CHEST -- Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS

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1 GE=] CHEST -- Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS A 73-Year-Old Woman With Mild Shortness of Breath and Multiple Central Calcified Pulmonary Nodules* Rani Kumaran, MD; Anthony Saleh, MD, FCCP; Bijal Amin, MD; and Suhail Raoof; MD, FCCP (CHEST 2008; 134: ) he diagnostic workup for multiple calcified pul- T monary nodules can be a challenge for clinicians. The differential diagnosis of multiple calcified pulmonary nodules includes a broad spectrum of etiologies, the most important of which are neoplastic and infectious. A detailed medical history and radiographic description, with particular emphasis on the location and, to a lesser extent, the morphology, number, and size of nodules and other associated radiographic abnormalities usually help to narrow the differential diagnosis. This discussion focuses on the differential diagnosis and the workup of multiple calcified pulmonary nodules. CASE PRESENTATION A 73-year-old woman who was a lifelong nonsmoker was referred to the pulmonary clinic for mild dyspnea and dry cough of several months' duration. Her medical history was significant for systemic hypertension and osteoarthritis. She was receiving therapy with metoprolol, 25 mdd. She denied having any other symptoms, including chest pain, weight loss, hemoptysis, fevers, chills, and night sweats. The findings of her physical examination were unremarkable. A chest radiograph with a posteroanterior view (Fig 1) showed multiple ill-defined nodules of varying sizes (range, 0.5 to 3.0 cm) in both lung fields. A CT scan of the chest *From the Department of Pulmonary and Critical Care Medicine (Drs. Kumaran, Saleh, and Raoof), New York Methodist Hospital, Brooklyn, NY; and the Department of Pathology (Dr. Amin), New York Weill Cornell Medical Center, New York, NY. The authors have reported to the ACCP that no significant conflicts of interest exist with any com anies/organizations whose 1... products or services may be discusse m this article. Manuscript received August 3,2007; revision accepted March 10, Reprodudion of this article is rohibited without written permission from the American College opchest Physicians ( org/misc/re rints shtml). CorresponLnce to: Suhail RaooA MD, FCCP, New York Methodist Hospital, 506 6th St, New York, NY 11215; sur901 R@nyp.or DOI: /$est FIGURE 1. The posteroanterior chest radiograph showing bilateral multiple pulmona nodules. The nodules vary in size from 0.5 to 3 cm. The norules show lobulated and irregular margins. (Fig 2) showed these nodules both in central and peripheral locations. The margins were irregular. No feeding vessels, cavitation, or predilection for the bases were noted. Some of the nodules demonstrated partial calcification. The interlobular septa were not thickened or nodular. No significant lymphadenopathy was seen in the hilum or mediastinum. No pleural effusions were noted. CBC count, comprehensive metabolic profile, and serum and urine protein electrophoresis findings were normal. Her age recommended screening tests, including mammogram and colonoscopy, the findings of which were normal. The findings of a 5-tuberculin unit purified protein derivative of tuberculin test were negative. Pulmonary function testing demonstrated normal spirometry results, lung volumes, and diffusion capacity. The patient underwent flexible bronchoscopy, which showed normal bronchial mucosa and no endobronchial lesions. Transbronchial biopsy showed only chronic inflammation. The patient underwent video-assisted thoracoscopy surgery. The patholoo is depicted in Figures Postgraduate Education Corner

2 FIGURE 2. Noncontrast axial CT scan images of the chest (lung window and mediastinal window) at the level of the upper lobes. The dominant nodule in the right upper lobe (bottom, b ) is peripheral, lobulated, and noncalcified. The dominant nodule in the left upper lobe (bottom, b ) is central, lobulated, and predominantly calcified. There are other smaller, multiple nodules seen bilaterally. FIGURE 3. Wedge biopsy of left upper lobe nodule by videoassisted thoracoscopy surgery. Top, a: histology at low power (hemato lin eosin, original X 4). At low power, there are nodular yeposits of homogenous eosinophilic material. A lynphoplasmacytic infiltrate is noted at the periphery of the nodules. The eosinophilic nodules stain strongly with Congo red, supporting a diagnosis of amyloidosis. Immunohistochemical stainin for amyloid rotein A is negative, indicating primary amyloickis. Bottom, %: histology at high power (Congo red stain under polarized light, original X 40). Under polarized light, Congo red-stained nodular deposits shows characteristic apple-green birefringence characteristic of amyloidosis. What is the clinical diagnosis? CHEST I 134 I 2 I AUGUST,

