Gastrointestinal Involvement in the Sézary Syndrome

73:145-149, 1977 Copyright © 1977 by the American Gastroenterological Association

Vol. 73, No. 1 Printed in U.S A.

GASTROENTEROLOGY

CASE REPORTS GASTROINTESTINAL INVOLVEMENT IN THE SEZARY SYNDROME MARTIN I. CoHEN, M .D., LAWRENCE W. WmERLITE , M .D., GERALDINE P . ScHECHTER, M.D., ELAINE JAFFE, M.D., A. BETTY FiscHMANN, MBBS, MRCPED, PHILIPS. ScHEIN, M.D., AND JoHNS. MACDONALD, M.D. V eterans Administration H ospital , Washington, D . C. , The George Washington Unive rsity , Washington, D.C ., Th Georgetown University, Washington , D . C., and National Institutes of Health , Bethesda, Maryland

A case of documented Sezary syndrome, a cutaneous T-celllymphoma, with gastrointestinal lymphocytic infiltration is presented. The symptom of diarrhea waxed and waned with the course of the disease process. Radiographic studies were normal, and no evidence of malabsorption was elicited. The diagnosis was established by endoscopic and biopsy techniques, with light and electron microscopy of colonic and small bowel biopsies demonstrating extensive infiltration with typical Sezary cells. To our knowledge this is the first reported case of gastrointestinal involvement in the Sezary syndrome. Neoplastic thymus derived (T) lymphocytes have been shown to have characteristic sites of tissue infiltration in the Sezary syndrome and mycosis fungo ides. 1-4 Skin infiltration with sparing of the bone marrow is typical of these conditions which have been classified as cutaneous T celllymphomas:H However, recent pathological and staging studies have demonstrated an increased awareness of visceral involvement in these disorders.6 Gastrointestinal involvement in autopsied cases of mycosis fungoides has been an uncommon finding and has not been previously reported in the Sezary syndrome. The documentation of functional and morphological gastrointestinal involvement in a patient with Sezary syndrome led to this report. Case Report D. 0 ., a 48-year-old black male, first developed a skin rash with localized areas of scaling plaques and skin papules on lichenoid areas and exfoliation in 1967. By 1973, the skin lesions had progressed to a generalized dermatitis with severe pruritus. Enlarged lymph nodes, and atypical lymphocytes in the peripheral blood were noted. Biopsy of the skin lesion was interpreted as a nonspecific dermatitis, and a lymph node biopsy revealed a dermatopathic lymphadenopathy. In 1974, the skin rash and adenopathy spontaneously subsided, only to recur several months later as a generalized hyperpigmented papular eczemoid and severely pruritic dermatitis .~ No erythroderma was present. Repeated skin biopsies demonstrated a dermal lymphocytic reticulosis with focal pleiomorphic infiltrates. 2 Atypical lymphocytes with indented nuclei were again noted in the peripheral blood (fig. 1). In the peripheral blood, 64% of the circulating lymphocytes had membrane characterReceived September 16, 1976. Accepted December 27, 1976. Address requests for reprints to: Lawrence W. Widerlite, M.D., Gastroenterology Section, Veterans Administration Hospital , Washington, D . C. 20422.

istics ofT cells, by sheep red cell rosetting assay, and 4% were shown to be B cells on the basis of complement-binding sites. The atypical lymphocytes were shown under electron microscopy to possess serpentine nuclei typical ofSezary cells.""' 2 The bone marrow was normal. Despite treatment with numerous topical emollients, prednisone and chlorambucil, 13 the rash and severe pruritus persisted. In July 1975 the patient developed extensive palatal and gingival lesions. Biopsies of these lesions revealed involvement with Sezary cells. At that time the peripheral white blood cell count was 11,000 with 30% atypical lymphocytes. A trial of leukapheresis 14 was associated with healing of oral lesions, but failed to ameliorate the over-all disease process. In October 1975 the patient developed general malaise, low grade fever, watery diarrhea, and a 15-pound weight loss. Stools numbered 10 to 12 per day, but he did not complain of tenesmus, hematochezia, or rectal discharge. He had enlarged cervical and axillary lymph nodes, hepatomegaly of 13 em, and a generalized papular and exfoliating dermatitis. Rectal examination revealed anal fissures and external and internal hemorrhoids. Pertinent laboratory data included a hematocrit of 35%, white blood count 16,000 with 49 % polymorphonuclear cells, 15% lymphocytes, 30% atypical lymphocytes, 4% monocytes, and 2% eosinophils. The serum albumin was 3.3 g per 100 ml, folic acid 3.6 ng per ml, vitamin B 12 576 pg per ml, iron 36 JLg per 100 ml, and iron-binding capacity 274 f.Lg per 100 ml. The urinary excretion of n-xylose was 6 g in 5 hr (normal 5 g per 5 hr), and there was no excess fecal fat on Sudan III stain. Numerous stools were negative for ova and parasites and cultures revealed no enteric pathogens. Barium enema and upper gastrointestinal series with small bowel follow-through were normal. Sigmoidoscopy revealed a boggy, edematous, exudative, and friable mucosa extending beyond 25 em from the anus. Colonoscopy with the Olympus CF colonoseope (Olympus Corporation of America, New Hyde Park, N . Y.) disclosed this abnormal mucosa to 40 em from the anus. A peroral Rubin tube small bowel biopsy' 5 was performed at the level of the ligament of Treitz under fluoroscopic control.

