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Case Report
November 2001

Cellulose Granulomatosis Presenting as Centrilobular Nodules: CT and Histologic Findings

Centrilobular nodules on high-resolution CT are characterized as nodular opacities localized to the region of the bronchioloarteriolar core of a secondary pulmonary lobule and separated at a distance of 2-3 mm from the lobular borders [1]. A tree-in-bud sign is defined as a nodular dilatation of the centrilobular branching structures that resemble a budding tree [2]; both centrilobular nodules and a tree-in-bud pattern are typically associated with small airways disease [1, 2]. Although arteriolar and perivascular disease can also theoretically result in centrilobular nodules, this association is not well documented in the literature. We report a biopsy-proven case of cellulose granulomatosis resulting in a diffuse pattern of centrilobular nodules and a tree-in-bud appearance. To our knowledge, this is the first case of an arteriolar cause of a tree-in-bud pattern to be reported with the corresponding CT and histologic findings.

Case Report

A 36-year-old man with a 2-year history of recurrent severe arterial vasospasm principally affecting the upper extremities was referred to our institution for a 3-week therapeutic trial of prostaglandin E1 (Alprostadil; Gensia Sicor Pharmaceuticals, Irvine, CA) in an attempt to promote arteriolar vasodilatation. Other compelling factors in the patient's medical history included chronic migraine headaches for which he was prescribed oral analgesics, including hydrocodone and acetaminophen (Vicodin; Knoll Laboratories, Mount Olive, NJ).
Five days after a peripherally inserted central catheter was placed for the daily prostaglandin infusions, the patient became febrile, with blood cultures positive for Klebsiella pneumoniae and Enterobacter cloacae. His temperature defervesced after initiation of the appropriate antibiotics and an exchange of the central line. Seven days after finishing the course of antibiotics, the patient again developed the same gram-negative bacteremia. On an abdominal CT scan ordered to exclude an intraabdominal source of sepsis, multiple 1- to 3-mm pulmonary nodules were identified in the visualized lung bases. A dedicated high-resolution CT scan of the thorax showed an enlarged main pulmonary artery measuring 3.0 cm in diameter and innumerable centrilobular nodules, some with a tree-in-bud appearance that were scattered diffusely in the lung parenchyma (Figs. 1A and 1B). The patient declined further workup of his lung disease and left the hospital with a course of IV antibiotics to be finished on an outpatient basis.
Fig. 1A. 36-year-old man with biopsy-proven cellulose granulomatosis. High-resolution CT images show innumerable bilateral small centrilobular nodules associated with tree-in-bud appearance (arrows). Insets show magnified views of centrilobular branching opacities in periphery of right upper and lower lobes, respectively.
Fig. 1B. 36-year-old man with biopsy-proven cellulose granulomatosis. High-resolution CT images show innumerable bilateral small centrilobular nodules associated with tree-in-bud appearance (arrows). Insets show magnified views of centrilobular branching opacities in periphery of right upper and lower lobes, respectively.
Five days after hospital discharge, the patient re-presented to the emergency room febrile, hypotensive, and in respiratory failure, requiring emergency intubation. A chest radiograph obtained at admission showed a diffuse bilateral reticular pattern. Pulmonary artery catheterization revealed pulmonary artery hypertension with a blood pressure of 80 over 44 mm Hg, a decreased cardiac output of 2.7 L, and an elevated wedge pressure of 19 mm Hg. Clinically, the patient was believed to have pulmonary edema associated with decompensated pulmonary artery hypertension. After treatment with empiric antibiotics, vasodilators, and diuretics, the patient became stabilized, allowing extubation. A subsequent thoracoscopic biopsy of the right lower lung lobe showed innumerable sharply delineated nodules centered in or around the pulmonary arterioles and muscular pulmonary arteries and ranging from 0.1 to 0.4 mm in diameter (Fig. 1C). Many of the vessels showed alternating dilatation and disruption of elastic lamina and musculature with replacement by granulomatous nodules and fibrosis (Fig. 1D). The intravascular and perivascular foreign body granulomas contained refractile pale crystals measuring 20-95 μm that were optically active under polarizable light (Fig. 1E). The crystals stained violet on a predigested periodic acid—Schiff stain, black on Gomori methenamine-silver stain, and orange on Congo red stain. Admixed with the crystals were variable numbers of histiocytes and foreign body—type giant cells and occasional aggregates of deeply basophilic amorphous material resembling charred tissue. Histologic sections of a Vicodin tablet displayed identical crystalline material. On directed questioning, the patient admitted to IV injection of his prescribed oral medications.
Fig. 1C. 36-year-old man with biopsy-proven cellulose granulomatosis. Photomicrograph of histopathologic specimen with low-power magnification shows normal pleura (arrows) and discrete nodular lesions centered on bronchovascular bundles with normal intervening lung parenchyma. (H and E, ×20)
Fig. 1D. 36-year-old man with biopsy-proven cellulose granulomatosis. Photomicrograph of histopathologic specimen shows branching muscular pulmonary artery with distal dilatation and luminal occlusion by foreign material and associated reaction. (elastica-van Gieson, ×100)
Fig. 1E. 36-year-old man with biopsy-proven cellulose granulomatosis. Photomicrograph of histopathologic specimen shows nodules containing optically active material under polarizable light. (H and E, ×40)

