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Sinus Histiocytosis With Massive Lymphadenopathy in a Japanese Male With Symptoms of Dyspnea and Visual Disturbance
Auris' Nasus ' Larynx (Tokyo) 17, 95-104 (\990)
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY IN A JAPANESE MALE WITH SYMPTOMS OF DYSPNEA AND VISUAL DISTURBANCE Michitaka JWANAGA, M. D.,* Yoichi NAGAYAMA, M. D.,** Kenkichi KITA, M. D.,** and Manabu FUKUMOTO, M. D.***
*Department of Otolaryngology, Kitano Hospital, Osaka, Japan **Department of Internal Medicine, Kyoto University, Kyoto, Japan ***Department of Pathology, Kyoto University. Kyoto, Japan A case study of sinus histiocytosis with massive lymphadenopathy is reported. A Japanese male developed lymphadenopathy in the nasal cavity 10 years ago. Biopsy specimens demonstrated massive histiocytosis with phagocytosis of lymphocytes, plasmacytes, and erythrocytes. During the course of his illness, the patient experienced an episode of massive nasal bleeding, and a tracheotomy was performed because of dyspnea. He had also an operation by Killian's approach to relieve a visual disturbance. The patient has been treated with cyclophosphamide and prednisolone for 6 months. Sinus histiocytosis with massive lymphadenopathy (SHML) was proposed as an independent clinical entity by ROSAI and DORFMAN in 1969. As indicated by its name, this disease causes lymph node enlargement throughout the entire body and especially in the neck region. The characteristic histological findings of lymph nodes include peri capsular fibrosis, dilatation of the sinus, remarkable increase of plasma cells, remarkable ipcrease of sinusoidal histiocytes, and presence of lymphocytes and other hematopoietic cells in their cytoplasms (ROSA I and DORFMAN, 1969; BANKACI, MORRIS, STOOL, and PARADISE, 1978). SHML features a long clinical course in many cases but it is said that during the course the sole sign usually is lymph node enlargement and few severe symptoms are manifested. In some cases, however, lesions are found in tissues other than the lymph nodes; for example, ocular, tracheal, bone, and cutaneous symptoms are manifested (CODLING, SONI, BARRY, and MARTIN-WALKER, 1972; FOUCAR, ROSAI, and DORFMAN, 1978; THAWERANI, SANCHEZ, ROSAI, and DORFMAN, 1978). A considerable number of cases of SHML has been reported from foreign Received for publication October 5, 1989 95
96
M. IWANAGA et al.
countries (SANCHEZ, ROSAI, and DORFMAN, 1977) but only a few cases from Japan (TANAKA and ASANO, 1978; TANAKA, ASANO, TAKAHASHI, MIYOSHI, TANAKA, HAYASHI, SAITO, and MUGURUMA, 1980; HANADA, KISHIMOTO, TAKAYAMA, KUBO, KOGA, NISHIYAMA, HANTO, SADA, TAKADA, ISHIKAWA, NAKAMOTO, and YOKOYAMA, 1982; AOYAMA, TERASHIMA, IMAI, KATSUSHIMA, OKUYAMA, NUKAWA, MUKADA, and TAKAHASHI, 1984). In this paper we report the fifth case reported from Japan. CASE REPORT
Case: A 34-year-old man (born on September 7, 1948). Chief complaint: Hemorrhagic rhinorrhea. Family history: No history of malignant tumor, collagen disease, or hereditary disease. His mother had diabetes. No tuberculosis. Past history: Pulmonary tuberculosis in 1977 (age 28). Left spontaneous pneumothorax in 1982 (age 33). Present illness: At the beginning of 1972 (age 24), nasal obstruction and hemorrhagic rhinorrhea occurred, swelling of the nasal region began to appear, and the patient underwent resection of tumors in both nasal cavities at the department of otorhinolaryngology of a certain medical university (after histological examination, the patient was told that the masses were lymphatoid tissues and not malignant). However, nasal discharge persisted and was hemorrhagic on occasions. The patient noticed a swelling of the right submandibular region around 1974 (age 26). In April 1976 (age 27) right epistaxis occurred. Nasal swelling was diminished by massive administration of steroids at a certain medical university hospital. In 1977, fever (38-39°C) occurred and the patient was hospitalized and treated with tuberculostatics at a certain medical university hospital during the period from March to the end of the same year, obtained relief, and was discharged from the hospital. Around March 1980 (age 31) the patient noted decreased vision in the right eye. Around this time, bilateral submandibular lymph node enlargement began to show a gradual augmentation. In January 1982, epistaxis was persistent and pneumothorax occurred. The patient was admitted to a certain hospital. On April 16, tracheotomy was performed for persistent dyspnea. Left visual disturbance increased and nasal swelling also increased. Therefore, the patient was admitted to the Department of Neurosurgery of Kyoto University where on August 11, 1982, operation (decompression of the left sinus using the Killian's approach and excision of the right submandibular lymph node) was performed. Thereafter, the patient was transferred to the Department of Otorhinolaryngology of the same university, where resection of intranasal tumors was performed and, then, further transferred to the Department of Internal Medicine for systemic treatment. Present status: Height, 168.2 cm; weight, 62.8 kg; pulse rate, 84jmin, reg-
SHML
97 Right
Left
It-paranasal cavity bl-nasal cavity
It-2nd finger
oral cavity
It-thigh 20 X 20mm
It-submandibular gl. 20 X 23mm rt-cervical gl. 20 X 23mm trachea
o Fig. J.
