SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY (ROSAI DORFMAN DISEASE) IN A PATIENT WITH ELEVATED EPSTEIN-BARR VIRUS TITERS Earl H. Harley, MD San Diego, California Sinus histiocytosis with massive lymphadenopathy (SHML) is a newly recognized disorder. The etiology of this disease is unknown. An exaggerated response to an offending agent such as the Epstein-Barr virus or KlebsielIa bacteria has been postulated. Its course is usually benign. Cervical adenopathy is seen in 97% of the patients, while 30% of patients have nodal involvement in other sites, and 30% have extranodal involvement. There is a 7% mortality rate that occurs primarily in patients with immunologic defects. Corticosteroids ameliorate the constitutional symptoms, but cyclophosphamide appears to have the most beneficial effect. This article presents the case of a patient with SHML who demonstrated elevated Epstein-Barr virus titers. (J NatI Med Assoc. 1991 ;83:922-924.) Key words * sinus histiocytosis * lymphadenopathy * adenopathy * cyclophosphamide
CASE REPORT A 47-year-old black male was discovered to have prominent bilateral posterior cervical adenopathy on a physical examination during admission for anaphylaxis. From the Departments of Otolaryngology and Clinical Investigation, Naval Hospital, San Diego, California. Presented at the 91 st Annual Convention and Scientific Assembly of the National Medical Association, July 22, 1986, New York, New York. The work reported herein was performed under the Navy Clinical Investigation Program case no. 84-16-1968-158. The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. Requests for reprints should be addressed to Capt Earl H. Harley, MC, USNR, c/o Clinical Investigation Department, Naval Hospital, San Diego, CA 92134-5000. 922
Over the next several months, these nodes were noted to enlarge; in the meantime, the anterior chain of nodes became involved. There was no discomfort associated with the adenopathy The patient denied chills, fever, anorexia, and weight loss. He was referred for a biopsy. On physical examination, a striking bilateral anterior and posterior cervical adenopathy was noted (Figure 1). The lymph nodes were nontender, firm, and barely movable, ranging in size from 1 cm to 6 cm. There was no generalized adenopathy. The remainder of the head and neck examination, including indirect mirror examination, was normal. The liver and spleen were normal on palpation. A complete blood count, electrolyte studies, and a serologic test for syphilis were normal. A T4/T8 ratio was 0.1 (helper/suppressor reversal, nl greater than 1.6). Total complement levels and C3 and C4 levels were normal. The antinuclear antibody titer was negative. The Epstein-Barr virus (EBV) titer was initially 1:640 but fell to 1:50. Immunoglobulin studies revealed a mildly elevated IgG of 910 mg/dL (5641765); the remainder of the gamma globulins were normal. Protein electrophoresis revealed a mildly elevated polyclonal hypergammaglobulinemia consistent with a mildly elevated IgG. Chest x-ray was negative. Computed tomography scan of the neck revealed bilateral adenopathy (Figure 2). Skin testing initially revealed a 15-mm reaction to the PPD antigen but eventually demonstrated anergy. This patient underwent open cervical biopsy in the summer of 1981 and again in the summer of 1982. Each time the pathologic diagnosis was SHML. Also, a subsequent fine needle aspiration corroborated the benign nature of his adenopathy. Two years into the course of the disease, the patient was placed on steroids on a trial basis; however, there was no clinical response, and the drug was discontinued. The patient has since JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
Figure 2. CT scan.
Figure 1. Posterior view of the patient. been lost to follow-up.
