T H E OPHTHALMOLOGIC MANIFESTATIONS O F SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY E L L I O T T F O U C A R , M.D.,
AND JUAN ROSAI,
M.D.
Minneapolis, Minnesota AND R O N A L D F. D O R F M A N , M.D. Stanford,
Four patients with a distinct pseudolymphomatous disorder designated as si nus histiocytosis with massive lymphadenopathy were described by two of us (J. R., R. F. D.) in 1969. 1 In a second report in 1972, 2 we described 30 additional pa tients with the same disease, establishing sinus histiocytosis with massive lymphadenopathy as a clinicopathologic entity. Histologic slides and clinical information from more than 100 patients with micro scopically confirmed sinus histiocytosis with massive lymphadenopathy have now been collected. 3 Although this large series has provided an excellent oppor tunity to study in great detail the clinical and pathologic features of this disease, the cause has remained unknown. Most patients are children or young adults with massive painless cervical adenopathy. Other node groups are also fre quently involved, but the liveT and spleen are usually of normal size. Additional characteristic findings are hypergammaglobulinemia, increased erythrocyte sedi mentation rate, and leukocytosis with neutrophilia. Of the 113 cases that have now been analyzed, 32 (28%) have in volvement of one or more extranodal sites. These sites include orbit and eye lid, 3,4 upper respiratory tract, 5 salivary From the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota (Drs. Foucar and Rosai); and the Department of Pathology, Stanford Univer sity Medical School, Stanford, California (Dr. Dorf man). Reprint requests to Juan Rosai, M.D., Department of Laboratory Medicine and Pathology, Box 609 Mayo Memorial Building, 420 Delaware St. S.E., Minneapolis, MN 55455. 354
California
gland, 5 skin, 6 bone, and testis. 7 Sinus histiocytosis with massive lymphadenop athy is therefore one of numerous system ic diseases, including such diverse enti ties as Graves' disease, histiocytosis X, and Wegener's granulomatosis, which may be associated with significant oph thalmic manifestations. Microscopic examination of involved lymph nodes reveals a distinctive poly morphous infiltrate composed predomi nantly of histiocytes which often contain phagocytized lymphocytes. These histio cytes fill and expand lymph node sinuses, and can result in complete effacement of lymph node architecture. Plasma cells are usually found in large numbers within and surrounding the expanded sinuses. Neutrophils are rare and eosinophils usu ally are absent. Extranodal infiltrates are composed of a cell population similar to that seen within lymph nodes, and some times the proliferation of histiocytes pro duces a histologic pattern that simulates lymph node architecture. However, in extranodal locations, lymphophagocytosis is often difficult to demonstrate. 5 ' 6 The alarming degree of lymphadenopa thy, the extensive alteration of lymph node structure, and the infiltration of nonlymphoid structures all suggest ma lignancy. However, the disease character istically pursues a benign although often chronic course, and in most instances the lymphadenopathy and other symptoms eventually regress. We describe herein the clinical and pathologic features of ophthalmic sinus histiocytosis with massive lymphadenop athy. We have also made comparisons
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:354-367, 1979
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
between the patients with ophthalmic in volvement and the large series of patients from which the ophthalmic cases were drawn. S U B J E C T S AND M E T H O D S
In the series of 113 patients with micro scopically documented disease, 14 had involvement of the orbit, eyelid, or globe. In 12, there were infiltrates of the orbit or eyelid. An additional patient who re quired enucleation for panuveitis was found to have infiltrates throughout the uveal tract. One patient with ophthalmic disease was excluded from this study be cause the relationship between sinus histiocytosis with massive lymphadenopathy and his chronic uveitis was unknown. We report herein clinical and microscopic findings from these 13 patients. RESULTS
Clinical results—At the onset of symp toms of sinus histiocytosis with massive lymphadenopathy, patients' ages ranged from 1.7 to 20 years, the average being 8.6 years (Table 1). Ophthalmic disease was an early manifestation in six patients, whereas in the remaining seven, ocular involvement followed the initial symp toms of disease, with the interval ranging between six months and 20 years. Four patients were white, seven were black, and the race of two was unknown. Nine of these were male and four were female. Seven patients lived in the United States; six lived in other countries. Cervical ade nopathy was present in ten cases, and several of these also had enlargement of other node groups. In one patient, the only lymph node involvement was mediastinal, and two did not develop lymph adenopathy. Seven cases had extranodal involvement in addition to their ophthal mic disease. In six of these the involve ment included nasal mucosa or salivary gland, or both, whereas the seventh pa tient had disease of the skin and testes.
