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Sinus histiocytosis with massive lymphadenopathy
Clinical r e v i e w s I
Sinus histiocytosis with massive lymphadenopathy Case report and review of a multisystemic disease with cutaneous infiltrates Elise A. Olsen, M.D., Jeffrey R. Crawford, M.D. ,* and Robin T. Vollmer, M.D.** Durham, NC A report of a patient with the rare syndrome of sinus histiocytosis with massive lymphadenopathy is presented here. This patient is unusual in several respects, including his longevity after diagnosis, the presence of a benign monoclonal gammopathy, and the characterization of his cutaneous infiltrates by immunofluorescent monoclonal antibody markers. A review of the literature on sinus histiocytosis with massive lymphadenopathy, with particular emphasis on cutaneous manifestations, is given. (J AM ACAD DERMATOL 1988;18:1322-32.)
Sinus histiocytosis with massive lymphadenopathy is a syndrome that was first characterized by Rosai and Dorfman I in 1969, although case reports antedate the full clinicopathologic description: -4 Typically, patients have cervical and, commonly, other lymphadenopathy, often accompanied by fever, anemia, leukocytosis with neutrophilia, an elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia: Extranodal disease may occur in 28% of c a s e s 6 and may be the initial manifestation of the disease. The extranodal sites most commonly affected are the orbit, upper respiratory tract, skin, and bone. 7 The microscopic appearance of involved lymph nodes is characteristic. ,5.6 We present here the case of a 69-year-old black man with nodal and extranodal sinus histiocytosis
From the Division of Dermatology, Duke University Medical Center, and the Division of Hematology/Oncology, Departments of Medicine* and Pathology,** Veterans Administration Hospital. Reprint requests to: Dr. Elise A. Olsen, Box 3294, Division of Dermatology, Duke University Medical Center, Durham, NC 27710.
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with massive lymphadenopathy whose disease is unusual in several respects. He is the longest-lived reported survivor of sinus histiocytosis with massive lymphadenopathy, despite involvement of the central nervous system at initial presentation, and the first reported patient with a benign IgA monoclonal gammopathy. In addition, our report is the first characterization of a cutaneous infiltrate of sinus histiocytosis with massive lymphadenopathy by immunofluorescent monoclonal antibody markers.
CASE REPORT Clinical course. Our patient is a 69-year-old black former laborer whose 30-year clinical course of sinus histiocytosis with massive lymphadenopathy is briefly diagrammed in Fig. 1. He first came to the Durham Veterans Administration Hospital in October 1956 at the age of 39 years with a 2-month history of left occipital headaches and a recent grand mal seizure. Physical examination, including neurologic testing, resulted in unremarkable findings, other than left external strabismus that had been present since childhood. Results of routine laboratory tests were normal, but an electroencephalogram showed consistent slow wave activ-
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Sinus histiocytosis with massive lymphadenopathy
R
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Seizures, headaches ~ e p l d u r a t temporal lobe mass, 6x5x4 cm. --~'hlstlocytoms" Ill Cervical node, 6 x 4 x 4 cm., end epidurel mass, 6x5x4 cm. "-t'hlstiocytoma"
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Fig. 1. Chronologic sequence of the time of documentation and duration of the major clinical and laboratory abnormalities that may be attributed to sinus histiocytosis with massive lymphadenopathy in our patient. ity in the left temporal region. The patient was treated with phenytoin (Dilantin) and phenobarbital with improvement in his headache and no further seizures until 1957. At that time, a spinal pneumoencephalogram, a colloidal gold curve, and an electroencephalogram all pointed to an abnormal temporal lobe focus. Carotid arteriograms showed poor filling on the left, but the study was thought to be inconclusive, surgery was deferred, and the patient continued to receive anticonvulsive medication. In January 1959 a right cervical lymph node was first noted and excised. After great debate, it was interpreted as a "histiocytoma." In October 1959, severe headaches recurred, along with early papilledema, right-sided weakness, a right seventh cranial nerve palsy, nuchal rigidity, and fever. A left carotid arteriogram showed a definite temporal mass, and craniotomy resulted in removal of a 6 x 5 x 4-cm epidural mass interpreted as a "histiocytoma." The patient's symptoms resolved postoperatively. In April 1960 the patient returned with right exophthalmos caused by a supraorbital mass without bony erosion. Funduscopic examination revealed a retinal fold in the premacular area toward the temporal bone, suggestive of infiltration. The supraorbital mass was excised and interpreted as "histiocytosis of unknown etiology." In November 1964, another right cervical node was
removed with a diagnosis of "histiocytoma." In April 1966 the patient was readmitted to the hospital because of a right parotid mass, which was also interpreted as a "histiocytoma." Another cervical node was removed in April 1970, and another in July 1977. The latter biopsy specimen was compared with all previous biopsy specimens and was found to be similar. With the knowledge of a newly described syndrome, the diagnosis of sinus histiocytosis with massive lymphadenopathy was first made. In May 1979 the patient was first noted to have subcutaneous infiltrates in the left breast and right cheek, and a biopsy specimen taken from the former was found to be consistent with sinus histiocytosis with massive lymphadenopathy (Fig. 2). During the 1980s, widespread lymphadenopathy has waxed and waned. Lymph nodes are occasionally painful and tender, with measurable enlargements, lor days to weeks at a time. Treatment with daily chlorambucil, 2 to 4 rag/day, failed to result in any significant resolution of the lymph node enlargement or skin involvement. Intralesional triamcinolone, 50 mg/ml administered by injection, did not affect the cutaneous infiltrates. Subsequently, the patient's sinus histiocytosis with massive lymphadenopathy has been managed simply with supportive care. In addition to sinus histiocytosis with massive lymphadenopathy, the patient has developed a number of other medical conditions in the last decade, including
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Fig. 2. Cutaneous lesions of sinus histiocytosis with massive lymphadenopathy.
hypertension, obesity, adult-onset diabetes mellitus, and gout, but his major medical problem has been spondylosis. In January 1965, a diagnosis of left-sided Brown-Srquard syndrome resulting from cervical spondylosis was made. A laminectomy of the third to sixth cervical vertebrae led to an improvement in symptoms, but the patient refused further examination until 1984, when he developed bladder incontinence, constipation, and paraparesis. Myelography revealed recurrent compression between the fourth and fifth cervical vertebrae and between the third and fourth lumbar vertebrae, but the neurosurgery service did not believe that surgical intervention would be beneficial at this point. The patient has subsequently been managed as a paraplegic at home, with a bowel and bladder regimen and assistance in activities of daily living. L a b o r a t o r y findings. Fig. 1 also presents, in chronologic order, some of the major laboratory findings obtained during this patient's 30-year clinical course. In terms of his associated dysproteinemia, an increase in serum globulins was first noted in October 1959, when his serum protein level was 7.3 gm/dl and serum albumin level was 3.5 gm/dl. Cellulose acetate tracing, in December 1977, first documented the presence of a monoclonal beta component of 2.7 gm/dl with a polyclonal increase in the gamma globulins. The total serum protein level was 8.2 gm/dl, and the albumin level was 3.3 gm/dl. Immunoelectrophoresis of this sample revealed monoclonal IgA lambda light chains. A 24-hour
urine total protein level in 1977 was 2.5 gin/24 hr with albumin predominantly present, with two monoclonal components of IgA lambda and free lambda light chains. The serum monoclonal component has been stable between 2.5 and 3.5 gm/dl since it was first quantitated in 1977. Skeletal surveys have shown no evidence of bone disease or changes other than cervical and lumbar spondylosis. Bone marrow examinations have not revealed > 5 % plasma cells in the bone I~alTOW.