Site of lymphadenopathy.
ular; blood pressure, 114/70 mmHg. Lymph node enlargement and proliferation of lymphoid tissue were found in both nasal cavities, left sinus, both submandibular regions, right cervical region, oral cavity, trachea, left second finger, and left femoral region (Fig. 1). The cardiac dullness and heart sounds were normal. Breath sounds were unremarkable. The liver was palpable 1.5 cm on the right mid clavicular line and the spleen edge palpable. No ascites was observed. There were no other abnormal signs of note. Lymph node enlargement and nasal swelling were first noticed in 1972, swelling of the left femur and left second finger in 1976, swelling of the left submandibular region in 1979, and swelling of bilateral subauricular regions in 1981, and swelling of the oral cavity and trachea in 1982. Laboratory findings 1. Routine examination findings. Anemia was not found in peripheral blood. WBC was normal. Differential WBC showed a decrease of lymphocytes. Erythrocyte sedimentation rate was 70 mm/h. CRP was strongly positive. Blood protein content was not abnormal except for the slight decrease in albumin found before treatment. Blood Ca2+ level was slightly decreased. Urinalysis was not remarkable. 2. Pathological findings. Light microscopy (Figs. 2, 3): The lymph node excised from the right submandibular region measured 2.0 X 2.3 cm and showed a yellow color on the cut surface and a thickening of the capsule. Microscopic examination revealed a marked fibrous thickening of the capsule and a remarkable proliferation of histiocytes in the lymphatic sinus, as well as a local destruction of the lymphatic parenchyma. The histiocytes had foamy or granular cell bodies, in which lymphocytes, plasma cells, and erythrocytes were frequently found. The histiocytes were poor in atypia and showed little karyomitosis. The cortex of the lymph node contained a large number of follicles having small germinal centers, with many plasma cells appearing between the follicles. Staining for immunoglobulins by the enzyme antibody method showed that plasma cells
98
M. IWANAGA et al.
Fig. 2. Note the markedly dilated sinuses with diffuse proliferation of histiocytes. RE. x 40.
Fig. 3. Detailed feature of histiocytes phagocytizing lymphocytes, plasmacytes, and erythrocytes. H. E. x 200.
were polyclonal. The masses in the nasal cavity and sinus consisted of proliferated and fibrotic histiocytes and plasma cells. Lymphocytes and plasma cells were often found in the cell bodies of the histiocytes. These findings were consistent with those described by ROSAT and DORFMAN (1969), for "sinus histiocytosis with massive lymphadenopathy." Electron microscopy (Figs. 4, 5): In electron microscopy, two kinds of phagocytizing histiocytes could be discerned : interdigitating histiocytes and ordinary histiocytes. The interdigitating histiocytes were characterized by interdigitating cytoplasmic extensions. The nucleus was round or oval, and
SHML
99
Fig. 4. Histiocytes with numerous interdigitations connect with another histiocyte containing electron-dense lipid granules. x 1,800.
Fig. 5. Histiocyte formed elongated filopodia. nent. x 2,800.
