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A 62-year-old African American man was admitted to the hospital with hemoptysis. He had a complicated medical history significant for active tobacco use (>50 pack-year history), coronary artery disease, and heart failure with reduced ejection fraction. He reported intermittent episodes of coughing up streaks of blood in the sputum for the past 3 years. For the past few days before this presentation, he had multiple episodes of coughing up over a tablespoon of only blood. He was not on any anticoagulant agents. There were no risk factors for TB, nor was there a history of fevers, chills, shortness of breath, leg swelling, changes in his urine color and frequency or urgency, or unintended weight loss. On admission, he was noted to be breathing comfortably. Vital signs revealed a temperature of 36.6ºC, BP of 138/70 mm Hg, heart rate of 66 beats/min, respiratory of rate of 18 breaths/min, and a blood oxygen saturation level of 98% on room air. Physical examination was significant for decreased bilateral breath sounds with no wheezing, crackles, or rhonchi. Cardiovascular examination revealed normal cardiac rhythm without murmur, rubs, or gallops. There was no clubbing or edema on his extremities.
Pulmonary function tests were significant for mild restrictive defect and mild reduction in diffusion capacity. His laboratory test results showed normal arterial blood gas, complete blood count, comprehensive metabolic panel, urinalysis, blood cultures, and sputum cultures. Autoimmune workups are negative for antinuclear antibody, centromere B, chromatin, double-stranded DNA, Jo-1, ribosomal-P, SS-A, SS-B, and Scl 70. The patient had no proteinuria, and his serum protein electrophoresis showed elevated gamma globulin with increased kappa/lambda ratio. A bone marrow biopsy of the left iliac crest showed normal cellularity with no evidence of plasma cell dyscrasia or lymphoproliferative disorder. A chest radiograph showed reticular interstitial opacities bilaterally in the mid to lower lung fields. Follow-up contrast CT scanning of the chest revealed paraseptal and centrilobular emphysema with multiple pulmonary cysts seen most prominently in the middle and lower lung zones. Many of these cystic spaces were noted to be traversed by normal-caliber blood vessels with associated calcifications (Fig 1A-D, F, G). Right middle lobe ground glass opacification with nodularity was present along the bronchovascular bundles (Fig 1E). He subsequently underwent BAL with transbronchial biopsies of the right middle lobe. The BAL cell count was significant for 19% lymphocytes with normal flow cytometry results. The transbronchial biopsy specimens revealed only minute fragments of benign endobronchial mucosa.
Given the hitherto negative workup, the patient subsequently underwent video-assisted thorascopic wedge resections of the right upper and lower lobes.
Microscopic examination of the resected specimens revealed, in addition to emphysema, focal to diffuse nodular thickening of bronchiolar and vessel walls by deposits of amorphous, homogeneous eosinophilic material on routine hematoxylin-eosin stain (Fig 2A and B). Similar well-circumscribed nodular deposits also were present focally in the lung parenchyma. Alveolar and septal wall-thickening was not prominent. Scattered small aggregates of lymphocytes, plasma cells, and rare multinucleated giant cells were present adjacent to or within the deposits.
Based on these histopathologic findings, a Congo red stain was performed that visually accentuated the orange-red nodular deposits (Fig 2C). Under polarized light microscopy, the Congo red-stained deposits showed the characteristic “apple-green” birefringence (Fig 2D).
What is the diagnosis?
Diagnosis: Pulmonary amyloidosis
In the lung there are three presentations of amyloid: diffuse alveolar-septal, nodular, or tracheobronchial. However, there can be variations in these presentations. Generally, diffuse alveolar septal amyloidosis is a result of systemic amyloidosis and tracheobronchial amyloidosis results in focal airway stenosis. We have presented an example of nodular amyloid, which is defined generally as one or more nodular amyloid deposits found in the lung that may show associated cavitation and calcification.
Pulmonary amyloidosis with lung parenchymal involvement often presents as incidental radiologic findings because patients are often asymptomatic. However, they can present with a variety of pulmonary symptoms that include, but not limited to, shortness of breath, wheezing, recurrent pneumonia, cough, hemoptysis and even pleural effusions.
For definitive diagnosis of amyloidosis, histologic evidence is required. Although often transbronchial biopsy is a safe and effective method for diagnosis, it is diagnostic in only approximately 60% of cases.
This patient ultimately underwent a surgical lung biopsy for definitive diagnosis after other workup remained inconclusive. His hemoptysis ultimately resolved, and the patient has not had any further progression of his parenchymal disease and remains on room air.
Diffuse cystic lung diseases are rare but can present a unique diagnostic challenge, given the number of diseases that share this presentation. A pulmonary cyst is a round airspace defined pathologically by an epithelial or fibrous outer wall that is less than 5 mm thick and radiographically as a round parenchymal lucency or low attenuation area with a well-defined interface with normal lung.