355
Information about fever or weight loss is incomplete; three patients are known to have been febrile during their disease course, and four experienced weight loss which varied from 2 to 30 lbs. Information about serum proteins was available in nine patients, and in all but one of these some abnormality was pressent (Table 2). Three patients (Cases 1, 2, and 4) had increased total serum protein, total globulin levels and -y globulin. In formation about 7 globulin was available for an additional three patients, and in two of these the level was increased. Immunoglobulin results were available for six cases, and IgG was increased in five. The sedimentation rate was in creased in seven of the nine patients for whom we have data. In addition to the data shown in Table 2, total leukocyte count with differential blood cell counts were available from ten of the 13 cases. The majority of the total leukocyte counts were within normal limits, and although a few of the patients from underdeveloped countries had mild eosinophilia, this finding is of doubtful significance. The most frequent location of ophthal mic involvement was orbital soft tissue. Eleven of 13 patients had disease in this area, and in six cases, the ophthalmic disease was confined to the orbital soft tissues. These patients had firm or rub bery nontender masses that sometimes involved the lacrimal gland. In five addi tional cases with orbital disease, there was also eyelid involvement. One of these patients had eyelid swelling, whereas the remainder had firm or rubbery, nontender circumscribed masses which were some times associated with periorbital puffiness. In one case, the nodular masses within the eyelid were described as being continuous with an orbital mass. One patient (Fig. 1) had only eyelid involve ment, which consisted of bilateral firm rubbery nodules. Although three patients in this series
05
24
27
11 9 10
ll28 12 13 6
l'/2
None
None None 2V2 Black, M ?, M Black, F
Black, M Black, M White, M
Africa Switzerland USA
USA USA Costa Rica
USA USA Martinique USA Pakistan Algeria
White, F White, M Black, F Black, M White, F ?, M
None 1 2 None None V2
USA
Residence
Black, M
Race, Sex
20
Time Interval (yrs) Before Development Of Ophthalmic Disease
*SHML signifies sinus histiocytosis with massive lymphadenopathy.
4 1.7 12
20 20 6 3 3 10
2.7
84 94 10
7
6
325 415 526
2
I
7
Case No.
Age (yrs) At Onset of SHML
Cervical None Cervical
Cervical, axillary, inguinal Diffuse Mediastinal Cervical Cervical Cervical, axillary Cervical, upper mediastinal, right hilar None Cervical Cervical
Lymphadenopathy
G E N E R A L OBSERVATIONS O N S H M L P A T I E N T S W I T H O P H T H A L M I C I N V O L V E M E N T *
TABLE 1
None None Salivary gland, nasal mucosa None Nasal sinus None
Nasal mucosa, skin None Nasal and oral mucosa None Nasal mucosa Salivary gland
Testis, skin
Extranodal Involvement Other Than Ophthalmic
357
SINUS HISTIOCYTOSIS
VOL. 87, NO. 3
TABLE 2 LABORATORY DATA FROM S H M L PATIENTS W I T H O P H T H A L M I C I N V O L V E M E N T *
Case No.
Total Plasma Protein (g/100 ml)
1
8.5
2
9.9
Erythroeyte Sedimentation Rate (mm/hr)
Total Plasma Globulin (g/100 ml)
Immunoglobulins (g/100 ml)
4.4
Unknown
25
T
53
( *> *'
Fig. 6 (Foucar, Rosai, and Dorfman). 39, Anterior chamber (star) contains large numbers of histiocytes, many of which are adherent to the iris. Similar histiocytes were prominent throughout the uveal tract (x 160). Inset, Higher magnification of histiocytes within the anterior chamber. Phagocytized melanin is present within the cell cytoplasm (hematoxylin-eosin, X400).
features. 8,9 The identification of increas ing numbers of cases points out the im portance of extranodal manifestations of this systemic disease. Approximately 11% of this series of 113 patients had ophthal mic infiltrates, and these lesions may con stitute the initial or principal manifesta tion of the disease. The soft tissue infiltrates surrounding the eye were composed of a cell popula tion similar to that found within involved lymph nodes. Occasionally the histologic pattern of these infiltrates was remarkably similar to that seen in involved lymph nodes. Even if the patient had no history of lymphadenopathy, pathologic exami
nation of the soft tissue infiltrates sur rounding the eye should have allowed the correct diagnosis to be made or strongly suggested in all of our cases. Involvement of the anterior and posterior chamber, uveal tract, and retina was much more difficult to recognize microscopically. Al though the histiocytes forming the infil trate were cytologically identical to those of involved lymph nodes, lymphocytes and plasma cells were inconspicuous components of the infiltrate, and the his tologic pattern of the infiltrate did not simulate lymph nodal architecture. Several lymphoreticular malignancies, including histiocytic lymphoma, Hodg-
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
kin's disease, malignant histiocytosis, and monocytic leukemia, may show a superfi cial microscopic resemblance to sinus histiocytosis with massive lymphadenop athy, but the presence of cytologic atypia, as well as an aggressive clinical course, establishes the diagnosis in such cases. 10 In most instances in which the eye or anatomically related structures are in volved by leukemia or lymphoma, the involvement occurs late in the disease course, and there is no diagnostic prob lem. 11 Hodgkin's disease rarely shows ophthalmic involvement, 12 but both sinus histiocytosis with massive lymphadenop athy and Hodgkin's disease are composed of a polymorphous cell population, and occasionally Hodgkin's disease may con tain large numbers of foamy histiocytes. 13 Although the histiocytes of sinus histio cytosis with massive lymphadenopathy may occasionally have large eosinophilic nucleoli, classic Reed-Sternberg cells have not been identified. The large foamy histiocytes character istic of sinus histiocytosis with massive lymphadenopathy have also suggested that the disease may be caused by an abnormal storage product. However, histochemical or biochemical examinations, or both, have not identified abnormal metabolic products. 2,7,14>1S Histiocytosis X (especially HandShuller-Christian disease), may have prominent orbital involvement, and like sinus histiocytosis with massive lymph adenopathy is composed of a polymor phous infiltrate, including histiocytes. 16 However, important differences between sinus histiocytosis with massive lymph adenopathy and histiocytosis X have been found at both a light and electron micro scopic level, and the two groups of pa tients are clinically different. 17 Rhinoscleroma should also be consid ered in the differential diagnosis of these ophthalmic infiltrates, because of micro scopic similarities, and because rhino-