Discussion

Foreign body granulomatosis is caused by IV injection of medications intended for oral use. The medications are typically crushed, mixed with water, heated, and then injected IV. Insoluble particles such as microcrystalline cellulose, talc, and cornstarch, which are used as fillers in oral tablets, become trapped in the pulmonary arterioles, causing thrombosis and inflammation; with time, these particles can penetrate the arteriolar wall and provoke a giant cell reaction. Histologically, foreign body granulomatosis is characterized by perivascular granulomas containing birefringent particles. Differentiation among various inciting agents can be made on the basis of the following morphology and staining characteristics: microcrystalline cellulose forms long crystals that stain with periodic acid—Schiff, methenamine silver, and Congo red stains; talc forms large irregular yellow plates; and cornstarch is identified by its round shape and Maltese cross pattern [3].
Clinical symptoms associated with cellulose granulomatosis are largely dependent on the extent of arteriolar involvement and the severity of the induced pulmonary artery hypertension; symptoms may range from none to exertional dyspnea to sudden death [4, 5]. On high-resolution CT, the findings of cellulose granulomatosis have been previously described as diffuse 1- to 2-mm interstitial nodules [6], some of which occur in a centrilobular distribution [7]. In our biopsy-proven case, nodules ranged from 1 to 3 mm, were centrilobular, and were associated with a tree-in-bud pattern.
The descriptor “tree-in-bud” was first applied to the appearance of micronodules distributed at the termination of bronchovascular bundles identified on high-resolution CT in patients with diffuse panbronchiolitis [8]. Since the initial description of tree-in-bud pattern, its differential diagnosis has remained largely limited to bronchiolar diseases in which the bifurcated or budding structures represent thick-walled or dilated bronchioles filled with mucus, fluid, or pus. Entities often included in the differential diagnosis are infectious bronchiolitis, respiratory bronchiolitis, constrictive bronchiolitis, and aspiration pneumonia. To our knowledge, our case is unique in that it is a pathologically proven case of a tree-in-bud appearance on CT caused by arteriolar disease. As documented by the histologic findings, the micronodules creating the bifurcating structures seen on high-resolution CT in patients with cellulose granulomatosis represent intraarteriolar accumulation of micro-crystalline cellulose with associated adjacent granulomatous reaction.
In summary, the CT manifestations of cellulose granulomatosis consist of diffuse centrilobular nodules and a tree-in-bud pattern. In the differential diagnosis of a tree-in-bud pattern, arteriolar diseases, such as cellulose granulomatosis, should be considered in addition to the more common small airways diseases, especially in the setting of pulmonary artery hypertension or IV drug abuse.

Footnote

Address correspondence to A. N. Leung.

References

1.
Murata K, Itoh H, Todo G, et al. Centrilobular lesions of the lung: demonstration by high-resolution CT and pathologic correlation. Radiology 1986; 161:641-645
2.
Austin JHM, Müller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the nomenclature committee of the Fleischner society. Radiology 1996; 200:327-331
3.
Thurlbeck WM, Churg AM. Pathology of the lung, 2nd ed. New York: Thieme, 1995: 1026-1035
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Tomashefski JF, Hirsch CS, Jolly PN. Microcystalline cellulose pulmonary embolism and granulomatosis. Arch Pathol Lab Med 1981; 105:89-93
5.
Zeltner TB, Nussbaumer U, Rudin O, Zimmermann A. Unusual pulmonary vascular lesions after intravenous injections of microcrystalline cellulose: a complication of pentazocine tablet abuse. Virchows Arch A Pathol Anat Histol 1982; 395:207-216
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Giuliano V, Velez-Rivera C, Carlone D. Cellulose granulomatosis of the lungs: CT findings. AJR 1994; 163:220-221
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Diaz-Ruiz MJ, Gallardo X, Castañer E, Mata JM, Catala J, Ferreres JC. Cellulose granulomatosis of the lungs. Eur Radiol 1999; 9:1203-1204
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Akira M, Kitatani F, Yong-Sik L, et al. Diffuse panbronchiolitis: evaluation with high-resolution CT. Radiology 1988; 168:433-438

Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: 1151 - 1153
PubMed: 11641191

History

Submitted: February 6, 2001
Accepted: April 24, 2001

Authors

Affiliations

Sandra E. Bendeck
Department of Radiology, Stanford University Medical Center, Rm. S072A, 300 Pasteur Dr., Stanford, CA 94305-5105.
Ann N. Leung
Department of Radiology, Stanford University Medical Center, Rm. S072A, 300 Pasteur Dr., Stanford, CA 94305-5105.
Gerald J. Berry
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305-5105.
Dawn Daniel
Division of Pulmonary and Critical Care, Stanford University Medical Center, Stanford, CA 94305-5105.
Stephen J. Ruoss
Division of Pulmonary and Critical Care, Stanford University Medical Center, Stanford, CA 94305-5105.

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