Massive Lymphadenopathy Mimicking Lymphoma in Leukemic Reticuloendotheliosis

DANIEL R. BUDMAN. M.D.*

BENJAMIN KOZINER, M.D. ZALMEN ARLIN, M.D.

NINA LAMPEN, B.A. TIMOTHY GEE, M.D.

New York. New York

From the Hematology Service, Department of Medicine, and the Laboratory of Biological Ul- trastructure, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York. This work was supported by National Cancer Institute Grants CA 08748, CA 05826 and CA 19119-01; and American Cancer Society Grants CH-GG, CF 3996 and PDT-95. Requests for reprints should be addressed to Dr. B. Ko- ziner, Department of Medicine, Hematology/ Lymphoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Manuscript accepted June 7, 1978.

* Present address: Division of Medical On- cology, North Shore University Hospital, Man- hasset, New York 11030.

Leukemic reticuloendotheliosis is increasingly noted to have a spectrum of laboratory findings suggestive of both lymphocytes and monocytes. However, previous reports have not noted a clinical presentation which may be confused with lymphoma. This report documents a case of leukemic reticuloendotheliosis in a 29 year old man with clinical findings of diffuse lymphadenopathy, organome- galy and cutaneous involvement. As cytotoxic agents may be dys- functional in leukemic reticuloendotheliosis, the ability to distinguish between this disorder and a lymphomatous process may be critical to the patient’s management. Both morphdlogic examination of the “hairy-cell” and cytochemistry may not gitre an unequivocal differ- entiation between these two diseases. However, functional studies of the neoplastic cell, such as cell-marker analysis, phagocytic function and ultrastructural morphology, can define by noninvasive methods the correct diagnosis in the atypical presentation of leuke- mic reticuloendotheliosis.

Leukemic reticuloendotheliosis or “hairy-cell leukemia” is a rare, poorly understood proliferation of mononuclear cells. These neoplastic cells may show morphologic and/or functional properties of mono- cytes, B lymphocytes or, rarely, T lymphocytes [l-5]. However, the clinical findings have been considered to be uniform with progressive splenic enlargement and minimal or absent lymphadenopathy [6].

This report documents that leukemic reticuloendotheliosis can on occasion present with adenopathy and cutaneous involvement sug- gestive of a lymphomatous process. In such patients, immunologic, morphologic and functional studies of the abnormal cell can be of use in determining the correct diagnosis.

CASE REPORT

The patient was a 29 year old white man who presented at another institution for evaluation of venous varicosities of his legs. A routine blood count showed a hematocrit value of 32 per cent, a white blood cell count of 8,600 cells/mm3 and a thrombocyte count of 30,0OO/mm3. Mononuclear cells with “hairy” projections were noted on peripheral smear. Because of this anemia and thrombocytopenia, a marrow aspirate and biopsy specimen were obtained, demonstrating an atypical mononuclear infiltrate “consistent with leukemic reticuloendotheliasis.” Fourteen per cent of these cells gave a positive stain for tartrate-resistant acid phosphatase. Physical examination was significant for generalized adenopathy and hepatosplenomegaly. The patient underwent laparotomy with removal of a 2,370 g spleen. The pathologic findings showed diffuse infiltration of the spleen consistent with leukemic reticuloendotheliosis. After splenectomy, he had a persistent leukocytosis [between 10,000 and

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MASSIVE LYMPHADENOPATHY IN LEUKEMIC RETICULOENDOTHELIOSIS-BUDMAN ET AL,

TABLE I Distribution of Surface Markers on Perlpheral Blood Mononuclear Cells

Latex SRBC’ Rosette Indirect Ingesting Forming Mouse Ripley Aggregate Immunoglobulin-Bearing Lymphocytes

Cells Lymphocytes Rosette Rosette Binding (%) (56) (%) (%) (%) (% ) PV+ IgG IgM IgA IgD I( h

Patient 30 16 5 1 81 87 11 74 18 4 72 0 Control 17 72 4 15 18 5 8

(Mean of 180 normal subjects)x f 8 f 11 f3 f7 f7 :: f4 f4 *“2 *“2 *88 *‘7

l Sheep erythrocyte. + Polyvalent antiserums. g f standard deviation.

