Peripheral T-cell lymphoma presenting as hypereosinophilia with vasculitis

Peripheral T Cell Lymphoma Presenting as Hypereosinophilia with Vasculitis

Clinical, Pathologic, and Immunologic Features

JOHN J. O’SHEA, M.D. ELAINE S. JAFFE, M.D. H. CLIFFORD LANE, M.D.

Bethesda, Maryland

RICHARD P. MacDERMOTT, M.D.

St. Louis, Missouri

ANTHONY S. FAUCI, M.D.

Bethesda, Maryland

From the Laboratories of Clinical Investigation and Immunoregulation, National Institute of Al- lergy and Infectious Diseases, the Laboratory of Pathology, National Cancer Institute, National In- stitutes of Health, Bethesda, Maryland, and Washington University School of Medicine, St. Louis, Missouri. Requests for reprints should be addressed to Dr. John J. O’Shea, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20205. Manuscript submitted November 5, 1985, and accepted December 17, 1985.

Peripheral T cell lymphoma developed in two patients several years after an initial clinical presentation of eosinophilia, pruritic skin rash, and vasculitis with lymphocytic infiltrates. Despite treatment with combination chemotherapy, the patients survived less than six months after the malignant lymphoma emerged. Immunologic characterization of tumor cells demonstrated features characteristic of peripheral T cell lymphoma. T lymphocytes from one patient had the uncommon phenotype of TS-negative, T4-positive, T8-negative. Extensive functional studies of this patient’s lymphocytes revealed a poor proliferative response as well as an inability to help in immunoglobulin production, despite the preponderance of T4 lymphocytes. It is hypothesized that this syndrome is a consequence of the activity of products elaborated by neoplastic T cells.

The hypereosinophilic syndrome encompasses a heterogeneous group of disorders that usually include prolonged idiopathic eosinophilia and organ system dysfunction related to the eosinophils themselves and/or their products [I]. Of the more than 50 patients with the idiopathic hypereosinophilic syndrome followed at the National Institutes of Health (NIH), two patients demonstrated a unique sequence of disorders. initially, these patients were found to have hypereosinophilia and lymphocytic vasculitis; however, over a period of several years, a peripheral T cell lymphoma ultimately developed. Post-thymic T cell neoplasia (excluding mycosis fungoides and the Sezary syndrome) is uncommon, and proba- bly includes several variants of mature or peripheral T cell lymphomas [2-71. Although the association of lymphoreticular malignancy and hypereosinophilia is well established, eosinophilia and vasculitis have not been described as features of T cell lymphomas in previous reports [2-71.

We herein present the clinical, pathologic, and immunologic features in these two unique patients and, in addition, consider the possibility that the primary clinical manifestations of hypereosinophilia and vascuiitis may be the result of factors generated by abnormal T cells with restricted immunocompetence.

METHODS AND CASE REPORTS

Immunologic Characterization of Tumor Cells. Peripheral blood mononuclear cells were obtained by density gradient centrifugation through Ficoll- Hypaque (Lymphoprep, Nygaard & Company; Oslo, Norway). Lymph node tissue was minced in RPMI 1640 (Gibco; Grand Island, New York) and filtered through a wire mesh to obtain a mononuclear cell suspension. The erythrocytes were lysed with an ammonium chloride lysate at 4% Mono- nuclear cells were assayed as previously described [8,9] for E rosette,

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HYPEREOSlNOPHlLlA AND VASCULITIS IN T CELL LYMPHOMA-O’SHEA ET AL

complement, and Fc receptors, surface immunoglobulin heavy and light chains, and terminal deoxynucleotidyl transferase, as well as acid phosphatase, beta-glucuronidase, alpha-naphthyl butyrate esterase, acid alpha-naphthyl acetate esterase, naphthol ASD-acetate esterase, and alkaline phosphatase. In addition, phenotypic analysis using monoclonal antibodies directed against T and B surface antigens was also performed [IO] : OKT3,OKT4,OKT6,OKT6 (Ortho Diagnostic; Raritan, New Jersey): Leul, LeuPa, Leu3a, Leu4, and HLA-DR (la) (Becton-Dickinson; Sunnyvale, Cali- fornia); Lyt3 (New England Nuclear; Boston, Massachu- setts); Bl, J5 (Coulter Monoclonal Antibodies; Hialeah, Flor- ida); 3Al (ATCC; Rockville, Maryland); and anti-TAC (Dr. T. Waldmann, NIH).