Although proteinuria was first noted on urinalysis in 1962, renal functional impairnaent, as documented by an increase in serum creatinine levels, was not present until 1970, when the serum creatinine level was 1.4 mg/dl, rising to 2.0 mg/dl in 1978 and 2.4 mg/dl in 1986. An abdominal computed tomography scan in 1986 suggested a bilateral renal infiltrative process. No renal biopsy has been performed. In 1982 a hematocrit value of 35% prompted an evaluation for anemia. A Coombs' test showed a positive reaction, with IgG present but no C3. The blood specimen had no spherocytes and was otherwise normocytic and normochromic. A reticulocyte count was less than 2%. Bone marrow examination revealed decreased iron stores but was otherwise normal. Trials of iron replacement failed to improve the patient's anemia, and in March 1986 the hematocrit value fell to 18%. Bone marrow iron stores at this time were absent, and there was no evidence of infiltration with sinus histio-
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Sinus histiocytosis with massive lymphadenopathy
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Fig. 3. Low magnification of a lymph node showing sinuses that are filled and expanded by histiocytes. The cortex is also focally infiltrated by histiocytes. ( x 33.) cytosis or an increase in plasma cells above the 5% previously noted. A reticulocyte count was 6% despite absent iron stores, and spherocytes were noted on the blood film. The autoantibody was characterized as anti-e. Endoscopy and colonoscopy failed to reveal a source of bleeding, although the patient had a long history of anti-inflammatory agent use for gout and spondylosis. No hemosiderin was present in a urine specimen. A presumptive diagnosis of iron deficiency and autoimmune hemolytic anemia was made, and the patient was treated with iron and prednisone. His hematocrit has stabilized with prednisone therapy. Itistolagic study. Four of the patient's biopsy specimens came from cervical lymph nodes, one from the brain, one from a node within the parotid gland, one from the orbit, and two from the skin lesions on the left breast. The samples of lymph node showed a histologic picture that is classic for sinus histiocytosis with massive lymphadenopathy: expansion of the sinuses by large, foamy histiocytes and by plasma cells (Figs. 3 and 4). These collections also formed larger nodules that focally replaced the cortex of the node, and in the brain the collections were largely spherical or confluent.
The histiocytes contained mildly atypical-appearing nuclei, and some had phagocytized lymphocytes (Fig. 4), but electron microscopic examination showed no Langerhans granules. Neither eosinophils nor atypical lymphocytes were present. In the skin (Fig. 5) the infiltrate was confined to the reticular dermis and the subcutis, where in one biopsy specimen there was a lymph node filled with sinus histiocytosis with massive lymphadenopathy. The infiltrate was composed of large histiocytes with foamy, granular cytoplasm, and it contained plasma cells, although fewer than were found in the lymph nodes, and many small lymphocytes. In general, both skin biopsy specimens showed poorer histologic preservation of the histiocytes than was found in the nodes. Analysis of cutaneous infiltrates with immunofluorescent markers.* Three-millimeter punch biopsy specimens from the left breast skin nodules were frozen in an ethanol-Dry Ice slurry embedded in OCT compound (American Scientific Products, McGaw Park, *We thank Dr. Barton F. Haynesfor help with the cutaneous phenotyping, including supplyingreagents.
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IL). Four- to six-micrometer sections were cut at - 2 0 ~ C. The acetone-fixed skin sections were incubated with a saturating amount of specific monoclonal antibody, washed, and then incubated with a saturating amount of affinity-pure fluorescein isothiocyanateconjugated goat antimouse antibody (Tago, Inc., Burlingame, CA). The slides were then read on an Nikon Optiphot fluorescent microscope (Nikon Inc., Instrument Group, Garden City, NY) for visual fluorescence. A battery of monoclonal antibodies to lymphocyte and monocyte-macrophage cell surface markers was used to better delineate the cell population in the cutaneous infiltrate of sinus histiocytosis with massive lymphadenopathy in this patient. The monoclonal markers, their specificity, and results are shown in Table I. Although two monocyte markers were negative, CMO2 confirmed the presence of monocytesmacrophages in the reticular dermis. A marker usually present in infiltrates of histiocytosis X (Nal/34) was negative. Both helper-inducer and suppressor-cytotoxic T cells were present in the papillary and reticular dermis.
DISCUSSION Sinus histiocytosis with massive lymphadenopathy is a pseudolymphomatous disorder with a diagnostic histopathologic picture and a common constellation of features. Any age group may be affected by sinus histiocytosis with massive lymphadenopathy, but 80% of cases occur in the first two decades of life. T M There appears to be both a male and a black race predilection. 7,t6 Worldwide, sinus histiocytosis with massive lymphadenopathy is more commonly seen in Africa and the West Indies.'6 Although cervical adenopathy is by far the most common sign, occurring in 95% of cases, 7 extranodal disease may instead be the presenting feature. 6 Extranodal disease has been reported in 28% to 32% 6,17 of cases of sinus histiocytosis with massive lymphadenopathy (the reported incidences of extranodal manifestations are listed in Table II). Our patient manifested many of the typical and atypical aspects of this diagnosis. Of eight reported
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Sinus histioo, tosis with massive lymphadenopathy
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Fig. 5. High magnification of sinus histiocytosis with massive lymphadenopathy in the skin. Large "histiocytic" cells, plasma cells, and small lymphocytes are present. ( • 400.)
cases of sinus histiocytosis with massive lymphadenopathy with a positive direct Coombs' test result, five of the patients have had hemolysis, one dying from this complication9 Our patient had a positive direct Coombs' test result, and the sensitization of his red blood cells may have contributed to his hemolysis 9 A peripheral leukocytosis was present, presumably interrelated to the observed lymphophagocytosis in tissue macrophages seen in this disease. ~Our patient had an IgA monoclonal gammopathy that was associated with 5% to 10% plasma cells in the bone marrow, positive results on urine immunoelectrophoresis, and normal bone survey findings. Benign hypergammaglobulinemia is present in 81% of cases of sinus histiocytosis with massive lymphadenopathy and has been polyclonal in all but o u r c a s e . 7 In one reported patient, a multiple myeloma containing IgA lambda and kappa light chains occurred 3 years before the onset of symptoms of sinus histiocytosis with massive lymphadenopathy.]7
It is not surprising that our patient had multiple extranodal sites of sinus histiocytosis with massive lymphadenopathy, because the incidence of other extranodal disease in patients with either ophthalmic, neurologic, or skin involvement is approximately 50%, 16'19'20 There are ~at least 21 reported cases of cutaneous invol.vement in sinus histiocytosis with massive lymphadenopathy, although a full clinical description with histologic confirmation has been reported in only 15 cases. 2J6,lv'z~ The overall incidence of cutaneous disease as reported by Thawerani et al.l~ is 9%. Among patients with sinus histiocytosis with massive lymphadenopathy, cutaneous disease has occurred more frequently in white patients and in male patients. 16 The cutaneous lesions have included macules, papules, plaques, and nodules. The majority of the lesions are multiple, and in at least one case the nodules have been painful. 16.22 One patient had a pruritic papulosquamous rash with a positive Koebner phenomenon resembling
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Table I. Monoclonal markers, specificity, and results Monoclonal markers
Findings in tissue
Specificity
Leu-4
80%-90% human peripheral blood lymphocytes8,9
35.1
Thymocytes, mature T cells ~~
Leu-3a
Cortical thymocytes, helper-inducer T lymphocytes8,9
Leu-2a
Cortical thymocytes, cytotoxic-suppressor T lymphocytes89 Monocytes~ MonocytesJ Monocytes and macrophagesj2 Cortical thymocytes, epidermal Langerhans cells ~3:4 Langerhans cells, other dendritic cells, macrophages, monocytes, B cells, some activated T cells t5
VI TE5 CMO2 NA1/34
