Table 6.3  Clinical features associated with systemic AL amyloidosis

Radiographically, the features can mimic a number of interstitial in ltrative diseases [83]. Plain lms often show a reticular pattern, and, on CT, interstitial in ltrates are seen mimicking more common interstitial lung diseases. Fine interlobular thickening is often seen peripherally and/or subpleurally. The ndings may be somewhat patchy depending on whether the amyloidosis arises from local parenchymal populations of clonal plasma cells or from a population of cells residing in the marrow. MRI often does not add to the diagnosis in this form of the disease. Similar to nodular amyloid deposits, the lesions are largely inert, showing low or no metabolic activity on PET imaging [84]. Persistent pleural effusions have been described in 5.5% of patients and are mostly associated with amyloid heart disease. Chronic effusions secondary to pleural amyloids are often refractory to diuretics and require recurrent drainage or pleurodesis [85]. Sleep-disordered breathing and sleep apnoea are increasingly recognised in systemic AL amyloidosis and other types of amyloidoses, presumably refecting cardiomyopathy, macroglossia, neuropathy and myopathy [86, 87].

The aim of treatment in AL amyloidosis is to suppress proliferation of the underlying B-cell clone and, therefore, production of the amyloid bril precursor protein; there are, however, many dif culties [88]. Chemotherapy regimens are based on those used in multiple myelomas, but the plasma cell dyscrasias in most AL patients are relatively low-grade and may be less chemosensitive. Diagnosis is dif-cult and can be delayed, and many patients have advanced multi-­system disease, which limits their options for chemotherapy. Regression of amyloidosis is a gradual process, which may not lead to measurable clinical improvement or recovery of organ function for months, or even years, after successful suppression of the causative plasma cell dyscrasia [89, 90]. The rate of mobilisation of amyloid deposits varies depending on the organ. Cardiac amyloid deposits are slower to show signs of regression compared to those of the liver or kidneys, and patients with cardiac or multi-system

dysfunction may not live long enough to bene t from chemotherapy [91]. However, despite these problems, many patients with AL amyloidosis do bene t substantially and chemotherapy has led to improved survival outcomes in this disease [92]. Treatment approaches need to be tailored to the individual patient based on their organ involvement. Staging systems have been developed to help guide treatment rationale and prognosis. The Mayo staging system is based on cardiac dysfunction, using cut-off values of 0.035 μg/L for troponin T and 332 pg/mL for NT-Pro- BNP. Patients can be classi ed into three stages: stage I, in which both biomarkers are below the cut-off value; stage II, in which one biomarker is elevated and stage III, in which both biomarkers are elevated. The reported median survivals are 26.4 months, 10.5 months and 3.5 months, respectively, for stages I, II and III [93]. Rigorous patient selection for high-dose chemotherapy is essential as procedure-related mortality is extremely high in individuals with multiple organ involvement [94, 95] and stage III patients should be excluded from stem cell transplantation [96]. The aim of treatment is to achieve adequate suppression of light-chain production with minimal treatment toxicity. Treatment response is routinely monitored using a serum-free lightchain assay. Reduction in serum-free light-­chain levels is associated with improved survival [97–99]. The degree of response needed to halt production may be different for individual patients. Achieving a >90 dFLC response has been associated with improved patient outcome and organ response with a higher chance of renal recovery [100].

Immunomodulatory therapies such as bortezomib, lenalidomide and thalidomide are now routinely used in patients with AL amyloidosis. Serious pulmonary side effects are extremely rare but are well-recognised complications following the use of the proteasome inhibitor bortezomib [101]. Patients present with fever and asthma-like symptoms and progress to respiratory failure with pulmonary in ltrates on CT imaging [102]. There have also been case reports of lung toxicity, following the use of thalidomide [103] and lenalidomide [104] with toxic granulomatous interstitial pulmonary disease, which is reported to be steroid-responsive.

Thromboembolic risk is increased in some patients with AL amyloidosis, nephrotic syndrome incurs an increased risk and treatment with thalidomide and lenalidomide has also been associated with higher rates of thrombosis [105]. The recommendation is therefore to consider anticoagulation in patients on treatment for nephrotic syndrome.

Amyloidosis Localised to the Respiratory Tract

First described by Lesser in 1877, localised amyloidosis of the respiratory tract ranges from asymptomatic pulmonary nodules to diffuse parenchymal deposits [83, 106]. Presenting

symptoms can mimic a variety of lung pathologies, and initial investigations with routine imaging can be unhelpful in con rming the diagnosis. A number of classi cations have been suggested based upon radiographic or bronchoscopicndings [11, 107]. In general, amyloidosis is best classi ed by bril proteins (Table 6.1) and then by the sites that are clinically involved [108]. Localised amyloid deposition is not uncommon, although often undiagnosed, and results from either local production of bril precursors [109, 110] or properties inherent to the particular microenvironment, which favour bril formation of a widely distributed precursor protein [111]. The vast majority of localised amyloid deposits are AL in type [106, 112–114], and symptomatic deposits occur most frequently in the eyes [115], skin [116] or respiratory [11, 117] or urogenital tracts [118, 119]. They are often associated with extremely subtle focal monoclonal B-cell proliferation con ned to the affected site, and surgical resection of these localised ‘amyloidomas’ can sometimes be curative [119]. Symptomatic and apparently localised amyloid deposits can rarely be manifestations of a systemic disease, and patients should always be fully investigated to exclude more generalised amyloid deposition [19].