quired. Because pathologic examination of the digital artery revealed severe lymphocytic vasculitis, the patient began receiving cyclophosphamide (2 mg/kg per day) in addition to prednisone. From 1979 to 1980, she was admitted with pyogenic cutaneous abscesses, asthma, and a recurrence of peripheral vasculitis.

A portion of the lymph node specimen and a 6 mm punch biopsy specimen of skin from Patient 2 were snap-frozen, and air-dried, acetone-fixed frozen sections were stained by the avidin-biotin-complex immunoperoxidase method as previously described [ IO], using the monoclonal antibodies and antiserum to the heavy and light chains just described. These studies allowed characterization of the patient’s neoplastic cells within the T, B, or monocyte/macrophage lineages. Immunologic Studies. Lymphocyte blastogenic responses to phytohemagglutinin and concanavalin A, helper and suppressor activity, and in vitro immunoglobulin production were determined as previously described [ 11,12]. Lympho- cyte subset ratios were determined by flow cytometry as described [12]. Detection of antibodies against human T cell leukemia virus I (HTLV-I) was performed as described [131. Case Reports. Patient 1: A 38-year-old black woman was admitted to the Clinical Center of the NIH in 1977 for evaluation of hypereosinophilia. She had been well until 1975 when eczematous dermatitis developed. In 1976, following the delivery of her fourth child, she experienced an exacerbation of the dermatitis, which did not respond to therapy with topical steroids, and she was hospitalized locally. She was found to have peripheral blood eosinophilia (absolute cell count, 13,000/mm3) as well as eosinophilic infiltrates of the skin, lymph nodes, liver, and bone marrow. She was therefore referred to the NIH for inclusion in the idiopathic hypereosinophilic syndrome protocol [ 11. Upon evaluation, she was found to have elevated immunoglobulin A and M levels with a normal IgG level and no Bence Jones proteinuria. Bone marrow examination revealed 25 percent eosinophils but no evidence of malignancy. The results of tests for underlying causes of eosinophilia, such as parasit- ic infestation, were negative. The hospital course was com- plicated by the development of a cutaneous staphylococcal abscess, recurrent splenic infarcts, and bronchospasm. Treatment with alternate-day systemic corticosteroids was begun, and the patient improved. From 1977 to 1979, she was admitted on several occasions with recurrent cutaneous abscesses and exacerbations of asthma.

In 1980, she was admitted with a sore throat, cough, and fever. Evaluation revealed Candida esophagitis. In addition, bone marrow biopsy revealed malignant lymphoma, further characterized as a mature T cell type. Treatment was begun with doxorubicin, nitrogen mustard, vincristine, and prednisone. Two days after the initiation of therapy, however, the patient died from pulmonary embolus and sepsis. Postmortem examination revealed evidence of malignant lymphoma and an erythrophagocytic syndrome (see later).

Patient 2: A 27-year-old man appeared to be healthy until 1974 when, after a routine inguinal hernia repair, a generalized erythematous skin rash associated with peripheral blood eosinophilia (absolute count, 5,000/mm3) developed. He was treated with systemic corticosteroids, which induced transient improvement; however, whenever the dosage of prednisone was tapered, the condition recurred. A trial of therapy with dapsone was also ineffective.