145

146

CASE REPORTS

FIG .

Vol . 73, No . 1

1. Atypical lymphocyte with convoluted nucleus from peripheral blood (x 600).

Rectal, colonic, and small bowel biopsies, under light microscopy, revealed normal surface cells with an extensive pleomorphic mononuclear cell infiltration of the lamina propria and submucosa. These lymphocytes demonstrated the cytological features of Sezary cells.ll- 12 One micron-thick Epon-embedded tissue sections of small bowel and colon biopsies demonstrated the presence of atypical lymphocytes with indented nuclei infiltrating the lamina propria (fig. 2). Electron microscopy showed these atypical lymphocytes to have serpentine nuclei and scant cytoplasm consistent with Sezary cells (fig. 3). It was noted, however, that these cells had less nuclear indentation than those in the peripheral blood. A single cell suspension was prepared from colonic biopsy specimens by mincing the tissue in tissue culture medium. Forty per cent of these cells formed rosettes with sheep erythrocytes, identifying them as T cells. Many of the rosetted cells were large and had indented nuclei typical ofSezary cells (fig. 4), and were similar to preparations made from the patient's peripheral blood. The patient refused further leukapheresis and a course of mediastinal or "thymic" irradiation was administered. 16 The watery diarrhea abated at this time. After receiving 1600 rads, the course was interrupted because of the development of agranulocytosis. His skin however showed marked improvement. Sigmoidoscopy was then repeated. The rectal mucosa appeared unchanged and biopsies again showed an infiltration of the lamina propria with atypical lymphocytes. Repeat single cell suspensions of the colonic biopsy were also prepared and studied for rosette formation in situ, using neuraminidasetreated sheep erythrocytes according to T0nder et alY The neoplastic infiltrate within the lamina propria strongly bound the sheep erythrocytes, again indicating aT cell nature (fig. 5).

The watery diarrhea recurred and was then followed by

FIG. 2. One micron-thick section of lamina propria of colonic biopsy demonstrating infiltration with Sezary cells ( x 388).

July 1977

CASE REPORTS

147

FIG. 3. Electron micrograph of an atypical lymphocyte consistent with a Sezary cell, in the lamina propria of a small intestinal biopsy (x 1600).

•w

FIG. 4. Large atypical lymphocyte with convoluted nucleus from colonic biopsy demonstrating rosette formation with sheep erythrocytes (X

600).

148

CASE REPORTS

Vol. 73, No.1

FIG. 5. Left, photomicrographs of a colonic biopsy section stained with hematoxylin and eosin, demonstrating a neoplastic lymphocytic infiltrate in the lamina propria; right , a corresponding dark field section demonstrating T-cell rosettes in situ (x 65).

exacerbation of the severly pruritic papular and exfoliating dermatitis. A repeat evaluation for possible malabsorption again yielded negative results.

Discussion In the patient presented, complaints of diarrhea led to an investigation of the gastrointestinal tract. No evidence of malabsorption could be determined. Radiographic evaluation of the gastrointestinal tract was normal. Rectal biopsies revealed normal surface mucosal cells, but the lamina propria and submucosa were infiltrated with atypical lymphocytes having the characteristics of Sezary cells. Further evaluation of the cells obtained from the peripheral blood and colon demonstrated rosette formation when incubated with sheep erythrocytes, characteristic of T lymphocytes. 16 In addition, using a frozen section technique, sheep erythrocyte binding was demonstrated by neoplastic cells in situ. The atypical lymphocytes from the peripheral blood, colon, and small bowel had the characteristic electron microscopic findings of serpentine nuclei with condensed heterochromatin, scant cytoplasm, and high nuclear cytoplasmic ratios.6 However, the infiltrating Sezary cells in tissue sections were noted to have less nuclear indentation than the cells obtained from the peripheral blood. The morphological, histological, immunological, and clinical similarities between mycosis fungoides and the Sezary syndrome have recently led to the conclusion that these diseases are manifestations of the same syndrome, now called cutaneous T cell lymphoma. 5 • r; Extracutaneous or visceral involvement with mycosis fungoides has been reported in several autopsy series, with