3 Prim y pulmona y amyloidosis (AL type) CLINICAL DISCUSSION The clinical presentation of multiple calcified pulmonary nodules varies with the etiology. Pertinent symptoms that should be elicited include cough, hemoptysis, dyspnea, chest pain, fevers, weight loss, and smoking history, which may help in narrowing the etiology. The differential diagnosis of multiple calcified pulmonary nodules includes infections (eg, tuberculosis; fungal, parasitic, and viral pneumonias), pneumoconiosis (eg, coal and silica occupational exposure), metabolic diseases (eg, end-stage renal failure with secondary hyperparathyroidism), primary malignancy or metastasis, and other systemic illnesses such as paraproteinemias, nodular sarcoidosis, and rheumatoid arthritis. Old granulomatous diseases (mycobacterial and fungal) are the most common benign conditions that may result in multiple calcified pulmonary nodules.2 Malignant conditions to consider include both primary lung cancer and metastasis from other organs. Metastatic mucinous adenocarcinoma originating from the thyroid gland, pancreas, small bowel, and ovaries can present as multiple calcified pulmonary nodules. Sarcomas, benign metastasizing leiomyomas, multiple hamartomatous chondromas, and choriocarcinomas rarely present as multiple calcified pulmonary nodule^.^ Uncommon disorders to consider include amyloidosis, metastatic pulmonary calcification, and pulmonary alveolar microlithiasis.4 Transbronchial biopsy specimens are obtained for the evaluation of lesions or localized parenchymal densities, in which neoplasms or infections are the leading causes. Patients with diffuse parenchymal lung disease undergo biopsy by this method, with a view to secure a definitive diagnosis, thereby avoiding a more invasive procedure.5 Our patient had mild dyspnea and dry cough of several months duration with no other symptoms. The long duration of symptoms, the absence of smoking, normal physical examination findings, and negative routine workup results led us to suspect a benign condition. However, due to the central location of some of the nodules and the need to exclude a neoplastic process, the less invasive transbronchial biopsy was initially performed. Later, an open-lung biopsy was performed, which showed nodular AL amyloidosis. Amyloidosis is a disease that is characterized by the deposition of different proteins in various organs resulting in a plethora of clinical symptoms.6 Pulmonary involvement may occur as part of the systemic or localized form of AL amyloidosis. Localized AL amyloidosis is commonly identified in the upper respiratory tract, the urogenital tract, and the GI tract, as well as the skin and orbits7 Pulmonary involvement in localized AL amyloidosis manifests as tracheobronchial, nodular, and diffuse types. The tracheobronchial involvement exhibits unifocal and diffuse submucosal disease, mimicking airway disorders. Diffuse parenchymal opacities constitute the uncommon form, which presents with gas exchange abnormalities6 Nodular disease cames a good prognosis. It may show slow progression with an increasing size or number of lesions, but does not usually impact lung gas exchange or patient survival. Systemic chemotherapy is not advocated for the treatment of localized disease.8 Synchronous multiorgan involvement, such as cardiac, renal, and pulmonary involvement, is absent in patients with localized AL disease. Radiologic Discussion The anatomic distribution and morphology of multiple pulmonary nodules differ based on the etiology. A CT scan helps to further characterize the size, number, location, borders, and distribution of these nodules. Smaller and less numerous nodules are more likely to be benign.9 A specific pattern of calcification within a pulmonary nodule may point toward a benign etiology. However, the pattern of stippled calcification has been described as an indicator of malignancy.1o Even though nodules of neoplastic origin usually exhibit a more rapid growth rate, this is not absolutely critical. Fungal infections, most commonly histoplasmosis, coccidioidomycosis, and certain viral infections, such as those with Varicella, may present as multiple calcified pulmonary nodules anywhere in the lung field. Metastasis from another malignancy may present as multiple calcified nodules of variable sizes with a predilection to peripheral, basal, and subpleural locations with sharply demarcated borders. Patients with coal worker pneumoconiosis or silicosis may show multiple nodules with calcifications, which may progress to conglomerate masses, ranging in size from 1 to 10 cm and usually located in the upper lobes.11 On high-resolution CT scans, metastatic pulmonary calcification may manifest as numerous calcified nodules (3 to 10 mm in diameter) or, more commonly, as fluffy and poorly defined nodular opacities mimicking airspace nodules, predominantly in apical and subapical lung zones.12 The distinct radiographic pattern of alveolar microlithiasis consists of punctate micronodules diffusely involving both lungs with slight perilobular predominance, resulting in apparent calcification of the interlobular septa. Calcified rheumatoid nod- 462 Postgraduate Education Corner

