tracheal lumen (a, CT image, arrow). The same features are identified in the main bronchi (b, CT image, arrows)
Similar to NPA, tracheobronchial amyloid deposits are comprised of Ig proteins. There is no association with systemic amyloidosis or involvement of other organs. However, the pathogenesis of this disease remains elusive. Previous studies have failed to link this condition with a clonal B-cell or plasma cell population, either residing in the bone marrow or at the site of the amyloid deposits. The lymphoplasmacytic infiltrate, if present, has phenotypic characteristics more consistent with chronic inflammation rather than a lymphoid neoplasm. The peptide composition of the amyloid may show predominance of either k or λ light chains but often a polytypic mixture of k and λ light chains, and sometimes heavy chains as well were identified .
Other “Non-amyloidogenic” Related Conditions Involving the Lung
The lung may also be involved in other Ig deposition syndromes including light chain deposition disease (LCDD) and crystal storing histiocytosis (CSH). These conditions are described more fully in other chapters and will only be briefly addressed here.
Light Chain Deposition Disease
LCDD is a multivisceral disorder presenting with a constant renal involvement. Heart and liver may be frequently involved [44, 45]. Lung involvement is asymptomatic and usually represents an incidental radiological finding. Nodular LCDD restricted to the lung occurs in a similar clinical setting to NPA, with increased frequency in patients with autoimmune disease, especially Sjogren syndrome. Therefore, it is postulated to represent abnormal Ig deposition deriving from an underlying low-grade MALT lymphoma . Multifocal lesions representing nodular LCDD of the lung have been identified concurrently in a patient with Sjogren syndrome. The lesions contained clonally distinct Ig light chains . LCDD may lead to cystic change and a new form of LCDD (i.e., cystic lung LCDD) has been recently described [48–50].
CSH is a rare disease in which crystalline material accumulates in the cytoplasm of histiocytes. The crystals are most often of Ig k light chain origin without a consistent association of any specific heavy chain . Approximately 90 cases of CSH have been reported so far [52, 53]. In most patients, CSH is a manifestation of an underlying lymphoproliferative disorder, such as multiple myeloma, lymphoplasmacytic lymphoma, and MGUS . The association of CSH and marginal-zone lymphoma has been also reported affecting different anatomic locations, including the lung and pleura [54–57]. The exact mechanism of crystal formation in CSH is not completely understood. It has been proposed that the aggregated histiocytes in the lung have engulfed the abnormal Ig proteins produced at the remote site. An abnormality of the Ig sequence may prevent normal proteolysis within the lysosomes of the histiocytes, allowing crystal formation to occur .