gastrointestinal involvement an uncommon occurrence.3, 4, 7, 18 Block et al. 3 reported 38 cases of mycosis fungo ides, none of which manifested gastrointestinal tract involvement. An additional 45 cases, of which 32 underwent postmortem examination, were reported by Rappaport and Thomas. 4 Of these, the esophagus was involved in 4, the stomach in 4, and the intestine in 6. Epstein et al. 18 reported a series of 144 patients with mycosis fungoides in which there were 120 deaths. Autopsies were performed in 86 patients, and involvement of the esophagus was seen in 7, the stomach in 7, the duodenum in 2, the gallbladder in 2, the ileum in 8, and the rectum in 1, respectively. However, the extent of gastrointestinal involvement in any given patient was not described in detail. Reports of visceral involvement in the Sezary syndrome other than the gastrointestinal tract have been uncommon. 19-22 Visceral involvement in 3 of 19 patients was reported by Winkelmann and Linman. 19 One of these patients was reported to have a gastric lymphoma. There are no other reports of gastrointestinal involvement in the Sezary syndrome. Involvement of the intestine with lymphomas arising from the Peyer's patches or lamina propria, as well as secondary leukemic and lymphomatous infiltration, are mostly of B lymphocyte origin, and have been previously described. 23-28 Symptoms of nausea, vomiting, abdominal pain, as well as those related to bowel obstruction, perforation, fistula formation, and rectal bleeding may occur. Malabsorption and steatorrhea have been described in cases of lymphoma with coexisting or preexisting celiac disease as well as in primary dis-

July 1977

CASE REPORTS

seminated intestinal lymphoma, and a chain disease. 2!f-32 The patient described in this report, however, has not demonstrated the symptoms, laboratory, or radiographic features of any of the forementioned. Whether Sezary cells have a predilection for infiltrating the lamina propria, as a manifestation of epithelial tropism, or whether these atypical lymphocytes are converted T cells from perifollicular areas or regions adjacent to the Peyers patches of the intestine is not certain. 33 • 34 In conclusion, gastrointestinal involvement has been described in a patient with Sezary syndrome. It appears that the diarrhea was attributable to the infiltrating process involving the bowel. It is our recommendatio11 that patients with Sezary syndrome, who develop diarrhea in the course of their illness, be evaluated with ~ndoscopic and biopsy techniques to determine systemic mvolvement with this disease process. Addendum Since submitting this paper for publication, the patient studied has died. Postmortem examination revealed an extensive atypical lymphocytic infiltration of the small and large bowel with involvement of the esophagus as well. Involvement of other visceral organs included lymph nodes, spleen, heart, and liver. The peritoneal surface was also studded with focal collections of atypical lymphocytes. REFERENCES

syndrome. Mayo Clin Proc 49:558-566, 1974 13. Winkelmann RK, Perry HO, Sigfrid AM, et al: Treatment of Sezary syndrome. Mayo Clin Proc 49:590-592 , 1974 14. Edelson R, Facktor M, Andrews A, et al: Successful manage-

15.

16. 17.

18.

19. 20.

21. 22.

23.

24. 25.

