https://orcid.org/0000-0002-9935-070X
ABSTRACT
Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of misfolded proteins that can affect either systemically or locally confined to one system. Pulmonary amyloidosis is rare and can be classified into three forms according to the anatomic site of involvement: nodular pulmonary amyloidosis, tracheobronchial amyloidosis and diffuse alveolar-septal amyloidosis. The former two usually represent localized amyloid disease and the latter represents systemic disease. Typically lung parenchymal and tracheobronchial amyloidosis do not present together in localized forms of pulmonary amyloidosis. Here we report a unique case of localized pulmonary immunoglobulin light-chain amyloidosis, manifested as both parenchymal nodules and tracheobronchial amyloid deposition.
INTRODUCTION
Amyloid are insoluble heterogenous proteins predominantly composed of β-sheet structure that characteristically bind to the dye Congo Red and produce an apple-green birefringence under polarized light microscopy [1]. With an estimated incidence of approximately 10 cases per million person-years, systemic amyloidosis are considered rare disease [2]. Localized amyloidosis, usually defined as only one type of tissue involved, are much rarer than systemic types [3]. The amyloidogenic protein is usually the deposition of immunoglobulin light-chain type and thought to be resulted from a focal monoclonal B-cell dyscrasia within the affected tissue [3]. Pulmonary amyloidosis can be localized or part of systemic amyloidosis [4]. Combined lung parenchymal and tracheobronchial involvement of amyloidosis are common in systemic amyloidosis on histologic exam, but rarely present together in localized pulmonary amyloidosis [5, 6]. We report a unique case of localized pulmonary amyloidosis who presented with multiple pulmonary nodules and tracheobronchial amyloid deposition.
CASE REPORT
In June 2014, a 53-year-old Caucasian female without significant past medical history presented to an outside pulmonary clinic with 4-month history of dry cough and dyspnea on exertion. She was a life-long non-smoker and worked as a medical transcriptionist. Computerized tomography (CT) of the chest revealed multiple bilateral lung nodules. She was placed on prednisone 40 mg daily for presumed sarcoidosis. At three months she reported subjective improvement, however a repeat chest CT confirmed persistence of bilateral lung nodules and circumferential mural thickening and narrowing the central airways (Figure 1a). She ultimately underwent CT-guided core needle biopsy of a right upper lobe lung nodule. The pathological examination demonstrated lung parenchyma with features consistent with amyloid deposition. Specimen was sent to Mayo Clinic to perform laser-capture microdissection with liquid chromatography-coupled tandem mass spectrometry for amyloid typing, which identified κ light chain as the amyloidogenic protein. Prednisone was tapered off, and she was referred to our institute for further management.
(a) Chest CT shows multiple bilateral lung nodules, some with central calcifications (arrowhead) and variable-sized cysts (white arrows) in all lung lobes. Note, airway involvement with circumferential mural thickening of the right lower lobe (RLL) bronchi (black arrows) and narrowing of right middle lobe (RML) bronchi (black arrows). (b) Chest CT angiography shows diffuse ground-glass opacities most suggestive of hemorrhage (in the setting of hemoptysis) with persistence of multiple bilateral lung nodules and cysts. Note, presence of endobronchial soft-tissues within RML segmental and subsegmental bronchi (black arrows).
Her complete blood count, kidney function and calcium level were within normal limit. Serum free light chain assay was normal. Serum protein electrophoresis was positive for M-protein (0.98 mg/dL). Serum immunofixation revealed mildly elevated IgG [1620 mg/dL (ref. 717–1411 mg/dL)] and κ level [1290 mg/dL (ref. 534–1267 mg/dL)]. A 24-hour urine protein was normal and no M-protein was identified on urine protein electrophoresis. Troponin and N-terminal-pro brain natriuretic peptide were normal. Echocardiogram showed normal left ventricular ejection fraction with normal diastolic function. Bone marrow biopsy showed no evidence of clonal plasma cells. Given normal serum light chain assay, normal bone marrow biopsy, and lack of systemic involvement, she was diagnosed with localized AL amyloidosis involving the lung. She was also diagnosed with monoclonal gammopathy of undetermined significance (MGUS) based on positive serum M-protein. No treatment was started, and she was followed with hematology/oncology every 6 months. Of note, bronchoscopy was initially not performed because airway involvement was not reported on the initial CT and the patient was largely asymptomatic when the follow-up chest CT reported evident airway involvement.
