Demyelinating disease

* Erdheim-Chester disease (lipoid granulomatosis) is a rare type II (non-Langerhans cell) histiocytosis with systemic manifestations. The disease causes nonspecific disturbances in the function of multiple extraosseous organs, most commonly the eyes, lungs, pituitary gland, and kidneys. Diagnosis is usually made on the basis of radiologic evidence of cortical expansion of long bones. While the osseous and systemic changes have been well documented in the current literature, pathologic changes in the myocardium have not been well characterized since Erdheim and Chester's first description of this disease in 1930. In the 2 autopsy cases from Dartmouth-Hitchcock Medical Center (Lebanon, NH) reported in the present study, myocardial involvement was severe and had contributed significantly to the patients' morbidity and death. We describe the autopsy results and correlate them with Erdheim's original descriptions of this disease. In neither of our cases was bony involvement characteristic of the disease, and the diagnosis was made postmortem on the basis of soft tissue findings at autopsy.

(Arch Pathol Lab Med. 2004;128:682-685)

The American cardiologist William Chester, while completing a fellowship in pathology in Vienna under the tutelage of Jakob Erdheim in 1930, first described 2 cases of "lipoid granulomatosis," later known as "ErdheimChester disease."1 Since 1972, when the third and fourth cases were described by Henry Jaffe,2 approximately 100 cases of Erdheim-Chester disease have been reported internationally. The accumulating case descriptions have promoted identification and recognition of the disease's protean clinical manifestations, including bone pain, diabetes insipidus, dyspnea, exophthalmos, pericardial tamponade, cutaneous xanthomas, ataxia, fatigue, and weight loss. In this report, we expand on the description of Erdheim-Chester disease by presenting 2 cases with extensive atrial myocardial involvement, which contributed to cardiac failure and the patients' deaths.

These 2 cases represent the only autopsy cases carrying the diagnosis of Erdheim-Chester disease in the case records of the Dartmouth-Hitchcock Medical Center (Lebanon, NH) between 1991 and 2001. In both cases, the diagnosis was made at autopsy.

REPORT OF CASES

Case 1

A previously healthy 61-year-old woman presented to her primary care physician with an insidious onset of ataxia, weakness, and dyspnea. On the basis of positive serology for anti-nuclear antibodies and double-stranded DNA antibodies, she was diagnosed with lupus erythematosus and treated accordingly. During the next 1½ years, she developed, in sequence, pericardial effusion requiring the placement of a pericardial window, pancytopenia, diplopia and a right superior-lateral visual field defect, hypothyroidism, congestive heart failure with left ventricular hypertrophy and intermittent pulmonary and peripheral edema, diabetes insipidus, and worsening ataxia and muscle weakness. A bone marrow biopsy showed noncaseating granulomata with no evidence of fungi or mycobacteria. Head imaging studies showed bilateral periorbital masses. The biopsy showed that these periorbital masses consisted of xanthogranulomatous tissue. At this time, the diagnosis of Erdheim-Chester disease was suggested, but radiographie studies of the long bones failed to show the characteristic cortical changes of Erdheim-Chester disease; therefore, the diagnosis was not made. Chest radiographs showed interstitial markings consistent with interstitial pulmonary fibrosis, and a repeat bone marrow biopsy showed myelofibrosis with no evidence of granulomatous disease. The patient's final hospitalization was characterized by refractory serum chemistries, pulmonary and peripheral edema, fever, elevated white blood cell counts, anemia, thrombocytopenia, and finally, hypotension and acidosis.

At autopsy, there were pleural effusions (250 mL right; 500 mL left), ascites (750 mL), and anasarca. There were multiple irregular, sharply demarcated, rubbery, pale yellow plaques and nodules scattered throughout the pericardium and on the epicardial surface. A 5.0 × 3.0 × 2.5-cm yellow rubbery mass extended from the ostium of the right coronary artery to the posterior aspect of the heart, surrounding the right coronary artery on its path through the atrioventricular sulcus but not involving the right coronary artery wall or lumen. The soft tissues around the aortic and pulmonary trunk roots, the thoracic and abdominal aorta, the pulmonary arteries, and the thoracic and abdominal arteries were replaced by dense, yellow fibrous tissue. Similar tissue replaced the retroperitoneal fat and surrounded the adrenals and pancreas. The larynx, thyroid, and parathyroid glands were also encased by the sclerotic, yellow tissue. A yellow plaque on the dura of a thoracic vertebra extended into the marrow space, where it formed a 4.0 × 3.0 × 1.0-cm nodule. There were scattered yellow plaques on the durai leaflets and falx.

