Case 351

Submitting Author: Liu, Yen-Chun, MD, PhD
Institution: Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, New York, NY, United States
Additional authors:Jiong Yan, Attilio Orazi
Session: AML with myelodysplasia-related changes

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HISTORY

A 64 year-old man presented with pancytopenia of unknown etiology for approximately 4 years and was felt clinically to be due to myelodysplastic syndrome (MDS). In 1998, the patient became transfusion dependent and developed significant splenomegaly. At that time the first bone marrow examination was performed. The bone marrow aspirate was a dry tap. The bone marrow biopsy showed findings consistent with myelodysplastic syndrome without excess of blasts (the latter result was also confirmed by CD34 immunohistology). Reticulin stain showed mild reticulin fibrosis. In an attempt at ameliorating the cytopenia, splenectomy was also performed in 1998 (submitted for workshop). Worsening anemia with continuously increasing transfusion requirement prompted another bone marrow biopsy in 1999 (submitted for workshop) which confirmed the suspicion of acute myeloid leukemia (AML). Patient was treated with conventional induction therapy for AML but did not achieve CR. A follow-up post-treatment bone marrow biopsy showed marked fibrosis with pockets of myeloid blasts. Unfortunately, patient died of refractory AML.

DETAILS

1. Spleen, splenectomy (1998) that weighed 2823 grams and measured 33.5 cm in the greatest dimension was fixed in formalin. The spleen showed a diffuse proliferation of immature myeloid cells diffusely expanding and infiltrating the splenic red pulp. Frequent small hypolobated megakaryocytes were found. 2. Bone marrow biopsy (1999) measuring 0.6 cm x 0.2 cm x 0.2 cm submitted in Bouin’s fixative was processed. The bone marrow biopsy showed hypercellular bone marrow (95% cellularity) with markedly increased left-shifted granulopoiesis admixed with numerous atypical megakaryocytes. Erythropoiesis was markedly decreased. The atypical megakaryocytes varied in size but contained numerous small hypolobated forms. The reticulin stain showed moderate fibrosis (2+).

IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY

1. Spleen, splenectomy (1998) immunohistochemical staining: MPO highlighted the diffuse proliferation of immature myeloid cells. They were also positive for lysozyme but negative for CD34. Flow cytometric analysis on the specimen revealed 7% of CD34 -positive cells. The majority of the CD34-positive cells were also positive for CD13. 2. Bone marrow biopsy (1999) immunohistochemical staining: CD34 highlighted the presence of a diffusely increased number of blasts. These were negative for MPO. The flow cytometric analysis performed on the bone marrow aspirate and the corresponding peripheral blood showed 45% and 60% CD34-positive cells separately. The CD34-positive cells were also positive for CD13, CD33, HLA-DR, CD41, and CD61, negative for CD10, TdT, B cell antigens and T cell antigens.

CYTOGENETIC FINDINGS

N/A

MOLECULAR FINDINGS

N/A

INTERESTING FEATURES

The bone marrow biopsy (1999) showed a hypercellular marrow mostly replaced by sheets of myeloid blasts admixed with numerous small hypolobated megakaryocytes that were also identified in patient’s prior bone marrow biopsy. Patient’s prior history of MDS supports the diagnosis of AML with myelodysplasia-related changes. The presence of marked splenomegaly is uncommon in MDS. In this case, however, the splenomegaly was the first sign of acute transformation of the MDS to AML-MDS related. This was confirmed by the presence of immature myeloid cells admixed with atypical megakaryocytes in red pulp, morphologically similar to those seen in the subsequent bone marrow examination. Flow cytometry of the spleen further confirmed the presence of an increased number of blasts. A similar case was reported as part of a case series describing splenic pathology in myelodysplasia (Kraus, M., et al. Am J Surg Pathol. 1998;22:1255-66.). The single case containing increased MPO-positive blasts in red pulp also developed AML transformation in the follow-up bone marrow examination.

PROPOSED DIAGNOSIS

Acute myeloid leukemia with myelodysplasia-related changes (ex MDS) preceded by extramedullary early transformation in spleen.