guttate psoriasis that on biopsy showed a typical pattern of sinus histiocytosis with massive lymphadenopathy. 2~Two patients have had brownish pigmentation, one diffuse and the other limited to the extremities. ~6,26What the pigment is and whether it is related to this disease process directly or is a secondary effect of extranodal sinus histiocytosis with massive lymphadenopathy is unknown. The cutaneous lesions may be the initial presentation of the disease, and therefore the histologic recognition of this entity in the skin is important. 16Our patient's dermatopathologic features were similar to those in other reported cases of sinus histiocytosis with massive lymphadenopathy and largely mimic those of involved lymph nodes. In general, there is a dense dermal infiltrate consisting of aggregates of histiocytes with lymphocytes.16 Plasma cells and polymorphonuclear leukocytes are also present in > 5 0 % of cases. 16 In the smaller skin lesions, the dense inflammatory infiltrate is generally confined to the papillary dermis, whereas the larger lesions may go down into fat. 16The histiocytes are similar to those described in lymph nodes, although lymphophagocytosis is
Rare positive epidermal cells; scattered positive mononuclear cells in papillary dermis and sheets of mononuclear cells in reticular dermis Many positive mononuclear cells in reticular dermis Scattered positive epidermal monocytes; >60% of dermal mononuclear cells positive, in papillary greater than in reticular dermis ~50% mononuclear cells in reticular dermis positive Negative Negative Positive cells in reticular dermis Keratinocytes rimmed; negative dermis Scattered positive cells in papillary dermis
less common. ~6Fibrosis is generally increased relative to that seen in lymph node abnormality. Foreign body and Touton giant cells, as well as lipophagic granulomas, have been reported in cutaneous infiltrates. 16The epidermis in skin lesions is generally normal or may be affected, as a bystander, with flattening and parakeratosis. One case report did mention exocytosis ~6 and another, patchy spongiosis of the epidermis. 22 The histologic picture of sinus histiocytosis with massive lymphadenopathy in the skin, by itself, is not diagnostic. 16 Other diseases can show large numbers of histiocytes in the d e r m i s - - f o r example, infection by atypical mycobacteria, leprosy, leishmaniasis, syphilis, histiocytosis X, and xant h o m a s - - b u t most often these cart be distinguished from sinus histiocytosis with massive lymphadenopathy by clinical information or by using special stains and electron microscopy. 29 The cutaneous histiocytic infiltrate in our patient was negative for the monocyte markers V~ and TE5 but were phenotypically positive when CMO2 was used. The lack of infiltrating mononuclear cells with cell surface markers positive for monoclonal antibody
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Sinus histiocytosis with massive lymphadenopathy
N a l / 3 4 eased differentiation from histiocytosis X in our patient and, along with OKT6, may provide a reliable differentiating procedure. The cutaneous infiltrate of our patient demonstrated the mixed inflammatory infiltrate typically seen in extranodal sinus histiocytosis with massive lymphadenopathy.16 Cells of the T helper-inducer phenotype were more prominent in the papillary dermis and in rare foci of epidermal exocytosis, whereas those of the suppressor cell phenotype were more prominent in the reticular dermis. Mir et a l ) ~ examined the central nervous system tumor of a patient with sinus histiocytosis with massive lymphadenopathy by immunofluorescence histologic study and found that although most of the lymphocytes were negative for T cell surface antigens, those which were positive were primarily T suppressor cells (OKT8-positive). 3~ It certainly is not surprising to see such a prominent juxtaposition of histiocytes (macrophages) and lymphocytes histologically, because macrophages synthesize factors that lead to lymphocyte proliferation, maturation, and lymphokine production) 1 Antibodies to N a l / 3 4 in the epidermis and to L243 in the dermis confirmed the presence of Langerhans or other dendritic cells, a common finding in a reactive lymphocytic infiltrate. The disease course in many patients with sinus histiocytosis with massive lymphadenopathy is one of spontaneous regression over a course of months to years: :6'24 However, only 21% of 215 patients followed in a registry of these cases actually became disease free, and at least 14 patients have died. 2S Our patient has survived 30 years since the onset of symptoms consistent with his diagnosis of sinus histiocytosis with massive lymphadenopathy; the longest reported survival before our patient was 24 years. 17 Usually the extranodal sinus histiocytosis with massive lymphadenopathy regresses first, and adenopathy alone may persist for years) Because of the rarity and benignity of sinus histiocytosis with massive lymphadenopathy in the majority of affected patients, a concerted approach to treatment has been lacking. Antibiotics have been of no benefit: and systemic steroids have, in general, shown the most benefit in a partial
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Table II. Reported incidences of extranodal manifestations Clinical features
Adenopathy Hypergammaglobulinemia Anemia + Coombs' test Fever Leukocytosis Neutrophilia Weight loss Splenomegaly, hepatomegaly Extranodal manifestations Ophthalmic Upper respiratory tract Tonsillitis Nasal discharge or obstruction Skin Bone GI involvement: Stomach/colon infiltration Amyloid Neurologic Salivary Testicular
Incidence [ Reference(s)
>95% 81% 78% >4% >56% 38% 45% 18% 12%
7 7 7 16 7 7 7 7 5
12% 12% 11% 8%
7, 20 7 7 7
9% 8%
7 7
1 case
18
2 cases 4% 3% > 1%
5, 17 19 7 7
and temporary decrease in nodal size or symptoms: ,6.2~ Intralesional steroids have been ineffective in this and one other case 22 in which skin lesions were specifically treated. There have been reports of a transient decrease in adenopathy or extranodal involvement with irradiation, but regrowth has often occurred after radiation therapy. 6.2~ Surgical excision alone has been lifesaving in cases where the disease impinged on vital organs .35 Case reports of various chemotherapeutic regimens for sinus histioeytosis with massive lymphadenopathy abound, but most have shown only partial clearing of signs, amelioration of symptoms, or both. 6'18'2~ One patient had an initial complete response to cyclophosphamide (Cytoxan) alone, with a second persistent complete remission after retreatment of a r e l a p s e . 34 A second patient had a dramatic response to eyclophosphamide with prednisone: Whether these complete responses were directly attributable to the drug
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therapy or to spontaneous remission is impossible to say. The cause of sinus histiocytosis with massive lymphadenopathy remains obscure. Two main theodes have been advanced: a primary infectious cause and a disturbance in cell-mediated immun i t y - t h e two not necessarily being mutually exclusive. Mycobacteria have been avidly searched for, but no acid-fast bacteria or granulomas have been found in histologic specimens, and antituberculous therapy has been of no benefit3 ~ Rhinoscleroma histologically resembles sinus histiocytosis with massive lymphadenopathy,2~ and one patient with sinus histiocytosis with massive lymphadenopathy had elevated KlebsieUa rhinoscleromatis and K. ozaenae antigen levels, 24 but the absence of organisms in pathologic specimens 3~ and negative Klebsiella titers in other reported cases make this cause unlikely: ~ Several potential viruses have been suggested as causative agents in sinus histocytosis with massive lymphadenopathy, including rubella4t-43 and cytomegalovirus. ~ Probably the strongest potential viral etiologic agent in sinus histiocytosis with massive lymphadenopathy is the Epstein-Barr virus. 2~.~ Although 15 of 22 patients in a registry of cases of sinus histiocytosis with massive lymphadenopathy had elevated Epstein-Barr virus titers, 7 in developing countries and socially deprived areas, where the majority of cases of sinus histiocytosis with massive lymphadenopathy are found, 80% of infants show a seropositive response/~ Despite bacterium and virus isolation procedures and electron microscopic techniques, no infectious agents have been found in sinus histiocytosis with massive lymphadenopathy. The histiocytic proliferation seen in sinus histiocytosis with massive lymphadenopathy could be the result of an intrinsic cellular defect, as exemplified by chronic granulomatous disease. There have been reports of both normal and decreased blast transformation of lymphocytes to phytohemagglutinin, concanavalin A, or pokeweed mitogen in patients with sinus histiocytosis with massive lymphadenopathy, making a uniform defect in lymphocyte-mediated cellular immunity unlikely: '2r Moreover, sinus histiocytosis