365
scleroma also involves the upper respira tory tract. Five of our 13 patients had disease of the nasal mucosa or nasal si nuses in addition to ophthalmic involve ment, and in one patient the orbital dis ease was continuous with a large mass in the adjacent nasal sinus. In contrast to sinus histiocytosis with massive lymph adenopathy, however, the histiocytes of rhinoscleroma (Mikulicz cells) have pyknotic nuclei with inconspicuous nucleo li, and their cytoplasm contains von Frisch bacilli (Klebsiella rhinoscleromatis), which have not been identified in sinus histiocytosis with massive lymph adenopathy. 1 8 - 2 0 In countries where tuberculous lym phadenitis is common, massive cervical adenopathy sometimes leads to consider ation of this diagnosis. However, no true granulomas have been identified in our cases, necrosis is seldom conspicuous, and acid-fast organisms have never been cultured or identified with special stains. A final consideration in the differential diagnosis is orbital pseudotumor, an idiopathic inflammatory lesion that is one of the more frequent causes of exophthalmos. The designation pseudotumor en compasses a histologically diverse group of lesions. 21,22 Like sinus histiocytosis with massive lymphadenopathy, the le sion may be composed of a polymorphous population of cells, including histiocytes, plasma cells, neutrophils, and eosinophils. Fibrosis, vascular proliferation, and lymphoid follicles may also be fea tures of both conditions. Although large numbers of histiocytes may be seen in orbital pseudotumor, this finding usually is associated with fat necrosis and foreign body reaction. 23 These two microscopic features were absent in all of our cases of sinus histiocytosis with massive lymph adenopathy. The frequency of lymphade nopathy in our cases of ophthalmic dis ease assisted in the differential diagnosis, but two patients had no evidence of
366
AMERICAN JOURNAL OF OPHTHALMOLOGY
lymph node involvement. Before the rec ognition of this clinicopathological enti ty, these patients' lesions might well have been considered unusual examples of or bital pseudotumor which in a sense they are. The original microscopic diagnosis made in several cases in this series was orbital pseudotumor, and we suspect that wider recognition of the occurrence of orbital sinus histiocytosis with massive lymphadenopathy will result in the dis covery of additional cases. We found one major difference between patients with ophthalmic involvement and the total group of patients with sinus histiocytosis with massive lymphadenop athy. Although only 28% of the latter had evidence of extranodal involvement, 54% of the patients with ophthalmic disease had some additional site of extranodal involvement. Studies of other anatomic sites of extranodal involvement by sinus histiocytosis with massive lymphadenop athy have also documented a high inci dence of additional areas of extranodal involvement. These include skin (50%), 6 upper respiratory tract (68%), 5 and bone (60%). A striking association exists be tween ophthalmic disease and disease of the nasal mucosa or nasal sinuses. Only 7% of the patients in our total series had infiltrates of the nasal mucosa or nasal sinuses, but 38% of the patients with ophthalmic involvement had disease in these areas. In spite of the presence of multisystem involvement, the clinical course of the patients with ophthalmic disease was much like that of other patients in our series. These two groups were also simi lar with regard to age, race, sex, residence, location of adenopathy, incidence of fever and weight loss, plasma protein abnormalities, and erythrocyte sedimen tation rate. Additionally, there was no difference in the lymph node histology between the groups that did and did not
MARCH, 1979
have ophthalmic disease. However, un like the larger group of patients with sinus histiocytosis with massive lymph adenopathy, patients with ophthalmic in volvement did not commonly manifest a leukocytosis. Although the total series of patients did not respond consistently to any form of therapy, seven of the 11 patients from the present series whose treatment included ophthalmic surgery were thought to have benefitted from the procedure. This improvement ranged from a patient who had no evidence of local recurrence five months postoperatively, to a patient who had previously received irradiation to involved lymph nodes and who had recovered completely and permanently from the disease. SUMMARY
Of 113 cases of sinus histiocytosis with massive lymphadenopathy, 13 patients had ophthalmic infiltrates. Eleven of the 13 had infiltrates in the orbital soft tis sues, and five of these patients also had eyelid disease. One patient had infiltrates only within the eyelid, and one without disease in the orbit or eyelid had exten sive infiltrates in the uveal tract. The microscopic differential diagnosis includ ed a variety of lymphoreticular malignan cies, storage diseases, histiocytosis X, rhinoscleroma, tuberculosis, and inflam matory pseudotumor of the orbit. These 13 patients with ophthalmic disease were similar clinically and pathologically to patients with sinus histiocytosis with massive lymphadenopathy who did not have ophthalmic disease. REFERENCES 1. Rosai, J., and Dorfman, R. F.: Sinus histiocyto sis with massive lymphadenopathy. A newly recog nized benign clinicopathological entity. Arch. Pathol. 87:63, 1969. 2. Rosai, J., and Dorfman, R. F.: Sinus histiocyto sis with massive lymphadenopathy. A pseudolymphomatous benign disorder. Cancer 30:1174, 1972.