The term diffuse implies that involvement of the cyst is found in all lobes of the lung; however, the distribution of these cysts and associated radiographic features can serve as important clues to defining the underlying nature of cystic lung disease and guide diagnostic evaluation.
Absence of multiorgan involvement and lymphoproliferative disorders make light change deposition disease unlikely. The lack of centrilobular ground glass opacities, absence of septal thickening, and the clinical absence of immunodeficiency disorders or autoimmune disease go against the diagnosis of lymphoid interstitial pneumonia. The diffuse distribution of the cysts in the lower lung zones with predominant nodules with sharp and smooth contours and calcification are noted in the images are suggestive of pulmonary amyloidosis.
Amyloidosis encompasses a heterogeneous group of rare disorders caused by extracellular deposition of approximately 20 different abnormally folded precursor proteins in the form of insoluble aggregates called amyloid fibrils. Accumulation of these fibrils causes disruption of normal tissue architecture, leading to progressive malfunction and eventually failure of the affected organs. The main subtypes of amyloidosis are primary amyloidosis, secondary or inflammatory amyloidosis, amyloid transthyretin amyloidosis (ATTR), and dialysis-associated amyloidosis. In primary amyloidosis, the amyloidogenic protein is usually the light chains of the λ isotype produced in excess by a clone of dysplastic plasma cells. In secondary or inflammatory amyloidosis, the precursor is the acute-phase reactant serum amyloid A protein synthesized by hepatocytes in response to recurring inflammatory stimuli. ATTR is a rare, progressive, and fatal disease caused by deposition of nonnative form of transthyretin protein (formerly known as prealbumin) in various organs, typically in the heart and nerves. The hereditary form of ATTR is caused by mutations in the transthyretin gene that result in accumulation of misfolded transthyretin proteins. The wild-type ATTR amyloidosis (also known as age-related or senile amyloidosis) occurs in the absence of gene mutations and more often in men >65 years old. Dialysis-associated amyloidosis is caused by abnormal aggregation in osteoarticular tissue of conformationally modified β2-microglobulin and other associated proteins.
Diagnosis of amyloidosis requires the demonstration of amyloid fibrils in a tissue sample taken from the affected organ or a “surrogate” site, such as abdominal fat pad, rectal biopsy, or bone marrow.
Irrespective of origin, all amyloid fibrils share a common denominator in their tendency to form β-pleated sheet structure of antiparallel fibrils as observed by radiographic diffraction. Their presence in tissue can be demonstrated histopathologically with the use of the Congo red stain. This textile dye binds avidly to amyloid material through an organized intercalation of the dye molecules between their antiparallel β-sheet architecture and confers the characteristic “apple-green” birefringence of Congophilic amyloid material when examined under polarized light microscopy. Although Congo red stain can demonstrate the presence of amyloid deposits, it cannot characterize the various subtypes of amyloidosis. Immunohistochemical stains for κ and λ light chains, amyloid A, and transthyretin can be performed, usually by reference laboratories, to determine the precursor protein. The current reference standard for amyloid protein classification involves laser microdissection of amyloid deposits from the tissue followed by mass spectrometry proteomic analysis to identify the precursor protein. This highly sensitive and specific diagnostic modality, however, is available at only large amyloidosis referral centers.
Table 1summarizes the key clinical, radiological, and pathological features of pulmonary amylodosis.
Table 1Key Clinical, Radiologic, and Pathologic Characteristics of Nodular Pulmonary Amyloidosis
Men in the sixth decade of life
Thin-walled cysts with internal septa abutting bronchocentric nodules
Nodular deposits of amyloid fibrils in peribronchiolar and associated vessel walls and focally in lung parenchyma, while sparing the alveolar-septal walls
Generally asymptomatic but can present with shortness of breath, cough hemoptysis, and even effusion
Nodules with associated calcification
Diagnostic “apple-green” birefringence of Congo red-stained amyloid fibrils under polarized light microscopy
Diffuse cystic lung diseases have a broad differential diagnosis and should be approached in a systematic method.
Cystic pulmonary amyloidosis, often associated with primary amyloidosis, is a rare entity in individuals with or without coronary vascular disease and should be on the differential diagnosis for cystic lung diseases with associated nodules and calcifications.
Partially calcified nodules without poorly formed centrilobular ground-glass nodules can assist radiographically in distinguishing cystic pulmonary amyloidosis from lymphoid interstitial pneumonia.
Lung biopsy is required to demonstrate the characteristic “apple-green” birefringence of Congophilic amyloid material under polarized microscopy for definitive histopathologic diagnosis of amyloidosis.