Submitting Author: Curry, Choladda Vejabhuti, MD
Institution: Department of Pathology & Immunology, Baylor College of Medicine, Houston TX, USA, and Texas Children's Hospital, Houston, TX, USA.
Additional authors:Jyotinder N Punia, M.D., Tarek Elghetany M.D.
Session: Therapy-related myeloid neoplasms

A two and a half year old male was diagnosed with craniopharyngioma and treated with subtotal tumour resection, and received intensity modulated radiotherapy (IMRT), with a total dose of 5400 cGy. No chemotherapy was given. The brain tumour was stable. His hematologic parameters were unremarkable. The patient developed hypopituitarism and was put on replacement hormonal therapy. He had had multiple episodes of candidemia and chronic sinusitis with fungal infection.

Approximately four years after therapy, he developed macrocytic anemia and moderate thrombocytopenia. CBC showed Hgb 10.5 g/dL, Hct 31.7%, MCV 93.0 fL (reference range 76.0-90.0), RDW 17.1%, Platelets 112,000 /uL, WBCs 6180/ul, ANC 2340/uL Thrombocytopenia progressed and a bone marrow examination five years after therapy showed mild dysplastic features. A repeat marrow approximately six years following therapy (at 8 years of age) showed normocellular marrow with multilineage dysplasia and ring sideroblasts with no reticulin fibrosis. A repeat marrow a few weeks later showed grade 1 reticulin fibrosis.

Peripheral blood smear shows pancytopenia with macrocytosis and anisopoikilocytosis of red blood cells as well as occasional dysplastic neutrophils (hypogranulation and hypolobulation). (Figure 1)

The first and subsequent bone marrow biopsies and aspirates show essentially similar features with slight progression and are summarized below.

The biopsies show normocellular marrow with 70% cellularity and an M:E ratio of 1:1. Megakaryocytes are increased and show moderate dysplasia including small size, hypolobulation, and multinucleation with widely separated nuclear lobes. (Figures 2-4)

Aspirate smears show dysplastic neutrophilic granulocytic elements including hypogranulation and pelgeroid nuclei and dysplastic erythroid precursors with multinucleation, irregular nuclear contours, and nuclear cytoplasmic dyssynchrony. (Figures 5-7)

Iron stain of the aspirate smears shows increased ring sideroblasts (41% of erythroid precursors). (Figure 8)

CD34 highlights scattered blasts that are not significantly increased and there is no significant clustering. CD61 shows increased megakaryocytes. CD61 also highlights small size and hypolobulated megakaryocytes. (Figure 9)

Reticulin stain of the most recent bone marrow biopsy shows mildly increased reticulin fibrosis (grade 1 reticulin fibrosis). (Figure 10)

Corresponding cytogenetic studies of the bone marrows show normal chromosome and FISH analyses showing no evidence of -5/5q- or -7/7q-.

Our case demonstrates the features typically observed in therapy-related myelodysplastic syndrome (t-MDS) which include trilineage dysplasia and markedly increased ring sideroblasts, and mild reticulin fibrosis, occurring in a child who received only a radiation therapy that was limited to the cranium. The differential diagnosis includes vitamin or mineral deficiency, such as B6 or copper. These deficiencies are usually not associated with macrocytosis or megakaryocytic dysplasia. Primary myelodysplastic syndrome, such as refractory anemia with ringed sideroblasts (RARS), is rare in children. The findings of multilineage dysplasia with increased ring sideroblasts and mild reticulin fibrosis therefore are more supportive of t-MDS.

A recent published article of studies in adult population (Nardi et al. JCO 2012) suggested that therapy related myeloid neoplasms (t-MN) after external-beam radiation (XRT) therapy alone are different from those occurring after cytotoxic chemotherapy or combined therapy, but are similar to de novo disease. The t-MN occurring after cytotoxic chemotherapy or combined therapy have a higher incidence of high-risk karyotype and have worse prognosis, compare to t-MN after XRT alone or de novo disease, both of which show no significant differences in survival or frequency of high-risk karyotypes between the two groups. Moreover, the clinical behavior of t-MDS following XRT alone is influenced by bone marrow blast count and IPSS score, like de novo MDS. However, t-MN following XRT or IMRT alone is not well-studied in children. Nonetheless, the above data raises the possibility that the category of t-MN may be subdivided based on the mode of therapy in the future.

References:

1. Vardiman JW, Arber DA, Brunning RD., et al. Therapy-related myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon 2008, pp 127-129.

2. Nardi V, Winkfield KM, Ok CY, et al. Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to deno disease and differ from other therapy-related myeloid neoplasms. Journal of Clinical Oncology July1, 2012 Vol.30(19):2340-2347.

Therapy-related myelodysplastic syndrome occurring in a child following local cranial irradiation alone.

Therapy-related myeloid neoplasm, myelodysplastic syndrome

Case 389