Chronic Cutaneous Graft-Versus-Host Disease in Man Howard M. Shulman, MD, George E. Sale, MD, Kenneth G. Lerner, MD, Edward A. Barker, MD, Paul L. Welden, MD, Keith Sullivan, MD, Betty Gallucci, RN, PhD, E. Donnall Thomas, MD, and Rainer Storb, MD

This clinicopathologic study of patients with chronic graft-versus-host disease (GVHD) after allogeneic marrow transplantation emphasizes the most prominent feature of the syndrome, the cutaneous aspects, and describes the ophthalmic-oral sicca syndrome with sialoadenitis and the neurologic findings. Chronic cutaneous GVHD affected 19 of 92 recipients surviving 150 days or more. In 6 patients chronic GVHD presented as a continuation of acute GVHD; in 8 it occurred after the resolution of acute GVHD; and in 5 it arose without prqceding acute GVHD, ie, de noto late onset. Two cutaneous types were distinguished. The generalized type affected 16 patients and ran a progressive course resulting in late complications of poikiloderma, diffuse dermal and subcutaneous fibrosis, and contractures. Microscopically, it resembled generalized morphea and lupus erythematosus hypertrophicus et profundus. The local type affected 3 patients with a more variable picture of poikiloderma, dermal sclerosis, and contractures. Microscopically, it resembled lupus erythematosus profundus and scleroderma. Guidelines for defining and subclassifying chronic cutaneous GVHD are proposed. (Am J Pathol 92:545-570, 1978)

INCREASING NUMBERS of human allogeneic bone marrow transplants have been performed for the treatment of aplastic anemia, leukemia, or combined immunodeficiency syndromes using HLA identical siblings as marrow donors. We have found that chronic graft-versus-host disease (GVHD) has emerged as a serious problem affecting 25% of all allogeneic patients surviving 150 days or more. The protean manifestations include debilitating skin disorders; chronic active liver disease; malabsorption; and oral, ophthalmic, and neurologic involvement, which may also combine with weight loss and recurrent infections contributing to failure to thrive or to death. This paper emphasizes the most prominent aspect of this syndrome, the cutaneous manifestations, in 19 patients and briefly describes related oral, ophthalmic, and neurologic findings. From the Fred Hutchinson Cancer Research Center, Seattle, Washington, and the Departments of Pathology, Medicine, and Physiological Nursing, Division of Oncology, University of Washington School of Medicine, Seattle, Washington. Supported by Grants CA 18029, CA 18221, and CA 15704 from the National Cancer Institute. Drs. Shulman and Sale were supported in part by Junior Faculty Clinical Fellowships from the American Cancer Society. Dr. Sullivan was supported in part by a Clinical Fellowship from the American Cancer Society. Dr. Thomas is the recipient of Research Career Award Al 02425 from the National Institute of Allergy and Infectious Diseases. Accepted for publication February 22, 1978. Address reprint requests to Dr. Howard Shulman, Division of Oncology, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104. 0002-9440/78/0608-0545$01.00 545

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American Journal of Pathology

Materials and Methods Between May 1969 and June 1976, 230 allogeneic bone marrow transplants were performed using HLA identical sibling donors selected on the basis of serologic typing and mutual nonreactivity in mixed leukocyte culture as previously described.1-,, Eighty-three patients had severe aplastic anemia and 147 had end stage acute leukemia. Patients with aplastic anemia were prepared for grafting with cyclophosphamide (CY), 200 mg/kg.2 Patients with leukemia were prepared for grafting with CY, 120 mg/kg, and 1000 rad total body irradiation (TBI) and, in some cases, with additional cytoreductive chemotherapy pretransplant.8 Methotrexate was given to all patients during the first 100 days as previously described in an attempt to ameliorate GVHD. Antithymocyte globulin prepared by previously described methods was administered to 11 patients with acute GVHD." At Day 150 ("day" refers to time after transplant, with the day of transplant being Day 0), there were 92 recipients surviving, 23 of whom had chronic GVHD. In 19 patients the manifestations of chronic GVHD included involvement of skin, which is described in detail in this report. Twelve of these patients had aplastic anemia and 7 had acute leukemia. Twentyfour long-term allogeneic survivors without chronic 6VHD served as a comparative population; 13 of these patients had aplastic anemia and 11 had acute leukemia. All survivors were followed for more than 18 months at the time of this report. Skin specimens from 17 of the 19 patients were obtained for evaluation after Day 99 (Table 1). The specimens consisted of 46 3- or 4-mm punch biopsies, four surgical ellipses, one circumcision, multiple sections of skin from five autopsies, and sections of tongue and parotid glands from the autopsy on UPN° 394. Sections of the paraffin-embedded tissue blocks were stained with H&E, PAS, PAS-alcian blue at pH 2, Verhoeff-van Gieson's stain for elastica, Masson or Gomori's trichrome, and Orcein-Giemsa. Six biopsy specimens and all autopsy tissues were stained with Congo red and viewed under polarized optics. A modification of Movat's hexachrome stain' with 2% ammonium hydroxide and 95% alcohol as the mordant was used on the elliptical biopsy specimens, autopsy sections, and several 4-mm punch biopsies. The long-term allogeneic survivors without chronic GVHD contributed 24 skin punch biopsies which were obtained between 1 and 5 years after transplant. After a survey of all specimens through 1975, we devised an evaluation form which stressed the principal recurrent histologic features of this disorder and the hallmarks of several similar appearing dermatologic disorders. t One observer (HS) reviewed all cases systematically using this evaluation form. Four pathologists simultaneously participated in a histologic review of most of the cases, all of which were coded. The results from these reviews showed close agreement among the four pathologists, with consistent ability to correctly sequence unknown slides and estimate their posttransplant intervals.

Results The incidence of acute and chronic GVHD among all marrow recipients who underwent marrow transplantation during the period of this study is depicted in Text-figure 1. Additional details regarding the 19 patients with cutaneous manifestations of chronic GVHD are presented in Tables 1 and 2. Fourteen patients had clinical acute GVHD, which was confirmed in 13 patients by skin biopsy specimens obtained before Day 40 (8 patients) and in biopsy specimens obtained between Days 41 and 99 (5 patients). Three of these 14 patients had clinical grade I GVHD1 and 11 had grade II to IV UPN = unique patient numbers. f The form is available on request.

Vol. 91, No.3

June 1978

CHRONIC CUTANEOUS GVHD

TEXT-FIGURE 1-Schematic

547

repre-

sentation of patients with chronic

GVHD. Numbers of patients are noted in boxes. ± = patients dying before Day 14 were unevaluable. Asterisk = inclusion of 4 patients without skin involvement felt to have chronic GVHD of the liver. As indicated, 23 of 230 (10%) of all allogeneic recipients and 23 of 92 (25%) of recipients surviving after Day 149 developed chronic GVHD. Among patients with aplastic anemia who survived more than 149 days, 13 of 40 developed chronic GVHD; among the patients with leukemia, only 10 of 53 developed chronic GVHD.


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Chronic cutaneous graft-versus-host disease in man.

Chronic Cutaneous Graft-Versus-Host Disease in Man Howard M. Shulman, MD, George E. Sale, MD, Kenneth G. Lerner, MD, Edward A. Barker, MD, Paul L. Wel...
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