A thorough evaluation of respiratory tract amyloidosis and biopsy con rmation is required to determine the need for treatment and the most suitable modality. The paucity of controlled clinical trials means that management decisions have to be made on an individual basis. Broadly speaking, systemic chemotherapy is usually indicated for systemic AL amyloidosis and local intervention, according to symptoms for its localised forms.

Laryngeal Amyloidosis

The larynx is the most frequent site of localised amyloidosis, affecting the head and neck [120, 121]. It represents 0.5–1% of benign laryngeal disease and its incidence increases with age, but it occasionally affects young adults or children [122]. Discrete nodular and diffuse in ltrative types of laryngeal amyloidoses were described in 1949 [123], with the diffuse pattern with an intact mucosa being more common, sometimes with tracheobronchial extension [114]. Macroscopic appearance is often seen as diffuse subepithelial oedema without a mucosa or nodular alterations [124]. The amyloid deposits most commonly occur in the ventricles followed by the subglottis, the aryepiglottic folds and the true vocal cords [114]. Presentation is usually with hoarseness or rarely stridor but can cause a sensation of ‘fullness’ in the throat, choking and dyspnoea on exertion [125]. The aetiology remains unclear, and there is no reported association with alcohol use, smoking, vocal abuse or infections [120]. One proposed explanation for the predilection of the larynx is that the production of light chains may be arising from the mucosa-associated lymphoid tissue (MALT) [117,

126]. Light-chain restriction is predominantly lambda in origin [118, 127].

A diagnosis is usually made following laryngoscopy and biopsy. It is important to identify the extent of in ltration with an MRI to decipher whether there is tracheobronchial extension. On MRI imaging, laryngeal amyloidosis has been reported to produce intermittent T1-weighted signal intensity and low T2-weighted signal intensity similar to the skeletal muscle. An MRI is believed to be superior to a CT scan when evaluating amyloidosis of the pharynx, larynx and trachea [128]. Systemic amyloidosis should be excluded, and investigation for an underlying plasma cell dyscrasia is imperative [121, 129]. There are case reports of extramedullary plasmacytomata with amyloid deposition affecting the larynx, and it is important to distinguish this from a localised deposit of amyloids [130].

Localised laryngeal amyloidosis is usually relatively benign but can be progressive or recur after treatment. Fatal haemorrhage has been reported [131]. Following a complete histological diagnosis and evaluation of the disease extent, endoscopic surgery [132, 133] or carbon dioxide laser excision [134, 135] is the treatment of choice, aiming to preserve voice quality and maintain airway patency [136]. As the underlying clonal plasma cell population is often diffuse and not excised, patients may require repeated removal of the amyloid deposits. Local and systemic corticosteroids have no effect on laryngeal amyloidosis [137]. There is some evidence of successful results, following external beam radiation therapy. The numbers of reported cases are small, and one patient developed grade one dysphagia and odynophagia following radiotherapy with hyperpigmentation of the skin over the treated area. However, the patient did achieve a signi cant improvement in voice strength and hoarseness and the treatment was deemed a success [138].

Very rarely, apparently localised laryngeal amyloid deposits can occur due to a feature of hereditary systemic apolipoprotein AI amyloidosis (AApoAI). Four separate apolipoprotein variants have been reported to cause this [110, 139–141], and, in three of these, the major site of organ damage is the heart. Apolipoprotein AI is a major constituent of high-density lipoprotein (HDL) [142]. Wild-type apolipoprotein AI is amyloidogenic and is present as traces of amyloids in human aortic atherosclerotic plaques in 10–20% of autopsies [143]. Numerous amyloidogenic variants have been reported, and, depending on the mutation, patients can present with massive abdominal visceral amyloid involvement [144], predominant cardiomyopathy [139] or a polyneuropathy syndrome [145]. Case reports suggest that the macroscopic appearances of the larynx in AApoAI amyloidosis differ from the localised AL form with deposits visible as small, irregular, foppy proliferations affecting the borders of the vocal folds in contrast to rm, bulky deposits in the localised AL form [146]. AApoAI amyloidosis is autosomal dominant inherited with variable penetrance, and a family history

of the disease is therefore often lacking. Performing immunohistochemistry on biopsy specimens for both kappa and lambda light chains and apolipoprotein AI is recommended. Genetic sequencing for Apo AI should also be performed.

