MULTICENTRIC CASTLEMAN DISEASE WITH OCULAR INVOLVEMENT: A CLINICOPATHOLOGIC CASE REPORT Geoffrey G. Emerson, MD, PHD,* Lyndell Lim, MD,* Marc Loriaux, MD,† Hazem M. Yassin, MD,‡ Christina J. Flaxel, MD,* Justine R. Smith, MBBS, PHD,* David J. Wilson, MD*
Purpose: To describe an ocular manifestation of Castleman disease, a rare lymphoproliferative disorder characterized by sheets of abundant plasma cells in the interfollicular spaces of lymph nodes, most commonly in the abdomen, mediastinum, and cervical chain. Methods: Clinicopathologic case report. Patient: A 69-year-old man with lymphadenopathy and bilateral choroidal infiltrates. Results: Initially, we suspected systemic lymphoma with ocular involvement. Lymph node biopsy revealed Castleman disease without a monoclonal component. Choroidal biopsy showed lymphocytic and plasma cell infiltration. Conclusion: To our knowledge, this is the first clinicopathologic report of multicentric Castleman disease involving the eye. RETINAL CASES & BRIEF REPORTS 3:197–199, 2009
From the *Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; the †Department of Pathology and Medicine, Oregon Health & Science University, Portland, Oregon; and ‡Health Associates of Peace Harbor, Florence, Oregon.
phoma may occur. The most common sites of involvement are the abdominal, mediastinal, and cervical lymph nodes. There are a few reports of Castleman disease affecting orbital structures and one report of intraocular involvement.2 To our knowledge, we report the first case of multicentric Castleman disease in which intraocular biopsy was performed.
C
astleman disease is a rare lymphoproliferative disorder first described in 1956.1 The plasma cell variant of this disease is characterized by fevers and widespread lymphadenopathy and is sometimes associated with human immunodeficiency virus, human herpesvirus 8, or Kaposi sarcoma. Histologically, lymph node biopsies show sheets of abundant plasma cells in the germinal centers and interfollicular spaces. Castleman disease is considered benign, but malignant transformation into Hodgkin or non-Hodgkin lym-
Case Report A 69-year-old man presented with progressive bilateral floaters, photophobia, periocular discomfort, and night sweats for 2 months. His history included a left upper lobe lung mass and diffuse abdominal lymphadenopathy noted during magnetic resonance imaging for back pain. Additional testing included protein electrophoresis and two computed tomography– guided lymph node biopsies that revealed nonspecific inflammation with no significant pathologic findings. Because follow-up imaging studies revealed no progression of lymphadenopathy for 4 years, the process was presumed benign. Best-corrected visual acuity at presentation was 20/40 in both eyes. Anterior segment examination revealed no inflammation. Dilated fundus examination revealed 0.5⫹ vitreal haze and numerous creamy ovoid lesions at the level of the choroid (Fig. 1) in both eyes that stained with fluorescein. B-Scan ultrasonography suggested no choroidal thickening or abnormalities within the orbit.
This study was supported in part by an unrestricted grant to Casey Eye Institute from Research to Prevent Blindness, Inc. (New York, NY). J.R.S. is supported by a Career Development Award from Research to Prevent Blindness, Inc. The authors have no proprietary interest in the material presented in this report. Reprint requests: Geoffrey G. Emerson, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197; e-mail: geoffrey_emerson@ yahoo.com.
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Fig. 1. Color fundus photograph of the right posterior pole showing creamy choroidal infiltrates. Similar infiltrates were observed in the left eye.
Fig. 3. Photomicrograph of an axillary lymph node showing atrophic follicles with scattered small lymphocytes and sheets of polyclonal plasma cells in the interfollicular areas (scale bar ⫽ 50 m).