with massive lymphadenopathy does not seem to be an antibody-mediated disorder, because macrophages retain the property of phagocytosis of other cells and microorganisms in vitro in the absence of specific stimulation, s~ Sinus histiocytosis with massive lymphadenopathy has been reported in siblings, 35 raising the possibility of either an inherited or acquired idiosyncratic response to infection or an immunologic disorder with a secondary infection. SUMMARY
Our patient is unusual in his lengthy survival despite multiorgan involvement with sinus histiocytosis with massive lymphadenopathy and the presence of a heretofore undescribed associated monoclonal gammopathy. Using monoclonal antibodies to a variety of cell surface markers, we have more fully described the concomitant lymphocytic portion of the cutaneous infiltrates and have differentiated sinus histiocytosis with massive lymphadenopathy from histiocytosis X. We also reviewed the literature pertinent to the dermatologic and other extranodal aspects of sinus histiocytosis with massive lymphadenopathy. REFERENCES 1. Rosai J, Doffman RF. Sinus histiocytosis with massive lymphoadenopathy. Arch Pathol 1969;87:63-70. 2. Azoury FJ, Reed RJ. Histiocytosis: report of an unusual case. N Engl J Med 1966;274:928-30. 3. Destombes P. Ad6nites avec surcharge lipidique, de l'enfant ou de l'adulte jeune, observe6s aux antilles et au mali. Bull Soc Pathol Exot Filiales 1965;6:1169-75. 4. Eighteenth seminar of the Penrose Cancer Hospital. Cancer Seminar 1967;3:246-250. 5. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Cancer 1972;30:1174-88. 6. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive ]ymphadenopathy. Arch Otolaryngol 1978;104: 687-93. 7. Sanchez R, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 113 cases with special emphasis on its extranodal manifestations. Ann Meet Abstr 1977;36:349-50. 8. Ledbetter SA, Evans RL, Lipinski M, CunninghamRundles C, Good RA, Herzenberg LA. Evolutionary conservation of surface molecules that distinguish T lymphocyte helper/inducer and T eytotoxic/suppressor populations in mouse and man. J Exp Med 1981;153:31023.
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Sinus histiocytosis with massive lymphadenopathy
9. Evans RL, Wall SW, Patsoucase CO, et al. Thymusdependent membrane antigens in man: inhibition of cellmediated lympholysis by monoclonal antibodies to TH2 antigen. Proc Natl Acad Sci USA 1981;78:544-8. 10. Martin PJ, Longston G, Ledbetter JA, et al. Identification and functional characterization of two distinct epitopes on the human T cell surface protein T. J Immunol 1983;131:180-5. 11. Weinberg JB, Hobbs MM, Misukonis MA. Phenotypic characterization of gamma interferon-induced human monocyte polykaryons. Blood 1985;66:1241-6. 12. Todd RF III, Schlossman SF. Analysis of antigenic determinants on human monocytes and macrophages. Blood 1982;59:775-86. 13. Haynes BF. Human T cell antigens as defined by monoclonal antibodies. Immunol Rev 1981,57:5-35. 14. McMichael AJ, Pilch JR, Galfre G, Mason DY, Fabre JW, Milstein C. A human thymocyte antigen defined by a hybrid myeloma monoclortal antibody. Eur J Immunol 1979;9:205-10. 15. Lampson LA, Levy R. Two populations of Ia-like molecules on a human B cell line. J lmmunol I980;125:2939. 16. Thawerani H, Sanchez RL, Rosai J, Dorfman RF. The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch Dermatol 1978;114: 191-7. 17. Foucar E, Rosai J, D0rfman RF, Eyman JM. Immunologic abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol 1984;82:515-25. 18. Osborne SM, Hagemeister FB, Butler J J. Extranodal gastrointestinal sinus histiocytosis with massive lymphadenopathy. Am J Surg Pathol 1981;5:603-11. 19. Foucar E, Rosai J, Dorfman RF, Brynes RK. The neurologic manifestations of sinus histiocytosis with massive lymphadenopathy. Neurology 1982;32:365-71. 20. Foucar E, Rosai J, Dorfman RF. The ophthalmologic manifestations of sinus histiocytosis with massive lymphadenopathy. Am J Ophthalmol 1979;87:354-67. 21. Woodcock AA, de V Hart PL. Diffuse cutaneous involvement and sinus histiocytosis with massive lymphadenopathy. Postgrad Med J 1980;56:521-25. 22. Miller JA, Kirby JD, Levison DA. Cutaneous involvement by sinus histiocytosis with massive lymphadenopathy. J R Soc Med 1980;73:746-8. 23. Penneys NS, Ahn YS, McKinney EC, et al. Sinus histiocytosis with massive lymphadenopathy: a case with unusual skin involvement and a therapeutic response to vinblastine-loaded platelets. Cancer 1982;49:1994-8. 24. Lampert F, Lennert K. Sinus histiocytosis with massive lymphadenopathy. Cancer 1976;37:783-9. 25. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 14 deaths occurring in a patient registry. Cancer 1984;54:183440. 26. Wright DH, Richards DB. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case with widespread nodal and extranodal dissemination. Histopathology 198 ] ;5:697-709. 27. Suarez CR, Zeller WP, Silberman S, Rust G, Messmore
28. 29. 30. 31. 32. 33.
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43. 44.
45.
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H. Sinus histiocytosis with massive lymphadenopathy: remission with chemotherapy. Am J Pediatr Hematol Oncol 1983;3:235-41. Buchino J J, Byrd RP, Kmetz DR. Disseminated sinus histiocytosis with massive lymphadenopathy. Arch Pathol Lab Med 1982;106:13-6. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott, 1983. Mir R, Aftalion B, Kahn LB. Sinus histiocytosis with massive lymphadenopathy and unusual extranodal manifestations. Arch Pathol Lab Med 1985;109:867-70. Groopman JE, Golde DW. The histioeytic disorders: a pathophysiologic analysis. Ann Intern Med 1981;94:95107. Haas RJ, Helmig MSE, Prechtel K. Sinus histiocytosis with massive lymphadenopathy and paraparesis: remission with chemotherapy. Cancer 1978;42:77-80. Hanchard B, McNeill R, Thomas S, Sparke B. Sinus histiocytosis with massive lymphadenopathy: clinicopathological features of four cases. West Indian Med J 1977 ;26:204-10. Newman SB, Sweet DL, Vardiman JW. Sinus histiocytosis with massive lymphadenopathy: response to cyclophosphamide therapy. Cancer Treat Rep 1984;68:9012. Bankaci M, Stool SE, Morris RF, Paradise JL. Sinus histiocytosis with massive lymphadenopathy: report of its occurrence in two siblings with retropharyngeal involvement in both. Ann Otol 1978;87:327-31. Sinclair-Smith CC, Kahn LB, Uys CJ. Sinus histiocytosis with massive lymphadenopathy: report of two additional cases with ultrastructural observations. S Afr Med J 1974;48:451-4. Siegel MJ, Shackelford GF, McAlister WH. Sinus histiocytosis: some radiologic observations. AJR 1979; 132:783-5. Naik KG. Sinus histiocytosis with massive Iymphadenopathy. Trop Geogr Med 1976;38:181-6. Adekeye EO, Edwards MB, Goubran GF. Sinus histiocytosis with massive lymphadenopathy in a Nigerian child. J Laryngol Otol 1982;96:89-94. Ngendahayo P, Roels H, Quatacker J, Boddaert J, Ntabomuvra V, Mbonyingabo P. Sinus histiocytosis with massive lymphadenopathy in Rwanda: report of eight cases with immunohistochemical and ultrastructural studies. Histopathology I983;7:49-63. Claman HN, Suvatte V, Githens JH, Hathaway WE. Histiocytic reaction in dysgammaglobulinema and congenital rubella. Pediatrics 1970;46:89-96. Sumaya CV, Cherry JD, Gohd R. Exaggerated antibody response following rubella vaccination in a child with sinus histiocytosis with massive lymphadenopathy. J Pediatr 1976;89:81-3. Kurlemann G, Kreth HW, Muller KM. Sinus histiocytosis with massive lymphadenopathy: a virus-associated disease? Monatsschr Kinderheilkd 1984;132:100-4. Lober M, Rawlings W, Newell GR, Reed RJ. Sinus histiocytosis with massive lymphadenopathy: report of a case associated with elevated EBV antibody titers. Cancer 1973;32:421-5. Tanaka N, Asao T. Sinus histiocytosis with massive
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lymphadenopathy (Rosai and Dorfman) and significant skin in~,olvement. Acta Pathol Jpn 1978;28:175-84. 46. Picketing LK, Phelan E. Sinus histincytosis. J Pediatr 1975;86:745-8. 47. Plaxico DT, Wray BB, Hsia S, Pierce A D . Sinus histiocytosis with massive lymphadenopathy: an immunologic assessment. South Med J 1982;75:346-8. 48. Becroft DMO, Dix MR, Gillman JC, MacGregor BJL, Shaw RL. Benign sinus histiocytosis with massive
lymphadenopathy; transient immunological defects in a child with mediastinal involvement. J Clin Pathol 1973;26:463-9. 49. Brostrom K, Baandrup U. Sinus histiocytosis with massive lymphadenopathy. Acta Paediatr Scand 1977;66: 257-60. 50. Karpas A, Arno J, Cawley J. Sinus histiocytosis with massive lymphadenopathy: properties of cultured histi0cytes. Eur J Cancer 1973;9:729-32.
