Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria

To the editor: A 69-year-old man presents with cough and SOB approximately 3.5 years following diagnosis of a poorly differentiated acute lymphocytic leukemia (progenitor cell phenotype). By flow cytometry, the initial leukemia in 1998 was positive for HLA-DR, CD34, and CD45 and negative for lymphoid and myeloid markers including: CD3, CD5, CD7, CD19, CD10, CD20, CD13, CD33, CD11b, and CD14; CD1a and S-100 protein staining were not available on this sample. A pathologic diagnosis of a progenitor cell leukemia most suggestive of acute lymphocytic leukemia was made. The patient received induction therapy in November 1998 and achieved a complete remission. Consolidation therapy was discontinued after one cycle due to severe cytopenias. Maintenance therapy was discontinued after 6 months secondary to methotrexate-induced hepatoxicity. Approximately 3.5 years after the initial diagnosis, the patient presented with back pain and leg weakness and found to have a paraspinal mass with cord compression. He underwent surgical resection followed by consolidative radiation. The lesion (see Fig. 1) was composed of sheets of medium to large sized mitotically active cells with relatively abundant cytoplasm. Occasional multinucleated tumor giant cells were also identified. The cell nuclei were vesicular with irregular contour and occasional grooves. Considering the remote history of a lymphocytic leukemia and the morphologic features which raised the possibility of an epithelioid/dendritic cell neoplasm, a panel of immunohistochemical stains was used to characterize the lesion. The tumor cells were positive for vimentin, CD1a, S-100 protein, CD43 and focally for keratins, CD45, CD68, and lysozyme. Negative immunostains included EMA, Melan-A, CD3, CD20, CD21, CD35, Kappa and Lambda light chains, and MPO. Leder’s histochemical stain was negative. Based on the morphology and the immunohistochemical profile, a diagnosis of a dendritic cell neoplasm most consistent with Langerhans cell sarcoma was rendered. Electron microscopic studies were not performed. Bone marrow biopsy revealed trilineage hematopoiesis with no evidence of leukemic involvement. Approximately 2 months later, he developed a similar soft tissue mass in the right upper chest extending into the right supraclavicular area. Radiation treatment resulted in a complete clinical response in the chest mass and he had no evidence of progression for 1 year. The patient then developed shortness of breath and fevers. A CXR showed a right upper lobe infiltrate. A bronchoscopy was performed and biopsy specimens showed LCH. The patient was treated with a course of Cladribine, but did not respond. The patient died from pulmonary complications of LCH. The morphologic features of the para spinal lesion and the autopsy lesions (in the lungs, thyroid, and multiple intra-abdominal lymph nodes) were similar. Langerhans cell histiocytosis (LCH) is a rare disorder involving the proliferation of the specialized langerhans histiocyte normally found primarily in the skin. LCH affects children in 66–90% of case reports and has an incidence in adults of 1–2 per million population based on case series [1–3]. LCH has been associated with malignancy, including malignant lymphoma and solid tumors in adults and children [3]. While LCH has been associated with acute leukemia, a literature review reveals only 15 cases where LCH occurred after acute leukemia; all but one case were in children [4,5,6,11]. LCH, formerly histiocytosis X, is a clonal proliferative disease, however, the pathogenesis remains unclear [3]. The disease ranges in severity and presentation and can affect virtually any organ system [2]. Diagnosis of LCH depends on the identification of the tumor cells. These cells are antigen presenting and express HLA-DR and CD1a. Langerhans cells have characteristic HX bodies (Birbeck granules) in the cytoplasm [3]. LCH is associated with a variety of neoplasms and chemotherapy. In one study of 47 patients over the age of 15, 17% had an associated hematological or solid tumor [7]. Of the cases currently reviewed in the literature, the relationship between malignancy and LCH remains unclear as LCH may precede, develop concurrently, or as in this case, develop after malignancy. The relationship between LCH and ALL may be explained by several mechanisms including a chance occurrence, treatment induced effect, a common progenitor cell, or a cytokine-mediated phenomenon. A registry of patients in whom LCH was associated with malignancy was established in 1991. LCH was most frequently associated with malignant lymphoma, leukemia, and lung carcinoma. A series looking at LCH in adults included an association with breast cancer as well [7]. The first review of the registry, in 1994, included 91 patients with LCH associated with malignancy. Of those 91 patients, five patients had LCH associated with ALL. In four of the five cases, ALL preceded the diagnosis of LCH by 6–12 months [6]. A later review of the registry included an additional seven cases of LCH preceded by ALL. In each of the seven cases, LCH was diagnosed while the patients were receiving chemotherapy [5]. Only patients less than 18 years of age at the time of diagnosis were included in the report, excluding two patients with LCH associated with malignancy ages 75 and 79. The time course in these cases suggests a chemotherapy-related pathogenesis of LCH either by chemo induced mutagenesis or immunosuppression. Raj et al. describe a case of a 7-year-old male who developed LCH 2 years after the completion of chemotherapy for ALL [8]. This time frame suggests that development of LCH was not related to immunosuppression. In support of this hypothesis, Raj et al. demonstrated that the standard tests for Tand B-cell function in their patient were normal [8]. More recent reports also support an alternative pathogenesis of LCH developing after ALL. Feldman et al. report on two cases of LCH developing after ALL in children. They demonstrate a clonal relationship between the two neoplasms in each patient with identical T-cell receptor rearrangements [9]. A follow-up study by Rodig et al. in these two patients investigating a role for NOTCH1 did not show evidence to suggest that the lineage switch was mediated through NOTCH1 down regulation [12]. However, progenitor cells with lymphoid and dendric cell potential remains a likely mechanism for the observed relationship of these two neoplasms. While NOTCH1 expression is known to influence cell fate, there are other epigenetic factors that play a role including the cytokine environment. Interestingly, Ko et al. describe two cases of LCH and T-lymphoblastic lymphoma in the same lymph node both of which were CD561. The Feldman cases were also CD561, although most LCH are not CD561 [9,10]. CD56 function in hematopoietic cells is unclear. Much of the literature regarding LCH and malignancy relies on pediatric populations. As noted by Tavernier et al., because adult patients with ALL Fig. 1. Infiltrate of atypical cells with occasional grooved nuclei and with scattered multinucleated cells. Insert shows that the tumor cells are positive for CD1a. [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com. ] Correspondence