A diagnosis of systemic lymphoma with ocular involvement was suspected. Complete blood cell count and findings of computed tomography of the head and cerebrospinal fluid cytology were normal. Computed tomography of the chest, abdomen, and pelvis showed new axillary, retropectoral, and mediastinal lymphadenopathy and new soft-tissue infiltration in the renal sinus fat and renal hila suggestive of lymphoma (Fig. 2). Biopsy of an axillary lymph node revealed atrophic follicles with scattered small lymphocytes and sheets of polyclonal plasma cells in the interfollicular areas (Fig. 3), findings consistent with the plasma cell variant of Castleman disease. Results of tests for human herpesvirus 8 and human immunodeficiency virus were negative. Because Castleman disease had not previously been confirmed to involve intraocular structures, there was concern that the choroidal lesions represented a malignant transformation. Diagnostic vitrectomy with chorioretinal biopsy was performed. Microscopic examination revealed dilated choroidal macrovessels and infiltration of the deep choroid (Fig. 4) by lymphocytes and plasma cells. Occasional Dutcher bodies were present. Flow cytometry and / in situ hybridization confirmed the absence of lymphocyte or
plasma cell monoclonality. Analysis of a Cytospin (Waltham, MA) preparation of the vitreous aspirate showed rare inflammatory cells of mixed phenotype with no cellular atypia. After consultation with the oncology service, the patient opted for single-agent therapy with rituximab. Five months postoperatively, the initial presenting symptoms of floaters and discomfort had improved. Vision was 20/80 in the right eye and 20/60 in the left eye. Examination revealed attached retina surrounding the biopsy site (Fig. 5) and no progression of the choroidal infiltrates compared with the preoperative photographs.
Fig. 2. Computed tomography of the abdomen with contrast showing retroperitoneal lymphadenopathy (asterisks) and lymphoid masses (arrows) adjacent to both kidneys invading the right renal pelvis.
Discussion We describe a patient with bilateral vitritis, choroidal infiltrates, and widespread lymphadenopathy. Initially, systemic lymphoma was suspected; however, axillary lymph node biopsy instead revealed Castleman disease. Because malignant transformation to lymphoma may occur, particularly in the plasma cell
Fig. 4. Photomicrograph of a choroidal biopsy specimen showing denuded Bruch membrane (arrowhead) with underlying dilated choroidal vessels (asterisk) and inflammatory cell infiltration particularly within the deep choroid (hematoxylin– eosin stain; scale bar ⫽ 100 m).
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Fig. 5. After biopsy, bare sclera was visible at the biopsy site. The bilateral choroidal infiltrates appeared similar to those before surgery (see Fig. 1).
variant of Castleman disease,2 ocular biopsy was performed. This analysis showed infiltration of the choroid by polyclonal lymphoid and plasma cells, similar to (albeit less organized than) those shown by lymph node biopsy. There are several options for treatment of Castleman disease.3 Single-agent chemotherapy with rituximab was elected based on recent treatment success4 and appears to have halted progression of the disease. Rituximab is a monoclonal antibody directed to CD20 antigen on leukocytes used in various hematologic malignancies. In the other reported case of intraocular Castleman disease,5 the globe was treated with radiation therapy; vision improved dramatically as the serous retinal detachment responded and remained stable for ⬎10 years (J.W. Gittinger, Jr, personal communication). In a separate series,6 a patient with reactive lymphoid hyper-
plasia in the uvea and benign systemic infiltrates (possible Castleman disease) was also treated with radiation without recurrence for 13 years. Distinguishing between intraocular Castleman disease and lymphoma was difficult in the current case because the appearance of vitreal and choroidal infiltrates mimicked those seen in systemic or central nervous system lymphoma with ocular involvement. Choroidal biopsy proved useful because it allowed the oncologist flexibility to choose therapy with a lowside-effect profile.4 If instead choroidal biopsy had shown malignancy, then combination chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone) might have been more appropriate. Key words: benign lymphadenopathy, Castleman disease, lymph node hyperplasia.
References 1.
2.
3. 4.
5. 6.
Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 1956; 9:822–830. Inatani M, Kashii S, Nosaka K, Arima N. Orbital pseudotumor as an initial manifestation of multicentric Castleman’s disease. Jpn J Ophthalmol 2005;49:505–508. Dispenzieri A, Gertz MA. Treatment of Castleman’s disease. Curr Treat Options Oncol 2005;6:255–266. Ide M, Ogawa E, Kasagi K, et al. Successful treatment of multicentric Castleman’s disease with bilateral orbital tumour using rituximab. Br J Haematol 2003;121:818–819. Gittinger JW Jr. Ocular involvement in Castleman’s disease. Response to radiotherapy. Ophthalmology 1989;96:1646–1649. Cockerham GC, Hidayat AA, Bijwaard KE, Sheng ZM. Reevaluation of “reactive lymphoid hyperplasia of the uvea.” Ophthalmology 2000;107:151–158.
