University of Virginia Health System

Acute Panmyelosis
(Acute or Malignant Myelofibrosis or Myelosclerosis)

(a) Acute panmyelosis with hypercellularity- Bone marrow biopsy, H&E stain, 100x

(b) Acute panmyelosis with hypercellularity- Bone marrow biopsy, H&E stain, 400x

(c) Acute panmyelosis with reticulin fibrosis- Bone marrow biopsy, Reticulin stain, 100x

(d) Acute panmyelosis with fibrosis- Bone marrow biopsy, Reticulin stain, 400x

(e) Acute panmyelosis with immature myeloid cells that are myeloperoxidase (MPO) positive- Bone marrow biopsy, Immunohistochemistry stain with MPO, 400x

(f) Acute panmyelosis with immature and atypical megakaryocytes- Bone marrow biopsy, Immunohistochemistry stain for Factor VIII, 500x

(g) Acute panmyelosis with erythroblasts- Bone marrow biopsy, Immunohistochemistry stain for Glycophorin A, 400x

(h) Acute panmyelosis with minimal poikilocytosis (few teardrop red blood cells)- Peripheral blood smear, Wright-Giemsa stain, 500x

(i) Acute panmyelosis with a micromegakaryoblast- Peripheral blood smear, Wright-Giemsa stain, 1000x

(j) Acute panmyelosis with a myeloblast- Peripheral blood smear, Wright-Giemsa stain, 1000x

Description:

All of the images shown are from a single patient with acute panmyelosis who survived 2 plus years with only supportative care measures. Even though micromegakaryoblasts (i) and myeloblasts (j) were noted in the peripheral blood at presentation, the predominant blasts were myeloblasts in the terminal phase.

The initial bone marrow biopsy (an attempt at aspiration was a "dry tap") revealed a marked hypercellularity comprised of a heterogeneous cellular process (a-g). A cardinal feature reticulin fibrosis, was present (c,d). The panmyelosis was demonstrated by selected immunohistochemistry stains: myeloid lineage (MPO) (e), megakaryocyte lineage (Factor VIII) (f), erythroid lineage (Glycophorin A) (g).

The fibrotic element was predominantly reticulin with only a minimal collagenous component. This feature together with the immaturity and atypia of the megakaryocytes and the presence of immature myeloid and erythroid elements is what morphologically defines this entity on a bone marrow biopsy. When compared to chronic idiopathic myelofibrosis (agnogenic myeloid metaplasia,) pancytopenia is more pronounced, poikilocytosis is less (h,) splenomegaly is usually absent or minimal, and the course is much more progressive.

Cytochemistry, Immunochemistry, Immunophenotype:

The trilineage proliferation can be demonstrated on a bone marrow biopsy specimen by immunohistochemical stains. Bone marrow aspirate material is usually not available to do flow cytometry. When blasts are present in the peripheral blood, cytochemistry and immunophenotyping can be performed to determine lineage.

Cytogenetics:

No signature cytogenetic abnormality has been identified. Complex abnormalities involving chromosomes 5 and 7 are found most frequently.

Differential Diagnosis:

