Churg-Strauss syndrome

A Case Report With Histologic and Immunophenotypic Analysis

* Allergic granulomatosis is a disorder of obscure etiology characterized by infiltration of lymph nodes with histiocytic granulomas and eosinophils. In this report, we describe a case of allergic granulomatosis that is consistent with Churg-Strauss disease limited to lymph nodes. The histologic findings of this patient's lymph nodes demonstrated eosinophilic abscesses and ring-shaped necrotizing and nonnecrotizing granulomas surrounding hyperplastic germinal centers. We report herein a rare type of reactive lymphadenopathy and present its histologic, immunohistochemical, and flow cytometric findings, which may allow its distinction from other lymphadenopathies.

(Arch Pathol Lab Med. 2001;125:954-957)

In 1951, Churg and Strauss1 first identified and described a rare, often fatal systemic syndrome that bears their name. The syndrome is characterized by asthma, hypereosinophilia, systemic vasculitis, and transient pulmonary infiltrates. Churg-Strauss syndrome (CSS) was also labeled allergic granulomatosis and angiitis because of the presence, predominantly in extranodal locations, of granulomatous inflammation along with eosinophilic vasculitis. More recently, a restricted indolent form with involvement limited to specific organs, including the eyes, the skin, or the gastrointestinal tract,2-4 has been described and labeled the limited form of CSS. To our knowledge, the pathology of CSS limited to the lymph nodes has not been characterized.

We describe a patient with a limited lymphadenopathic form of CSS and report the histologic, immunohistochemical, and flow cytometric findings. Because of the unusual histologic presentation in this case, a wide set of differential diagnoses was entertained. This type of lymphadenopathy has to be differentiated from malignant lymphomas histologically accompanied by granulomas and tissue eosinophils, as well as from other benign lymphadenopathies associated with tissue eosinophils. Because of the clinical presentation of submandibular and mediastinal lymph node enlargement, this patient was thought to have lymphoma on radiologic examination. Biopsies of these lymph nodes histologically showed eosinophils and granulomas not unlike what Gall and Rappaport previously described in a group of patients with benign lymphadenopathy.5,6 This patient was treated with prednisone and immunosuppressive therapy (cyclophosphamide), with subsequent disappearance of lymphadenopathy. He has had no recurrence of lymphadenopathy during the ensuing 48 months. During this time, he was discovered to have prostatic adenocarcinoma, for which a radical prostatectomy was performed. The periprostatic regional lymph nodes did not show malignant lymphoma and were also free of features observed in the previously diagnosed lymphadenopathy, confirming their focal, limited nature.

REPORT OF A CASE

A 56-year-old African American man with a history of asthma presented to the University of Cincinnati Oral Surgery Clinic (Cincinnati, Ohio) in the first week of April 1996 for evaluation of a neck mass. He was edentulous, and neck examination showed an enlarged, tender, right submandibular lymph node that had been present for 8 to 9 months without associated fever or weight loss. For his asthma, he was on daily flunisolide, albuterol, and nizatidine. Because of a suspicion of lymphoma, computed tomographic scans of the chest and abdomen were performed, which showed moderate bilateral hilar, pretracheal, and subcarinal adenopathy (Figure, A). The lungs were unremarkable. These findings were considered to most likely represent lymphoma, and excision of lymph nodes and bone marrow biopsies were done. Computed tomography of the sinuses showed marked mucosal thickening of bilateral sphenoid sinuses, which was interpreted as allergic sinusitis. His family history was also remarkable for a brother who died of Richter transformation of chronic lymphocytic leukemia.

Laboratory studies disclosed the following values: white blood cell count, 9.3 x 10^sup 9^/L (reference range, 4.8-10.8 x 10^sup 9^/L); hemoglobin, 12 mmol/L (14-18 mmol/L); hematocrit, 0.37 (0.42-- 0.52); platelets, 193 X 10^sup 9^/L (150-450 x 10^sup 9^/L); mean corpuscular volume, 88.6 fL (80-94 fL); red cell distribution width, 16.6 (11.5-- 14.5); granulocytes, 41.6% (30%-80%); eosinophils, 0.048 (