4 ules have been described in the setting of Caplan syndrome with coal worker pneumoconi~sis.~~ The development of calcifications within one or more rapidly enlarging pulmonary nodules is frequently seen in patients with metastatic osteosar~oma.~~ In patients with localized AL amyloidosis, the radiologic manifestation depends on the type of the dsease. In the tracheobronchial type, chest radiograph findings are normal in 50% of patients. Findings in other patients include atelectasis or lobar collapse, calcified extraluminal amyloid deposits, bronchiectasis, or hilar adenopathy. A CT scan of the chest may show calcified amyloid deposits in the airway walls, resulting in irregularity, thickening, and narrowing of the airway lumen. The tracheobronchid involvement includes the posterior membranous part of the trachea as well. In patients with the diffuse type of AL amyloidosis, reticulonodular and peripheral alveolar opacities may be present. In patients with the nodular type of AL amyloidosis, a chest CT scan may show nodules with smooth or spiculated borders, cavitation, and calcification. No concurrent pleural effusions or lymphadenopathy are seen. Nodules are preferentially located in the subpleural and mid-lung-zone region. If a dyssynchronous growth is identified in one of the nodules, the possibility of carcinoma should be sought.6 Our patient had multiple ill-defined nodules both in the subpleural and central locations. Pathology Discussion A definitive diagnosis requires histologic con firmation. In granulomatous diseases, the special stains may show a particular organism, well or poorly formed granulomas, with or with out necrosis, depending on the underlying etiology. Various pathologies can be seen in metastatic nodules, depending on the primary malignancy. Pathologcally metastatic calcification is characterized by the presence of strong hematoxylin staining in the alveolar septa, and in the walls of small pulmonary vessels and bronchi. The proposed theory for the pathogenesis of calcified pulmonary metastases is that dystrophic calcification or ossification occurs in areas of cellular necrosis. In our patient, a gross examination of wedge biopsy specimens obtained from the left upper and lower lobes of the lung demonstrated ill-defined firm areas within the lung parenchyma. Microscopically, the lung tissue was extensively replaced with nodular deposits of homogeneous eosinophilic material (Fig 3, top, a) that strongly reacted with Congo red stain. The specimen showed characteristic apple-green birefringence under polarized light, indicating the presence of amyloidosis (Fig 3, bottom, b). At the periphery of these deposits, a moderately dense lymphoplasmacytic infiltrate was noted. The result of immunohistochemical staining for amyloid protein A was negative, which supports the pulmonary origin of the deposits. The presence of amyloid nodules on histologic sampling almost uniformly indicates localized disease (ie, AL type). Amyloidosis is classified based on the type of subunit protein deposited in various organs. The classification includes an A for amyloid and a letter indicating the type of protein involved. Primary or Ig light-chain (AL) disease, secondary or amyloid protein A (AA) disease, hereditary or mutant transthyretin (ATI R) disease, and dialysis-associated or p2- microglobulin (P2M) disease are the four major forms of systemic amyloidosis.6 AL monoclonal Igs (A or K light chains), which is the primary type of amyloid protein deposition, are seen in patients with both systemic and localized forms of amyloidosis.6 Organ involvement in patients with AL disease, whether it is systemic or localized, is due to the deposition of monoclonal K or A Ig light chains. In patients with systemic disease, excessive monoclonal KI or XIV subtypes are secreted by clonally expanded plasma cells residing in the bone marrow and are deposited in different organs. In patients with localized disease, monoclonal KI and A111 subtypes are secreted by a small number of plasma cells surrounding the lesion.5.15 CONCLUSIONS Although AL-type nodular pulmonary amyloidosis classically presents in a peripheral, subpleural location, occasionally it can present as central nodules. Nodular amyloidosis carries a good prognosis, and no systemic therapy is warranted. Our patient underwent an extensive workup, which failed to show any malignancy or other etiology as the cause of her nodules. The histopathology confirmed the diagnosis of primary pulmonary nodular amyloidosis. She is being followed up periodically without further therapy. REFERENCES 1 Weber CK, Friedrich JM, Merkle E, et al. Reversible metastatic pulmonary calcification in a patient with multiple myeloma. Ann Hematol 1996; 72: Lee JY, Lee KS, Jung KJ, et al. Pulmonary tuberculosis: CT and pathologic correlation. J Comput Assist Tomogr 2000; 24: Aquino SL. Imaging of metastatic disease to the thorax. Radiol Clin North Am 2005; 43: Chunga MJ, Leea KS, Franquet T, et al. Metabolic lung disease: imaging and histopathologic findings. Eur J Radiol 2005: 54: CHEST! /AUGUST,

5 5 Utz JP, Swensen SJ, Gertz MA. Pulmonary amyloidosis: the Mayo Clinic experience from 1980 to Ann Intern Med 1996; 124~ Berk JL, O Regan A, Skinner M, et al. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002; 23: Thompson PJ, Citron KM. Amyloid and the lower respiratory tract. Thorax 1983; 38: Pickford HA, Swensen SJ, Utz JP. Thoracic cross-sectional imaging of amyloidosis. AJR Am J Roentgenol 1997; 168: Raoof S, Amchentsev A, Vlahos 1, et al. Pictorial essay: multinodular disease: a high-resolution CT scan diagnostic algorithm. Chest 2006; Webb WR. Radiologic evaluation of the solitary pulmonary nodule. AJR Am J Roentgenol 1990; 154: Stark P, Jacobson F, Shaffer K. Standard imaging in silicosis and coal worker s pneumoconiosis. Radiol Clin North Am 1992; 30: Hartman TE, Miiller NL, Primack SL, et al. Metastatic pulmonary calcification in patients with hypercalcemia: findings on chest radiographs and CT scans. AJR Am J Roentgeno1 1994; 162: Srinivasa S, Dhelariab R, Pai D, et al. Multiple calcified pulmonary nodules: an unusual presentation of rheumatoid lung. Clin Radiol 2007; Meyer CA, White CS. Cartilaginous disorders of the chest. Radiographics 1998; 18: Hui AN, Koss MN, Hochholzer L, et al. Amyloidosis presenting in the lower respiratory tract: clinicopathologic, radiologic, immunohistochemical, and histochemical studies on 48 cases. Arch Pathol Lab Med 1986; 110: Postgraduate Education Corner