CONSENSUS DIAGNOSIS

Acute myeloid leukemia with myelodysplasia-related changes (history of myelodysplastic syndrome), preceded by extramedullary early transformation in spleen

Patient’s first marrow biopsy (1998, not submitted) showed findings consistent with myelodysplastic syndrome. Low power H&E image showed a hypercellular bone marrow with numerous dysplastic megakaryocytes. Patient’s first marrow biopsy (1998, not submitted) showed findings consistent with myelodysplastic syndrome. Low power H&E image showed a hypercellular bone marrow with numerous dysplastic megakaryocytes.
Patient’s first marrow biopsy (1998, not submitted): High power image showed dwarf/hypolobated megakaryocytes. Patient’s first marrow biopsy (1998, not submitted): High power image showed dwarf/hypolobated megakaryocytes.
Patient’s first marrow biopsy (1998, not submitted): Reticulin stain showed mild reticulin fibrosis (1+). Patient’s first marrow biopsy (1998, not submitted): Reticulin stain showed mild reticulin fibrosis (1+).
Patient’s first marrow biopsy (1998, not submitted): CD34 immunohistochemical stain highlighted the blood vessels but not an increased number of blasts. Patient’s first marrow biopsy (1998, not submitted): CD34 immunohistochemical stain highlighted the blood vessels but not an increased number of blasts.
Spleen, splenectomy (1998, submitted) showed MDS in spleen with increased blasts and immature myeloid cells consistent with early acute transformation. Low power H&E image showed markedly expanded red pulp and atrophic white pulp.Spleen, splenectomy (1998, submitted) showed MDS in spleen with increased blasts and immature myeloid cells consistent with early acute transformation. Low power H&E image showed markedly expanded red pulp and atrophic white pulp.
Spleen, splenectomy (1998, submitted): A diffuse proliferation of immature myeloid cells infiltrated the red pulp. Spleen, splenectomy (1998, submitted): A diffuse proliferation of immature myeloid cells infiltrated the red pulp.
Spleen, splenectomy (1998, submitted): High power image showed cells with blastic morphology displaying high nucleo-cytoplasmic ratio. Numerous dwarf/hypolobated megakaryocytes morphologically similar to the ones in patient’s bone marrow were also identified. Spleen, splenectomy (1998, submitted): High power image showed cells with blastic morphology displaying high nucleo-cytoplasmic ratio. Numerous dwarf/hypolobated megakaryocytes morphologically similar to the ones in patient’s bone marrow were also identified.
Spleen, splenectomy (1998, submitted): Numerous dwarf/hypolobated megakaryocytes were identified. Spleen, splenectomy (1998, submitted): Numerous dwarf/hypolobated megakaryocytes were identified.
Spleen, splenectomy (1998, submitted): The immature myeloid cells were positive for MPO. An increased number of CD34-positive myeloid blasts were identified by flow cytometric analysis further supporting a diagnosis of early transformation. Spleen, splenectomy (1998, submitted): The immature myeloid cells were positive for MPO. An increased number of CD34-positive myeloid blasts were identified by flow cytometric analysis further supporting a diagnosis of early transformation.
Submitted marrow (1999) showed AML with myelodysplasia-related changes. Low power H&E image showed hypercellular bone marrow with sheets of blasts, admixed with numerous dysplastic megakaryocytes.Submitted marrow (1999) showed AML with myelodysplasia-related changes. Low power H&E image showed hypercellular bone marrow with sheets of blasts, admixed with numerous dysplastic megakaryocytes.
Submitted marrow (1999): Numerous blasts admixed with dysplastic megakaryocytes.Submitted marrow (1999): Numerous blasts admixed with dysplastic megakaryocytes.
Submitted marrow (1999): High power image showed numerous dwarf hypolobated dysplastic megakaryocytes and blasts. Submitted marrow (1999): High power image showed numerous dwarf hypolobated dysplastic megakaryocytes and blasts.
Submitted marrow (1999): Blasts were mainly small to medium in size with high nucleo-cytoplasmic ratio.Submitted marrow (1999): Blasts were mainly small to medium in size with high nucleo-cytoplasmic ratio.
Submitted marrow (1999): The blasts were diffusely positive for CD34. Submitted marrow (1999): The blasts were diffusely positive for CD34.
Submitted marrow (1999): The blasts were mostly negative for MPO. The strongly MPO-positive cells most likely represented promyelocytes. Submitted marrow (1999): The blasts were mostly negative for MPO. The strongly MPO-positive cells most likely represented promyelocytes.
Follow-up post-treatment marrow (1999, not submitted) showed persistent AML. The bone marrow was extensively diffusely fibrotic with pockets of blasts and dwarf megakaryocytes. Follow-up post-treatment marrow (1999, not submitted) showed persistent AML. The bone marrow was extensively diffusely fibrotic with pockets of blasts and dwarf megakaryocytes.