PATHOLOGIC FINDINGS

Microscopic examination of the submandibular lymph node biopsy showed multiple C-shaped and ring-shaped epithelioid granulomas (Figure, B), some closely apposed to hyperplastic follicles and medium-sized blood vessels. There was florid follicular hyperplasia with misshapen and polarized germinal centers. Some epithelioid granulomas were nonnecrotizing, but many others contained an intense collection of eosinophils and centralized necrosis (Figure, C). Arterioles and venules were thick and showed prominent sclerosis and eosinophilic angiitis (Figure, D). There were few follicles exhibiting progressive transformation of germinal centers. The interfollicular areas contained eosinophils, transformed lymphocytes, histiocytes, and proliferation of endothelial venules (Figure, E). Rare Warthin-Finkeldey giant cells were present in the interfollicular areas. Occasional large immunoblasts were present, but no Reed-Sternberg cells were identified. No microorganisms were seen by Grocott, periodic acid-Schiff, or Giemsa stains. The mediastinal lymph node biopsy sections revealed fibrosis and anthracosis, and similarly showed activated germinal centers associated with more florid epithelioid granulomas with eosinophils and centralized necrosis.

The pattern of immunostaining in the lymph nodes showed preserved B-cell as well as T-cell areas typical of a reactive lymph node. Immunohistochemical stains to rule out Hodgkin disease and non-Hodgkin lymphomas were done. The CD15 and CD30 markers for Hodgkin lymphoma did not show immunoreactive Reed-Sternberg cells. Few interfollicular CD20-positive B cells and CD30-- positive immunoblasts were observed. There were no atypical "popcorn-polylobated" CD20-reactive large cells identified. CD45RO decorated small background T lymphocytes. Scattered S100-positive histiocytes were seen in the ring granulomas, indicating scattered Langerhans accessory cells with numerous reactive histiocytes (results not shown). The sources and specificities of the antibodies and the results of flow cytometry are listed in Table 1. The lymph node and bone marrow biopsy specimens were tested by paraffin section immunohistochemistry. Immunohistochemistry was performed on an automated immunostainer (Techmate 1000, Ventana System, Tucson, Ariz) using the antibodies listed in Table 2 with diaminobenzidine as the chromogen.

The submandibular and mediastinal lymph nodes showed similar results using flow cytometry cell suspension immunophenotyping (Table 1). Cytoplasmic immunofluorescent stains for plasma cells using anti-kappa and anti-- lambda light chain reagents were also polyclonal. The majority of gated cells were T-helper cells without an aberrant loss of CD7 (pan T) marker. These results were not supportive of non-Hodgkin lymphoma of either a B-cell or T-cell type.

The bone marrow was hypercellular with mildly increased eosinophils and plasma cells. There were no granulomas or lymphoid aggregates. The flow cytometric results of the bone marrow specimen showed no evidence of non-Hodgkin lymphoma.

COMMENT

The radiologic and gross findings in previous reports of CSS4 suggested a lymphoma. The features of these lymph nodes were reminiscent of the cases of allergic lymphadenopathies described by Gall and Rappaport5 in a monograph published in 1958. They described 8 patients with lymphadenopathies associated with allergic granulomas, albeit without a clearly defined etiology. Like their cases, our case clinically presented as a diagnostic quandary and raised a differential diagnosis of Hodgkin disease or histiocytosis Chi. The eosinophilic granuloma type of histiocytosis Chi was ruled out based on the absence of infiltrate of characteristic S100-positive Langerhans cell histiocytes in a diffuse sinusoidal pattern. Although granulomas may frequently be seen in Hodgkin disease, this diagnosis was unlikely because of the absence of Reed-Sternberg cells or the variant "popcorn" cells of the lymphocyte-predominant type and the absence of typical immunoreactivity for Hodgkin disease (Table 3). Peripheral T-cell lymphomas, many of which have associated eosinophilia, were ruled out because of the absence of atypical pleomorphic small to large T cells and the lack of aberrant flow cytometry T-- cell reactivities. Tissue eosinophilia may be observed in B-- cell non-Hodgkin lymphomas with eosinophilia, but in those cases reported by Navarro-Roman et al,7 none showed granulomatous lesions as observed in this case.

Among the reactive conditions, Kimura disease was considered because of the clinical presentation of a tumorlike swelling in the submandibular subcutaneous area with typical lymphadenopathy. Kimura disease tends to have a triad of follicular hyperplasia, infiltration by eosinophils, and proliferation of postcapillary venules.8 However, in this case, Kimura disease was ruled out because of the presence of well-formed noncaseating granulomas, which have not been described in those cases. Sarcoidosis was ruled out because eosinophilic abscesses were not features of sarcoidal lymphadenopathy. Granulomatous angitiis of Wegener was ruled out because of the clinical presentation of asthma, lymphadenopathy, and absence of antineutrophil cytoplasmic antibody seroreactivity. The absence of cutaneous and mucosal allergic reaction associated with a particular medication tends to rule out drug effect. After these considerations, we were drawn to the associated clinical background of this patient, that is, a long-standing asthma and a possibility that these lymphadenopathies were all secondary to a forme fruste CSS.