DISCUSSION Sinus histiocytosis with massive lymphadenopathy is a pseudolymphomatous disorder that was initially described by Rosai and Dorfman in 1969.1 This disease is a benign self-limiting illness and was originally felt to be most prevalent among black youths. Two thirds of the cases are reported to occur in the first decade of life, while a full 81% present before the age of 20. However, some older patients have been reported to be affected by this disorder.2'3 The disease has a male preponderance and is characterized by fever, weight loss, and a striking, painless bilateral cervical lymphadenopathy.2,3 Ninetyseven percent of patients have cervical adenopathy, while 30% of patients have involvement in other nodal sites such as axillary, inguinal, and paravertebral areas. Extranodal site involvement occurs in 30% of patients.3'4 These sites include the central nervous system, the orbit and eyelids, the nose and paranasal sinuses, the oral cavity, salivary glands, the trachea and bronchi, liver, spleen, kidneys, pancreas, testicles, long bones, and skin.3'4 The nasal cavity and the salivary glands are thought to be the most common sites JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
involved in the head and neck.4 Laboratory studies for this disorder can be remarkable for leukocytosis and neutrophilia, an elevated erythrocyte sedimentation rate, and mild anemia. 1-3 Hypergammaglobulinemia has been reported.2'3 Elevated EBV titers also have been reported.3'5 Diagnosis can be made only by biopsy of the involved node or biopsy of the involved extranodal organ. The exact etiology of this disease is unknown. Perhaps it represents an immunologic reaction. Foucar et al examined a computerized registry of 200 patients with SHML.6 Twenty-three of these patients had evidence of an immune dysfunction as indicated by hematologic autoantibodies, arthritis, glomerulonephritis, Wiskott-Aldrich syndrome, unusual infections, systemic amyloidosis, multiple myeloma, Raynaud's phenomenon with sclerodactyly, asthma, and the hyperviscosity syndrome.6 Perhaps this entity represents an exaggerated response to an offending agent. Lober et al reported a case of a 6-year-old male with SHML who on three occasions had elevated antibodies levels against the EBV viral capsid antigen.5 This case suggested a role for the EBV, such as an atypical sequela of infectious mononucleosis. Lampert and Lennert further corroborated the idea of an exaggerated response to an infectious agent when they reported a case of a child with SHML who had high antibody titers against Klebsiella ozaenae antigens.7 This tends to implicate Klebsiella rhinoscleromatis and K ozaenae. Histologically, lymph nodes in SHML are characterized by a marked alteration of the normal architecture. There is fibrosis of the capsule with bands of fibrous tissue involving the entire node. There is hyperplasia of 923
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
t#*'*%. 'X..
the possibility of inducing a secondary malignancy. There are apparently no deaths secondary to malignant transformation.9 However, the mortality rate secondary to this disease has been reported to be 7%. Seventy-one percent of the fatalities suffered some immunologic derangement.3'9
.. # .,)~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. M..%;... CONCLUSION
Sinus histiocytosis is a recently discovered disease whose course is usually benign. There is a 7% mortality rate, which is usually associated with immunologic disorders. Antibiotics are uniformly useless while agents such as cyclophosphamide appear to be useful. Figure 3. Photomicrograph of SHML. the sinuses and effacement of the follicles and germinal centers. The sinuses are distended and include histiocytes, lymphocytes, erythrocytes, plasma cells, and occasional neutrophils. The mature histiocytes exhibit intracytoplasmic vacuoles with phagocytized lymphocytes, erythrocytes, or neutrophils (Figure 3).1 The natural history of this disorder is one of spontaneous regression over a period of months to years.2'3 Antibiotics are uniformly useless in the management of this disease.1 2 Corticosteroids have an ameliorative effect on the constitutional symptoms but do not alter the lymphadenopathy.3'8 Radiation therapy has been used with mixed success. In an early report, Rosai and Dorfman described four patients who had undergone radiotherapy for SHML.2 Two of these patients experienced a mild decrease in adenopathy while the other two patients were unchanged by this modality. Chemotherapeutic agents appear to be the most efficacious treatment of SHML. Newman et al successfully managed a patient with cyclophosphamide who failed on corticosteroid and radiation therapies.8 However, they warned against the routine use of such agents because of their toxicity and
924