In all the areas in which they occurred, the dense, rubbery yellow lesions consisted histologically of aggregates of foamy histiocytes and sparse collections of lymphocytes in a dense, fibrous stroma (Figure 1). This xanthogranulomatous tissue involved the adventitia of large-caliber vessels and infiltrated the atrial myocardium (Figure 2). It also infiltrated the thyroid, pancreas, spleen, and adrenal glands. The neurohypophysis was replaced by fibrotic tissue containing perivascular macrophages and activated microglia, and in the cerebellum, there were large areas of myelin pallor. The histiocytes in all the lesional sites stained positively with CD68 (Figure 3) and weakly and variably for S100 but showed no reactivity for CD1a (Figure 4). Electron microscopy did not show Birbeck granules.

Case 2

A 69-year-old man with a history of atherosclerotic coronary artery disease, peripheral vascular disease, and idiopathic diabetes insipidus controlled by desmopressin acetate for several years was admitted for evaluation and treatment of light-headedness, dyspnea on exertion, easy bruising, and edema. Echocardiography showed pericardial effusion with tamponade, hypertrophy of the right atrium with a right atrial mass, and dilatation of the aorta from the bulb to the iliac bifurcation. The erythrocyte sedimentation rate and partial thromboplastin time were elevated, and serologie studies were positive for anti-nuclear antibody and lupus anticoagulant. A work-up of iron-deficiency anemia led to the discovery and subsequent resection of a T2 N2 MO moderately differentiated adenocarcinoma of the colon. The patient's postoperative course was complicated by severe tachyarrhythmias and bradyarrhythmias. The day after a permanent cardiac pacemaker was inserted, he developed large pleural effusions, refused thoracentesis, and died.

At autopsy, there were pleural effusions (700 mL bilaterally) but no appreciable ascites or anasarca. There were yellow, dense, rubbery lesions reaching up to 10 cm in greatest dimension diffusely coating the adventitial surface of the severely atherosclerotic and dilated aorta. The wall of the right atrium was diffusely thickened and stiff, and there were nodules measuring up to 5 cm in greatest dimension scattered throughout the atrial wall (Figure 5). The cut surface of these nodules showed yellow fibrous tissue. The right kidney was atrophie. The hilar fat of both kidneys and the perirenal fat on the right were replaced by dense, rubbery yellow tissue, as were the right adrenal and the pancreas. No pituitary tissue was identified. There were yellow, firm, irregularly shaped plaques scattered diffusely over the dura and aggregating on the falx to form nodules measuring up to 2.5 cm in their greatest dimension. There was a solitary, well-circumscribed, 1.5 × 1.0 × 1.0-cm cavitary lesion in the cranium filled with dense, yellow fibrous tissue.

Histologically, the yellow fibrous lesions consisted of sheets of histiocytes and sparse chronic inflammatory aggregates in a background of dense fibrosis. There were occasional Touton giant cells. The xanthogranulomatous process diffusely infiltrated the pancreas but respected the capsules of the adrenals and kidneys. It diffusely replaced and expanded the adventitia of the aorta, the atrial myocardium, the remnant of the pituitary stalk, and the pleura and interlobular septae of the lungs. Special stains did not yield evidence of infectious organisms. The histiocytes stained positively for CD68 and faintly for S100 but were negative for CD1a. Electron microscopy was not performed.