50,000 cells/mm3). The majority of the peripheral white blood cells were “hairy.”

Seven months after diagnosis, he was first evaluated at Memorial Sloan-Kettering Cancer Center with complaints of fatigue, dyspnea on exertion and frontal headaches. His he- moglobin level was 6.5 g/dl, white blood cell count 57,000 c/mm3 and platelets 28.000/mm3. Peripheral smear showed 1 per cent neutrophils, 1 per cent band forms, 1 per cent mo- nocytes, 33 per cent lymphocytes and 64 per cent “hairy-cells.” Cr5l red blood cell scan showed no evidence for residual splenic tissue. A chest film demonstrated bilateral adenopathy with hilar nodes at least 2 cm in diameter. Repeat bone marrow aspirate and a biopsy specimen showed diffuse infiltration of the marrow with “hairy-cells.”

One year after diagnosis, hyperpigmented skin lesions de- veloped on his legs. A skin biopsy specimen of these lesions confirmed the presence of a “hairy-cell” infiltrate. Physical examination once again demonstrated diffuse adenopathy with some nodes greater than 3 cm in diameter. A chest film, intravenous pyelogram and computerized axial tomography showed massive adenopathy in the mediastinum and in the retroperitoneum. Urinary lysozyme levels were negative.

Progressive anemia, neutropenia and thrombocytopcnia developed. In an attempt to reverse the patient’s deteriorating hematologic picture, he was treated with sequential trials of vincristine and prednisone, localized irradiation (100 rads to a nodal area), high-dose cyclophosphamide (30 mg/kg), and a combination of vincristine, phenylalanine mustard, pred- nisone, cyclophosphamide and BCNU. He had no response to therapy and died of Escherichia coli pneumonia 16 months

after initial diagnosis. Autopsy revealed massive tumor infil- tration of the skin, bone marrow, colon, small bowel, liver, pelvic peritoneum, heart, genitalia, adrenals, kidneys, cav- ernous sinus and lymph nodes. Many of the lymph nodes were greater than 7 cm in diameter.

MATERIALS AND METHODS

All studies were carried out prior to therapy. The mononuclear cells were separated from heparinized blood by isopycnic centrifugation [7]. Viability by Trypan blue dye exclusion al- ways exceeded 90 per cent. Phagocytic cells were identified by incubation of 5-10 X lo6 mononuclear cells for 1 hour with 0.8 p polystyrene particles. Surface immunoglobulins were detected by previous immunofluorescent methods [8] as was binding of aggregated immunoglobulin G (IgG] to the cell surface [9]. Intracytoplasmic immunoglobulin was assayed

after in vitro mitogen stimulation at 1:l ratio with pokeweed mitogen (Grand Island Biological Co.) and culture in 5 per cent carbon dioxide for six days. Spontaneous sheep erythrocyte rosette formation (SRBC-rosette) and mouse erythrocyte rosette formation were determined by past methods [lO,ll]. High affinity F, receptors were detected by a modification [12] of previous human EA [Ripley) technic [13]. The tritiated (sH)- thymidine labeling index of marrow mononuclear “hairy cells” was measured with 1,000 “hairy cells” counted [14].

For electron microscopic study, the separated circulating mononuclear cells were layered onto polylysine-coated cov- erslips [15]. The cells were fixed with 2.5 per cent glutaral- dehyde in RPMI-1640, dehydrated in ethanol, stained with a 100 8, gold coating and examined by a JEOL 35 scanning electron microscope. The cells were studied by transmission electron microscopy in a similar way.