Literature Cited 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70. 2. Rosai J, Dorfman RF Sinus histiocytosis with mass lymphadenopathy: a pseudolymphomatous benign disorder. Cancer 1972;30: 1174-1188. 3. Schweittzer VG, Bobier GD. Sinus histiocytosis with massive lymphadenopathy. Ann Otol Rhinol Laryngol. 1986;95:331-335. 4. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: ear, nose and throat manifestations. Arch Otolaryngol Head Neck Surg. 1978;1 04:687-693. 5. Lober M, Rawlings W, Newell GR, Reed RJ. Sinus histiocytosis with massive lymphadenopathy: report of a case with elevated EBV antibody titers. Cancer 1973;32:421-425. 6. Foucar E, Rosai J, Dorfman RF, Eyman JM. Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol. 1 984;82:51 5-525. 7. Lampert F, Lennert K. Sinus histiocytosis with massive lymphadenopathy: fifteen new cases. Cancer 1976;37:783789. 8. Newman SB, Sweet DL, Vardiman JW. Sinus histiocytosis with massive lymphadenopathy: response to cyclophosphamide therapy. Cancer Treatment Reports. 1984;68:901-902. 9. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 14 deaths occurring in a patient registry. Cancer 1984;54:1834-1839.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
CASE REPORT A 47-year-old black male was discovered to have prominent bilateral posterior cervical adenopathy on a physical examination during admission for anaphylaxis. From the Departments of Otolaryngology and Clinical Investigation, Naval Hospital, San Diego, California. Presented at the 91 st Annual Convention and Scientific Assembly of the National Medical Association, July 22, 1986, New York, New York. The work reported herein was performed under the Navy Clinical Investigation Program case no. 84-16-1968-158. The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. Requests for reprints should be addressed to Capt Earl H. Harley, MC, USNR, c/o Clinical Investigation Department, Naval Hospital, San Diego, CA 92134-5000. 922
Over the next several months, these nodes were noted to enlarge; in the meantime, the anterior chain of nodes became involved. There was no discomfort associated with the adenopathy The patient denied chills, fever, anorexia, and weight loss. He was referred for a biopsy. On physical examination, a striking bilateral anterior and posterior cervical adenopathy was noted (Figure 1). The lymph nodes were nontender, firm, and barely movable, ranging in size from 1 cm to 6 cm. There was no generalized adenopathy. The remainder of the head and neck examination, including indirect mirror examination, was normal. The liver and spleen were normal on palpation. A complete blood count, electrolyte studies, and a serologic test for syphilis were normal. A T4/T8 ratio was 0.1 (helper/suppressor reversal, nl greater than 1.6). Total complement levels and C3 and C4 levels were normal. The antinuclear antibody titer was negative. The Epstein-Barr virus (EBV) titer was initially 1:640 but fell to 1:50. Immunoglobulin studies revealed a mildly elevated IgG of 910 mg/dL (5641765); the remainder of the gamma globulins were normal. Protein electrophoresis revealed a mildly elevated polyclonal hypergammaglobulinemia consistent with a mildly elevated IgG. Chest x-ray was negative. Computed tomography scan of the neck revealed bilateral adenopathy (Figure 2). Skin testing initially revealed a 15-mm reaction to the PPD antigen but eventually demonstrated anergy. This patient underwent open cervical biopsy in the summer of 1981 and again in the summer of 1982. Each time the pathologic diagnosis was SHML. Also, a subsequent fine needle aspiration corroborated the benign nature of his adenopathy. Two years into the course of the disease, the patient was placed on steroids on a trial basis; however, there was no clinical response, and the drug was discontinued. The patient has since JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
Figure 2. CT scan.
Figure 1. Posterior view of the patient. been lost to follow-up.
DISCUSSION Sinus histiocytosis with massive lymphadenopathy is a pseudolymphomatous disorder that was initially described by Rosai and Dorfman in 1969.1 This disease is a benign self-limiting illness and was originally felt to be most prevalent among black youths. Two thirds of the cases are reported to occur in the first decade of life, while a full 81% present before the age of 20. However, some older patients have been reported to be affected by this disorder.2'3 The disease has a male preponderance and is characterized by fever, weight loss, and a striking, painless bilateral cervical lymphadenopathy.2,3 Ninetyseven percent of patients have cervical adenopathy, while 30% of patients have involvement in other nodal sites such as axillary, inguinal, and paravertebral areas. Extranodal site involvement occurs in 30% of patients.3'4 These sites include the central nervous system, the orbit and eyelids, the nose and paranasal sinuses, the oral cavity, salivary glands, the trachea and bronchi, liver, spleen, kidneys, pancreas, testicles, long bones, and skin.3'4 The nasal cavity and the salivary glands are thought to be the most common sites JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