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
3. 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. Lab. Invest. 36:21, 1977. 4. Friendly, D. S., Font, R. L., and Rao, N. A.: Orbital involvement in "sinus" histiocytosis. A re port of four cases. Arch. Ophthalmol. 95:2006, 1977. 5. Foucar, E., Rosai, J., and Dorfman, R. F.: The ENT manifestations of sinus histiocytosis with mas sive lymphadenopathy. Arch. Otolaryngol. In press. 6. Thawerani, H., Sanchez, R., Rosai, J., and Dorfman, R. F.: The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy (SHML). Arch. Dermatol. 114:191, 1978. 7. Azoury, F. J., and Reed, R. J.: Histiocytosis. Report of an unusual case. N. Engl. J. Med. 274:928, 1966. 8. A new lymphoma syndrome, editorial. Lancet 1:139, 1973. 9. Lampert, F., and Lennert, K.: Sinus histiocyto sis with massive lymphadenopathy. Fifteen new cases. Cancer 37:783, 1976. 10. Rappaport, H.: Tumors of the hematopoietie system. In Atlas of Tumor Pathology. Armed Forces Institute of Pathology, 1966, section 3, pt. 8, pp. 99-101; 156-160; 49-63; 37-48. 11. Hogan, M. J., and Zimmerman, L. E.: Oph thalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 776. 12. Forrest, A. W.: Intraorbital tumors. Arch. Ophthalmol. 41:198, 1949. 13. Variakojis, D., Strum, S. B., and Rappaport, H.: The foamy macrophages in Hodgkin's disease. Arch. Pathol. 93:453, 1972. 14. Marie, J., Bernard, J., Nezelof, C , Leveque, B., Schaison, G., Desbois, J., Walchi, J., and Lemaigre-Voreaux, J.: Adenopathies chroniques avec proliferation reticulo-histiocytaire et sucharge lipidique. Ann. Pediatr. 13:2689, 1966. 15. Destombes, P., and Destombes, M.: Lipidic pseudotumoral histiocytosis of lymph nodes. Pahlavi Med. J. 3:548, 1972.
367
16. Nolan, J.: Reticuloendothelial tumors of the orbit. Br. J. Ophthalmol. 52:532, 1968. 17. Williams, J. W., and Dorfman, R. F.: Lymph node involvement by histiocytosis X, abstracted. Lab. Invest. 36:352, 1977. 18. Becker, B. J. P., and Dorfman, R. F.: Rhinoscleroma (scleroma). Report of a case in South Africa. S. Afr. Med. J. 30:581, 1956. 19. Hoffmann, E. O., Loose, L. D., and Harkin, J. C.: The Mikulicz cell in rhinoscleroma. Am. J. Pathol. 73:47, 1973. 20. Fisher, E. R., and Dimling, C : Rhinoscle roma. Light and electron microscopic studies. Arch. Pathol. 78:501, 1964. 21. Garner, A.: Pathology of pseudotumors of the orbit. From the Proceedings of the 2nd International Symposium on Orbital Disorders, Amsterdam, 1973. Mod. Probl. Ophthalmol. 14:349, 1975. 22. Heersink, B., Rodrigues, M. R., and Flanagan, J. C.: Inflammatory pseudotumor of the orbit. Ann. Ophthalmol. 9:17, 1977. 23. Hogan, M. J., and Zimmerman, L. E.: Oph thalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 769. 24. Malignant Tumors of the Lymphoid Struc tures. In del Regato, J. A. (ed.): Cancer Seminar, vol. 3, No. 6. Colorado Springs, Colorado, Democrat Publishing Co., 1967, p. 246. 25. Zimmerman, L. E.: Syllabus. Seminar on ocu lar and orbital lesions. Washington, D. C , American Registry of Pathology (Armed Forces Institute of Pathology), 1974, pp. 2; 7. 26. Pickering, L. K., and Phelan, E.: Sinus histio cytosis. J. Pediatr. 86:745, 1975. 27. Codling, B. W., Soni, K. C , Barry, D. R., and Martin-Walker, W.: Histiocytosis presenting as a swelling of the orbit and eyelid. Br. J. Ophthalmol. 56:517, 1972. 28. Dhermy, P., Destombes, P., and Rousselie, F.: Localisation orbitaire de l'histiocytose macrophagique lymphocytaire. (Histiocytose sinusale de Rosai). Arch. Ophtalmol. 35:871, 1975.
AND JUAN ROSAI,
M.D.
