therapy for mild chronic GVHD. Two years after BMT he developed KS localized to the skin. The KS improved blue maculas, interpreted as ecchymosis.
Bone Marrow Transplantation, (1997) 19, 629–631 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Kaposi’s sarcoma after allogeneic bone marrow transplantation B Erer1, E Angelucci1, P Muretto2, M Ripalti1, S Rapa1, D Gaziev1 and D Baronciani1 1
Divisione Ematologica e Centro Trapianto Midollo Osseo; and 2Servizio Anatomia Patologica, Azienda Ospedale di Pesaro, Pesaro, Italy
Summary: A case of Kaposi’s sarcoma (KS) in an allogenic BMT recipient is reported. A 26-year-old man underwent allogeneic bone marrow transplantation for microdrepanocytosis. He received prolonged immunosuppressive therapy for mild chronic GVHD. Two years after BMT he developed KS localized to the skin. The KS improved rapidly and outcome was complete remission after cessation of immunosuppression. Keywords: Kaposi’s sarcoma; thalassemia; BMT
KS, first described in 1872, has three clinical forms: the ‘classic’, the ‘endemic’ and the ‘epidemic’ form that occurs in association with AIDS. Recently, this neoplasm has been diagnosed with high frequency in patients who receive immunosuppressive treatment for organ transplantation. 1 More recently, a case of KS in a patient after autologous bone marrow transplantation has been reported.2 Here we report a case of KS occurring after allogeneic BMT. Case report A 26-year-old patient (Table 1) was transplanted for microdrepanocytosis from an HLA-identical sibling in July 1990. He had been regularly transfused since the age of 14. Conditioning included busulfan given orally at a dose of 14 mg/kg for 4 consecutive days, cyclophosphamide given i.v at a dose of 120 mg/kg for 2 consecutive days and antilymphocyte globulin from day −5 to +5.3 He received CsA and ‘short’ methotrexate (up to day +6) for prevention of GVHD. Complete donor engraftment was documented on day +39 by hemoglobin chain synthesis and cytogenetic analysis of bone marrow. The patient was discharged on day +20 in good clinical condition and without signs of GVHD. He developed grade II acute GVHD (skin involvement) on day +42 and was treated with CsA and methylprednisolone. The GVHD showed a chronic evolution and had completely resolved 12 months after BMT. The patient stopped immunosuppressive treatment in July Correspondence: Dr E Angelucci, Divisione Ematologica di Muraglia e Centro Trapianto Midollo Osseo, Azienda Ospedale di Pesaro 61100, Italy Received 1 July 1996; accepted 8 November 1996
1991 (+12 months); 2 months later, he developed skin GVHD reactivation (mild) and oral CsA (6 mg/kg) and methylprednisolone (1 mg/kg) were reintroduced. In February 1992 (+19 months) no clinical evidence of chronic GVHD was detectable and the patient started tapering his immunosuppressive treatment. In April 1992 (+21 months) he presented with edema of the left leg and scanty reddish blue maculas, interpreted as ecchymosis. The edema of the left foot improved with time but bilateral perimalleolar nodules appeared. In December 1992 (+29 months) a skin biopsy was performed in his own town and the diagnosis of KS was made. The diagnosis of KS was confirmed by our pathologist; on the specimens taken from a lesion at plague stage, the dermis was involved by a proliferation of small and slit-like vessels containing erythrocytes. The proliferating cells frequently had a spindled shape with mild mitotic activity, without pleomorphism; intracytoplasmic or extracellulary hyaline Pas-positive globules were occasionally observed; scattered hemosiderin granules were also present free or inside macrophages (Figures 1 and 2). Computed tomography examination of chest and abdomen did not reveal any internal visceral or nodal involvement. The patient continued to reduce the immunosuppressive therapy, stopping 6 months later. After cessation of immunosuppressive treatment the lesions regressed within 8 months. A skin biopsy performed in February 1994 (+43 months) showed residual chronic GVHD with complete disappearance of the proliferating vessels; the dermis was involved by collagenation with presence of scattered lymphocytes and frequent hemosiderin granules. The biopsy specimens were not studied for presence of human herpes virus as DNA analysis on tissue samples by PCR was not available. Lymphocyte subpopulations were examined four Table 1
Pre-transplant characteristics of patient
Age/Sex: 26/M Diagnosis: microdrepanocytosis bs = 90 Transfusions received: 162 units Iron chelation: irregular3 Serum ferritin: 1913 mg/l Class of risk: 33 HBsAg: negative AntiHBc: negative CMV IgG: present CMV IgM: absent
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of CMV infection before or after BMT or at the onset of KS; human immune deficiency virus HIV-1 and HIV-2 titers were negative before and after diagnosis. The patient is currently in complete remission for KS and cured from his congenital disease without signs of chronic GVHD at .60 months from BMT. Discussion
Figure 1 Proliferation of miniature vessels, as small slit-like spaces in the dermis (hematoxylin and eosin × 120).