In July 1975, the patient was re-evaluated and found to have a white blood cell count of 16,200/mm3 with 31 percent eosinophils, an elevated IgM level of 3,450 mg/dl (normal, less than 266), an elevated IgE level of 518 IU/ml (normal, less than 300), cryoglobulinemia, and a mild hemolytic anemia with antibody directed against I antigen. His other immunoglobulin levels were normal, and results of tests for hepatitis B surface antigen, antinuclear antibody, and anti-DNA antibody were negative. Skin biopsy performed at this time demonstrated extensive dermal perivascular infiltration by plasma cells, eosinophils, and lymphocytes. Pathologic study of a bone marrow aspiration sample revealed granulocytic hyperplasia and eosinophilia. Lymph node biopsy demonstrated normal tissue architecture without evidence of lymphoma. Findings on radiographic studies of the upper and lower gastrointestinal tracts as well as intravenous pyelography were all normal.

In 1979, she was admitted with digital ischemic necrosis. Atteriography demonstrated arteritis of the medium-sized vessels of the hand and fingers. Visceral angiography, however, showed no abnormalities. The digital lesion healed poorly, and surgical amputation was ultimately re-

Because of this patient’s immunologic abnormalities (in- cluding elevated immunoglobulin and cryoglobulin values) and his poor response to therapy, he was referred to the NIH in August 1979. Evaluation revealed a white blood cell count of 27,400/mm3 with 18 percent eosinophils. His IgM and IgE levels remained elevated. The results of immunoglobulin electrophoretic studies of this patient and his serum protein and total hemolytic complement levels were unremarkable. At this time, the patient complained of dis- comfort and blanching of the fingers of his right hand in response to exposure to cold. Arteriography demonstrated occlusion of the digital arteries of the first finger, with beading and microaneurysms. Renal, splenic, superior mesenteric, and hepatic arteriography revealed no abnormalities. Because of the evidence of vasculitis, we initiated therapy with cyclophosphamide at 2 mg/kg per day in addition to prednisone. With this regimen, his skin lesions improved, and his eosinophilia was promptly reduced to the range of 600/mm3.

In February 1980, the development of hemorrhagic cysti-

540 March 1987 The American Journal of Medicine Volume 82

Figure 1. Skin rash in Patient 2, phot& graphed in June 1981, on left flank and thighs.

Figure 2. lmmunohistochemical stub ies of skin biopsy samples from Patient 2. Lefl, the dermis contains a dense atypical lymphoid infiltrate. The neoplas tic cells show positive results, with anti- Leu3a monoclonal antibody. Compara- ble staining was observed with OKT4. Right, a parallel frozen section is stained with OKT3. Most infiltrating lymphoid cells show negative results. Occasional positive cells are seen (ABC immune peroxidase technique, methyl green counterstain).

HYPEREOSINOPHILIA AND VASCIJLITIS IN T CELL LYMPHOMA-O’SHEA ET AL

tis necessitated discontinuation of cyclophosphamide and initiation of azathioprine at 125 mg daily. Subsequently, however, he was found to have a rising eosinophil count (5,130/mm3), a rising erythrocyte sedimentation rate, and an increase in circulating immune complexes. Later, digital pain and new skin lesions developed. The dose of azathioprine was increased, but neither his clinical nor laboratory parameters improved. Therefore, bolus methylprednisone therapy was begun; this was administered in 1 g doses for three consecutive days every eight weeks. With this regimen, his skin condition improved, and his erythrocyte sedimentation rate, eosinophilia, and level of circulating immune complexes decreased.

In June 1981, his skin lesions appeared to change in character (Figure 1). Another skin biopsy was performed (Figure 2). The findings from this biopsy were diagnostic of a diffuse type of malignant lymphoma, with a mix of small and large cells, which was further characterized as a peripheral T cell lymphoma. Evaluation at that time revealed

an absolute eosinophil count of 3,200/mm3. Lumbar punc- ture and analysis of cerebrospinal fluid revealed no abnormalities. Findings on chest radiography; mediastinal, ab- dominal, and head computed tomography; liver-spleen and gallium scanning; and skeletal survey were all negative. Lymph node biopsy demonstrated the presence of lymphoma, and the patient was classified as having stage IV lymphoma.