Minneapolis, Minnesota AND R O N A L D F. D O R F M A N , M.D. Stanford,
Four patients with a distinct pseudolymphomatous disorder designated as si nus histiocytosis with massive lymphadenopathy were described by two of us (J. R., R. F. D.) in 1969. 1 In a second report in 1972, 2 we described 30 additional pa tients with the same disease, establishing sinus histiocytosis with massive lymphadenopathy as a clinicopathologic entity. Histologic slides and clinical information from more than 100 patients with micro scopically confirmed sinus histiocytosis with massive lymphadenopathy have now been collected. 3 Although this large series has provided an excellent oppor tunity to study in great detail the clinical and pathologic features of this disease, the cause has remained unknown. Most patients are children or young adults with massive painless cervical adenopathy. Other node groups are also fre quently involved, but the liveT and spleen are usually of normal size. Additional characteristic findings are hypergammaglobulinemia, increased erythrocyte sedi mentation rate, and leukocytosis with neutrophilia. Of the 113 cases that have now been analyzed, 32 (28%) have in volvement of one or more extranodal sites. These sites include orbit and eye lid, 3,4 upper respiratory tract, 5 salivary From the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota (Drs. Foucar and Rosai); and the Department of Pathology, Stanford Univer sity Medical School, Stanford, California (Dr. Dorf man). Reprint requests to Juan Rosai, M.D., Department of Laboratory Medicine and Pathology, Box 609 Mayo Memorial Building, 420 Delaware St. S.E., Minneapolis, MN 55455. 354
California
gland, 5 skin, 6 bone, and testis. 7 Sinus histiocytosis with massive lymphadenop athy is therefore one of numerous system ic diseases, including such diverse enti ties as Graves' disease, histiocytosis X, and Wegener's granulomatosis, which may be associated with significant oph thalmic manifestations. Microscopic examination of involved lymph nodes reveals a distinctive poly morphous infiltrate composed predomi nantly of histiocytes which often contain phagocytized lymphocytes. These histio cytes fill and expand lymph node sinuses, and can result in complete effacement of lymph node architecture. Plasma cells are usually found in large numbers within and surrounding the expanded sinuses. Neutrophils are rare and eosinophils usu ally are absent. Extranodal infiltrates are composed of a cell population similar to that seen within lymph nodes, and some times the proliferation of histiocytes pro duces a histologic pattern that simulates lymph node architecture. However, in extranodal locations, lymphophagocytosis is often difficult to demonstrate. 5 ' 6 The alarming degree of lymphadenopa thy, the extensive alteration of lymph node structure, and the infiltration of nonlymphoid structures all suggest ma lignancy. However, the disease character istically pursues a benign although often chronic course, and in most instances the lymphadenopathy and other symptoms eventually regress. We describe herein the clinical and pathologic features of ophthalmic sinus histiocytosis with massive lymphadenop athy. We have also made comparisons
AMERICAN JOURNAL O F OPHTHALMOLOGY 87:354-367, 1979
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
between the patients with ophthalmic in volvement and the large series of patients from which the ophthalmic cases were drawn. S U B J E C T S AND M E T H O D S
In the series of 113 patients with micro scopically documented disease, 14 had involvement of the orbit, eyelid, or globe. In 12, there were infiltrates of the orbit or eyelid. An additional patient who re quired enucleation for panuveitis was found to have infiltrates throughout the uveal tract. One patient with ophthalmic disease was excluded from this study be cause the relationship between sinus histiocytosis with massive lymphadenopathy and his chronic uveitis was unknown. We report herein clinical and microscopic findings from these 13 patients. RESULTS
Clinical results—At the onset of symp toms of sinus histiocytosis with massive lymphadenopathy, patients' ages ranged from 1.7 to 20 years, the average being 8.6 years (Table 1). Ophthalmic disease was an early manifestation in six patients, whereas in the remaining seven, ocular involvement followed the initial symp toms of disease, with the interval ranging between six months and 20 years. Four patients were white, seven were black, and the race of two was unknown. Nine of these were male and four were female. Seven patients lived in the United States; six lived in other countries. Cervical ade nopathy was present in ten cases, and several of these also had enlargement of other node groups. In one patient, the only lymph node involvement was mediastinal, and two did not develop lymph adenopathy. Seven cases had extranodal involvement in addition to their ophthal mic disease. In six of these the involve ment included nasal mucosa or salivary gland, or both, whereas the seventh pa tient had disease of the skin and testes.
