Sezary Syndrome-an Unusual Case

B. H. WEINERMAN, MD, FRCP, AND L. C. LU, MD, FRCP

A case of Sezary syndrome is presented. Coincident with topical treatment by nitrogen mustard, an enormous rise in circulating Sezary cells was seen in the peripheral blood. The possibility of this rise as a result of the topical treatment is discussed as a possible danger in topical therapy for individuals with Sezary syndrome.

Cancer 47:2946-2951, 1981.

~ Z A R Y S Y N D R O M E (SS) was described by Sezary S in 1949 on the basis of four women who presented with pruritus. erythroderma, and circulating atypical mononuclear cells." Sezary noted a relationship to malignancy even then, and now this disease is grouped with mycosis fungoides (MF) as a cutaneous T-cell lymphoma." Both these T-cell conditions are regarded as chronic lymphoproliferative disorders,'1."' which will terminate eventually, if infection or other diseases do not intervene, in a disseminated T-cell lymphoma made up of Sezary-like cells, with widespread involve- ment of internal organs.'.",' l o

However. since the disease may be chronic," there is no consistent attitude toward treatment. Various treatments have been dsed, including total skin electron beam therapy. ' systemic chemotherapy (both single- and multiple-agent),' photochemotherapy,X leukopho- resis,' and topical chemotherapy agents,x with topical nitrogen mustard having the most extensive study. '.'.I '

I t has been noted that there is probably a relatively short turnover time of Sezary cells in primary cell production (in the range of 3-5 days),12 but these high rates of production are usually balanced by a high rate of cell loss since SS is usually clinically indolent. Our case relates both to the malignant nature of this cohdition and to a form of treatment which may have either mobilized cells out of the primary production compartment or perhaps decreased the rate of cell loss from the skin.

From the Division of Oncology, Department of Medicine, St. Boniface Hospital and the Manitoba Cancer Research Foundation ( B H W ) , and the Department of Pathology, St. Boniface Hospital (LCL). Winnipeg, Manitoba, Canada.

Address for reprints: Dr. B. H. Weinerman. Department of Medi- cine, St. Boniface Hospital. 409 Tache Avenue. Winnipeg. Manitoba R2H 2A6, Canada.

Accepted for publication June 9, 1980.

Case History

The patient presented to the St. Boniface Hospital On- cology Clinic in April 1976 with a history of several years of pruritus dating back to March 1974. The pruritus had been largely unresponsive to topical steroid treatment as well as diazepam-like agents. On physical examination she had a diffuse, red maculopapular skin rash. The skin was thickened diffusely and the entire surface seemed to be involved. It was dry and some scaling was evident on the palms and soles but no fissures were seen. She had no alopecia or loss of eyebrows. There was no hepatosplenomegaly but there was a 1.5-cm node in the left axilla. Her leukocyte coirnt was 12,200imm:' with 22% Sezary-like cells in the peripheral blood (Fig. I ) .

A lymph node biopsy of the left axillary node (Fig. 2) was read as a poorly differentiated diffuse lymphocyte lymphoma with some sparing of the follicles: however, review of the node revealed that the lymphocytic infiltrate in the node was composed of three types of cells: most were small with a dark stained oval to round nuclei and indistinct cytoplasm; the second type had a nucleus with an irregular contour and clovelike appearance; and a third type of cell, larger than the previous ones, had a large vesicular nucleus with a cen- tral o r eccentric nucleolus (Fig. 3).

Skin biopsy (Fig. 4) showed mild epidermal hyperplasia with occassional elongated rete pegs and no para- or hyper- keratosis present. The superficial venous plexus were sur- rounded by mononuclear cells, some of which were small lymphocytes, and others which had had an irregular-shaped elongated or a cerebriform nucleus (Fig. 5). Mitoses were rarely present, and liquefaction degeneration of basal layers was found. The morphology was compatible with Sezary syndrome. Bone marrow biopsy and aspirate demon- strated usual cellularity without abnormal lymphocyte in- filtrate. IgE levels were normal as was serum protein im- munoelectrophoresis. The peripheral blood lymphocytes were examined for receptors. Of the lymphocytes, 722/mm:' were T-cells, by the E-Rosette techniques (normal raiige 850- 1500). and 2limm:' had complement receptors with 851

0008-543X18 1/06 1512946 $0.85 0 American Cancer Society

2946

No. 12 SEZARY SYNDROME . Weirierman utid Lir

FIG. 1 , Initial peripheral blood showing Sezary cells with clefted nuclei ( x 1250).

