June 2013

A 60-year-old female with right lower quadrant pain

Y. Daous, MD and O. Esan, MD


A 60-year-old female presented to the emergency department with a two-day history of right lower quadrant abdominal pain associated with anorexia, nausea, vomiting, and diarrhea. The patient also reported a 15 pounds weight loss within the past 3 months and easy bruising. Physical examination revealed right lower quadrant tenderness, rebound tenderness, and a positive psoas sign. The skin showed extensive ecchymosis.

Laboratory Tests

Patient Result: 9.5 g/dl
Reference Range:
 13.1 -17.3 g/dl

Patient Result: 29.5%
Reference Range:
39.8 – 50.2 %

Platelet count
Patient Result: 76 × 109/L
Reference Range:
140-450 × 109/L

White blood cell count
Patient Result: 159 × 109/L
Reference Range:
3.5 -11.0 × 109/L

An abdominal computed tomography scan showed inflammation adjacent to the cecum and right lower quadrant stranding.

Gross Description

The peripheral blood smear showed:

Figure 1: Peripheral blood smear.

Flow cytometry of the peripheral blood showed 87% atypical cells with the following phenotype: CD33, CD13, CD34 (subset), CD4 (subset), CD36 (subset), and HLA-DR (subset).

The patient was taken to the operating room and had a laparoscopic appendectomy. Grossly, the appendix showed focal serosal hemorrhage. Microscopic examination of the appendix showed:

Figure 2. Cross section of appendix, x4.
Figure 3. Appendix, lumen, x40.
Figure 4. Appendix, serosa, x40.
Figure 5. Lysozyme x40.
Figure 6. Myeloperoxidase x40.

Post operatively, further hematologic evaluation was done. The bone marrow aspirate was a dry tap. The touch imprint and core biopsy showed:

Figure 7. Bone marrow core biopsy touch imprint.
Figure 8. Bone marrow core biopsy, H& E.

Chromosomal analysis by fluorescent in-situ hybridization showed normal cytogenetics. Gene mutation analysis was positive for FLT3-ITD and NPM1 gene mutations, while negative for CEBPA gene mutation.


What is the diagnosis ?


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The present WHO classification of acute myeloid leukemias (AML) is based on the presence or absence of recurrent genetic abnormalities, myelodysplasia related changes or previous therapy. Patients are generally classified into 3 main risk groups based on cytogenetics: favorable, intermediate/standard or poor risk disease. Patients with a normal karyotype (40-49% of adults) have a variation in their prognosis. Specific gene mutations have been found in some AML patients with normal karyotypes, which have known prognostic implications and are used in the selection of appropriate therapy. The most common are the mutations of fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), and less commonly, mutations of the CEBPA gene, KIT, MLL, WT1, NRAS and KRAS. These mutations can either occur alone or in combination, and have been found to occur less frequently in AML patients with abnormal karyotypes.

FLT3 is located at chromosome 13q12, it encodes a tyrosine kinase receptor that is involved in hematopoietic stem cell differentiation and proliferation and is expressed on both progenitor cells as well as blast cells in AML. FLT3 mutation occurs in 20-40% of AML and in myelodysplastic syndrome, but most commonly in AML with t(6;9)(p23;q34), acute promyelocytic leukemia t(15;17), and AML with normal karyotype. There are two types of FLT3 mutations: internal tandem duplication (FLT3-ITD)(75-80%) and mutations affecting codons 835 or 836 of the second tyrosine kinase domain (TKD)(20-35%). FLT3-ITD mutations carry a poor prognosis in AML patients with normal karyotype. They are associated with shorter complete remission duration and disease-free survival, as well as event-free survival and overall survival. The significance of FLT-3 TKD mutations is still being investigated and the findings are non-conclusive at present.

NPM1 mutations are one of the most common recurring genetic mutations in AML. They usually involve exon 12 of the NPM1 gene. This leads to an aberrant localisation of nucleophosmin within the cytoplasm. These AMLs frequently have myelomonocytic or monocytic features, typically present in older patients (prevalence ranges from 2-8% in childhood to 27-35% in adulthood) with normal karyotype, and have a female predominance. Patients usually have anemia, thrombocytopenia,and extramedullary involvement (most commonly gingiva, lymph nodes, and skin) without a history of a myelodysplastic or myeloproliferative neoplasm. Blasts in AMLs with NPM1 mutations usually express markers of monocytic differentiation such as CD14, CD11b, and CD68 in addition to myeloid antigens (CD13, CD33, MPO) and usually lack CD34 expression. Cytogenetically normal AML with NPM1 mutations respond well to chemotherapy and have a favorable prognosis.

Approximately 40% of AML with NPM1 mutations have a conconcurrent FLT3- ITD mutation. Cytogenetically normal AML with FLT3-ITD mutation has a poor prognosis with standard chemotherapy which is mildly improved by the concomitant presence of an NPM1 mutation. There are ongoing clinical trials with FLT3-ITD targeted inhibitors in patients with mutated FLT3.

This patient presented with acute appendicitis and pre-operative work-up demonstrated her peripheral blood to have numerous blasts with ovoid to indented nuclei and moderate amount of basophilic vacuolated cytoplasm. These were confirmed to be myeloblasts with monocytic differentiation by flow cytometric studies. Appendectomy was performed and her appendix was infiltrated with the blasts. Further work-up showed she had AML with normal cytogenetics with both FLT3-ITD and NPM1 mutations. Her AML was refractory to chemotherapy and she succumbed to her disease within six months of diagnosis. AML with normal cytogenetics with both FLT3-ITD and NPM1 mutations is associated with a poor prognosis.


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