ABSTRACTS Physiological study of pruritus ani Allan A, Ambrose NS, Silverman S, Keighley MRB. Br J Surg 1987;74:576-9 A surgical faculty with fecal fascination found a fertile field for expository, imaginative, and innovative investigation. These serious speleologic searchers used history, rectal examination, proetoscopy, sigmoidoscopy, linear analog severity scale, Wood's lamp, Sellotapo, and Sabouraud's agar, as well as saline infusion tests, to assess anal sphincter competence for fluids; an ischial tuberosityjig and rod to measure perineal descent; a soft rubber rectal balloon and fine tube with a ballon probe and strain gauge amplifier and recorder to evaluate maximal resting and squeeze pressures; a rectal sensation balloon; a rectal balloon with an air-filled
pressure transducer to assess rectal compliance; and balloon proctography with a radiolucent lavatory seat and videorecorder to measure the degree of perineal descent in relation to the pubococcygeal line, as well as anorectal angles. Patients with pruritus ani showed a marked increase in leakage through the anal canal compared with controls; perhaps the hermeneuties of this hermetic failure is linked to coexisting occult anal disease or an exaggerated rectoanal inhibitory reflex. Alas, even excremental exegesis by manometry and radiology failed to find a fundamentally fatal flaw that could be consistently corrected in an effort to expunge or expurgate the persistent pruritus in patients with this pathogenetically poorly understood, common, and disabling disorder. Steven R. Kohn, M.D.
Sinus histiocytosis with massive lymphadenopathy Case report and review of a multisystemic disease with cutaneous infiltrates Elise A. Olsen, M.D., Jeffrey R. Crawford, M.D. ,* and Robin T. Vollmer, M.D.** Durham, NC A report of a patient with the rare syndrome of sinus histiocytosis with massive lymphadenopathy is presented here. This patient is unusual in several respects, including his longevity after diagnosis, the presence of a benign monoclonal gammopathy, and the characterization of his cutaneous infiltrates by immunofluorescent monoclonal antibody markers. A review of the literature on sinus histiocytosis with massive lymphadenopathy, with particular emphasis on cutaneous manifestations, is given. (J AM ACAD DERMATOL 1988;18:1322-32.)
Sinus histiocytosis with massive lymphadenopathy is a syndrome that was first characterized by Rosai and Dorfman I in 1969, although case reports antedate the full clinicopathologic description: -4 Typically, patients have cervical and, commonly, other lymphadenopathy, often accompanied by fever, anemia, leukocytosis with neutrophilia, an elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia: Extranodal disease may occur in 28% of c a s e s 6 and may be the initial manifestation of the disease. The extranodal sites most commonly affected are the orbit, upper respiratory tract, skin, and bone. 7 The microscopic appearance of involved lymph nodes is characteristic. ,5.6 We present here the case of a 69-year-old black man with nodal and extranodal sinus histiocytosis
From the Division of Dermatology, Duke University Medical Center, and the Division of Hematology/Oncology, Departments of Medicine* and Pathology,** Veterans Administration Hospital. Reprint requests to: Dr. Elise A. Olsen, Box 3294, Division of Dermatology, Duke University Medical Center, Durham, NC 27710.
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with massive lymphadenopathy whose disease is unusual in several respects. He is the longest-lived reported survivor of sinus histiocytosis with massive lymphadenopathy, despite involvement of the central nervous system at initial presentation, and the first reported patient with a benign IgA monoclonal gammopathy. In addition, our report is the first characterization of a cutaneous infiltrate of sinus histiocytosis with massive lymphadenopathy by immunofluorescent monoclonal antibody markers.
CASE REPORT Clinical course. Our patient is a 69-year-old black former laborer whose 30-year clinical course of sinus histiocytosis with massive lymphadenopathy is briefly diagrammed in Fig. 1. He first came to the Durham Veterans Administration Hospital in October 1956 at the age of 39 years with a 2-month history of left occipital headaches and a recent grand mal seizure. Physical examination, including neurologic testing, resulted in unremarkable findings, other than left external strabismus that had been present since childhood. Results of routine laboratory tests were normal, but an electroencephalogram showed consistent slow wave activ-
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Sinus histiocytosis with massive lymphadenopathy
R
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Seizures, headaches ~ e p l d u r a t temporal lobe mass, 6x5x4 cm. --~'hlstlocytoms" Ill Cervical node, 6 x 4 x 4 cm., end epidurel mass, 6x5x4 cm. "-t'hlstiocytoma"
o~
t~ t-
I I Exophthslmus, supraorbital mass .,.*'histlocytosis" ill Cervical node, ,..* "hisnocytoma"
"O r
I I Parotld mass, 7x3x2 cm. ~ " h l s t l o c y t o m a "
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! Cervical node, 5x4x2 cm. "*"hlsnocytoma"
to
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o
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1956
1962
1968
1974 Years
.
