Haematologica 2002; 87:(02)ELT11
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Paroxysmal nocturnal hemoglobinuria following breast cancer radiotherapy
Brigitte Granel,* Jacques Serratrice,* Martine David,° Chantal Fossat,° Patrick Disdier,* Pierre-Jean Weiller*
*Service de Médecine Interne; Laboratoire d'Hématologie, Hôpital de la Timone, Marseille; °Service de Médecine Interne, Hôpital de Martigues, Martigues, France

Correspondence: Patrick Disdier, M.D., Service de Médecine Interne, 264 rue Saint-Pierre, 13385 Marseille Cedex 5, France. Phone: international +33.491386039. Fax: international +33.491347401.E-mail : pdisdier@ap-hm.fr
The factors involved in clinical manifestations of paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder of hematopoietic cells, have not been clearly distinguished. We report the case of a 55-year-old woman treated with radiotherapy and hormone therapy for a breast cancer, who later presented a hemolytic anemia and a venous thrombosis related to paroxysmal nocturnal hemoglobinuria. As modification of normal hematopoietic cells leading to an acquired myelodysplastic syndrome is observed after radiotherapy, our case report raises the question of a relationship between radiotherapy and the occurrence of paroxysmal nocturnal hemoglobinuria. To our knowledge, our observation is the second one in the literature concerning paroxysmal nocturnal hemoglobinuria following radiation therapy for cancer. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoietic cells caused by somatic mutation in the X-linked PIGA gene involved in the synthesis of the glycosylphosphatidylinositol (GPI) anchor. Clinical manifestations of PNH usually occur in the setting of an underlying haematopoietic defect, as classically observed after aplastic anaemia. However, other triggering factors acting on hematopoietic cells could also be involved in its occurrence. We report an exceptional case of PNH occurring after treatment for breast carcinoma. A 55-year-old woman, with a past medical history of right ovariectomy (encapsulated carcinoma) at the age of 42, required in 1996 (at the age of 51) a tumorectomy with axillary lymph nodes resection for left breast adenocarcinoma. Adjuvant treatment included radiotherapy (50 grays on left breast, 50 Grays on internal mammary chain, 50 Grays to the supraclavicular area and 15 Grays to the operative zone) and oral tamoxifen (20 mg/day). Regular surveillance was satisfactory without any relapse. There was no familial history of neoplasia. In January 2000, an unexplained macrocytic and regenerative anemia was noticed with a hemoglobin level of 98 g/L. Thoraco-abdominal CT-scan was normal. Three months of oral steroids only permitted stabilization of the hemoglobin level around 90 g/L. Intravenous polyvalent immunoglobulin treatment failed to improve the anemia. In November 2000, the patient suffered from a left lower limb venous thrombosis and she received two months of oral anticoagulant. The patient first consulted our medical department in February 2001. Physical examination revealed cutaneo-conjunctival pallor and left arm lymphedema (post-breast surgery), tachycardia and mild systolic heart murmur. Biological evaluation showed white a blood cell count of 3.58x109/mm3 with 57% neutrophils, 32% lymphocytes, hemoglobin 74 g/L, platelet count 180x109/mm3 and reticulocytes 200x109/mm3. Blood smear analysis showed anisocytosis with macrocytosis, hypochromia and no schizocytes. Electrolytes, kidney and liver function tests were normal. LDH level was 1978 UI/l (N <320), total bilirubin level was 28 mmol/L (N<25) and haptoglobulinemia was < 0.08 g/L. Ferritinemia was low (18 ng/mL, N: 15-150). PNH was rapidly diagnosed by peripheral blood flow cytometry analysis using monoclonal anti-CD55 and anti-CD59 (Table 1). A bone marrow aspiration revealed erythroblastic hyperplasia without myelodysplasia, and with a normal karyotype. We concluded that the patient had hemolytic anemia related to PNH. Folic acid supplementation and oral anticoagulants were prescribed. In our observation, hemolytic anemia and venous thrombosis strongly suggested PNH as well as, to a minor degree, associated leukopenia and iron deficiency.1,2 To our knowledge, only one case of PNH occurring in a patient treated with radiation alone for a lung cancer has been reported in the Japanese literature.3 Development of PNH in a woman previously treated with dose-intensive chemotherapy and hormonal therapy without radiotherapy for breast cancer was also published.4 In this article, the authors concluded a probable relationship between the development of PNH and the chemotherapy received. Transient expansion of lymphocytes lacking GPI-anchored proteins after treatment with CAMPATH (anti-CD52 reagent) for a non-Hodgkin's lymphoma refractory to other treatments has also been reported,5 as has PNH after bone marrow transplantation.6 Moreover, myelodysplastic syndrome is a complication of conventional antineoplastic therapy (including radiochemotherapy) and has also been observed after radiotherapy alone.7 PNH has been described in the setting of myelodysplastic disorders and it can be considered as a premyelodysplastic state. Acute leukemia can occur with a leukemic clone evolving from the abnormal HPN clone.1
Hypothetic mechanisms proposed to explain the occurrence of PNH after therapy for cancer are the following : expansion of a previously undetectable number of pig-A muted clones, alteration of the pig-A gene and alteration of the hematopoietic cells membrane. In our observation, radiotherapy could represent an external factor exerting a selective pressure in favor of the PNH clone, leading to a relative growth advantage. More generally, this has been defined as the "relative growth advantage hypothesis" of the "escape theory".8 In our observation, structural perturbations of the erythrocyte membrane possibly induced by tamoxifen could have made erythrocytes more sensitive to the hemolytic action of complement.9 Thus, although a chance association cannot be excluded, our case must alert physicians to search for PNH when faced with an unexplained hemolytic anemia, particularly in the context of treatment for cancer. As PNH is a rare disease, only future observations such as ours can permit better understanding of the role of radiotherapy in the occurrence of PNH.

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