Four years later, she developed an episode of hemoptysis. Chest CT angiography showed diffuse ground-glass opacities most suggestive of hemorrhage with persistence of multiple bilateral lung nodules and airway involvement (Figure 1b). She underwent bronchoscopy, which revealed multiple yellowish plaques in the mucosal areas involving the subglottic space, trachea, segmental and subsegmental bronchi and a number of infiltrative nodules (Figure 2). Endobronchial biopsies were performed. Pathology of fragments of bronchial mucosa showed extensive amyloid deposits on Congo red stain, consistent with endobronchial amyloidosis (Figure 3). She was treated with bronchoscopic therapy twice at 3 months interval using argon plasma coagulation with resolution of symptoms.
Flexible fiberoptic bronchoscopy shows multiple yellowish plaques (short arrows) and raised nodular infiltration (long arrows) of airway mucosa in (a) right upper lobe (b) right middle lobe.
Photomicrographs of the endobronchial biopsy (a) deposits of amorphous, eosinophilic, waxy-like material (A) with ossification (B), underlying the bronchial epithelium (arrow), H&E, 10x. (b) When stained with Congo red, the material is bright orange on light microscopy, H&E, 4x and (c) apple green birefringence under polarizing microscopy, Congo red, 10x.
Of note, the patient also had abdominal fat aspirate performed in July 2016 to assess for signs of systemic amyloid, which failed to demonstrate such condition. She was incidentally noted to have an enlarged right submandibular salivary gland on CT imaging and underwent biopsy in December 2016, which revealed AL (κ) amyloid deposition. By the time this manuscript was being prepared, she remained asymptomatic. She has had stable MGUS with faint serum M protein (0.99 mg/dL) and mildly elevated serum free κ light chain [25.5 mg/L (ref. 3.3–19.4 mg/L)] on the most recent follow-up studies.
DISCUSSION
Pulmonary amyloidosis can be localized or part of systemic amyloidosis [4]. Based on the anatomic site of involvement, pulmonary amyloidosis can be classified into 3 forms: nodular pulmonary amyloidosis, tracheobronchial amyloidosis and diffuse alveolar-septal amyloidosis [4]. The former two are usually seen in localized pulmonary amyloidosis [5]. Nodular amyloidosis is slightly more prevalent than tracheobronchial amyloidosis. In a cases series of 55 patients with pulmonary amyloidosis reported by Mayo Clinic from 1980 to 1993, 11 patients had localized pulmonary amyloidosis. Among them, 7 patients had nodular pulmonary amyloidosis, and 4 patients had tracheobronchial amyloidosis [5]. Both lung parenchymal and tracheobronchial amyloidosis can be seen in systemic amyloidosis, but rarely present together in localized forms of pulmonary amyloidosis [6, 7]. In an autopsy study of 11 patients who had lung involvement of systemic amyloidosis, amyloid deposition was found in both alveolar and tracheobronchial mucosa in all 7 patients in whom both alveolar and tracheobronchial histologic examination were available [7]. Only 1 case reported a large solitary pulmonary amyloid tumor protruding into the bronchus lumen, however it did not mention if that patient had systemic or localized disease [8]. In our case, although amyloid deposition was noted in the parotid gland, there was no evidence of other systemic involvement, thus the patient was thought to have localized amyloidosis.
Localized AL amyloidosis generally has an excellent long-term prognosis and rarely evolves into systemic amyloidosis [3]. In a study of 606 patients with localized amyloidosis (defined as amyloid deposition at one non-vital organ site and with no evidence of systemic organ involvement such as heart, kidney, liver, nerve or tongue), including 35 cases (6%) with tracheobronchial amyloidosis and 47 cases (8%) of nodular pulmonary amyloidosis, only 7 patients (1%) progressed to systemic amyloidosis at a median follow-up of 74 months [3]. Patients with isolated lymph node amyloidosis and excess of free light chains are at increased risk of progression to systemic disease [3]. The estimated 5-year overall survival was 90% and 10-year overall survival was 80% [3].
In summary, our case demonstrated that combined pulmonary nodular and tracheobronchial amyloid deposition can be seen in localized pulmonary amyloidosis; presence of one doesn’t rule out the other.
CONFLICT OF INTEREST
None declared.
FUNDING
No source of funding for this report.
ETHICAL APPROVAL
Ethical approval is waived for this study.
CONSENT
Patient’s written consent has been obtained.
GUARANTOR
Atul C. Mehta MD (corresponding author).
ACKNOWLEDGEMENTS
We greatly appreciated our patient for her support in writing up this case report.