1. Sezary A: A new cutaneous reticulosis. Ann Dermatol Syphiligr (Paris) 9:5-22, 1949

2. Holdaway DR, Winkelmann RK: Histopathology of Sezary syndrome. Mayo Clin Proc 49:541-547, 1974 3. Block JB, Eddgcomb J, Eisen A, et al: Mycosis fungoides. Natural history and aspects of the relationship to other malignant lymphomas. Am J Med 34:228-235, 1963 4. Rappaport H, Thomas LB: Mycosis fungoides. The pathology of extracutaneous involvement. Am J Clin Pathol 50:625, 1968 5. Edelson RL, Kirkpatrick CH, Sherlock EM, et al: Preferential cutaneous infiltration by neoplastic thymus derived lymphocytes: morphologic and functional studies. Ann Intern Med 80:685-692, 1974 6. Lutzner M, Edelson R, Schein P, et al: Cutaneous T-celllymphomas: the Sezary syndrome, mycosis fungoides and related disorders. Ann Intern Med 83:534-552, 1975 7. Dahl MV: Mycosis fungoides. Clinical features of twenty-two patients. Minn Med 58:301-304, 1975 8. Bluefarb SM: Cutaneous manifestations of the malignant lymphomas. Am Lect Ser No. 330, 1959 9. Hoogland HC: Atypical lymphocytes: morphologic features. Mayo Clin Proc 49:526-530, 1974 10. Flandrin G, Brouet JC: The Sezary cell: cytologic, cytochemical and immunologic studies. Mayo Clin Proc 49:575-583, 1974 11. Zucker-Franklin D: Properties of the Sezary lymphoid cell: an ultrastructural analysis. Mayo Clin Proc 49:567-574, 1974 12. Edelson RL, Lutzner MA, Kirkpatrick CH: Morphologic and functional properties of the atypical T-lymphocytes of the Sezary

149

26.

27 .

28. 29. 30.

31. 32.

33.

34.

ment of the Sezary syndrome. Mobilization and removal of extravascular neoplastic T-cells by leukapheresis. N Engl J Med 291:293-294, 1974 Brandborg LL, Rubin CE, Quinton WE: A multipurpose instrument for suction biopsy of the esophagus, stomach, small bowel and colon. Gastroenterology 37:1-16, 1959 Richards F II, Spurr CC, Pajak PF, et al: Thymic irradiation. Am J Med 57:862-869, 1974 Tonder 0 , Morse PA, Humphrey LJ: Similarities ofFc receptors in human malignant tissue and normal lymphoid tissue . J Immunol 113:1162-1169, 1974 Epstein EH Jr, Levin DC, Croft JD Jr, et al: Mycosis fungoides: survival, prognostic features, response to therapy and autopsy findings. Medicine 15:61-72, 1972 Winklemann RK, Linman JW: Erythroderma with atypical lymphocytes: Sezary syndrome. Am J Med 55:192-198, 1973 Long JC, Mihm MC: Mycosis fungoides with extracutaneous dissemination: a distinct clinicopathologic entity. Cancer 34:1745-1755, 1974 Rappaport H, Thomas LB: Mycosis fungoides: the pathology of extracutaneous involvement. Cancer 34:1198-1229, 1974 Paradinal FJ, Harrison KM: Visceral lesions in an unusual case of Sezary syndrome. Cancer 33:1068-1074, 1974 Ehrlich AN, Stadler G, Geller W, et al: Gastrointestinal manifestations of malignant lymphoma. Gastroenterology 54:11151121, 1968 Prolla JC, Kirsner JB: The gastrointestinal lesions and complications of the leukemias. Ann Intern Med 61:1084-1103, 1964 Fromke VL, Wever LW: Extensive leukemic infiltration of the gastrointestinal tract in chronic lymphosarcoma cell leukemia. Am J Med 56:875-882, 1974 Pincus S, Bianco C, Nussenzweig V: Increased proportion of complement receptor lymphocytes in the peripheral blood of patients with chronic lymphocytic leukemia. Blood 40:303-310, 1972 Wilson JD, Nosal GJV: Identification of human T and B lymphocytes in normal peripheral blood and in chronic lymphocytic leukemia. Lancet 2:788-791, 1971 Piessens WF, Schur PH, Maloney WC, et al: Lymphocyte surface immunoglobulins. N Engl J Med 288:176-180, 1973 Eidelman S, Parkins RA, Rubin CE, et al: Abdominal lymphoma presenting as malabsorption. Medicine 45:111-137 , 1966 Harris OD, Cooke WT, Thompson H, et al: Malignancy in adult celiac disease and idiopathic steatorrhea. Am J Med 42:899-912, 1967 Barry RE, Baker P, Read AE: The clinical presentation of adult celiac disease. Clin Gastroenterol 3:55-67, 1974 Ramboud JC, Bognel C, Prost A, et al: Clinico-pathological study of a patient with "Mediterranean" type of abdominal lymphoma and a new type of IgA abnormality ("Alpha-chain disease") . Digestion 1:321-336, 1968 Thomas LB, Rappaport H: Mycosis fungoides and its relationship to other malignant lymphomas. In The Reticuloendothelial System. Edited by JW Rebuck, CW Berard, MR Abell. Williams & Wilkins Co, 1975, p 243-261 Parrott DMV: The gut as a lymphoid organ. Clin Gastroenterol 5:211- 228, 1976