Rough endoplasmic reticulum was promi-
100
M. IWANAGA et al.
occasionally indented. Rough endoplasmic reticula were few in number. The Golgi apparatus was developed. Mitochondria were rich. Several lymphocytes were engulfed in the cytoplasm. Some interdigitating histiocytes had a number of fat droplets. The ordinary histiocytes were also found in the sinuses phagocytizing many lymphocytes and neutrophils. In contrast with the interdigitating histiocytes, the ordinary histiocytes had blunt cytoplasmic extensions. 3. Results of immunological tests (Table 1). Antinuclear antibody was negative. The serum complement values (C3 and C4) were normal. The CH50 level showed high levels occasionally. The direct Coombs test was negative. Rheumatoid arthritis test (RAT) was positive. The antistreptolysin-O (ASO) value was normal. The DNA antibody titer was normal. Mantoux reaction (MaR) was positive. Table 1. Serological examination on admission. ( ): normal range. CRP ANF Anti-DNA-Ab C3
4 (+) (- )
5U/ml 177 (80-200) mg/dl 40 (15-60) mg/dl 80.0 (33-49) V/ml (+) X20 (0-60) Ox Omm (+ )
C4
CH50 RAT ASO Mantoux reaction
17 x 14mm Coombs test (D) IgG IgM IgA Table 2.
(- )
1,432 (750-1,800) mg/dl 391 (50-280) mg/dl 203 (65-420) mg/dl
Antibody titer to viruses. ( ): normal range.
Influenza virus RS virus Cytomegalovirus Mycoplasma pneumoniae Herpes zoster virus Parainfluenza virus
Rubella virus Rubeola virus EB virus capsid antigen
EB virus early antigen EB virus nuclear antigen
type A type B
type 1 type 2 type 3
IgG JgM IgA
8 (4) 16 (4) 16 (4) 8 (4) 4 (4) 16 (4) 256 (4) 128 (4) 128 (4) 1,028 (4) 128 (4) 320 (4) 10 (4) 10 (4) 80 (4) 80 (4)
SHML
101
Table 3. Immunological analysis. A.
B.
Left submandibular lymph node (81-11-30) E-rosette 32.8 % Surface IgG 45.1 % Surface IgM 0% Surface C3b 1.9% Ia antigen 25.1 % Tcell 35.4 % OKT 3 32 % 4 0% 6 0% 8 30 % Peripheral blood lymphocyte (82-10-19) T cell 81 .5 % B cell 18.1 % OKT 4 14.0 % 8 15.3 %
4. Viral antibody tite.rs. As seen in Table 2, elevation of antibody to EB virus, particularly capcid antigen (IgG) , was found. Otherwise, elevations of antibodies to rubella virus, measles virus, and parainfluenza virus were found. 5. Immunological analysis. Rosette formation with sheep red cells, surface immunoglobulin with FITC-Iabeled anti-human immunoglobulins, and T cellsubsets with OKT 3, 4, 6, and 8 mice monoclonal antibodies which were absorbed with human vivid spleen cells, were tested. Rosette formation and surface immunoglobulins were tested with suspended lymph node cells. T cell-subsets were tested with lymph node cells and lymphocytes in peripheral blood. The results of examination of lymphocyte surface markers in the lymphoid tissue obtained by biopsy are shown in Table 3: OKT 3 and 8 were positive and OKT 4 and 6 were negative. The results of examination of peripheral lymphocyte surface markers were slightly different from those found in the lymph node: OKT 4 (+) 14% and OKT 8 (+ ) 15.3%. DISCUSSION
The present case showed generalized, extensive proliferation of lymph nodes and lymphatic tissues and featured histological findings of lymph nodes such as a) remarkable fibrous thickening of the capsule, b) marked proliferation of histiocytes, c) foamy or granular cell bodies in histiocytes, d) frequent presence of lymphocytes, plasma cells, and erythrocytes in these cell bodies, and e) appearance of many plasma cells. Based on these findings, the diagnosis of SHML was made. This case required tracheotomy for dyspnea due to tracheal lesions and neurosurgical and otorhinological treatments for visual disturbance in the left eye
102
M. [WANAGA et
at.