The patient began receiving combination chemotherapy in August 1981. He received four cycles of therapy with nitrogen mustard (8 mg/m*), vincristine (1.4 mg/m*), prednisone (40 mg/m* for 14 days), and procarbazine (100 mg/m* for 14 days). During the fourth cyc!e of chemotherapy, herpes zoster developed and was treated with arabi- nose arabinoside and improved. However, Pneumocystis carinii pneumonia then developed, and despite vigorous therapy with trimethoprim/sulfamethoxazole and later pen- tamidine, the patient died of respiratory failure. Postmortem examination showed no residual lymphoma.


HYPEREOSINOPHILIA AND VASCULITIS IN T CELL LYMPHOMA-O’SHEA ET AL

Figure 3. E rosette-forming neoplastic cell from the pt+ ripheral blood of Patient 1. Neoplastic cells had markedly basophilic cytoplasm and hyperchromatic nuclei (Wright- Giemsa stain).

TABLE I Relative Proportions of T Cell Subsets in Two Patients with Hypereosinophilia, Vasculitis, and Peripheral T Cell Lymphoma*

Percent of T Cells T&Positive T4-Positive T&Positive

Patient 1 76.5 f 6.5 76.3 f 8.8 10.5 f 0.5 (n = 3)

Patient 2 16.0 f 4.8 95.2 f 2.2 2.3 f 3.2 (n = 2)

Normal subjects 83.5 f 2.5 54.5 f 2.0 31.0 f 3.1 (n = 38 [12])

*Peripheral blood lymphocytes were stained with indicated monoclonal antibodies, and flow cytometry was performed to quantitate T cell subsets. Data are expressed as means f SEM.

TABLE II Phenotype of Peripheral Blood T Lymphocytes of Patlent 2 Compared with Normal Subjects*

Absolute Number of T Cells Tt-Positive T4-Positive T&Positive

Normal 1,761.0X/+ 1.06 1,205 X/3 1.07 406 Xl+ 1.01 subjects (n = 38 [121)

Patient 2 9180 706.9 3198 5.5 6181 397.6 3081 0 7181 489 3178 5.5

“Peripheral blood lymphocytes were stained with the indicated monoclonal antibodies, and flow cytometry was performed to quantitate T cell subsets. Data are expressed as geometric means Xl+ SEM.

RESULTS

Pathologic Findings. Patient 1: Multiple punch biopsy samples of the skin were obtained from 1977 to 1980. All of these samples showed a varying degree of lymphocytic vasculitis with infiltrates of normal-appearing lymphocytes around and within the walls of small blood vessels. The lymphocytes did not show cytologic atypia. The lymphocytes were admixed with varying numbers of eosinophils, which were numerous in some samples. The over- lying epidermis did not show infiltration or Pautrier mi- croabscesses, although one epidermal specimen showed acute necrosis. The amputation representing the tip of the right index finger showed gangrenous necrosis of skin, soft tissue, and bone with acute osteomyelitis. A bone marrow sample obtained in 1980 revealed infiltration by abnormal large lymphoid cells with basophilic cytoplasm, reticulated chromatin, and prominent nucleoli. Similar cells were identified in the peripheral blood where they represented 87 percent of all circulating mononuclear cells. Postmortem examination disclosed widespread dis- semination by a malignant lymphoma classified as a large cell, immunoblastic type. Tumorous tissue was present in the spleen, liver, lymph nodes, lung, and skin, but no bone marrow involvement was seen. The postmortem findings indicated that the distribution of the tumor was primarily perivascular or angiocentric. Also noted was histologic evidence of an erythrophagocytic syndrome with prominent erythrophagocytosis in the splenic red pulp, hepatic sinusoids, bone marrow, and focally within the sinuses of the lymph nodes. The histologic features of this erythrophagocytic syndrome have been previously described [8].

