Submitting Author: Cogbill, Christopher Hull, MD
Institution: University of Pittsburgh School of Medicine
Additional authors:Lydia Contis, MD, Jess Peterson, MD
Session: Therapy-related myeloid neoplasms

62-year-old male with severe chronic atopic dermatitis since childhood and progressive arthritis at multiple sites; the latter is currently being worked up to exclude a rheumatologic etiology. Since childhood, he has been treated for severe atopic dermatitis, including many years of prednisone at low oral doses. Because of prednisone’s immunosuppressive effects and difficulty controlling the skin disease, azathioprine was also prescribed by his dermatologist and was taken for two years prior to presentation. He was not taking any other immunosuppressive agents or cytotoxic therapy.

The patient was weaned off prednisone and was doing well until at least a month prior to presentation, when he was taken off azathioprine for leukopenia and was followed with serial complete blood counts. A platelet count was subsequently found to be low and the patient was scheduled for an outpatient bone marrow procedure but presented acutely with flu-like symptoms to an outside hospital. He was found to have pancytopenia and blasts in the peripheral blood. A bone marrow examination was performed.

Peripheral blood examination:

Pancytopenia with 40% blasts (WBC 2500/microliter, Hgb 8.0g/dL, MCV 106 fL, Plt 62,000/microliter). Blasts were large with mildly irregular nuclei, fine to mildly condensed chromatin, prominent large nucleoli, and contained moderately abundant cytoplasm. Several blasts had multiple small vacuoles. Auer rods were absent although rare blasts contained large Chediak-Higashi-like granules. Granulocytes were dysplastic with hypolobated nuclei, hypogranulated cytoplasm, and abnormal granulation. Many monocytes appeared dysplastic, including some that were difficult to distinguish from granulocytes. Platelets were frequently giant-sized and hypogranular.

Bone Marrow Aspirate:

59% blasts with residual, dysplastic trilineage hematopoiesis. Blasts appeared similar to those in the peripheral blood. Granulocyte maturation was progressive but had extreme dysplasia and pleomorphism, including ultra-hypersegmented, megakaryocyte-like neutrophils with hyperchromatic nuclei and frequent hypolobate, hypogranular forms in varying stages of maturation. Erythroids were moderately megaloblastoid with nuclear budding and asymmetric nuclear separation. Few megakaryocytes were present without overt morphologic dysplasia.

Bone Marrow Trephine Biopsy, posterior iliac crest (B-plus fixative):

Hypercellular (60%) with trilineage hematopoiesis and moderate numbers of interstitially distributed immature hematopoietic cells. Many had prominent nucleoli, moderately irregular nuclei, and were clustered. Frequent maturing granulocytic elements had similar, ultra-hypersegmented and hyperchromatic nuclei. Many resembled megakaryocytes at first glance. True megakaryocytes had unusual morphologic features but most did not have overtly dysplastic findings.

Iron stain (aspirate smear):

Storage iron present with a moderate number of ring sideroblasts (~10-15% of erythroids).

Flow cytometry:

Flow cytometric analysis from peripheral blood and bone marrow aspirate showed similar findings.

A large myeloid blast population (34% in the blood and 32% in the marrow aspirate) showed the following immunophenotype: dimCD45+, CD34+, CD117+, HLA-DR+, CD13+, CD33+, CD15+(partial), and negative for other monocytic markers (CD4, CD14, CD36, and CD64). Myeloperoxidase was predominantly negative and TdT was negative. Aberrantly expressed lymphoid antigens included CD7 (partial) and CD56.

Granulocytes in both samples demonstrated significantly decreased side scatter.

Chromosome analysis:

44~45,XY,der(5;21)(q10;p10),del(9)(q13q22),add(10)(p13),der(11)t(11;21)(p15;q11.2),add(17)(p11.1),-18,add(19)(q12),-21,+mar [cp12]/46,XY[2]

Mosaic abnormal male bone marrow blood chromosome analysis with an abnormal hypodiploid clone with multiple numerical and structural abnormalities (complex karyotype). The abnormalities include loss of 5q, a 9q deletion, loss of 17p, and a marker chromosome with a homogenously staining region. In addition, two tetraploid cells with 88 chromosomes and two copies of each chromosome abnormality were noted.

Therapy-related neoplasms are uncommonly linked directly to use of a single agent such as azathioprine. It is more likely for such agents to be used in conjunction with other cytotoxic medications for the synergistic/complementary effect. Azathioprine in association with the development of myeloid neoplams has only been reported infrequently in non-pathology journals. No large series has addressed if these neoplasms have particular morphologic or immunophenotypic abnormalities. The extreme granulocytic dysplasia was particularly striking in this case and correlated with an extremely abnormal, complex karyotype with multiple poor prognostic indicators. The finding of tetraploid cells containing the same numerous chromosomal abnormalities may be morphologically evident as ultra-hypersegmented (megakaryocyte-like) neutrophils. Although some specific cytogenetic abnormalities such as loss of chromosome 7 have been linked to azathioprine-related myeloid neoplasms, this abnormality was not present in our case. It is also unclear if a survival difference exists between azathioprine-only related myeloid neoplasms and other therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasm (therapy-related acute myeloid leukemia) in association with azathioprine monotherapy for severe chronic atopic dermatitis.

Acute myeloid leukemia, possibly therapy-related following azathioprine

Case 212