due to the compression caused by the lesion extending from the sinus to the orbit. Thus, the case presented with the progression and aggravation of symptoms which are often seen in malignant diseases. SHML has generally been considered to be a benign disease and presents only a swelling of lymph nodes in many cases (SANCHEZ et al., 1977; TANAKA and ASANO, 1978). Therefore, we once hesitated to make a diagnosis of SHML in this case. The etiology of SHML remains yet to be established but several etiological presumptions have been attempted on the basis of clinical, biochemical, and histopathological findings. Among the hypotheses proposed is an infection theory (ROSAI and DORFMAN, 1972) based on such findings as fever, leukocytosis, positive CRP, and increased antibodies to bacteria and fungi such as Salmonella, Klebsiella, Histoplasma, and to EB virus. Another factor that has been pointed out in this disease is an immunologic abnormality (ROSAI and DORFMAN, 1972) as allegedly evidenced by biochemical and histological findings such as increased r-globulin, lymphophagocytosis, hematopoietic cell phagocytosis. We may now venture some speculations about the nature of SHML on the basis of findings in the present case. First, with regard to the infection theory, the findings in this case of increased erythrocyte sedimentation rate, strongly positive CRP, and increased titer to EB virus capsid and of increased titers to rubella virus, measles virus, and parainfluenza virus suggest that the infection theory cannot be denied. However, in our case, the abnormalities may be results of decreased resistance to infection owing to some cause or other in SHML. As to immunologic abnormalities, MaR, a parameter of cellular immunity, was normal. As to humoral immunity, only slight increases in r-globulin and IgM were found and antinuclear antibody and complement were normal. Though various radiation therapies and chemotherapies have so far been attempted for SHML, none of these treatments have been reported to be effective (FOUCAR et al., 1978; ROSAI and DORFMAN, 1972). In our case, such subjective symptoms as visual disturbance in the left eye, dyspnea, nasal bleeding were recognized. In view of the fact that the cardinal sign of SHML was the abnormality of lymph nodes and lymphatic tissues, oral treatment with prednisolone and oral and inhalation treatments with cyclophosphamide were performed for 6 months for alleviating the subjective symptoms through suppression of the lesions. These treatments resulted in some reduction in the size of lymph nodes and lymphatic tissues where the symptoms were manifested by compression. Subsequently, decreases in nasal obstruction and nasal discharge and in swelling of the nasal region were found. However, histological examination by intranasal biopsy performed on 3 occasions during the 6-month treatment period revealed no histological changes attributable to the administration of prednisolone and cyclophosphamide. The therapy given so far in this case has not been effective, just as in other reported cases (Fig. 6).
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REFERENCES AOYAMA, K., TERASHIMA, K., IMAI, Y., KATSUSHlMA, N., OKUYAMA, Y., NIlKAWA, K., MUKADA, T., and TAKAHASHI, K.: Sinus histiocytosis with massive lymphadenopathy. Acta Patho!.
Jpn. 34: 375-388, 1984. BANKACI, M., MORRIS, R. F., STOOL, S. E., and PARADISE, J. L.: Sinus histiocytosis with massive lymphadenopathy. Report of its occurrence in two siblings with retropharyngeal involvement in both. Ann. Oto!aryngol. 87: 327-331, 1978. CODLING, B. W., SONI, K. G., BARRY, D. R., and MARTIN-WALKER, W.: Histiocytosis presenting as swelling of orbit and eyelid. Br. J. Ophthalmol. 56: 517-530, 1972. FOUCAR, E., ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. Ear, nose and throat manifestations. Arch. Otolaryngol. 104: 687-693, 1978. HANADA, T., KISHIMOTO, H., TAKAYAMA, T., KUBO, S., KOGA, H., NISHIYAMA, Y., HANTO, T., SADA, M., TAKADA, M., ISHIKAWA, H., NAKAMOTO, 0., and YOKOYAMA, S.: A case of sinus histiocytosis with massive lymphadenopathy with elevated EBV antibody titers. J.
Jpn. Soc. Reticuloendothel. Syst. 22: 13-20, 1982. ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch. Pathol. 87: 63-70, 1969. ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. A pseudo lymphomatous benign disorder. Analysis of 34 cases. Cancer 30: 1174-1188,
1972. SANCHEZ, R., ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. An analysis of 113 cases with special emphasis on its extranodal manifestations. Ann.
Meet. Abstr. 36(3): 349-350, 1977. TANAKA, N., and ASANO, T.: Sinus histiocytosis with massive lymphadenopathy (Rosai and Dorfman) and significant skin involvement. Arch. Patho!. Jpn. 28: 175-184, 1978. TANAKA, T., ASANO, S., TAKAHASHI, K., MIYOSHI, I., TANAKA, M., HAYASHI, T., SAITO, R., and MUGURUMA, M.: Sinus histiocytosis with massive lymphadenopathy in Japanese adult with unusually elevated EBV antibody titers. Acta Patho!. Jpn. 30: 121-135, 1980.
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THAWERANr, H ., SANCHEZ, R. L., ROSA!, J., and DORFMAN, R. F.: The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch. Dermatol. 114: 191-
197, 1978.