Patient 2: Skin biopsy samples obtained in 1979 showed lymphocytic vasculitis with admixed eosinophils. Cytologic atypia was not identified in the infiltrating lymphocytes. In 198 1, at the time of clinical change in the character of the skin lesion, repeated biopsy of the skin showed an extensive dermal infiltrate composed of afypi- cal small and large lymphoid cells characteristic of malignant lymphoma of the diffuse mixed small and large cell type (Figure 2). The small cells had condensed nuclear chromatin and irregular nuclear contours with sparse cytoplasm. The large cells had vesicular nuclei, prominent nucleoli, and a moderate amount of pale indistinct cytoplasm. Numerous eosinophils and occasional plasma cells were noted within the dermal infiltrates. The overly- ing epidermis was unremarkable. Biopsy of a right inguinal lymph node showed paracortical infiltration by small atypical lymphoid cells without large transformed lymphoid cells. The medullary cords showed marked plasma- cytosis. Postmortem examination showed no residual lymphoma nor any residual evidence of P. carinii pneumonia. Immunologic Characterization of Tumor Cells. The abnormal peripheral blood mononuclear cells from Patient 1 gave positive results for Leul and la, but lacked most


other T or B cell-associated antigens. Nine percent of the ceils formed E rosettes (Figure 3), and 19 percent reacted with Lyt3 or Ti 1, both antibodies directed against the E rosette receptor. Seventy-five percent of the cells from the lymph node sample from Patient 2 were E rosette- forming T cells. Both the lymph node T cells and the abnormal cells identified in the skin had a similar antigenic phenotype. The cells gave positive results for Leul, Leu3a/OKT4, Leu4, Lyt3, and la, and negative results for Leu2a/OKT8,OKT3, OKT6, 3A1, TAG, Bl, J5, and immunoglobulin heavy and light chains. Neoplastic cells from both cases were negative for terminal deoxynucleo- tidy1 transferase and lacked diffuse lysosomal enzyme activity characteristic of mononuclear phagocytes. The neoplastic cells did show focal punctate reactivity for acid phosphatase and acid alpha-naphthyl esterase. Thus, in both patients, the cells had T cell-associated antigens but had an abnormal phenotype, features characteristic of peripheral T cell lymphoma. Immunologic Studies. Phenotypic analysis of the peripheral T lymphocytes of Patients 1 and 2 revealed a de- crease in the proportion of T8-positive lymphocytes and an increase in TCpositive lymphocytes (Table I). Table II shows the serial phenotypic analysis of the lymphocytes from Patient 2 compared with results in the normal subjects studied by this laboratory [ 121. In addition, his peripheral T cells were 12.5 percent 3Al-positive (normal, more than 83 percent). Thus, the peripheral T cells of Patient 1 had the unusual phenotype of T3-positive, T4- positive, T&negative. As noted earlier, lymph node T cells and the abnormal cells identified in the skin had the same phenotype.

The nature of the clinical course of Patient 1 precluded extensive immunologic study. However, Patient 2 under- went extensive immunologic study over the period from 1978 to 198 1. The first of these studies was performed in 1978, prior to the patient’s referral to the NIH. At that time, he was receiving alternate-day treatment with 30 mg doses of prednisone. He was noted to have an absolute increase in his peripheral T lymphocyte count (7,400, with a normal value of less than 4,800 determined by sheep erythrocyte resetting). However, his mitogenic responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen were markedly below normal. Mixed lymphocyte culture responses were markedly below normal (data not shown). Lymphocyte cytotoxicity (allogenic, spontaneous, and antibody-dependent) was consistently absent (data not shown). Over the following three years, Patient 2 was evaluated periodically at NIH to obtain a record of his immunologic parameters. The patient’s se- verely diminished lymphocyte proliferative responses to mitogens and allogeneic cells remained diminished throughout his illness (Table Ill).

The in vitro immunoglobulin production by lymphocytes, which was tested on multiple occasions in Patient 2, also was found to be markedly below normal (Table

TABLE Ill Lymphocyte Blastogenic Responses of Patient 2*

Tritiated Thymidine incorporation (cpm) Phyto-

hemagglu- Concana- Pokeweed Allo- tinin valin A Mitogen reactivity

Patient 2 2,130 2,291 266 289 Normal subject 61,481 48,712 30,324 10,121

*Data indicate a representative study of several determinations performed from 1978 through 1981.