355
Information about fever or weight loss is incomplete; three patients are known to have been febrile during their disease course, and four experienced weight loss which varied from 2 to 30 lbs. Information about serum proteins was available in nine patients, and in all but one of these some abnormality was pressent (Table 2). Three patients (Cases 1, 2, and 4) had increased total serum protein, total globulin levels and -y globulin. In formation about 7 globulin was available for an additional three patients, and in two of these the level was increased. Immunoglobulin results were available for six cases, and IgG was increased in five. The sedimentation rate was in creased in seven of the nine patients for whom we have data. In addition to the data shown in Table 2, total leukocyte count with differential blood cell counts were available from ten of the 13 cases. The majority of the total leukocyte counts were within normal limits, and although a few of the patients from underdeveloped countries had mild eosinophilia, this finding is of doubtful significance. The most frequent location of ophthal mic involvement was orbital soft tissue. Eleven of 13 patients had disease in this area, and in six cases, the ophthalmic disease was confined to the orbital soft tissues. These patients had firm or rub bery nontender masses that sometimes involved the lacrimal gland. In five addi tional cases with orbital disease, there was also eyelid involvement. One of these patients had eyelid swelling, whereas the remainder had firm or rubbery, nontender circumscribed masses which were some times associated with periorbital puffiness. In one case, the nodular masses within the eyelid were described as being continuous with an orbital mass. One patient (Fig. 1) had only eyelid involve ment, which consisted of bilateral firm rubbery nodules. Although three patients in this series
05
24
27
11 9 10
ll28 12 13 6
l'/2
None
None None 2V2 Black, M ?, M Black, F
Black, M Black, M White, M
Africa Switzerland USA
USA USA Costa Rica
USA USA Martinique USA Pakistan Algeria
White, F White, M Black, F Black, M White, F ?, M
None 1 2 None None V2
USA
Residence
Black, M
Race, Sex
20
Time Interval (yrs) Before Development Of Ophthalmic Disease
*SHML signifies sinus histiocytosis with massive lymphadenopathy.
4 1.7 12
20 20 6 3 3 10
2.7
84 94 10
7
6
325 415 526
2
I
7
Case No.
Age (yrs) At Onset of SHML
Cervical None Cervical
Cervical, axillary, inguinal Diffuse Mediastinal Cervical Cervical Cervical, axillary Cervical, upper mediastinal, right hilar None Cervical Cervical
Lymphadenopathy
G E N E R A L OBSERVATIONS O N S H M L P A T I E N T S W I T H O P H T H A L M I C I N V O L V E M E N T *
TABLE 1
None None Salivary gland, nasal mucosa None Nasal sinus None
Nasal mucosa, skin None Nasal and oral mucosa None Nasal mucosa Salivary gland
Testis, skin
Extranodal Involvement Other Than Ophthalmic
357
SINUS HISTIOCYTOSIS
VOL. 87, NO. 3
TABLE 2 LABORATORY DATA FROM S H M L PATIENTS W I T H O P H T H A L M I C I N V O L V E M E N T *
Case No.
Total Plasma Protein (g/100 ml)
1
8.5
2
9.9
Erythroeyte Sedimentation Rate (mm/hr)
Total Plasma Globulin (g/100 ml)
Immunoglobulins (g/100 ml)
4.4
Unknown
25
T
53
( *> *'
Fig. 6 (Foucar, Rosai, and Dorfman). 39, Anterior chamber (star) contains large numbers of histiocytes, many of which are adherent to the iris. Similar histiocytes were prominent throughout the uveal tract (x 160). Inset, Higher magnification of histiocytes within the anterior chamber. Phagocytized melanin is present within the cell cytoplasm (hematoxylin-eosin, X400).
features. 8,9 The identification of increas ing numbers of cases points out the im portance of extranodal manifestations of this systemic disease. Approximately 11% of this series of 113 patients had ophthal mic infiltrates, and these lesions may con stitute the initial or principal manifesta tion of the disease. The soft tissue infiltrates surrounding the eye were composed of a cell popula tion similar to that found within involved lymph nodes. Occasionally the histologic pattern of these infiltrates was remarkably similar to that seen in involved lymph nodes. Even if the patient had no history of lymphadenopathy, pathologic exami
nation of the soft tissue infiltrates sur rounding the eye should have allowed the correct diagnosis to be made or strongly suggested in all of our cases. Involvement of the anterior and posterior chamber, uveal tract, and retina was much more difficult to recognize microscopically. Al though the histiocytes forming the infil trate were cytologically identical to those of involved lymph nodes, lymphocytes and plasma cells were inconspicuous components of the infiltrate, and the his tologic pattern of the infiltrate did not simulate lymph nodal architecture. Several lymphoreticular malignancies, including histiocytic lymphoma, Hodg-
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
kin's disease, malignant histiocytosis, and monocytic leukemia, may show a superfi cial microscopic resemblance to sinus histiocytosis with massive lymphadenop athy, but the presence of cytologic atypia, as well as an aggressive clinical course, establishes the diagnosis in such cases. 10 In most instances in which the eye or anatomically related structures are in volved by leukemia or lymphoma, the involvement occurs late in the disease course, and there is no diagnostic prob lem. 11 Hodgkin's disease rarely shows ophthalmic involvement, 12 but both sinus histiocytosis with massive lymphadenop athy and Hodgkin's disease are composed of a polymorphous cell population, and occasionally Hodgkin's disease may con tain large numbers of foamy histiocytes. 13 Although the histiocytes of sinus histio cytosis with massive lymphadenopathy may occasionally have large eosinophilic nucleoli, classic Reed-Sternberg cells have not been identified. The large foamy histiocytes character istic of sinus histiocytosis with massive lymphadenopathy have also suggested that the disease may be caused by an abnormal storage product. However, histochemical or biochemical examinations, or both, have not identified abnormal metabolic products. 2,7,14>1S Histiocytosis X (especially HandShuller-Christian disease), may have prominent orbital involvement, and like sinus histiocytosis with massive lymph adenopathy is composed of a polymor phous infiltrate, including histiocytes. 16 However, important differences between sinus histiocytosis with massive lymph adenopathy and histiocytosis X have been found at both a light and electron micro scopic level, and the two groups of pa tients are clinically different. 17 Rhinoscleroma should also be consid ered in the differential diagnosis of these ophthalmic infiltrates, because of micro scopic similarities, and because rhino-