FIG. 2. Initial lymph node biopsy; diffuse perifollicular infiltrate of cells ( X 125).

2947

2948 CANCER Jirnr 15 1981 No. 12

FIG. 3 . Infiltrate is composed of small dark cells: however, some cells have crescent-shaped nuclei. and other large cells are present with large vesicular nuclei and a central or eccentric nucleolus (higher magnification of node. ~ 5 0 0 ) .

Flci. 4. Skin biopsy: note focal abnormal mononuclear cells in dermis and the peripheral perivascular infiltrate ( X 125).

No. 12 S ~ Z A R Y SYNDROME . Weitiertiiriti cind Lir 2949

FIG. 5. Skin biopsy; note cells with cerebriform (deeply indented) nuclei ( ~ 5 2 0 ) .

mm:' displaying immunoglobulin on the surface (both of these number5 heing lowinormal). She had an expanded null cell pool (lymphocyte\ which did not display T or B-cell charac- teristics by these techniques).

She was treated with chlorambucil ranging from 2 - 12 mg daily for several months. followed by chlorambucil and prednisone (10-50 mg daily) for three months without any noticeable: response in her rash and with a gradual increase in pruritus. Osteoporosis was noted after three months of steroids, and severe back pain developed from collapse of the third lumhar vertebrae. This necessitated admission to the orthopedic ward. At the time of her admission, her leukocyte count was 19,000/mm:1 with 4000 cells/mm'l of the Sezary type. Preclnisone was tapered gradually over two weeks and discontinued. and chlorambucil was stopped. In view of her intense pruritus, topical nitrogen mustard was administered to the skin on October 2 5 , three weeks after admission, at which time leukocyte count was 40.U00 and Sezary cell count was 28,000 (see Fig. 6). (The patient applied 10 mg mechlorefhane powder dissolved in 2 ounces of water daily for three days over the entire cutaneous surface, sparing mucoti\ membranes and eyes).

After three days of topical treatment on October 28, leukocyte count was 396,000/mm3 with 95% of the cells of the Sezury type (Fig. 7). In view of this sudden rise in leukocyte count, the patient was phlebotomized for 2 - 3 units of blood a day with cell spinning and retransfusion of buffy-poor blood for five conbecutive days. There was no great change in leukocyte count,

(245,000 on October 31, 473,000 on November 2 , and 575,000 on November 3 (Fig. 6)). Cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP) were given November 3 and leukocytes decreased slightly to 438,000/mm7 on November 10 (see Fig. 6). At this time the patient was anergic to Candida, 1 varidase and mumps and displayed a diffuse increase in gamma- globulin on serum protein electrophoresis. During this time the patient became progressively confused and somnolent, developed uric acid renal obstruction despite allopurinol, and was put on peritoneal dialysis. She subsequently developed peritonitis and pneumonia which did not respond to multiple- agent antibiotic administration. E . coli was grown from her peritoneum. On November 1 1 , with leukocyte count of 50,000 she died. N o autopsy was allowed.

Discussion

This is a somewhat unusual case of Sezary syn- drome. The most striking finding was the sudden rise of the patient's leukocyte count, concurrent with a three- day course of nitrogen mustard skin painting. Two hypotheses are possible. Since it is thought that the Sezary cell migrates between a third cell pool, the peripheral blood, and the skin,'? and that leuko- phoresis may work in decreasing pruritus by "draw- ing" the cells from the skin,' it is possible that the topical nitrogen mustard actually contributed to the

CANCER June 15 1981 V O l . 47

FIG. 6 . Graph of patient's total leukocyte count and Sezary cell number in relationship to treatment events.

. T O T A L r E 1 . L N U M B E R

m S E Z A R Y C E L L N U M B E R

L 1. E 11 K O P H O R E S I S

N l T R O G E N M U ST A H D S K I N T R E A T M E N T

I

sudden rise in the Sezary cell count. Since it is thought that the skin and the peripheral blood represent slowly proliferating pools in balance with a large blood com- partment which is rapidly turning over (3-5 days)," the mustard may have in some way blocked egress of the circulating Sezary pool into the skin. Alternately topical therapy may have caused a migration of cells from skin to blood. I t is of interest that the patient's skin did not improve during the treatment, suggesting however, that there was no massive migration of Sezary cells from the skin. Of course, the topical treat- ment may have simply coincided with the aggressive stage of her disease, and the sudden rise of her Sezary cell counts, therefore, may be totally unrelated to topical treatment. This rapid increase could, in fact, have been related to the discontinuation of her systemic treatment (chlorambucil and prednisone) coupled with the entrance into an accelerated phase. (It is noted that leukocyte count was higher than it had been at the time of hospital admission.)