Tracheobronchial Amyloidosis

Tracheobronchial amyloidosis is an uncommon diagnosis, although it too may well be underreported. It is characterised by amyloid deposits primarily in the trachea and large bronchi, with extension at times into the segmental bronchi and frequent involvement of the submucosal vessels, single or multiple nodules, luminal stenosis and obstruction; luminal wall thickening and rigidity; rough or uneven inner luminal walls and oedema of the mucosa with contact bleeding [11, 147, 148]. A literature review in 1983 identi ed 67 cases, of which 57 were diffusely in ltrative (multifocal submucosal plaques) and the remainder were nodular or ‘tumour-like’ [107]. Subsequently, 107 cases seen in China over a 34-year period have been reported [149] with a mean age at onset of 52.16 (±11.33) years and a median disease duration of 2 years.

Presenting symptoms include dyspnoea, persistent cough, which may be productive, haemoptysis, chest tightness and hoarseness [150]. Narrowing of the airways can cause wheezing, and cases of tracheobronchial amyloidosis simulating asthma have been reported. Deposits may cause distal atelectasis, recurrent pneumonia or lobar collapse [151], and solitary nodules may be mistaken for endobronchial neoplasia [152]. In the large Chinese series, 45% of cases were initially misdiagnosed; a CT was performed in 82 cases, and the major abnormalities were tracheal stenosis, tracheal wall thickening and calci cation, patchy shadows, atelectasis and hilar lesions. Chest X-ray examination was reported in 59 patients with described features including increased lung markings, atelectasis, patchy shadows, bronchitis, emphysema, luminal stenosis and enlarged hilar shadows. In a review of 64 cases, 70% had normal radiographic ndings [153]. Magnetic resonance imaging (MRI) may be more helpful in demonstrating more speci c features suggestive of amyloidosis. Typically, deposits have intermediate T1-weighted signal intensity and low T2-weighted signal intensity similar to the skeletal muscle [128]. Dual-phase fuorodeoxyglucose (FDG) PET/CT imaging can be used to differentiate between a malignancy and amyloid deposits. Early phase FDG metabolic activity can be seen, but delayed images show reduced activity, which would not be seen with a malignancy [154]. Given the non-speci c nature of the imaging of tracheobronchial amyloidosis, the diagnosis is often delayed and made following bronchoscopy and biopsy [155]. Tracheobronchopathia osteoplastica, characterised by calci ed or cartilaginous submucosal nodules within the airways [156–158], and relapsing polychondritis are the principle differential diagnoses [159, 160].

Although symptomatic tracheobronchial amyloidosis is usually localised, its course is not always benign, and overall survival has been reported in only 31–43% of patients at 4–6 years: 8 of 66 cases followed up by Lu died and three of four Mayo Clinic patients died within 79 months of diagnosis, although survival in the more recent Chinese series seems better over a limited follow-up [11].

The management of tracheobronchial amyloidosis is largely dependent upon symptoms; there is no proven drug therapy for tracheobronchial amyloidosis, although systemic chemotherapy has been tried in patients with progressive disease [150] with some anecdotal reports of success using dimethyl sulphoxide. The most common management strategies reported in the large series of Lu were bronchoscopic with 53 patients receiving interventions including Nd-YAG laser, argon plasma coagulation, cryotherapy, topical drugs, clamping, resection, high-frequency electrotome cautery, stent implantation and microwaves. Among these patients, 20 received bronchoscopic therapy alone, 32 received bronchoscopic therapy combined with drug therapy, whereas one received bronchoscopic therapy combined with external beam radiation therapy. The series did considerably better than previously reported cases as 51 patients improved, one worsened and one died. Extensive airway involvement may require open resection [161]. Endobronchial brachytherapy has been reported in a handful of cases with encouraging early results [162]. Management will always need to be tailored to each patient depending on the degree of amyloid in ltration.

Parenchymal Pulmonary Amyloidosis

Amyloids within the lung parenchymal tissue are the most frequently detected respiratory manifestations of amyloidosis [163]. It can be radiographically divided into solitary/ multiple nodules or a diffuse alveolar septal pattern [164, 165] (Fig. 6.4c); the latter is usually a manifestation of systemic amyloidosis, most commonly AL, but is also reported with the TTR type [5].

Nodular pulmonary amyloidosis is almost always due to localised AL deposits and is usually an incidental nding on chest radiography. Although the lesions may be dramatic and need to be differentiated from neoplasia, the prognosis is usually excellent. In theory, CT/PET should be useful in distinguishing between amyloid nodules and malignancies, but case reports suggest that PET imaging can yield false-­ positive results in nodular pulmonary amyloidosis and thus, although it may be a helpful investigation, it must be a con-rmed histological diagnosis. Amyloid nodules in the lung parenchyma are usually peripheral and subpleural, occurring preferentially in the lower lobes; they may be bilateral and range in diameter from 0.4 to 15 cm. They grow slowly and may cavitate or calcify [163, 164, 166]. Larger nodules can