• Polycythemia vera (PV)- The panmyelosis seen in PV does not show the degree of left shift and atypical features of acute panmyelosis, and reticulin fibrosis usually is not present unless transformation to primary myelofibrosis is occurring. As the name implies, there is usually a polycythemia in the peripheral blood with the erythroid lineage predominant (high hematocrit and hemoglobin). The JAK-2 mutation is found in 95% of cases.
• Chronic idiopathic myelofibrosis (myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia)- Although panmyelosis is a feature of this disorder, it is the megakaryocyte lineage that is usually predominant. The atypical megakaryocytes, a cardinal feature, are more mature, and immature granulocytic and erythroid elements are not present unless an accelerated phase or blast crisis is occurring. Fibrosis, by definition, is a necessary finding for diagnosis, and collagenous fibrosis is the rule as the disease progresses. A variable degree of pancytopenia is present, although thrombocytosis is commonly seen. Teardrop red cells with a variable degree of leukoerythroblastosis is the rule, as is the finding of splenomegaly. The course is a chronic and the JAK-2 mutation is found in approximately 50% of cases.
• Essential Thrombocythemia- This disorder is characterized by a unilineage (megakaryocytic) hyperplasia in the bone marrow and thrombocytosis in the peripheral blood with usually a normal leukocyte count and a normal or mildly decreased hematocrit. Teardrop red cells are uncommon. The megakaryocytes in the bone marrow are atypical and tend to clump, but they are less immature than in acute panmyelosis. Reticulin fibrosis usually is not present or is minimal. Splenomegaly usually absent or mild. JAK-2 mutation found in 50% of cases.
• Chronic myelocytic leukemia- This disorder is characterized by a granulocytic hyperplasia in the bone marrow and reticulin fibrosis is absent. In the peripheral blood a variable degree of granulocytosis, predominantly neutrophilic, is seen, but a variable degree of eosinophilia and basophilia may be present. The platelet count may be high, low, or normal and the hematocrit is usually low, but may be normal. Teardrop red cells are unusual, and no dysplasia is seen except for some mild atypia of the platelets in some cases. The signature cytogenetic abnormality, t(9;22) defines this entity.
• M7 AML (Acute megakaryoblastic leukemia)- The findings in this AML subtype may be impossible to distinguish from acute panmyelosis. Some have used M7 AML as a synonym for acute panmyelosis, but de novo M7 AML, especially the micromegakaryoblastic subtype presents as a leukemia with unilineage (megakaryocyte) features.
• Accelerated phase or leukemic transformation (blast crisis) in chronic myeloproliferative disorders- During the accelearted or acute leukemic phase of the chronic myeloproliferative disorders, especially if fibrosis is present, a morphologic distinction frequently cannot be made. A history of a longstanding myeloproliferative disorder is an important differential factor.
• Unilineage acute leukemias with fibrosis- These cases should be classified as acute leukemia with fibrosis, and according to the lineage of the proliferating blasts present. Unusual in the AMLs except for M7. A background of reticulin fibrosis is a common finding in ALL, but the lymphoblastic element is so dominant that diagnosis is not difficult.
• Hybrid myeloproliferative-myelodysplastic disorders- A clear distinction cannot be made in some cases, especially if leukemic transformation is occurring. These disorders generally have a more chronic course, and in absence of leukemic transformation, the cellular elements in the bone marrow show more differentiation. Dysplastic changes are seen in both.
• Multiple myeloma- a background of mild reticulin fibrosis is often present, but the plasmacytic element is so dominant, that diagnosis is not difficult.
• Non-hematopoietic tumors metastatic to the bone marrow- Immunohistochemistry and cytochemistry is necessary to evaluate for a variety of metastatic tumors that tend to invade the bone marrow (e.g. breast, prostate, small cell lung, and certain neuroendocrine tumors). A fibrotic element is often present.

*Note: Many other disorders may be manifested by fibrosis in the bone marrow. (e.g. tuberculosis, autoimmune disorders) but the pattern, often only focal, the other elements present, and the clinical setting allow for easy diagnosis.

Prognosis and Course:

Survival generally is short but some smolder for 2 years or longer with support measures only, as was the case presented above. Response to induction chemotherapy is generally very poor. Allogeneic bone marrow transplant has been effective in some cases.

General References:

• Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors, Lyon, France: IARC Press, 2001 
• Bearman RM, Gerassimos A, Pangalis MD, Rappaport H: Acute (malignant) myelosclerosis. Cancer 43: 279, 1979
• Kroener JF, McMillan R, Beutler E: Acute myelofibrosis: treatment with allogeneic bone marrow transplantation. JAMA 249:1189, 1983
• Lewis SM, Szur L: Malignant myelosclerosis. Brit Med J 2: 472, 1963
• Wickramasinghe SN, McCullough J, eds. Blood and bone marrow pathology. Churchill Livingstone, Edinburgh, 2003

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