RESULTS

As shown in Table I, the distribution of mononuclear cells isolated from this patient differed markedly from control values. Three-quarters of the circulating mo- nonuclear cells were “hairy” on light microscopy. Ap- proximately the same number of isolated cells demon- strated F, surface membrane receptor by their ability to bind aggregated immunoglobulin. Phagocytic func- tion, measured by the ability to ingest latex particles, was also detected in one third of these cells. In contrast, a relative depression of the number of SRBC-rosette forming cells was present. There was no increase in the percentage of mouse red cell-rosette forming cells.

An immunofluorescent analysis of the cell-membrane surface immunoglobulin revealed a pattern of restricted heterogeneity with IgM kappa. This surface immuno- globulin persisted for six days in culture. Despite in vitro stimulation of the cells with pokeweed mitogen, no in- tracytoplasmic immunoglobulin was found. However, the “hairy” cells were noted by light microscopy to have developed plasmacytoid morphologic features after exposure to pokeweed mitogen.

The morphologic features of the “hairy” cell were studied by both transmission and scanning electron microscopy. Transmission electron microscopy re- vealed a monocytoid ultrastructure, with scanning electron microscopy showing extensive ruffling of the surface membrane.

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MASSIVE LYMPHADENOPATHY IN LEUKEMIC RETICULOENDOTHELIOSIS-BUDMAN ET AL.

COMMENTS

Leukemic reticuloendotheliosis is an interesting disease which has received much attention because the neo- plastic cell demonstrates both lymphocytic and mono- cytic characteristics [l-4]. This syndrome also has similarities with chronic lymphocytic leukemia and some lymphomas. In all these diseases the patients may present with organomegaly, have neoplastic cells with a low mitotic index, and the abnormal cells may remain in the circulation for extended periods of time [16]. In addition, patients with lymphomas may have circulating “hairy cells” which are acid-phosphatase positive [17]. Hence, both morphologic and histochemical technics cannot be considered definitive procedures in sepa- rating these diseases.

involvement has not been previously associated with leukemic reticuloendotheliosis. This case demonstrates that leukemic reticuloendotheliosis may present with findings suggestive of a lymphomatous process. In such cases, cell surface markers, functional studies, ultra- structural morphology and histochemistry may be needed to make a noninvasive diagnosis of leukemic reticuloendotheliosis.

A combination of laboratory and histologic technics can be used to distinguish leukemic reticuloendothe- liosis from other lymphoid neoplasms. Diffuse splenic involvement with “hairy cells” in the peripheral blood is more characteristic of leukemic reticuloendotheliosis [7,18]. Cell surface determinants showing lymphoid characteristics with the presence of phagocytic function is also more characteristic of leukemic reticuloen- dotheliosis [2,3,18]. In this patient, all these studies confirmed the diagnosis of leukemic reticuloendothel- iosis. Ultrastructural studies by electron microscopy demonstrating the monocytic morphology of the neo- plastic cell add additional support to the diagnosis.

The distinction between a lymphomatous disorder and leukemic reticuloendotheliosis assumes critical importance when consideration of therapy arises. Pa- tients with leukemic reticuloendotheliosis are known to have a limited granulocyte reserve and to do poorly when treated with cytotoxic agents [16,19]. With the current recognition that a lymphoma may show “hairy cells” with a positive acid-phosphatase stain in the pe- ripheral blood, patients with leukemic reticuloen- dotheliosis presenting with findings such as those in this case might mistakenly be treated with cytotoxic agents early in the course of the disease. Such treatment would obviously be dysfunctional and, perhaps, fatal. Hence, all patients with a lymphomatous clinical picture and “hairy cells” in the peripheral blood need in vitro studies to define the correct disease. In the uncertain patient, splenic pathology might also be needed if noninvasive studies are equivocal.

ACKNOWLEDGMENT

However, in contrast to chronic lymphocytic leukemia We wish to thank Dr. Bayard Clarkson and Dr. Etienne or lymphoma, massive lymphadenopathy or cutaneous de Harven for their critical review of the manuscript.

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