365
scleroma also involves the upper respira tory tract. Five of our 13 patients had disease of the nasal mucosa or nasal si nuses in addition to ophthalmic involve ment, and in one patient the orbital dis ease was continuous with a large mass in the adjacent nasal sinus. In contrast to sinus histiocytosis with massive lymph adenopathy, however, the histiocytes of rhinoscleroma (Mikulicz cells) have pyknotic nuclei with inconspicuous nucleo li, and their cytoplasm contains von Frisch bacilli (Klebsiella rhinoscleromatis), which have not been identified in sinus histiocytosis with massive lymph adenopathy. 1 8 - 2 0 In countries where tuberculous lym phadenitis is common, massive cervical adenopathy sometimes leads to consider ation of this diagnosis. However, no true granulomas have been identified in our cases, necrosis is seldom conspicuous, and acid-fast organisms have never been cultured or identified with special stains. A final consideration in the differential diagnosis is orbital pseudotumor, an idiopathic inflammatory lesion that is one of the more frequent causes of exophthalmos. The designation pseudotumor en compasses a histologically diverse group of lesions. 21,22 Like sinus histiocytosis with massive lymphadenopathy, the le sion may be composed of a polymorphous population of cells, including histiocytes, plasma cells, neutrophils, and eosinophils. Fibrosis, vascular proliferation, and lymphoid follicles may also be fea tures of both conditions. Although large numbers of histiocytes may be seen in orbital pseudotumor, this finding usually is associated with fat necrosis and foreign body reaction. 23 These two microscopic features were absent in all of our cases of sinus histiocytosis with massive lymph adenopathy. The frequency of lymphade nopathy in our cases of ophthalmic dis ease assisted in the differential diagnosis, but two patients had no evidence of
366
AMERICAN JOURNAL OF OPHTHALMOLOGY
lymph node involvement. Before the rec ognition of this clinicopathological enti ty, these patients' lesions might well have been considered unusual examples of or bital pseudotumor which in a sense they are. The original microscopic diagnosis made in several cases in this series was orbital pseudotumor, and we suspect that wider recognition of the occurrence of orbital sinus histiocytosis with massive lymphadenopathy will result in the dis covery of additional cases. We found one major difference between patients with ophthalmic involvement and the total group of patients with sinus histiocytosis with massive lymphadenop athy. Although only 28% of the latter had evidence of extranodal involvement, 54% of the patients with ophthalmic disease had some additional site of extranodal involvement. Studies of other anatomic sites of extranodal involvement by sinus histiocytosis with massive lymphadenop athy have also documented a high inci dence of additional areas of extranodal involvement. These include skin (50%), 6 upper respiratory tract (68%), 5 and bone (60%). A striking association exists be tween ophthalmic disease and disease of the nasal mucosa or nasal sinuses. Only 7% of the patients in our total series had infiltrates of the nasal mucosa or nasal sinuses, but 38% of the patients with ophthalmic involvement had disease in these areas. In spite of the presence of multisystem involvement, the clinical course of the patients with ophthalmic disease was much like that of other patients in our series. These two groups were also simi lar with regard to age, race, sex, residence, location of adenopathy, incidence of fever and weight loss, plasma protein abnormalities, and erythrocyte sedimen tation rate. Additionally, there was no difference in the lymph node histology between the groups that did and did not
MARCH, 1979
have ophthalmic disease. However, un like the larger group of patients with sinus histiocytosis with massive lymph adenopathy, patients with ophthalmic in volvement did not commonly manifest a leukocytosis. Although the total series of patients did not respond consistently to any form of therapy, seven of the 11 patients from the present series whose treatment included ophthalmic surgery were thought to have benefitted from the procedure. This improvement ranged from a patient who had no evidence of local recurrence five months postoperatively, to a patient who had previously received irradiation to involved lymph nodes and who had recovered completely and permanently from the disease. SUMMARY
Of 113 cases of sinus histiocytosis with massive lymphadenopathy, 13 patients had ophthalmic infiltrates. Eleven of the 13 had infiltrates in the orbital soft tis sues, and five of these patients also had eyelid disease. One patient had infiltrates only within the eyelid, and one without disease in the orbit or eyelid had exten sive infiltrates in the uveal tract. The microscopic differential diagnosis includ ed a variety of lymphoreticular malignan cies, storage diseases, histiocytosis X, rhinoscleroma, tuberculosis, and inflam matory pseudotumor of the orbit. These 13 patients with ophthalmic disease were similar clinically and pathologically to patients with sinus histiocytosis with massive lymphadenopathy who did not have ophthalmic disease. REFERENCES 1. Rosai, J., and Dorfman, R. F.: Sinus histiocyto sis with massive lymphadenopathy. A newly recog nized benign clinicopathological entity. Arch. Pathol. 87:63, 1969. 2. Rosai, J., and Dorfman, R. F.: Sinus histiocyto sis with massive lymphadenopathy. A pseudolymphomatous benign disorder. Cancer 30:1174, 1972.