1980
"
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"
1986
Fig. 1. Chronologic sequence of the time of documentation and duration of the major clinical and laboratory abnormalities that may be attributed to sinus histiocytosis with massive lymphadenopathy in our patient. ity in the left temporal region. The patient was treated with phenytoin (Dilantin) and phenobarbital with improvement in his headache and no further seizures until 1957. At that time, a spinal pneumoencephalogram, a colloidal gold curve, and an electroencephalogram all pointed to an abnormal temporal lobe focus. Carotid arteriograms showed poor filling on the left, but the study was thought to be inconclusive, surgery was deferred, and the patient continued to receive anticonvulsive medication. In January 1959 a right cervical lymph node was first noted and excised. After great debate, it was interpreted as a "histiocytoma." In October 1959, severe headaches recurred, along with early papilledema, right-sided weakness, a right seventh cranial nerve palsy, nuchal rigidity, and fever. A left carotid arteriogram showed a definite temporal mass, and craniotomy resulted in removal of a 6 x 5 x 4-cm epidural mass interpreted as a "histiocytoma." The patient's symptoms resolved postoperatively. In April 1960 the patient returned with right exophthalmos caused by a supraorbital mass without bony erosion. Funduscopic examination revealed a retinal fold in the premacular area toward the temporal bone, suggestive of infiltration. The supraorbital mass was excised and interpreted as "histiocytosis of unknown etiology." In November 1964, another right cervical node was
removed with a diagnosis of "histiocytoma." In April 1966 the patient was readmitted to the hospital because of a right parotid mass, which was also interpreted as a "histiocytoma." Another cervical node was removed in April 1970, and another in July 1977. The latter biopsy specimen was compared with all previous biopsy specimens and was found to be similar. With the knowledge of a newly described syndrome, the diagnosis of sinus histiocytosis with massive lymphadenopathy was first made. In May 1979 the patient was first noted to have subcutaneous infiltrates in the left breast and right cheek, and a biopsy specimen taken from the former was found to be consistent with sinus histiocytosis with massive lymphadenopathy (Fig. 2). During the 1980s, widespread lymphadenopathy has waxed and waned. Lymph nodes are occasionally painful and tender, with measurable enlargements, lor days to weeks at a time. Treatment with daily chlorambucil, 2 to 4 rag/day, failed to result in any significant resolution of the lymph node enlargement or skin involvement. Intralesional triamcinolone, 50 mg/ml administered by injection, did not affect the cutaneous infiltrates. Subsequently, the patient's sinus histiocytosis with massive lymphadenopathy has been managed simply with supportive care. In addition to sinus histiocytosis with massive lymphadenopathy, the patient has developed a number of other medical conditions in the last decade, including
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Fig. 2. Cutaneous lesions of sinus histiocytosis with massive lymphadenopathy.
hypertension, obesity, adult-onset diabetes mellitus, and gout, but his major medical problem has been spondylosis. In January 1965, a diagnosis of left-sided Brown-Srquard syndrome resulting from cervical spondylosis was made. A laminectomy of the third to sixth cervical vertebrae led to an improvement in symptoms, but the patient refused further examination until 1984, when he developed bladder incontinence, constipation, and paraparesis. Myelography revealed recurrent compression between the fourth and fifth cervical vertebrae and between the third and fourth lumbar vertebrae, but the neurosurgery service did not believe that surgical intervention would be beneficial at this point. The patient has subsequently been managed as a paraplegic at home, with a bowel and bladder regimen and assistance in activities of daily living. L a b o r a t o r y findings. Fig. 1 also presents, in chronologic order, some of the major laboratory findings obtained during this patient's 30-year clinical course. In terms of his associated dysproteinemia, an increase in serum globulins was first noted in October 1959, when his serum protein level was 7.3 gm/dl and serum albumin level was 3.5 gm/dl. Cellulose acetate tracing, in December 1977, first documented the presence of a monoclonal beta component of 2.7 gm/dl with a polyclonal increase in the gamma globulins. The total serum protein level was 8.2 gm/dl, and the albumin level was 3.3 gm/dl. Immunoelectrophoresis of this sample revealed monoclonal IgA lambda light chains. A 24-hour
urine total protein level in 1977 was 2.5 gin/24 hr with albumin predominantly present, with two monoclonal components of IgA lambda and free lambda light chains. The serum monoclonal component has been stable between 2.5 and 3.5 gm/dl since it was first quantitated in 1977. Skeletal surveys have shown no evidence of bone disease or changes other than cervical and lumbar spondylosis. Bone marrow examinations have not revealed > 5 % plasma cells in the bone I~alTOW.
Although proteinuria was first noted on urinalysis in 1962, renal functional impairnaent, as documented by an increase in serum creatinine levels, was not present until 1970, when the serum creatinine level was 1.4 mg/dl, rising to 2.0 mg/dl in 1978 and 2.4 mg/dl in 1986. An abdominal computed tomography scan in 1986 suggested a bilateral renal infiltrative process. No renal biopsy has been performed. In 1982 a hematocrit value of 35% prompted an evaluation for anemia. A Coombs' test showed a positive reaction, with IgG present but no C3. The blood specimen had no spherocytes and was otherwise normocytic and normochromic. A reticulocyte count was less than 2%. Bone marrow examination revealed decreased iron stores but was otherwise normal. Trials of iron replacement failed to improve the patient's anemia, and in March 1986 the hematocrit value fell to 18%. Bone marrow iron stores at this time were absent, and there was no evidence of infiltration with sinus histio-
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Sinus histiocytosis with massive lymphadenopathy
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Fig. 3. Low magnification of a lymph node showing sinuses that are filled and expanded by histiocytes. The cortex is also focally infiltrated by histiocytes. ( x 33.) cytosis or an increase in plasma cells above the 5% previously noted. A reticulocyte count was 6% despite absent iron stores, and spherocytes were noted on the blood film. The autoantibody was characterized as anti-e. Endoscopy and colonoscopy failed to reveal a source of bleeding, although the patient had a long history of anti-inflammatory agent use for gout and spondylosis. No hemosiderin was present in a urine specimen. A presumptive diagnosis of iron deficiency and autoimmune hemolytic anemia was made, and the patient was treated with iron and prednisone. His hematocrit has stabilized with prednisone therapy. Itistolagic study. Four of the patient's biopsy specimens came from cervical lymph nodes, one from the brain, one from a node within the parotid gland, one from the orbit, and two from the skin lesions on the left breast. The samples of lymph node showed a histologic picture that is classic for sinus histiocytosis with massive lymphadenopathy: expansion of the sinuses by large, foamy histiocytes and by plasma cells (Figs. 3 and 4). These collections also formed larger nodules that focally replaced the cortex of the node, and in the brain the collections were largely spherical or confluent.
The histiocytes contained mildly atypical-appearing nuclei, and some had phagocytized lymphocytes (Fig. 4), but electron microscopic examination showed no Langerhans granules. Neither eosinophils nor atypical lymphocytes were present. In the skin (Fig. 5) the infiltrate was confined to the reticular dermis and the subcutis, where in one biopsy specimen there was a lymph node filled with sinus histiocytosis with massive lymphadenopathy. The infiltrate was composed of large histiocytes with foamy, granular cytoplasm, and it contained plasma cells, although fewer than were found in the lymph nodes, and many small lymphocytes. In general, both skin biopsy specimens showed poorer histologic preservation of the histiocytes than was found in the nodes. Analysis of cutaneous infiltrates with immunofluorescent markers.* Three-millimeter punch biopsy specimens from the left breast skin nodules were frozen in an ethanol-Dry Ice slurry embedded in OCT compound (American Scientific Products, McGaw Park, *We thank Dr. Barton F. Haynesfor help with the cutaneous phenotyping, including supplyingreagents.
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9
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IL). Four- to six-micrometer sections were cut at - 2 0 ~ C. The acetone-fixed skin sections were incubated with a saturating amount of specific monoclonal antibody, washed, and then incubated with a saturating amount of affinity-pure fluorescein isothiocyanateconjugated goat antimouse antibody (Tago, Inc., Burlingame, CA). The slides were then read on an Nikon Optiphot fluorescent microscope (Nikon Inc., Instrument Group, Garden City, NY) for visual fluorescence. A battery of monoclonal antibodies to lymphocyte and monocyte-macrophage cell surface markers was used to better delineate the cell population in the cutaneous infiltrate of sinus histiocytosis with massive lymphadenopathy in this patient. The monoclonal markers, their specificity, and results are shown in Table I. Although two monocyte markers were negative, CMO2 confirmed the presence of monocytesmacrophages in the reticular dermis. A marker usually present in infiltrates of histiocytosis X (Nal/34) was negative. Both helper-inducer and suppressor-cytotoxic T cells were present in the papillary and reticular dermis.