COMMENT

Erdheim-Chester disease is a class II (non-Langerhans cell) histiocytosis in which fibroxanthogranulomatous tissue diffusely infiltrates and causes sclerosis of connective tissues and fat. The clinical manifestations of ErdheimChester disease are attributable to the functional compromise of organs by the infiltrate.1 The replacement of fatty or hematopoietic marrow can cause bone pain, pathologic fracture, tooth loss, and/or pancytopenia. Most commonly, however, the bony lesions are not discovered until the suspicion of Erdheim-Chester disease is raised on the basis of extraosseous symptoms and until radiographie or scintigraphic studies are performed. Erdheim-Chester disease may involve the pituitary, causing diabetes insipidus and other endocrine abnormalities. It may cause interstitial lung disease by diffusely involving the pleura, interlobular septa, and pulmonary bronchovascular bundles. It may involve the pericardium and result in a symptomatic pericardial effusion. The fibrosis of retroperitoneal fat and connective tissue in Erdheim-Chester disease can lead to the constriction of the ureteral system, causing flank pain, hydronephrosis, and renal failure. The dense fibroxanthogranulomatous tissue can also extend to the periaortic tissues and into the mediastinum, constricting arteries and causing end-organ atrophy or failure. Radiographically, the fibrosis of periaortic tissue results in the "coated-aorta" sign.4 The formation of bilateral retrobulbar masses by the fibroxanthogranulomatous tissue leads to visual disturbances, exophthalmos, and facial pain. A demyelinating response to Erdheim-Chester disease in the cerebellum and pons leads to an ataxia of gait. Mass lesions involving the dura can result in a sudden onset of seizures.5 Focal collections of lesional tissue in the skin can cause xanthelasma, disseminated xanthomas, and pruritic rashes.6 Rarely, Erdheim-Chester disease has been reported to affect the skeletal muscle in the form of painful soft tissue masses.7 Even the involvement of the testis8 and liver9 has been reported.

Histologically, the lesions of Erdheim-Chester disease are diffuse, densely collagenous masses in which are nested sheets of histiocytes, sparse pockets of chronic inflammatory cells, and occasional Touton giant cells. With routine stains, the lesions of Erdheim-Chester disease resemble those of class I (Langerhans cell) histiocytosis, but Langerhans and non-Langerhans histiocytes have distinct immunohistochemical phenotypes. As opposed to Langerhans cells, non-Langerhans cells stain with CD68, are negative for CDIa and other dendritic cell markers (FDRC, CD21, and CD35), and give a variable response to SlOO.10 Birbeck granules are not detected by electron microscopy in non-Langerhans cells. Erdheim-Chester disease lesions can therefore be differentiated from Langerhans cell histiocytoses (eosinophilic granuloma, Hans-Schuller-Christian disease, and Letterer-Siwe disease), xanthogranulomatous pyelonephritis, malakoplakia, eosinophilic granuloma, inflammatory pseudotumors, and lymphoproliferative disorders by proper immunohistochemistry (and electron microscopy). With respect to the clinical presentation and radiologically demonstrated organ system involvement, Erdheim-Chester disease lesions can be differentiated from other non-Langerhans cell histiocytoses such as hemophagocytic lymphohistiocytosis (familial erythrophagocytic lymphohistiocytosis), virus-associated hemophagocytic syndrome, sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease), xanthogranuloma, xanthoma disseminatum, reticulohistiocytoma, and juvenile xanthogranulomatosis.

In the 2 cases presented in this study, the diagnosis of Erdheim-Chester disease was made on the basis of histologie and immunohistochemical findings and a characteristic tissue distribution of lesions. Radiologie findings did not contribute to the diagnosis.

An unusual feature of these 2 cases of Erdheim-Chester disease is the involvement of the right atrial myocardium by the fibroxanthogranulomatous infiltrate. Bundles of atrophie, necrotic myocytes diffusely infiltrated by histiocytes remain scattered throughout the myocardium (Figures 2 and 3). Since 1996, when a review of 59 cases of Erdheim-Chester disease1 reported no cases of myocardial involvement, only a few such instances have been described.8,11 As in the cases presented in this study, the cardiac involvement in the previously reported cases was restricted to the right atrium, and in one of them,11 the infiltrate caused a radiologically demonstrable "tumor" in the right atrial wall similar to that in our second case.