TABLE IV In Vitro lmmunoglobulin Production in Lymphocytes Obtained from Patient 2”

Pokeweed Mitogen Unstimulated Stimulation

W I@ &G WJ

Normal subject <0.5 1.7 16 14 Patient 2 <0.5 0.8 <0.5 0.8 Patient + allo-

geneic T cells - - 15.8 23.0

“Unfractionated lymphocytes (5 X 105) from a normal donor or from Patient 2 were incubated with medium alone or with pokeweed mitogen. At the end of a lo-day incubation period, the supernatants were assayed by enzyme-linked immunosorbent assay for immunoglobulins @g/ml). Lymphocytes from Patient 2 failed to produce immunoglobulin in response to pokeweed mitogen. However, immunoglobulin production was restored when the patient’s lymphocytes were cultured with irradiated T lymphocytes from a normal donor.

TABLE V lmmunoglobulin Production: Suppression Assay*

IgG @lM (ng) 044

Unfractionated normal 7,666 f 756 6,133 f 801 lymphocytes

Unfractionated normal 9,900 f 1,539 9,267 f 945 lymphocytes -I- normal T lymphocytes

Unfractionated normal 9,267 f 945 6,833 f 1,097 lymphocytes i- lymphocytes from Patient 2

“T cells (2.5 X 105) from a normal donor or Patient 2 were added to unfractionated lymphocytes from a second normal donor. Poke- weed mitogen was added, and the cells were incubated for 10 days. At the end of the incubation period, supernatants were assayed for immunoglobulin by enzyme-linked immunosorbent assay. There was no evidence of excessive suppressor function in the T cells of the patient.

IV). Normal immunoglobulin production was reconstituted when allogeneic T cells from a normal donor were added to cultures of the patient’s lymphocytes. Since decreased immunoglobulin production may have been due to either excessive suppressor function or the lack of helper function, these functions were assayed. As shown in Table V, no evidence of excessive suppressor function was seen



. 1

1 5 10 50

T CELLS ADDED (x10 ‘1

Figure 4. Lymphocytes from Patient 2 lacked helper a@ tivity. The T lymphocytes of the patient (open circles) or a normal donor (solid circles) were added in increasing num bers to unfractionated lymphocytes and cultured for 10 days. The patient’s lymphocytes were unable to provide help in normal production of immunoglobulin despite the preponderance of T4-positive (helper) cells.

when T cells from Patient 2 were added to normal lymphocytes. However, when the patient’s T cells were added to normal lymphocytes, they were unable to provide help in normal immunoglobulin synthesis (Figure 4). Thus, although the T cells from Patient 2 were of the T4- positive (helper-inducer) phenotype, they were found to be markedly deficient in their ability to mediate helper function. We were unable to make a direct functional evaluation of the patient’s isolated B cells because of the extremely low numbers of B cells in most samples obtained (less than 1 percent). Most striking was the consis- tent observation of profound immunologic abnormalities that predated the emergence of overt lymphoma by nearly three years. In both patients, assays to determine the presence of antibody to HTLV-I gave negative results.

COMMENTS

In this report, we present two cases in which peripheral T cell lymphoma developed several years after the patients had been found to have hypereosinophilia, skin rash (Fig- ure l), and lymphocytic vasculitis. The clinical courses were striking because of the separation in time between the initial manifestation of symptoms and the subsequent emergence of lymphoma. The lymphocytic phenotypes and cellular functions studied were markedly abnormal (Tables I to V and Figure 4). Moreover, all the immunologic abnormalities predated clinical lymphoma by months to years. Finally, both patients died from infectious compli-


cations within months after the emergence of overt lymphoma.