DISCUSSION Sinus histiocytosis with massive lymphadenopathy is a pseudolymphomatous disorder with a diagnostic histopathologic picture and a common constellation of features. Any age group may be affected by sinus histiocytosis with massive lymphadenopathy, but 80% of cases occur in the first two decades of life. T M There appears to be both a male and a black race predilection. 7,t6 Worldwide, sinus histiocytosis with massive lymphadenopathy is more commonly seen in Africa and the West Indies.'6 Although cervical adenopathy is by far the most common sign, occurring in 95% of cases, 7 extranodal disease may instead be the presenting feature. 6 Extranodal disease has been reported in 28% to 32% 6,17 of cases of sinus histiocytosis with massive lymphadenopathy (the reported incidences of extranodal manifestations are listed in Table II). Our patient manifested many of the typical and atypical aspects of this diagnosis. Of eight reported
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Sinus histioo, tosis with massive lymphadenopathy
:
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1327
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Fig. 5. High magnification of sinus histiocytosis with massive lymphadenopathy in the skin. Large "histiocytic" cells, plasma cells, and small lymphocytes are present. ( • 400.)
cases of sinus histiocytosis with massive lymphadenopathy with a positive direct Coombs' test result, five of the patients have had hemolysis, one dying from this complication9 Our patient had a positive direct Coombs' test result, and the sensitization of his red blood cells may have contributed to his hemolysis 9 A peripheral leukocytosis was present, presumably interrelated to the observed lymphophagocytosis in tissue macrophages seen in this disease. ~Our patient had an IgA monoclonal gammopathy that was associated with 5% to 10% plasma cells in the bone marrow, positive results on urine immunoelectrophoresis, and normal bone survey findings. Benign hypergammaglobulinemia is present in 81% of cases of sinus histiocytosis with massive lymphadenopathy and has been polyclonal in all but o u r c a s e . 7 In one reported patient, a multiple myeloma containing IgA lambda and kappa light chains occurred 3 years before the onset of symptoms of sinus histiocytosis with massive lymphadenopathy.]7
It is not surprising that our patient had multiple extranodal sites of sinus histiocytosis with massive lymphadenopathy, because the incidence of other extranodal disease in patients with either ophthalmic, neurologic, or skin involvement is approximately 50%, 16'19'20 There are ~at least 21 reported cases of cutaneous invol.vement in sinus histiocytosis with massive lymphadenopathy, although a full clinical description with histologic confirmation has been reported in only 15 cases. 2J6,lv'z~ The overall incidence of cutaneous disease as reported by Thawerani et al.l~ is 9%. Among patients with sinus histiocytosis with massive lymphadenopathy, cutaneous disease has occurred more frequently in white patients and in male patients. 16 The cutaneous lesions have included macules, papules, plaques, and nodules. The majority of the lesions are multiple, and in at least one case the nodules have been painful. 16.22 One patient had a pruritic papulosquamous rash with a positive Koebner phenomenon resembling
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Table I. Monoclonal markers, specificity, and results Monoclonal markers
Findings in tissue
Specificity
Leu-4
80%-90% human peripheral blood lymphocytes8,9
35.1
Thymocytes, mature T cells ~~
Leu-3a
Cortical thymocytes, helper-inducer T lymphocytes8,9
Leu-2a
Cortical thymocytes, cytotoxic-suppressor T lymphocytes89 Monocytes~ MonocytesJ Monocytes and macrophagesj2 Cortical thymocytes, epidermal Langerhans cells ~3:4 Langerhans cells, other dendritic cells, macrophages, monocytes, B cells, some activated T cells t5
VI TE5 CMO2 NA1/34
guttate psoriasis that on biopsy showed a typical pattern of sinus histiocytosis with massive lymphadenopathy. 2~Two patients have had brownish pigmentation, one diffuse and the other limited to the extremities. ~6,26What the pigment is and whether it is related to this disease process directly or is a secondary effect of extranodal sinus histiocytosis with massive lymphadenopathy is unknown. The cutaneous lesions may be the initial presentation of the disease, and therefore the histologic recognition of this entity in the skin is important. 16Our patient's dermatopathologic features were similar to those in other reported cases of sinus histiocytosis with massive lymphadenopathy and largely mimic those of involved lymph nodes. In general, there is a dense dermal infiltrate consisting of aggregates of histiocytes with lymphocytes.16 Plasma cells and polymorphonuclear leukocytes are also present in > 5 0 % of cases. 16 In the smaller skin lesions, the dense inflammatory infiltrate is generally confined to the papillary dermis, whereas the larger lesions may go down into fat. 16The histiocytes are similar to those described in lymph nodes, although lymphophagocytosis is
Rare positive epidermal cells; scattered positive mononuclear cells in papillary dermis and sheets of mononuclear cells in reticular dermis Many positive mononuclear cells in reticular dermis Scattered positive epidermal monocytes; >60% of dermal mononuclear cells positive, in papillary greater than in reticular dermis ~50% mononuclear cells in reticular dermis positive Negative Negative Positive cells in reticular dermis Keratinocytes rimmed; negative dermis Scattered positive cells in papillary dermis
less common. ~6Fibrosis is generally increased relative to that seen in lymph node abnormality. Foreign body and Touton giant cells, as well as lipophagic granulomas, have been reported in cutaneous infiltrates. 16The epidermis in skin lesions is generally normal or may be affected, as a bystander, with flattening and parakeratosis. One case report did mention exocytosis ~6 and another, patchy spongiosis of the epidermis. 22 The histologic picture of sinus histiocytosis with massive lymphadenopathy in the skin, by itself, is not diagnostic. 16 Other diseases can show large numbers of histiocytes in the d e r m i s - - f o r example, infection by atypical mycobacteria, leprosy, leishmaniasis, syphilis, histiocytosis X, and xant h o m a s - - b u t most often these cart be distinguished from sinus histiocytosis with massive lymphadenopathy by clinical information or by using special stains and electron microscopy. 29 The cutaneous histiocytic infiltrate in our patient was negative for the monocyte markers V~ and TE5 but were phenotypically positive when CMO2 was used. The lack of infiltrating mononuclear cells with cell surface markers positive for monoclonal antibody
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Sinus histiocytosis with massive lymphadenopathy
N a l / 3 4 eased differentiation from histiocytosis X in our patient and, along with OKT6, may provide a reliable differentiating procedure. The cutaneous infiltrate of our patient demonstrated the mixed inflammatory infiltrate typically seen in extranodal sinus histiocytosis with massive lymphadenopathy.16 Cells of the T helper-inducer phenotype were more prominent in the papillary dermis and in rare foci of epidermal exocytosis, whereas those of the suppressor cell phenotype were more prominent in the reticular dermis. Mir et a l ) ~ examined the central nervous system tumor of a patient with sinus histiocytosis with massive lymphadenopathy by immunofluorescence histologic study and found that although most of the lymphocytes were negative for T cell surface antigens, those which were positive were primarily T suppressor cells (OKT8-positive). 3~ It certainly is not surprising to see such a prominent juxtaposition of histiocytes (macrophages) and lymphocytes histologically, because macrophages synthesize factors that lead to lymphocyte proliferation, maturation, and lymphokine production) 1 Antibodies to N a l / 3 4 in the epidermis and to L243 in the dermis confirmed the presence of Langerhans or other dendritic cells, a common finding in a reactive lymphocytic infiltrate. The disease course in many patients with sinus histiocytosis with massive lymphadenopathy is one of spontaneous regression over a course of months to years: :6'24 However, only 21% of 215 patients followed in a registry of these cases actually became disease free, and at least 14 patients have died. 2S Our patient has survived 30 years since the onset of symptoms consistent with his diagnosis of sinus histiocytosis with massive lymphadenopathy; the longest reported survival before our patient was 24 years. 17 Usually the extranodal sinus histiocytosis with massive lymphadenopathy regresses first, and adenopathy alone may persist for years) Because of the rarity and benignity of sinus histiocytosis with massive lymphadenopathy in the majority of affected patients, a concerted approach to treatment has been lacking. Antibiotics have been of no benefit: and systemic steroids have, in general, shown the most benefit in a partial
