Bone marrow neoplastic

• Histologic morphology of lymphoblastic leukemia / lymphoma
• Early T cell precursor (ETP) blasts have the following immunophenotype: positive for cytoplasmic CD3, absent (< 5% positive blasts) CD1a and CD8 expression, absent or dim (< 75% positive blasts) CD5 expression, positive (≥ 25% positive blasts) for ≥ 1 myeloid (CD11b, CD13, CD33, CD65, CD117) or stem cell (CD34, HLA-DR) marker and negative (< 3%) myeloperoxidase (Lancet Oncol 2009;10:147)

• 12 - 17% of T cell acute lymphoblastic leukemia (TALL) (Lancet Oncol 2009;10:147, Blood 2016;127:1863)
• M:F = 4:1
• Incidence of 3 cases per million person years; does not vary by ethnicity

• Unknown etiology in most cases
• A study has demonstrated an association between germline RUNX1 variants and ETP ALL; it has been observed that mice with RUNX1 variants and mutated JAK3 induce ETP ALL (J Clin Invest 2021;131:e147898)

Contributed by Kamran M. Mirza, M.D., Ph.D. and Yazan Alhalaseh, M.D.

Contributed by Kamran M. Mirza, M.D., Ph.D. and Yazan Alhalaseh, M.D.

• Flow cytometry phenotyping of the blasts (dim CD45 gate) feature (Lancet Oncol 2009;10:147)
  • Absent (< 5% positive cells) CD1a and CD8 expression
  • Absent or dim (< 75% positive cells) CD5 expression
  • Expression (> 25% positive cells) of 1 or more myeloid (CD11b, CD13, CD33, CD117) or stem cell (CD34, HLA-DR) markers

Contributed by Kamran M. Mirza, M.D., Ph.D. and Yazan Alhalaseh, M.D.

• Not relevant for diagnostic evaluation

A 57 year old man presents to his primary care physician with a 2 month history of persistent fatigue. Vital signs are within normal limits. Physical examination is remarkable for pallor and hepatosplenomegaly. Laboratory workup reveals white blood cell (WBC) count of 17,000, hemoglobin of 9.0 and platelet count of 78,000. A peripheral blood smear shows 30% circulating blasts. A bone marrow core biopsy shows hypercellular bone marrow with 80% blasts. Immunohistochemical stains on the bone marrow core biopsy highlight the blast population that are positive for CD34 and CD3. Flow cytometry shows blasts that are positive for cytoplasmic CD3, CD34, dim CD4, CD56, CD33, CD13 and CD117. Genetic testing for BCR::ABL1 by cytogenetics was negative. Which of the following is the most likely diagnosis?

1. Chronic myeloid leukemia
2. Early T cell precursor lymphoblastic leukemia
3. Myelodysplastic neoplasm
4. Natural killer cell (NK) large granular lymphocytic leukemia

B. Early T cell precursor lymphoblastic leukemia. The patient presents with symptoms with concern for hematologic malignancy. Workup is notable for leukocytosis. The bone marrow biopsy shows hypercellular bone marrow with increased blasts. The immunohistochemical features are specific for early T cell precursor (ETP) given the CD3, CD56 and CD34 expression but absent CD1a, CD8 and myeloperoxidase.

Answer C (myelodysplastic neoplasm) is incorrect because the patient's blasts are significantly increased in the peripheral blood and bone marrow biopsy. Answer A (chronic myeloid leukemia) is incorrect because it can have increased blasts in the blast phase; however, the absence of BCR::ABL1 translocation rules out this diagnosis. Answer D (natural killer cell [NK] large granular lymphocytic leukemia) is incorrect because it is not characterized by increased CD34+ blasts.

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Reference: Early T cell precursor lymphoblastic leukemia

A 48 year old woman presents for evaluation of shortness of breath and fatigue over a 4 month period. She notes swelling in her neck and axillary region. Physical examination shows generalized lymphadenopathy and hepatosplenomegaly. Her complete blood count shows a white blood cell (WBC) count of 22,000, hemoglobin of 8.0 and platelet count of 100,000. A peripheral blood smear and flow cytometry on the peripheral blood are shown above. A bone marrow biopsy is performed as shown above and there is a neoplastic lymphoid population that is positive for cytoplasmic CD3, CD5 and CD34 and negative for CD1a, CD8 and myeloperoxidase. Which of the following is the most likely diagnosis?

1. Adult T cell leukemia
2. Early T cell precursor lymphoblastic leukemia
3. Mixed phenotype acute leukemia (MPAL), T / myeloid
4. Natural killer cell (NK) large granular lymphocytic leukemia

B. Early T cell precursor lymphoblastic leukemia. The patient presents with history and exam with concern for hematologic malignancy. The peripheral blood smear demonstrates atypical lymphocytes. The third figure above depicts flow cytometry revealing blasts (red) with low side scatter and dim CD45. The fourth figure shows blasts are positive for CD7 and negative for CD2. The fifth figure demonstrates blasts are positive for CD56 and dim positive for CD3. The sixth figure shows that the blasts have no expression of CD5. In the first figure, bone marrow biopsy is notable for hypercellularity. Given these findings in the setting of positive cytoplasmic CD3, CD5 and CD34 and negative CD1a, CD8 and myeloperoxidase, early T cell precursor lymphoblastic leukemia is the most likely diagnosis.

Answer C (mixed phenotype acute leukemia [MPAL], T / myeloid) is incorrect because the tumor cells in this case lack the expression of CD8 and myeloperoxidase and the immunoprofile meets criteria for early T cell precursor acute lymphoblastic leukemia. Answer D (natural killer cell [NK] large granular lymphocytic leukemia) is incorrect because it is not characterized by increased CD34 positive blasts. Answer A (adult T cell leukemia) is incorrect because the tumor cells of this entity do not express stem cell markers such as CD34.

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Reference: Early T cell precursor lymphoblastic leukemia