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Request reprints to:
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Dr. M. Iwanaga, Department of Otolaryngology, Kitano Hospital, Kamiyamacho , Kita-ku, Osaka 530, Japan
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY IN A JAPANESE MALE WITH SYMPTOMS OF DYSPNEA AND VISUAL DISTURBANCE Michitaka JWANAGA, M. D.,* Yoichi NAGAYAMA, M. D.,** Kenkichi KITA, M. D.,** and Manabu FUKUMOTO, M. D.***
*Department of Otolaryngology, Kitano Hospital, Osaka, Japan **Department of Internal Medicine, Kyoto University, Kyoto, Japan ***Department of Pathology, Kyoto University. Kyoto, Japan A case study of sinus histiocytosis with massive lymphadenopathy is reported. A Japanese male developed lymphadenopathy in the nasal cavity 10 years ago. Biopsy specimens demonstrated massive histiocytosis with phagocytosis of lymphocytes, plasmacytes, and erythrocytes. During the course of his illness, the patient experienced an episode of massive nasal bleeding, and a tracheotomy was performed because of dyspnea. He had also an operation by Killian's approach to relieve a visual disturbance. The patient has been treated with cyclophosphamide and prednisolone for 6 months. Sinus histiocytosis with massive lymphadenopathy (SHML) was proposed as an independent clinical entity by ROSAI and DORFMAN in 1969. As indicated by its name, this disease causes lymph node enlargement throughout the entire body and especially in the neck region. The characteristic histological findings of lymph nodes include peri capsular fibrosis, dilatation of the sinus, remarkable increase of plasma cells, remarkable ipcrease of sinusoidal histiocytes, and presence of lymphocytes and other hematopoietic cells in their cytoplasms (ROSA I and DORFMAN, 1969; BANKACI, MORRIS, STOOL, and PARADISE, 1978). SHML features a long clinical course in many cases but it is said that during the course the sole sign usually is lymph node enlargement and few severe symptoms are manifested. In some cases, however, lesions are found in tissues other than the lymph nodes; for example, ocular, tracheal, bone, and cutaneous symptoms are manifested (CODLING, SONI, BARRY, and MARTIN-WALKER, 1972; FOUCAR, ROSAI, and DORFMAN, 1978; THAWERANI, SANCHEZ, ROSAI, and DORFMAN, 1978). A considerable number of cases of SHML has been reported from foreign Received for publication October 5, 1989 95
96
M. IWANAGA et al.
countries (SANCHEZ, ROSAI, and DORFMAN, 1977) but only a few cases from Japan (TANAKA and ASANO, 1978; TANAKA, ASANO, TAKAHASHI, MIYOSHI, TANAKA, HAYASHI, SAITO, and MUGURUMA, 1980; HANADA, KISHIMOTO, TAKAYAMA, KUBO, KOGA, NISHIYAMA, HANTO, SADA, TAKADA, ISHIKAWA, NAKAMOTO, and YOKOYAMA, 1982; AOYAMA, TERASHIMA, IMAI, KATSUSHIMA, OKUYAMA, NUKAWA, MUKADA, and TAKAHASHI, 1984). In this paper we report the fifth case reported from Japan. CASE REPORT
Case: A 34-year-old man (born on September 7, 1948). Chief complaint: Hemorrhagic rhinorrhea. Family history: No history of malignant tumor, collagen disease, or hereditary disease. His mother had diabetes. No tuberculosis. Past history: Pulmonary tuberculosis in 1977 (age 28). Left spontaneous pneumothorax in 1982 (age 33). Present illness: At the beginning of 1972 (age 24), nasal obstruction and hemorrhagic rhinorrhea occurred, swelling of the nasal region began to appear, and the patient underwent resection of tumors in both nasal cavities at the department of otorhinolaryngology of a certain medical university (after histological examination, the patient was told that the masses were lymphatoid tissues and not malignant). However, nasal discharge persisted and was hemorrhagic on occasions. The patient noticed a swelling of the right submandibular region around 1974 (age 26). In April 1976 (age 27) right epistaxis occurred. Nasal swelling was diminished by massive administration of steroids at a certain medical university hospital. In 1977, fever (38-39°C) occurred and the patient was hospitalized and treated with tuberculostatics at a certain medical university hospital during the period from March to the end of the same year, obtained relief, and was discharged from the hospital. Around March 1980 (age 31) the patient noted decreased vision in the right eye. Around this time, bilateral submandibular lymph node enlargement began to show a gradual augmentation. In January 1982, epistaxis was persistent and pneumothorax occurred. The patient was admitted to a certain hospital. On April 16, tracheotomy was performed for persistent dyspnea. Left visual disturbance increased and nasal swelling also increased. Therefore, the patient was admitted to the Department of Neurosurgery of Kyoto University where on August 11, 1982, operation (decompression of the left sinus using the Killian's approach and excision of the right submandibular lymph node) was performed. Thereafter, the patient was transferred to the Department of Otorhinolaryngology of the same university, where resection of intranasal tumors was performed and, then, further transferred to the Department of Internal Medicine for systemic treatment. Present status: Height, 168.2 cm; weight, 62.8 kg; pulse rate, 84jmin, reg-
SHML
97 Right
Left
It-paranasal cavity bl-nasal cavity
It-2nd finger
oral cavity
It-thigh 20 X 20mm
It-submandibular gl. 20 X 23mm rt-cervical gl. 20 X 23mm trachea
o Fig. J.