Classic CSS is a fatal systemic disease usually seen in middle-aged patients with a history of long-standing asthma, allergic rhinitis, and eosinophilia.1 The most frequently involved organs are the lungs, heart, gastrointestinal tract, and peripheral nervous system. A spectrum of more benign, limited formes frustes lesions of CSS have been described in extranodal areas. These include necrotizing granulomatous conjunctivitis,2 cutaneous lesions,3 and gastrointestinal eosinophilic infiltrates.4 Our case appeared to have a florid form of CSS lymphadenopathy characterized histologically as a reactive lymph node architecture with a mixed reactive pattern manifesting as well-formed circumferential granulomas, eosinophilic adenitis and angiitis, and florid follicular hyperplasia. Like the limited cases, peripheral eosinophilia was not prominent, especially in those patients exposed to steroids, but like our case, most limited CSS patients exposed to steroids had elevated levels of serum IgE. The absence of blood eosinophilia combined with retention of a florid tissue eosinophilia in our patient was likely due to flunisolide, an anti-inflammatory steroid with the ability to cause reduction of circulating eosinophils. Because of the clinical presentation of asthma and allergic sinusitis, and the histologic findings of angiitis and extravascular necrotizing and nonnecrotizing granulomas with eosinophilic infiltrate in our patient, we believe the lymphadenopathy to be a manifestation of CSS. The good response to therapy with prednisone (completely resolved adenopathy and clearing of the oral and nasal mucosa lesions) without recurrence supported a reactive adenopathy. The last followup examination, 48 months after diagnosis, revealed a patient who was clinically and radiologically stable.

Although splenic lesions of Churg-Strauss syndrome have been described and consist of extravascular granulomas, eosinophilic abscess, and perivasculitis,9 similar findings in the lymph nodes have not been likewise documented. Lymphadenopathy was a described complication,10 often in radiologic reference to pulmonary findings in CSS.

In summary, we describe the histologic and immunophenotypic findings of allergic granulomatosis secondary to a limited Churg-Strauss disease. It is important to differentiate this entity from other reactive lymphadenopathies associated with eosinophils, but more importantly from malignant lymphomas with tissue eosinophils.

We thank Irina Sheyn, MD, for reviewing a prior manuscript for this article. We also thank Jay Card for reproducing photographs.

References

1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol. 1951;27:277-294.

2. Nissm F, Von der Valde J, Czernobilsky B. A limited form of Churg-Strauss syndrome. Arch Pathol Lab Med. 1982;106:305-307.

3. Vogel P, Nemer J, Sau P, Hnatiuk 0. Churg-Strauss syndrome. J Am Acad Dermatol. 1992;27:821-824.

4. Suen KC, Burton JD. The spectrum of eosinophilic infiltration of the gastrointestinal tract and its relationship to other disorders of angiitis and granulomatosis. Hum Pathol. 1979;10:31-43.

5. Gall EA, Rappaport H. Seminar on diseases of lymph nodes and spleen. In: Proceedings of the 23rd Seminar of the American Society of Clinical Pathologists. Chicago, Ill: American Society of Clinical Pathologists Press; 1956.

6. Rosai J. Lymph nodes. In: Rosai J, ed. Ackerman's Surgical Pathology. 7th ed. St Louis, Mo: CV Mosby Co; 1989:1301.

7. Navarro-Roman L, Medeiros LJ, Kingma DW, et al. Malignant lymphomas of B-cell lineage with marked tissue eosinophilia: a report of five cases. Am J Surg Pathol. 1994;18:347-356.

8. Kuo T, Shih L, Chan H. Kimura's disease. Am J Surg Pathol. 1988;12:843-- 854.

9. Wolf B, Neiman RS. Disorders of Spleen. Philadelphia, Pa: WB Saunders Co; 1989;20:182-188. Major Problems in Pathology.

10. Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine. 1984;63:65.

Hernani Cualing, MD; Louis Schroder, MD; Charles Perme, MD

Accepted for publication January 26, 2001.

From the Departments of Pathology and Laboratory Medicine (Dr Cualing), Internal Medicine (Dr Schroder), and Radiology (Dr Perme), University of Cincinnati, Cincinnati, Ohio.

Reprints: Hernani Cualing, MD, Department of Pathology and Laboratory Medicine, University of Cincinnati, PO Box 670529, Cincinnati, OH 45267-0529 (e-mail: cualinh@email.uc.edu).

Copyright College of American Pathologists Jul 2001
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