VOL. 87, NO. 3
SINUS HISTIOCYTOSIS
3. 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. Lab. Invest. 36:21, 1977. 4. Friendly, D. S., Font, R. L., and Rao, N. A.: Orbital involvement in "sinus" histiocytosis. A re port of four cases. Arch. Ophthalmol. 95:2006, 1977. 5. Foucar, E., Rosai, J., and Dorfman, R. F.: The ENT manifestations of sinus histiocytosis with mas sive lymphadenopathy. Arch. Otolaryngol. In press. 6. Thawerani, H., Sanchez, R., Rosai, J., and Dorfman, R. F.: The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy (SHML). Arch. Dermatol. 114:191, 1978. 7. Azoury, F. J., and Reed, R. J.: Histiocytosis. Report of an unusual case. N. Engl. J. Med. 274:928, 1966. 8. A new lymphoma syndrome, editorial. Lancet 1:139, 1973. 9. Lampert, F., and Lennert, K.: Sinus histiocyto sis with massive lymphadenopathy. Fifteen new cases. Cancer 37:783, 1976. 10. Rappaport, H.: Tumors of the hematopoietie system. In Atlas of Tumor Pathology. Armed Forces Institute of Pathology, 1966, section 3, pt. 8, pp. 99-101; 156-160; 49-63; 37-48. 11. Hogan, M. J., and Zimmerman, L. E.: Oph thalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 776. 12. Forrest, A. W.: Intraorbital tumors. Arch. Ophthalmol. 41:198, 1949. 13. Variakojis, D., Strum, S. B., and Rappaport, H.: The foamy macrophages in Hodgkin's disease. Arch. Pathol. 93:453, 1972. 14. Marie, J., Bernard, J., Nezelof, C , Leveque, B., Schaison, G., Desbois, J., Walchi, J., and Lemaigre-Voreaux, J.: Adenopathies chroniques avec proliferation reticulo-histiocytaire et sucharge lipidique. Ann. Pediatr. 13:2689, 1966. 15. Destombes, P., and Destombes, M.: Lipidic pseudotumoral histiocytosis of lymph nodes. Pahlavi Med. J. 3:548, 1972.
367
16. Nolan, J.: Reticuloendothelial tumors of the orbit. Br. J. Ophthalmol. 52:532, 1968. 17. Williams, J. W., and Dorfman, R. F.: Lymph node involvement by histiocytosis X, abstracted. Lab. Invest. 36:352, 1977. 18. Becker, B. J. P., and Dorfman, R. F.: Rhinoscleroma (scleroma). Report of a case in South Africa. S. Afr. Med. J. 30:581, 1956. 19. Hoffmann, E. O., Loose, L. D., and Harkin, J. C.: The Mikulicz cell in rhinoscleroma. Am. J. Pathol. 73:47, 1973. 20. Fisher, E. R., and Dimling, C : Rhinoscle roma. Light and electron microscopic studies. Arch. Pathol. 78:501, 1964. 21. Garner, A.: Pathology of pseudotumors of the orbit. From the Proceedings of the 2nd International Symposium on Orbital Disorders, Amsterdam, 1973. Mod. Probl. Ophthalmol. 14:349, 1975. 22. Heersink, B., Rodrigues, M. R., and Flanagan, J. C.: Inflammatory pseudotumor of the orbit. Ann. Ophthalmol. 9:17, 1977. 23. Hogan, M. J., and Zimmerman, L. E.: Oph thalmic Pathology. An Atlas and Textbook, 2nd ed. Philadelphia, W. B. Saunders, 1962, p. 769. 24. Malignant Tumors of the Lymphoid Struc tures. In del Regato, J. A. (ed.): Cancer Seminar, vol. 3, No. 6. Colorado Springs, Colorado, Democrat Publishing Co., 1967, p. 246. 25. Zimmerman, L. E.: Syllabus. Seminar on ocu lar and orbital lesions. Washington, D. C , American Registry of Pathology (Armed Forces Institute of Pathology), 1974, pp. 2; 7. 26. Pickering, L. K., and Phelan, E.: Sinus histio cytosis. J. Pediatr. 86:745, 1975. 27. Codling, B. W., Soni, K. C , Barry, D. R., and Martin-Walker, W.: Histiocytosis presenting as a swelling of the orbit and eyelid. Br. J. Ophthalmol. 56:517, 1972. 28. Dhermy, P., Destombes, P., and Rousselie, F.: Localisation orbitaire de l'histiocytose macrophagique lymphocytaire. (Histiocytose sinusale de Rosai). Arch. Ophtalmol. 35:871, 1975.
