The Hematopathology Section of the Laboratory of Pathology, NCI, offers expert diagnostic services in the field of hematopathology. Dr. Stefania Pittaluga, Staff Clinician, and I handle diagnostic service responsibilities equally, each rotating as the staff on service 50% of the time. However, because of the challenging nature of the material we receive for review, and obligations related to specific clinical protocols and teaching conferences, our clinical obligations extend well beyond the designated on-service time. We provide assistance in the diagnosis and classification of reactive and neoplastic lymphoproliferative disorders, immunodeficiency states, and diverse hematological malignancies. We provide consultative and collaborative services to physicians in the National Cancer Institute, as well as to physicians studying patients with hematolymphoid disorders in other institutes, in particular NIAID, NHLBI, NHGRI, and NIAMSD. We serve as Associate Investigators on more than 35 clinical protocols being conducted in the NCI and other NIH institutes. These protocols frequently mandate specialized testing to illuminate biological markers relevant to the particular study. We receive more than 2000 cases in consultation each year. Because of the demands that the consultation service places on our time, we try to restrict consultations to difficult or challenging cases. Many cases are submitted by other academic institutions, based on diagnostic uncertainty, or because of differences of opinion among several institutions. We frequently make novel observations based on this unique clinical practice, and a number of publications have emanated these experiences. Thus, I believe our clinical work enhances, rather than detracts, from our academic productivity. Our diagnostic efforts support the work of the Lymphoma Leukemia Molecular Profiling Project (LLMPP). This mutiinstitutional international cooperative study is a model for translational studies in cancer, and combines the efforts from experts in multiple disciplines. Our diagnostic efforts have contributed to multiple publications stemming from these clinical and investigational trials. I will highlight some of those in which important new diagnostic tools or insights have been identified. Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis with a distinct clinical phenotype which results from an accumulation of lymphocytes due to impaired apoptosis and leads to childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias and an increased risk of B-cell lymphoma. In 1999, investigators at the National Institutes of Health (NIH) suggested criteria to establish the diagnosis of ALPS. Since then, there have been significant advances in our understanding of the disease with approximately 500 ALPS patients studied worldwide;prompting consideration of revisions to the current diagnostic criteria and classification scheme. The rationale and recommendations outlined in a publication in Blood (Oliveira et al. Blood 2010) stem from an international consensus conference held at NIH in the fall of 2009 of investigators from the USA and Europe engaged in clinical and basic science research pertaining to ALPS and related disorders. This effort will harmonize the diagnosis and classification of ALPS, and will facilitate collaborative research and better understanding of the pathogenesis of autoimmune cytopenias and B cell lymphomas Patients with autoimmune lymphoproliferative syndrome (ALPS) have defective lymphocyte apoptosis, with increased risk for lymphoid malignancies. We reported a patient with ALPS who developed histiocytic sarcoma in a background of sinus histiocytosis and massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD). (Venkataraman et al. Am J Surg Pathol, 2010). This patient had documented ALPS type Ia with a germline missense mutation in exon 9 of the TNFRSF6 gene (973 A greater than T, D244V) encoding Fas (CD95/Apo-1). He was diagnosed with ALPS at an early age. At age 6 and, he developed classical Hodgkin lymphoma, which was treated using standard chemotherapy. Two years later, biopsy of a PET-positive axillary node showed features of ALPS and focal involvement by SHML. Thereafter, the patient continued to have continued lymphadenopathy and progressive splenomegaly, leading to exploratory surgery at age 13 for suspicion of lymphoma. Paraabdominal nodes revealed sheets of malignant-looking histiocytes with increased mitotic activity and areas of necrosis, indicative of histiocytic sarcoma. Spleen and lymph nodes also showed involvement by RDD. Both components had an identical phenotype of S-100+/CD68+/CD163+. The occurrence of malignancies involving two separate hematopoietic lineages in ALPS is not previously reported. Given the central role of defective Fas signaling in ALPS, histiocytes may be yet another lineage at risk for neoplastic transformation secondary to a block in apoptosis. Blastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course in adults, whereas the pediatric experience with this disease is very limited. We analyzed the pathologic and clinical findings in 9 cases presenting in patients under the age of 18 years that were reviewed at the NIH (Jegalian et al., Haematologica, in press. In addition, we identified 20 well-documented additional pediatric cases in the literature.In the combined analysis, the overall survival rate among the 25 patients with available follow-up, all having received chemotherapy, was 72% (follow-up ranging from 9 months to 13 years, with a median of 30 months). The event-free survival rate was 64%. Nine patients were alive 5 years after the original diagnosis, although only 3 of them had undergone hematopoietic stem cell transplantation 1 in first complete remission and 2 in second remission. Of the 7 patients who lacked cutaneous disease at presentation, 100% survived, including 5 with survival beyond 5 years, although only 2 had undergone stem cell transplantation. Among the 18 patients who presented with cutaneous disease and had follow-up available, only 11 survived (61%). In contrast to adult cases, where long-term survival depends on stem cell transplatation in first complete remission, blastic plasmacytoid dendritic cell neoplasms are clinically less aggressive in children. Treatment with high-risk acute lymphoblastic leukemia-type chemotherapy appears to be effective, and stem cell transplantation may be reserved for children who relapse and achieve a second remission. Outcomes were more favorable in cases that lacked cutaneous disease at presentation, although comparison of cutaneous and noncutaneous cases might be confounded by differences in treatment regimens. This study provided important guidelines regarding the management of these tumors in the pediatric age group.
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