Purpose: To describe an ocular manifestation of Castleman disease, a rare lymphoproliferative disorder characterized by sheets of abundant plasma cells in the interfollicular spaces of lymph nodes, most commonly in the abdomen, mediastinum, and cervical chain. Methods: Clinicopathologic case report. Patient: A 69-year-old man with lymphadenopathy and bilateral choroidal infiltrates. Results: Initially, we suspected systemic lymphoma with ocular involvement. Lymph node biopsy revealed Castleman disease without a monoclonal component. Choroidal biopsy showed lymphocytic and plasma cell infiltration. Conclusion: To our knowledge, this is the first clinicopathologic report of multicentric Castleman disease involving the eye. RETINAL CASES & BRIEF REPORTS 3:197–199, 2009
From the *Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; the †Department of Pathology and Medicine, Oregon Health & Science University, Portland, Oregon; and ‡Health Associates of Peace Harbor, Florence, Oregon.
phoma may occur. The most common sites of involvement are the abdominal, mediastinal, and cervical lymph nodes. There are a few reports of Castleman disease affecting orbital structures and one report of intraocular involvement.2 To our knowledge, we report the first case of multicentric Castleman disease in which intraocular biopsy was performed.
C
astleman disease is a rare lymphoproliferative disorder first described in 1956.1 The plasma cell variant of this disease is characterized by fevers and widespread lymphadenopathy and is sometimes associated with human immunodeficiency virus, human herpesvirus 8, or Kaposi sarcoma. Histologically, lymph node biopsies show sheets of abundant plasma cells in the germinal centers and interfollicular spaces. Castleman disease is considered benign, but malignant transformation into Hodgkin or non-Hodgkin lym-
Case Report A 69-year-old man presented with progressive bilateral floaters, photophobia, periocular discomfort, and night sweats for 2 months. His history included a left upper lobe lung mass and diffuse abdominal lymphadenopathy noted during magnetic resonance imaging for back pain. Additional testing included protein electrophoresis and two computed tomography– guided lymph node biopsies that revealed nonspecific inflammation with no significant pathologic findings. Because follow-up imaging studies revealed no progression of lymphadenopathy for 4 years, the process was presumed benign. Best-corrected visual acuity at presentation was 20/40 in both eyes. Anterior segment examination revealed no inflammation. Dilated fundus examination revealed 0.5⫹ vitreal haze and numerous creamy ovoid lesions at the level of the choroid (Fig. 1) in both eyes that stained with fluorescein. B-Scan ultrasonography suggested no choroidal thickening or abnormalities within the orbit.
This study was supported in part by an unrestricted grant to Casey Eye Institute from Research to Prevent Blindness, Inc. (New York, NY). J.R.S. is supported by a Career Development Award from Research to Prevent Blindness, Inc. The authors have no proprietary interest in the material presented in this report. Reprint requests: Geoffrey G. Emerson, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197; e-mail: geoffrey_emerson@ yahoo.com.
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Fig. 1. Color fundus photograph of the right posterior pole showing creamy choroidal infiltrates. Similar infiltrates were observed in the left eye.
Fig. 3. Photomicrograph of an axillary lymph node showing atrophic follicles with scattered small lymphocytes and sheets of polyclonal plasma cells in the interfollicular areas (scale bar ⫽ 50 m).