We believe that this latter explanation, however, has many difficulties with i t as well. The chlorambucil- prednisone treatment never seemed to have a marked effect on the patient's counts over the previous months, so that it is difficult to believe that their discon- tinuation would have resulted in such a marked rise in leukocytes. We also feel that the suddenness of the rise is uncharacteristic of Sezary syndrome. We are un- aware of similar reports of such a rapid rise, even in patients with an advanced stage of disease, as deter- mined by her expanded null cell pool.!'

Thus this case was exceedingly interesting and the rapid deterioration seen might have been the results of topical treatment. We subsequently followed one other patient's peripheral counts following skin treat- ment, but did observe a minor increase in Sezary cells, which quickly returned to normal.

Our study represents an aggressive case of Sezary syndrome and furthermore may point out a danger in topical treatment.

No. 12 295 1

FIG. 7. Sudden increase in peripheral blood content of Sezary cells after patient had topical nitrogen mustard. Cells show more hyper- chromasia I han previous cells

REFERENCES

I . Edelson R. Facktor M . Andrews A , Lutzner M , Schein P. Successful management of the Sezary syndrome mobilization and removal of extravascular neoplastic T-cells by leukophoresis. N E/r,q/ J ,Mcd 1974; 291-293.

2. Erkman-Balis B. Rappaport H. Cytogenetic studies in mycosis fungoides. C ' r r n c ~ ~ r 1974: 34:626-633.

3 . Haynes HA, Van Scott EJ. Therapy of mycosis fungoides lymphoma. Pro(. Nrri Ctr/ic,rr Co/z/' 1970: 6:553-557.

4 . Hoppe RT, Fuks, Z, Bagshaw MA. Radiation therapy in the management of cutaneous T-cell lymphomas. Corrc,cv Trecci Rep 1979; 63:62 5-632.

5 . Long JC, Mihm MC. Mycosis fungoides with extracutaneous dissemination: A distinct clinicopathological entity. Ctrrlcev 1974; 34: 1745- 1755.

6. Lutzner M , Edelson R , Schein P, c i t i / . Cutaneous T-cell lymphomas. The Sezary syndrome. mycosis fungoides, and related disorders. A H / I f t i r Med 1975: 83:534-552.

7. Lutzner MA. Hobbs JW, Horvath P. Ultrastructure of ab- normal cells in Sezary syndrome, mycosis fungoides and parap- soriasis in plaque. Arch Dennciiol 1971; 103:375-386.

8. Minna JD, Roenigk HR. Glatstein E. Report of the committee on therapy for mycosis fungoides and Sezary syndrome. Crrricer Trccri Rcp 1979; 63:729-735.

9 . Nordquist BC, Kinney JP. T and B-Cells and cell mediated immunity in mycosis fungoides. Ca/rcc,r 1976; 37:714-718.

10. Rappaport H. Thomas LB. Mycosis fungoides: The pathology of extracutaneous involvement. Caticcr 1974; 34: 1198- 1229.

1 1 . Sezary A. Une nouvelles reticulare cutanee: La reticulase maligne leucemque a histio-monocytes manstreu et a forme d'eryth- rodermie oe dermateuse et pigmentree. AUII D c r n i ~ i / r J l Syphiligr (Paris) 1949: 9:s-22.

12. Shackney SE. Edelson R, Bunn PA. The kinetics of Sezary cell production. Carrc.c>r Treat Rep 1979: 63:659-661.

13. Szur L. The treatment of mycosis fungoides and related conditions with particular emphasis on electron therapy. BrJ Canwr (Suppl 11) 1975; 31:368.

14. Vonderheid EC. VanScott EJ. Wallner PE, Johnson WC. A ten year experience with topical mechlorethomine for mycosis fungoides. Cancer Treoi Rep 1979; 63:68 1-689.

IS. Winkleman R K . Clinical studies of T-cell erythroderma in the Sezary syndrome: M n w Clin Prac 1974: 49:s 19-525.