involved in the head and neck.4 Laboratory studies for this disorder can be remarkable for leukocytosis and neutrophilia, an elevated erythrocyte sedimentation rate, and mild anemia. 1-3 Hypergammaglobulinemia has been reported.2'3 Elevated EBV titers also have been reported.3'5 Diagnosis can be made only by biopsy of the involved node or biopsy of the involved extranodal organ. The exact etiology of this disease is unknown. Perhaps it represents an immunologic reaction. Foucar et al examined a computerized registry of 200 patients with SHML.6 Twenty-three of these patients had evidence of an immune dysfunction as indicated by hematologic autoantibodies, arthritis, glomerulonephritis, Wiskott-Aldrich syndrome, unusual infections, systemic amyloidosis, multiple myeloma, Raynaud's phenomenon with sclerodactyly, asthma, and the hyperviscosity syndrome.6 Perhaps this entity represents an exaggerated response to an offending agent. Lober et al reported a case of a 6-year-old male with SHML who on three occasions had elevated antibodies levels against the EBV viral capsid antigen.5 This case suggested a role for the EBV, such as an atypical sequela of infectious mononucleosis. Lampert and Lennert further corroborated the idea of an exaggerated response to an infectious agent when they reported a case of a child with SHML who had high antibody titers against Klebsiella ozaenae antigens.7 This tends to implicate Klebsiella rhinoscleromatis and K ozaenae. Histologically, lymph nodes in SHML are characterized by a marked alteration of the normal architecture. There is fibrosis of the capsule with bands of fibrous tissue involving the entire node. There is hyperplasia of 923
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
t#*'*%. 'X..
the possibility of inducing a secondary malignancy. There are apparently no deaths secondary to malignant transformation.9 However, the mortality rate secondary to this disease has been reported to be 7%. Seventy-one percent of the fatalities suffered some immunologic derangement.3'9
.. # .,)~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. M..%;... CONCLUSION
Sinus histiocytosis is a recently discovered disease whose course is usually benign. There is a 7% mortality rate, which is usually associated with immunologic disorders. Antibiotics are uniformly useless while agents such as cyclophosphamide appear to be useful. Figure 3. Photomicrograph of SHML. the sinuses and effacement of the follicles and germinal centers. The sinuses are distended and include histiocytes, lymphocytes, erythrocytes, plasma cells, and occasional neutrophils. The mature histiocytes exhibit intracytoplasmic vacuoles with phagocytized lymphocytes, erythrocytes, or neutrophils (Figure 3).1 The natural history of this disorder is one of spontaneous regression over a period of months to years.2'3 Antibiotics are uniformly useless in the management of this disease.1 2 Corticosteroids have an ameliorative effect on the constitutional symptoms but do not alter the lymphadenopathy.3'8 Radiation therapy has been used with mixed success. In an early report, Rosai and Dorfman described four patients who had undergone radiotherapy for SHML.2 Two of these patients experienced a mild decrease in adenopathy while the other two patients were unchanged by this modality. Chemotherapeutic agents appear to be the most efficacious treatment of SHML. Newman et al successfully managed a patient with cyclophosphamide who failed on corticosteroid and radiation therapies.8 However, they warned against the routine use of such agents because of their toxicity and
924
Literature Cited 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70. 2. Rosai J, Dorfman RF Sinus histiocytosis with mass lymphadenopathy: a pseudolymphomatous benign disorder. Cancer 1972;30: 1174-1188. 3. Schweittzer VG, Bobier GD. Sinus histiocytosis with massive lymphadenopathy. Ann Otol Rhinol Laryngol. 1986;95:331-335. 4. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: ear, nose and throat manifestations. Arch Otolaryngol Head Neck Surg. 1978;1 04:687-693. 5. Lober M, Rawlings W, Newell GR, Reed RJ. Sinus histiocytosis with massive lymphadenopathy: report of a case with elevated EBV antibody titers. Cancer 1973;32:421-425. 6. Foucar E, Rosai J, Dorfman RF, Eyman JM. Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol. 1 984;82:51 5-525. 7. Lampert F, Lennert K. Sinus histiocytosis with massive lymphadenopathy: fifteen new cases. Cancer 1976;37:783789. 8. Newman SB, Sweet DL, Vardiman JW. Sinus histiocytosis with massive lymphadenopathy: response to cyclophosphamide therapy. Cancer Treatment Reports. 1984;68:901-902. 9. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 14 deaths occurring in a patient registry. Cancer 1984;54:1834-1839.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 83, NO. 10