Site of lymphadenopathy.
ular; blood pressure, 114/70 mmHg. Lymph node enlargement and proliferation of lymphoid tissue were found in both nasal cavities, left sinus, both submandibular regions, right cervical region, oral cavity, trachea, left second finger, and left femoral region (Fig. 1). The cardiac dullness and heart sounds were normal. Breath sounds were unremarkable. The liver was palpable 1.5 cm on the right mid clavicular line and the spleen edge palpable. No ascites was observed. There were no other abnormal signs of note. Lymph node enlargement and nasal swelling were first noticed in 1972, swelling of the left femur and left second finger in 1976, swelling of the left submandibular region in 1979, and swelling of bilateral subauricular regions in 1981, and swelling of the oral cavity and trachea in 1982. Laboratory findings 1. Routine examination findings. Anemia was not found in peripheral blood. WBC was normal. Differential WBC showed a decrease of lymphocytes. Erythrocyte sedimentation rate was 70 mm/h. CRP was strongly positive. Blood protein content was not abnormal except for the slight decrease in albumin found before treatment. Blood Ca2+ level was slightly decreased. Urinalysis was not remarkable. 2. Pathological findings. Light microscopy (Figs. 2, 3): The lymph node excised from the right submandibular region measured 2.0 X 2.3 cm and showed a yellow color on the cut surface and a thickening of the capsule. Microscopic examination revealed a marked fibrous thickening of the capsule and a remarkable proliferation of histiocytes in the lymphatic sinus, as well as a local destruction of the lymphatic parenchyma. The histiocytes had foamy or granular cell bodies, in which lymphocytes, plasma cells, and erythrocytes were frequently found. The histiocytes were poor in atypia and showed little karyomitosis. The cortex of the lymph node contained a large number of follicles having small germinal centers, with many plasma cells appearing between the follicles. Staining for immunoglobulins by the enzyme antibody method showed that plasma cells
98
M. IWANAGA et al.
Fig. 2. Note the markedly dilated sinuses with diffuse proliferation of histiocytes. RE. x 40.
Fig. 3. Detailed feature of histiocytes phagocytizing lymphocytes, plasmacytes, and erythrocytes. H. E. x 200.
were polyclonal. The masses in the nasal cavity and sinus consisted of proliferated and fibrotic histiocytes and plasma cells. Lymphocytes and plasma cells were often found in the cell bodies of the histiocytes. These findings were consistent with those described by ROSAT and DORFMAN (1969), for "sinus histiocytosis with massive lymphadenopathy." Electron microscopy (Figs. 4, 5): In electron microscopy, two kinds of phagocytizing histiocytes could be discerned : interdigitating histiocytes and ordinary histiocytes. The interdigitating histiocytes were characterized by interdigitating cytoplasmic extensions. The nucleus was round or oval, and
SHML
99
Fig. 4. Histiocytes with numerous interdigitations connect with another histiocyte containing electron-dense lipid granules. x 1,800.
Fig. 5. Histiocyte formed elongated filopodia. nent. x 2,800.