One of the patients in the original report by Erdheim and Chester1 had lesions in the right atrial wall grossly resembling those of the first patient described in this study: "exclusively in the right heart (there are) lipoidgranulomas, three in number. One is in the form of an almost finger-thick strand, lying exactly in the coronary sulcus and involving the subepicardial tissue along its entire length. Cut surface is transparent grey with many yellow inclusions. . . . Two further tumor-like inclusions lie in the wall of the atrium, one, 12 mm thick, at the junction of the 2 great veins, the other, 14 mm thick, at the origin of the superior vena cava. Both are elevated from the surface of the heart and shine yellowishly through the epicardium; both involve the entire thickness of the atrial wall from endo- to epicardium; on cut surface the musculature of the heart wall is interrupted by the lipoidgranuloma" (personal translation).1(p578) The observation that the "lipoidgranuloma" involves the entire thickness of the heart wall was borne out by microscopic examination,1(p581) which, in turn, led to the observation that the process appears to have begun within the subepicardial fatty tissue, extending from this point secondarily into the epicardium and the myocardium.

The protean clinical manifestations of Erdheim-Chester disease have increasingly been recognized in the medical, pathologic, and radiographie literature. The histologie appearance and pattern of distribution of the lesional tissue should alert physicians to the presence of Erdheim-Chester disease, even in the absence of evidence of radiographie changes. In this context, atrial myocardial involvement needs to be recognized not only as yet another manifestation but also as one that can contribute to the affected patients' morbidity and their deaths. The typical radiologie appearance of symmetric cortical sclerosis of the diaphysis and metaphysis of long bones with sparing of the epiphyses,2 found in approximately 75% of patients,3 is a valuable adjunct to histologie diagnosis.

The authors thank C. Harker Rhodes, MD, and Nora Ratcliffe, MD, for their suggestions and support in preparation of this manuscript.

References

1. Chester W. Uber Lipoidgranuolmatose. Virchows Archiv fur pathologische Anatomie und Physiologie. New York, NY: Springer International; 1930.

2. Jaffe HL. Metabolie, Degenerative and Inflammatory Disease of Bones and Joints. Philadelphia, Pa: Lea & Febiger; 1972.

3. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. Erdheim-Chester disease: clinical and radiologie characteristics of 59 cases. Medicine. 1996;75: 157-169.

4. Serratrice), Cranel B, de Roux C, et al. "Coated aorta": a new sign of Erdheim-Chester's disease. J Rheumatol. 2000:27:1550-1553.

5. Siadati A, Powell SZ, Shahab I, et al. A 48-year-old woman with a duralbased intracranial tumor. Arch Pathol Lab Med. 2001 ;125:1115-1116.

6. Watermann DF, Kieswetter F, Frosch PJ. Hautmanifestationen der ErdheimChester Krankheit. Fallbericht und Literaturubersicht. Hautarzt. 2001;52:510-517.

7. Yamamoto T, Mizuno K. Erdheim-Chester disease with intramuscular lipogranuloma. Skeletal Radiol. 2000:29:227-230.

8. Fink MC, Levinson D), Brown NL, et al. Erdheim-Chester disease: case report with autopsy findings. Arch Pathol Lab Med. 1991;115:619-623.

9. Ivan D, Neto A, Lemos L, et al. Erdheim-Chester disease: a unique presentation with liver involvement and vertebral osteolytic lesions. Arch Pathol Lab Med. 2003;127:e337.

10. Kenn W, Eck M, Allolio B, et al. Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis?: three cases with detailed radiological and immunohistochemical analysis. Hum Pathol. 2000;31: 734-739.

11. Ammann P, Bosch B, Bucholz S, et al. Cardiac tumor due to ErdheimChester disease. Am J Med. 2001 ;111:672-673.

Agnes C. Loeffler, MD, PhD; Vincent A. Memoli, MD

Accepted for publication January 28, 2004.

From the Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Agnes C. Loeffler, MD, PhD, Department of Pathology, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756 (e-mail: agl@hitchcock.org).

Copyright College of American Pathologists Jun 2004
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