This syndrome has not been reported previously in association with T cell lymphomas [2-71. In 1970, Liao et al [ 141 described four patients who were initially identified as having generalized lymphadenopathy, hepatomegaly, and eosinophilia with fever and pruritic skin rash. On the basis of pathologic findings that showed infiltration of organs with atypical histiocytes, eosinophils, lymphocytes, and plasma cells, the authors concluded that malignant histiocytosis was the underlying condition. However, classic criteria for the diagnosis of malignant histiocytosis were clearly lacking in those patients, and the polymor- phic character of the infiltrates was more typical of peripheral T cell lymphoma, which had not been described at the time of that report. They observed no evidence of erythrophagocytosis. Thus, the patients described by Liao et al somewhat resemble those we have just described and may well represent part of the spectrum of T cell neoplasms.

The pathogenesis of the hypereosinophilia in our patients also deserves comment. It has previously been demonstrated that neoplastic T cells can function immu- nologically [5,6]. Moreover, Jaffe et al [8] demonstrated that T cell lymphomas may simulate malignant histiocytosis, which, they proposed, was likely to have resulted from the production of lymphokines by neoplastic lymphocytes. In fact, Simrell et al [ 151 identified a phagocytosis-inducing factor in culture supernatants from concanavalin A-stimulated T cell neoplasms, and Margolick et al [ 161 have recently further characterized this factor as distinct from other lymphokines such as interleukin-2 and interferons. It should be noted that this protein is produced primarily by T4-positive cells and not by clones derived from T8-positive cells.

The in vivo development of eosinophilia also has been shown to be dependent on the the presence of a functional T cell immune system. Moreover, lymphocyte products that induce eosinophil proliferation have been identified, although they have not been thoroughly characterized [ 17- 191. We therefore propose that in the two patients described herein, the profound eosinophilia that predated overt lymphoma is likely to have been due to lymphokine production by functionally abnormal and perhaps neoplastic T cells.

Of particular interest was the finding of TS-negative, T4-positive, T8-negative peripheral blood T cell lymphocytes in Patient 2. This finding as well as abnormalities noted are of considerable importance in view of the elucidation of the T cell antigen receptor and is association with the T3 antigen [20]. Ordinarily, all mature T cells (of either the helper-inducer, or T4-positive, and the suppressor-cytotoxic, or T&positive, subpopulations) ex- press both the T3 complex and the T cell antigen receptor on their cell surface. Lymphocytes from Patient 2 ex-



pressed T4, but the T3 complex was altered or absent. Thus, it may be hypothesized that although these cells expressed the T4-positive molecule, their ability to provide normal helper function may have been impaired because of the absence of a functional T3 complex. Such patients will be important in further defining the role of T3- antigen receptor complex in cell-to-cell interactions by genetic and molecular analysis of their defects as well as functional studies.

We considered the possibility that the emergence of lymphoma in these two patients was the result of treatment with cytotoxic agents, but we believe that this is unlikely for several reasons. First, functional and phenotypic abnormalities of lymphocytes from Patient 2 were clearly evident before treatment was begun. Moreover, although secondary malignancy is a well-recognized complication of cyclophosphamide therapy, this complication is uncommon when low-dose (2 mg/kg per day) regimens are employed. For example, of the approxi- mately 150 patients with systemic vasculitis followed

over the past 20 years at the NIH and treated with low- dose cyclophosphamide for at least one year, a secondary malignancy developed in only one patient (who had been treated with cyclophosphamide for nine years) [2 11. In contrast, the patients described herein were treated for periods of one year (Patient 1) and six months (Patient 2). Thus, although we cannot formally exclude the possibility of lymphoma arising as a secondary complication, we believe the more likely explanation is that lymphoma was the primary event.

Finally, with regard to treatment of this syndrome, it is clear that combination chemotherapy induced at least a temporary remission in Patient 2. On postmortem examination, no evidence of residual lymphoma was found. Thus, with prompt recognition of the neoplastic nature of this entity and with vigorous therapy, it may be possible to improve the chances of survival for these patients. None- theless, because of the primary defect of T cell function, these patients are highly susceptible to infectious compli- cations, as evidenced by their clinical courses.

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REFERENCES


Peripheral T-cell lymphoma presenting as hypereosinophilia with vasculitis

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