Rough endoplasmic reticulum was promi-
100
M. IWANAGA et al.
occasionally indented. Rough endoplasmic reticula were few in number. The Golgi apparatus was developed. Mitochondria were rich. Several lymphocytes were engulfed in the cytoplasm. Some interdigitating histiocytes had a number of fat droplets. The ordinary histiocytes were also found in the sinuses phagocytizing many lymphocytes and neutrophils. In contrast with the interdigitating histiocytes, the ordinary histiocytes had blunt cytoplasmic extensions. 3. Results of immunological tests (Table 1). Antinuclear antibody was negative. The serum complement values (C3 and C4) were normal. The CH50 level showed high levels occasionally. The direct Coombs test was negative. Rheumatoid arthritis test (RAT) was positive. The antistreptolysin-O (ASO) value was normal. The DNA antibody titer was normal. Mantoux reaction (MaR) was positive. Table 1. Serological examination on admission. ( ): normal range. CRP ANF Anti-DNA-Ab C3
4 (+) (- )
5U/ml 177 (80-200) mg/dl 40 (15-60) mg/dl 80.0 (33-49) V/ml (+) X20 (0-60) Ox Omm (+ )
C4
CH50 RAT ASO Mantoux reaction
17 x 14mm Coombs test (D) IgG IgM IgA Table 2.
(- )
1,432 (750-1,800) mg/dl 391 (50-280) mg/dl 203 (65-420) mg/dl
Antibody titer to viruses. ( ): normal range.
Influenza virus RS virus Cytomegalovirus Mycoplasma pneumoniae Herpes zoster virus Parainfluenza virus
Rubella virus Rubeola virus EB virus capsid antigen
EB virus early antigen EB virus nuclear antigen
type A type B
type 1 type 2 type 3
IgG JgM IgA
8 (4) 16 (4) 16 (4) 8 (4) 4 (4) 16 (4) 256 (4) 128 (4) 128 (4) 1,028 (4) 128 (4) 320 (4) 10 (4) 10 (4) 80 (4) 80 (4)
SHML
101
Table 3. Immunological analysis. A.
B.
Left submandibular lymph node (81-11-30) E-rosette 32.8 % Surface IgG 45.1 % Surface IgM 0% Surface C3b 1.9% Ia antigen 25.1 % Tcell 35.4 % OKT 3 32 % 4 0% 6 0% 8 30 % Peripheral blood lymphocyte (82-10-19) T cell 81 .5 % B cell 18.1 % OKT 4 14.0 % 8 15.3 %
4. Viral antibody tite.rs. As seen in Table 2, elevation of antibody to EB virus, particularly capcid antigen (IgG) , was found. Otherwise, elevations of antibodies to rubella virus, measles virus, and parainfluenza virus were found. 5. Immunological analysis. Rosette formation with sheep red cells, surface immunoglobulin with FITC-Iabeled anti-human immunoglobulins, and T cellsubsets with OKT 3, 4, 6, and 8 mice monoclonal antibodies which were absorbed with human vivid spleen cells, were tested. Rosette formation and surface immunoglobulins were tested with suspended lymph node cells. T cell-subsets were tested with lymph node cells and lymphocytes in peripheral blood. The results of examination of lymphocyte surface markers in the lymphoid tissue obtained by biopsy are shown in Table 3: OKT 3 and 8 were positive and OKT 4 and 6 were negative. The results of examination of peripheral lymphocyte surface markers were slightly different from those found in the lymph node: OKT 4 (+) 14% and OKT 8 (+ ) 15.3%. DISCUSSION
The present case showed generalized, extensive proliferation of lymph nodes and lymphatic tissues and featured histological findings of lymph nodes such as a) remarkable fibrous thickening of the capsule, b) marked proliferation of histiocytes, c) foamy or granular cell bodies in histiocytes, d) frequent presence of lymphocytes, plasma cells, and erythrocytes in these cell bodies, and e) appearance of many plasma cells. Based on these findings, the diagnosis of SHML was made. This case required tracheotomy for dyspnea due to tracheal lesions and neurosurgical and otorhinological treatments for visual disturbance in the left eye
102
M. [WANAGA et
at.