A diagnosis of systemic lymphoma with ocular involvement was suspected. Complete blood cell count and findings of computed tomography of the head and cerebrospinal fluid cytology were normal. Computed tomography of the chest, abdomen, and pelvis showed new axillary, retropectoral, and mediastinal lymphadenopathy and new soft-tissue infiltration in the renal sinus fat and renal hila suggestive of lymphoma (Fig. 2). Biopsy of an axillary lymph node revealed atrophic follicles with scattered small lymphocytes and sheets of polyclonal plasma cells in the interfollicular areas (Fig. 3), findings consistent with the plasma cell variant of Castleman disease. Results of tests for human herpesvirus 8 and human immunodeficiency virus were negative. Because Castleman disease had not previously been confirmed to involve intraocular structures, there was concern that the choroidal lesions represented a malignant transformation. Diagnostic vitrectomy with chorioretinal biopsy was performed. Microscopic examination revealed dilated choroidal macrovessels and infiltration of the deep choroid (Fig. 4) by lymphocytes and plasma cells. Occasional Dutcher bodies were present. Flow cytometry and / in situ hybridization confirmed the absence of lymphocyte or
plasma cell monoclonality. Analysis of a Cytospin (Waltham, MA) preparation of the vitreous aspirate showed rare inflammatory cells of mixed phenotype with no cellular atypia. After consultation with the oncology service, the patient opted for single-agent therapy with rituximab. Five months postoperatively, the initial presenting symptoms of floaters and discomfort had improved. Vision was 20/80 in the right eye and 20/60 in the left eye. Examination revealed attached retina surrounding the biopsy site (Fig. 5) and no progression of the choroidal infiltrates compared with the preoperative photographs.
Fig. 2. Computed tomography of the abdomen with contrast showing retroperitoneal lymphadenopathy (asterisks) and lymphoid masses (arrows) adjacent to both kidneys invading the right renal pelvis.
Discussion We describe a patient with bilateral vitritis, choroidal infiltrates, and widespread lymphadenopathy. Initially, systemic lymphoma was suspected; however, axillary lymph node biopsy instead revealed Castleman disease. Because malignant transformation to lymphoma may occur, particularly in the plasma cell
Fig. 4. Photomicrograph of a choroidal biopsy specimen showing denuded Bruch membrane (arrowhead) with underlying dilated choroidal vessels (asterisk) and inflammatory cell infiltration particularly within the deep choroid (hematoxylin– eosin stain; scale bar ⫽ 100 m).
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Fig. 5. After biopsy, bare sclera was visible at the biopsy site. The bilateral choroidal infiltrates appeared similar to those before surgery (see Fig. 1).
variant of Castleman disease,2 ocular biopsy was performed. This analysis showed infiltration of the choroid by polyclonal lymphoid and plasma cells, similar to (albeit less organized than) those shown by lymph node biopsy. There are several options for treatment of Castleman disease.3 Single-agent chemotherapy with rituximab was elected based on recent treatment success4 and appears to have halted progression of the disease. Rituximab is a monoclonal antibody directed to CD20 antigen on leukocytes used in various hematologic malignancies. In the other reported case of intraocular Castleman disease,5 the globe was treated with radiation therapy; vision improved dramatically as the serous retinal detachment responded and remained stable for ⬎10 years (J.W. Gittinger, Jr, personal communication). In a separate series,6 a patient with reactive lymphoid hyper-
plasia in the uvea and benign systemic infiltrates (possible Castleman disease) was also treated with radiation without recurrence for 13 years. Distinguishing between intraocular Castleman disease and lymphoma was difficult in the current case because the appearance of vitreal and choroidal infiltrates mimicked those seen in systemic or central nervous system lymphoma with ocular involvement. Choroidal biopsy proved useful because it allowed the oncologist flexibility to choose therapy with a lowside-effect profile.4 If instead choroidal biopsy had shown malignancy, then combination chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone) might have been more appropriate. Key words: benign lymphadenopathy, Castleman disease, lymph node hyperplasia.
References 1.
2.
3. 4.
5. 6.
Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 1956; 9:822–830. Inatani M, Kashii S, Nosaka K, Arima N. Orbital pseudotumor as an initial manifestation of multicentric Castleman’s disease. Jpn J Ophthalmol 2005;49:505–508. Dispenzieri A, Gertz MA. Treatment of Castleman’s disease. Curr Treat Options Oncol 2005;6:255–266. Ide M, Ogawa E, Kasagi K, et al. Successful treatment of multicentric Castleman’s disease with bilateral orbital tumour using rituximab. Br J Haematol 2003;121:818–819. Gittinger JW Jr. Ocular involvement in Castleman’s disease. Response to radiotherapy. Ophthalmology 1989;96:1646–1649. Cockerham GC, Hidayat AA, Bijwaard KE, Sheng ZM. Reevaluation of “reactive lymphoid hyperplasia of the uvea.” Ophthalmology 2000;107:151–158.