Figure 2 The proliferating vascular channels have spindled shape and appear to contain erythrocytes and hyaline globules. Scattered hemosiderin granules are present (hematoxylin and eosin × 400).
times between the 32nd and 52nd months of follow-up (Table 2). A persistent abnormal CD4/CD8 ratio with an increased absolute number of CD8 lymphocytes and altered CD16 count were observed without significant modifications during and after immunosuppression tapering (Table 2). In view of the suggested role of CMV infection in the etiology of KS, virologic examinations were repeatedly performed, with no detection of the virus in blood, sputum and urine. The patient did not suffer a reactivation Table 2
Lymphocyte subpopulation of patient +32
+35
+43
+52
16 500 6600
12 300 6519
14 000 7980
10 200 6018
2072 4429 0.46 422
1656 3840 0.43 176
2474 4524 0.54 1190
1589 2564 0.61 193
Months post-BMT WBC/mm 3 Lymphocyte/mm3 (1675–3150) a CD4 (620–1660)a CD8 (486–918)a CD4/CD8 (1.8 ± 0.6)a CD16 (250–600)a a
Normal laboratory ranges/mm3 .
Kaposi’s sarcoma (KS) was first described by Moritz Kaposi in 1872 as ‘idiopathic, multiple, pigmented sarcomas of the skin’. It was recognized as an unusual tumor primarily affecting elderly males of Mediterranean or Ashkenazic Jewish origin.4 This form, called ‘classic’ or European, has an indolent clinical course with rare nodal involvement and extracutaneous localization. The endemic form of KS was recognized in Central Africa with an incidence of 15% of all tumors and with a wide spectrum of clinical severity.5 The epidemic form of KS that occurs in association with AIDS was recognized two decades ago among male homosexuals in the USA.6 In the last few years the tumor has also been frequently diagnosed in patients with impaired immunologic function after an organ transplant.1 Porta et al2 reported a case of KS after an autologous bone marrow transplant. One of the long-term complications of organ or bone marrow transplant is the development of secondary tumors.7 The intensive chemotherapy during preparation for transplant, use of irradiation-based conditioning therapy and the severe immunosuppression after transplant may play a role in the development of second neoplasms.7,8 Disturbance of immunity does not include only depression of immunity, but impaired immunostimulation and chronic antigenic stimulation can lead to the onset of eventual neoplasm. 1,9 The etiology of KS is still unknown. Viral infections are considered to be a factor that may activate neoplasm formation.1,10 Recently, a new human herpes virus has been suggested as the cause of AIDS-associated Kaposi’s sarcoma.11 The neoplasm has a different clinical course in each form, but the behavior of this tumor in patients with compromised immunity due to immunosuppressive therapy because of organ and bone marrow transplant is characteristic; in fact the tumor usually dramatically regresses upon withdrawal or reduction of immunosuppressive therapy.12 The patient reported here has received prolonged and severe immunosuppressive treatment for GVHD. The neoplasm arose 29 months after BMT, during the tapering of immunosuppression and was confined to the skin of the lower limbs. With the aim of preventing reactivation of GVHD, the immunosuppressive therapy was tapered gradually and complete cessation required a period of 6 months. The lesions regressed with time and resolved after complete cessation of immunosuppression. No significant variations were observed on immunologic analyses during and after tapering of immunosuppression, nor was there evidence of viral activation. Therefore, the prolonged immunosuppression remains the only factor to have played a role in the development of KS in this patient. As is well recognised in the literature,12 withdrawal of immunosuppressive therapy in solid organ transplant recipients usually leads to
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graft rejection. In this case, regression of KS was accompanied by persistence of the transplanted tissue without any evidence of GVHD reactivation. This is the only case of KS we have observed in over 1000 alloBMTs performed in our Institution since 1980. Kaposi’s sarcoma, even if infrequent, should be suspected in bone marrow transplant recipients with unusual skin lesions. References 1 Penn I. Kaposi sarcoma’s in organ transplant recipients: report of 20 cases. Transplantation 1979; 27: 8–11. 2 Porta F, Bongiorno M, Franco L et al. Kaposi’s sarcoma in a child after autologous bone marrow transplantation. Cancer 1991; 68: 1361–1364. 3 Lucarelli G, Galimberti M, Polchi P et al. Bone marrow transplantation in patients with thalassemia. New Engl J Med 1990; 322: 417–421. 4 Santucci M, Pimpinelli M, Moretti S, Gianotti B. Classic and immunodeficiency-associated Kaposi’s sarcoma: clinical, histologic and immunologic correlations. Arch Pathol Lab Med 1988; 112: 1214–1220.
5 Safai B, Good RA. Kaposi’s sarcoma: a review and recent developments. Cancer 1981, 31: 3–10. 6 Hymes K, Cheung T, Greene JB et al. Kaposi’s sarcoma in homosexual men. Lancet 1981; 2: 598–600. 7 Witherspoon RP, Fisher LD, Schoch G et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. New Engl J Med 1989; 21: 784–789. 8 Socie G, Henry-Amar M, Bacigalupo A et al. Malignant tumors occurring after treatment of aplastic anemia. New Engl J Med 1993; 329: 1152–1157. 9 Shmueli D, Shapira Z, Yussim A et al. The incidence of Kaposi’s sarcoma in renal transplant patients and its relation to immunosuppression. Transplant Proc 1989; 21: 3209–3210. 10 Giraldo G, Beth F, Huang ES. Kaposi’s sarcoma and its relationship to cytomegalovirus (CMV), CMV DNA and CMV early antigens in Kaposi’s sarcoma. Int J Cancer 1980; 26: 23–29. 11 Chang Y, Cesarman E, Pession MS et al. Identification of herpes-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 1994; 266: 1865–1869. 12 Winjveen A-C, Bjo¨rck S, Blohme I. Disseminated Kaposi’s sarcoma: full regression after withdrawal of immunosuppressive therapy. Report of case. Transplant Proc 1987; 19: 3735–3736.
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