due to the compression caused by the lesion extending from the sinus to the orbit. Thus, the case presented with the progression and aggravation of symptoms which are often seen in malignant diseases. SHML has generally been considered to be a benign disease and presents only a swelling of lymph nodes in many cases (SANCHEZ et al., 1977; TANAKA and ASANO, 1978). Therefore, we once hesitated to make a diagnosis of SHML in this case. The etiology of SHML remains yet to be established but several etiological presumptions have been attempted on the basis of clinical, biochemical, and histopathological findings. Among the hypotheses proposed is an infection theory (ROSAI and DORFMAN, 1972) based on such findings as fever, leukocytosis, positive CRP, and increased antibodies to bacteria and fungi such as Salmonella, Klebsiella, Histoplasma, and to EB virus. Another factor that has been pointed out in this disease is an immunologic abnormality (ROSAI and DORFMAN, 1972) as allegedly evidenced by biochemical and histological findings such as increased r-globulin, lymphophagocytosis, hematopoietic cell phagocytosis. We may now venture some speculations about the nature of SHML on the basis of findings in the present case. First, with regard to the infection theory, the findings in this case of increased erythrocyte sedimentation rate, strongly positive CRP, and increased titer to EB virus capsid and of increased titers to rubella virus, measles virus, and parainfluenza virus suggest that the infection theory cannot be denied. However, in our case, the abnormalities may be results of decreased resistance to infection owing to some cause or other in SHML. As to immunologic abnormalities, MaR, a parameter of cellular immunity, was normal. As to humoral immunity, only slight increases in r-globulin and IgM were found and antinuclear antibody and complement were normal. Though various radiation therapies and chemotherapies have so far been attempted for SHML, none of these treatments have been reported to be effective (FOUCAR et al., 1978; ROSAI and DORFMAN, 1972). In our case, such subjective symptoms as visual disturbance in the left eye, dyspnea, nasal bleeding were recognized. In view of the fact that the cardinal sign of SHML was the abnormality of lymph nodes and lymphatic tissues, oral treatment with prednisolone and oral and inhalation treatments with cyclophosphamide were performed for 6 months for alleviating the subjective symptoms through suppression of the lesions. These treatments resulted in some reduction in the size of lymph nodes and lymphatic tissues where the symptoms were manifested by compression. Subsequently, decreases in nasal obstruction and nasal discharge and in swelling of the nasal region were found. However, histological examination by intranasal biopsy performed on 3 occasions during the 6-month treatment period revealed no histological changes attributable to the administration of prednisolone and cyclophosphamide. The therapy given so far in this case has not been effective, just as in other reported cases (Fig. 6).
SHML
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REFERENCES AOYAMA, K., TERASHIMA, K., IMAI, Y., KATSUSHlMA, N., OKUYAMA, Y., NIlKAWA, K., MUKADA, T., and TAKAHASHI, K.: Sinus histiocytosis with massive lymphadenopathy. Acta Patho!.
Jpn. 34: 375-388, 1984. BANKACI, M., MORRIS, R. F., STOOL, S. E., and PARADISE, J. L.: Sinus histiocytosis with massive lymphadenopathy. Report of its occurrence in two siblings with retropharyngeal involvement in both. Ann. Oto!aryngol. 87: 327-331, 1978. CODLING, B. W., SONI, K. G., BARRY, D. R., and MARTIN-WALKER, W.: Histiocytosis presenting as swelling of orbit and eyelid. Br. J. Ophthalmol. 56: 517-530, 1972. FOUCAR, E., ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. Ear, nose and throat manifestations. Arch. Otolaryngol. 104: 687-693, 1978. HANADA, T., KISHIMOTO, H., TAKAYAMA, T., KUBO, S., KOGA, H., NISHIYAMA, Y., HANTO, T., SADA, M., TAKADA, M., ISHIKAWA, H., NAKAMOTO, 0., and YOKOYAMA, S.: A case of sinus histiocytosis with massive lymphadenopathy with elevated EBV antibody titers. J.
Jpn. Soc. Reticuloendothel. Syst. 22: 13-20, 1982. ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch. Pathol. 87: 63-70, 1969. ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. A pseudo lymphomatous benign disorder. Analysis of 34 cases. Cancer 30: 1174-1188,
1972. SANCHEZ, R., ROSAI, J., and DORFMAN, R. F.: Sinus histiocytosis with massive lymphadenopathy. An analysis of 113 cases with special emphasis on its extranodal manifestations. Ann.
Meet. Abstr. 36(3): 349-350, 1977. TANAKA, N., and ASANO, T.: Sinus histiocytosis with massive lymphadenopathy (Rosai and Dorfman) and significant skin involvement. Arch. Patho!. Jpn. 28: 175-184, 1978. TANAKA, T., ASANO, S., TAKAHASHI, K., MIYOSHI, I., TANAKA, M., HAYASHI, T., SAITO, R., and MUGURUMA, M.: Sinus histiocytosis with massive lymphadenopathy in Japanese adult with unusually elevated EBV antibody titers. Acta Patho!. Jpn. 30: 121-135, 1980.
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THAWERANr, H ., SANCHEZ, R. L., ROSA!, J., and DORFMAN, R. F.: The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch. Dermatol. 114: 191-
197, 1978.
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Request reprints to:
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Dr. M. Iwanaga, Department of Otolaryngology, Kitano Hospital, Kamiyamacho , Kita-ku, Osaka 530, Japan