1329
Table II. Reported incidences of extranodal manifestations Clinical features
Adenopathy Hypergammaglobulinemia Anemia + Coombs' test Fever Leukocytosis Neutrophilia Weight loss Splenomegaly, hepatomegaly Extranodal manifestations Ophthalmic Upper respiratory tract Tonsillitis Nasal discharge or obstruction Skin Bone GI involvement: Stomach/colon infiltration Amyloid Neurologic Salivary Testicular
Incidence [ Reference(s)
>95% 81% 78% >4% >56% 38% 45% 18% 12%
7 7 7 16 7 7 7 7 5
12% 12% 11% 8%
7, 20 7 7 7
9% 8%
7 7
1 case
18
2 cases 4% 3% > 1%
5, 17 19 7 7
and temporary decrease in nodal size or symptoms: ,6.2~ Intralesional steroids have been ineffective in this and one other case 22 in which skin lesions were specifically treated. There have been reports of a transient decrease in adenopathy or extranodal involvement with irradiation, but regrowth has often occurred after radiation therapy. 6.2~ Surgical excision alone has been lifesaving in cases where the disease impinged on vital organs .35 Case reports of various chemotherapeutic regimens for sinus histioeytosis with massive lymphadenopathy abound, but most have shown only partial clearing of signs, amelioration of symptoms, or both. 6'18'2~ One patient had an initial complete response to cyclophosphamide (Cytoxan) alone, with a second persistent complete remission after retreatment of a r e l a p s e . 34 A second patient had a dramatic response to eyclophosphamide with prednisone: Whether these complete responses were directly attributable to the drug
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therapy or to spontaneous remission is impossible to say. The cause of sinus histiocytosis with massive lymphadenopathy remains obscure. Two main theodes have been advanced: a primary infectious cause and a disturbance in cell-mediated immun i t y - t h e two not necessarily being mutually exclusive. Mycobacteria have been avidly searched for, but no acid-fast bacteria or granulomas have been found in histologic specimens, and antituberculous therapy has been of no benefit3 ~ Rhinoscleroma histologically resembles sinus histiocytosis with massive lymphadenopathy,2~ and one patient with sinus histiocytosis with massive lymphadenopathy had elevated KlebsieUa rhinoscleromatis and K. ozaenae antigen levels, 24 but the absence of organisms in pathologic specimens 3~ and negative Klebsiella titers in other reported cases make this cause unlikely: ~ Several potential viruses have been suggested as causative agents in sinus histocytosis with massive lymphadenopathy, including rubella4t-43 and cytomegalovirus. ~ Probably the strongest potential viral etiologic agent in sinus histiocytosis with massive lymphadenopathy is the Epstein-Barr virus. 2~.~ Although 15 of 22 patients in a registry of cases of sinus histiocytosis with massive lymphadenopathy had elevated Epstein-Barr virus titers, 7 in developing countries and socially deprived areas, where the majority of cases of sinus histiocytosis with massive lymphadenopathy are found, 80% of infants show a seropositive response/~ Despite bacterium and virus isolation procedures and electron microscopic techniques, no infectious agents have been found in sinus histiocytosis with massive lymphadenopathy. The histiocytic proliferation seen in sinus histiocytosis with massive lymphadenopathy could be the result of an intrinsic cellular defect, as exemplified by chronic granulomatous disease. There have been reports of both normal and decreased blast transformation of lymphocytes to phytohemagglutinin, concanavalin A, or pokeweed mitogen in patients with sinus histiocytosis with massive lymphadenopathy, making a uniform defect in lymphocyte-mediated cellular immunity unlikely: '2r Moreover, sinus histiocytosis
with massive lymphadenopathy does not seem to be an antibody-mediated disorder, because macrophages retain the property of phagocytosis of other cells and microorganisms in vitro in the absence of specific stimulation, s~ Sinus histiocytosis with massive lymphadenopathy has been reported in siblings, 35 raising the possibility of either an inherited or acquired idiosyncratic response to infection or an immunologic disorder with a secondary infection. SUMMARY
Our patient is unusual in his lengthy survival despite multiorgan involvement with sinus histiocytosis with massive lymphadenopathy and the presence of a heretofore undescribed associated monoclonal gammopathy. Using monoclonal antibodies to a variety of cell surface markers, we have more fully described the concomitant lymphocytic portion of the cutaneous infiltrates and have differentiated sinus histiocytosis with massive lymphadenopathy from histiocytosis X. We also reviewed the literature pertinent to the dermatologic and other extranodal aspects of sinus histiocytosis with massive lymphadenopathy. REFERENCES 1. Rosai J, Doffman RF. Sinus histiocytosis with massive lymphoadenopathy. Arch Pathol 1969;87:63-70. 2. Azoury FJ, Reed RJ. Histiocytosis: report of an unusual case. N Engl J Med 1966;274:928-30. 3. Destombes P. Ad6nites avec surcharge lipidique, de l'enfant ou de l'adulte jeune, observe6s aux antilles et au mali. Bull Soc Pathol Exot Filiales 1965;6:1169-75. 4. Eighteenth seminar of the Penrose Cancer Hospital. Cancer Seminar 1967;3:246-250. 5. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Cancer 1972;30:1174-88. 6. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive ]ymphadenopathy. Arch Otolaryngol 1978;104: 687-93. 7. Sanchez R, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: an analysis of 113 cases with special emphasis on its extranodal manifestations. Ann Meet Abstr 1977;36:349-50. 8. Ledbetter SA, Evans RL, Lipinski M, CunninghamRundles C, Good RA, Herzenberg LA. Evolutionary conservation of surface molecules that distinguish T lymphocyte helper/inducer and T eytotoxic/suppressor populations in mouse and man. J Exp Med 1981;153:31023.
Volume 18 Number 6 June 1988
Sinus histiocytosis with massive lymphadenopathy
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ABSTRACTS Physiological study of pruritus ani Allan A, Ambrose NS, Silverman S, Keighley MRB. Br J Surg 1987;74:576-9 A surgical faculty with fecal fascination found a fertile field for expository, imaginative, and innovative investigation. These serious speleologic searchers used history, rectal examination, proetoscopy, sigmoidoscopy, linear analog severity scale, Wood's lamp, Sellotapo, and Sabouraud's agar, as well as saline infusion tests, to assess anal sphincter competence for fluids; an ischial tuberosityjig and rod to measure perineal descent; a soft rubber rectal balloon and fine tube with a ballon probe and strain gauge amplifier and recorder to evaluate maximal resting and squeeze pressures; a rectal sensation balloon; a rectal balloon with an air-filled
pressure transducer to assess rectal compliance; and balloon proctography with a radiolucent lavatory seat and videorecorder to measure the degree of perineal descent in relation to the pubococcygeal line, as well as anorectal angles. Patients with pruritus ani showed a marked increase in leakage through the anal canal compared with controls; perhaps the hermeneuties of this hermetic failure is linked to coexisting occult anal disease or an exaggerated rectoanal inhibitory reflex. Alas, even excremental exegesis by manometry and radiology failed to find a fundamentally fatal flaw that could be consistently corrected in an effort to expunge or expurgate the persistent pruritus in patients with this pathogenetically poorly understood, common, and disabling disorder. Steven R. Kohn, M.D.