Submitting Author: King, Rebecca L, MD
Institution: The Children's Hospital of Philadelphia
Session: T Lymphoblastic Leukemia/Lymphoma

The patient is a 10 year old, previously healthy, female who presented to a local hospital in June 2012 with fevers, fatigue and weight loss. A CBC revealed WBC of 1.7, hemoglobin of 7.3, with an MCV of 71.2 and a platelet count of 150,000. Additional laboratory studies revealed an elevated ferritin and soluble IL-2 receptor (exact values not available) which led to clinical suspicion for hemophagocytic lymphohistiocytosis (HLH). Bone marrow biopsy and aspirate were performed and rare activated macrophages showing hemophagocytosis were seen on a hemodilute aspirate smear. Flow cytometry was reportedly negative for malignancy.

She was treated with Etoposide and Dexamethasone for a total of eight weeks for a diagnosis of HLH. All genetic studies for familial HLH predisposition genes were reportedly negative. In early October, she developed nausea, vomiting, and fevers, and was found to have hepatosplenomegaly and pancytopenia, while laboratory values confirmed relapse. She was once again started on Etoposide and Dexamethasone.

In December 2012, she was transferred to our hospital to begin preparation for bone marrow transplant for her presumed diagnosis of primary HLH. At our institution, CT scan revealed diffuse lymphadenopathy and ferritin was 43,000 on admission. Biopsy of a cervical lymph node and bone marrow were performed. The bone marrow from June was also sent to us for review.

December 2012 Bone marrow, right iliac crest, aspirate and biopsy (decalcified and fixed in AZF): The bone marrow was inaspirable. A touch prep of the core biopsy showed approximately 25% blasts with L1 morphology (Image 1). The bone marrow core biopsy showed a small focus of normal hematopoiesis but was largely effaced by sheets of necrosis and serous stromal change. Within these areas were foci of viable blasts. (Images 2 and 3)

December 2012 Lymph node, left cervical, biopsy (formalin): The lymph node biopsy showed completely effaced architecture with extensive necrosis and apoptotic debris. Viable areas showed blasts similar in appearance to those seen in the bone marrow. (Images 4 and 5)

June 2012 Bone marrow, sent for our review in December 2012: The bone marrow biopsy from June revealed foci of blasts with morphology identical to those seen in the December specimen. Foci of single cell necrosis and extensive serous stromal change were present in this biopsy (Images 6 and 7). A reactive lymphoid infiltrate was also present. The bone marrow aspirate was hemodilute without an obvious blast population. Rare histiocytes showing hemophagocytosis were present (Image 8).

Flow cytometry from both the lymph node biopsy (Image 9) and bone marrow aspirate from December 2012 demonstrated a population of blasts (2% of total events in the bone marrow, 56% in lymph node) with low side scatter and dim CD45 with the following immunophenotype: CD2+ sCD3 (dim)+ CD4- CD5- CD7+ CD8- CD10- CD11b(subset)+ CD33(dim, subset)+ CD38(dim)+ CD34- HLA-DR+ cCD3+ cMPO- TdT-CD1a-.

By immunohistochemistry the blasts express CD3, CD45(dim), BCL6 (subset), TCR-BF1 and MUM-1. They are negative for TdT, CD1a, CD5, CD4, CD8, CD117, CD20, PAX5, CD10, CD30, ALK-1, and TdT and EBER (ISH), TCR-gamma, CD33, and CD99.

We performed immunohistochemistry on the outside bone marrow biopsy from June and demonstrated a population of blasts with the same immunophenotype. (Image 10)

Unsuccessful due to poor tissue viability.

This is an interesting case of T lymphoblastic leukemia (T ALL) presenting with hemophagocytic lymphohistiocytosis (HLH). This case highlights the importance of thoroughly evaluating patients presenting with HLH for an underlying hematologic neoplasm. Although primary HLH is more common in children than in adults, the majority of primary HLH cases occur in infants < 1 year of age (1). As such, thorough evaluation for an underlying infectious, autoimmune, or neoplastic process is essential not only in adults, but also in older children with HLH. Both acute leukemia as well as B and T cell lymphomas have been reported in association with HLH, and the HLH may precede or follow the neoplastic diagnosis (1). Although chemotherapy followed by bone marrow transplant is the recommended course of treatment for primary HLH, therapy in secondary cases relies on adequate management of the underlying hematologic neoplasm. Because of the aggressive clinical course of HLH, timely identification of an underlying etiology is important not only to properly manage the HLH, but also to avoid sub-optimal pre-treatment of an undiagnosed malignancy.

In this case, the chemotherapy given for the HLH likely further delayed the diagnosis of her lymphoblastic leukemia, and also altered the course and options for therapy.

In addition to the association with HLH, this case of T ALL is notable for its immunophenotype, which is that of the recently recognized early T cell precursor (ETP) subgroup of T ALL. This subgroup of ALL derives from T cell precursors that have recently migrated from the bone marrow to the thymus, and retain some potential for multilineage differentiation (2). ETP leukemias can be identified based on their immunophenotype (CD1a-, CD8-, CD5 dim/-, with co-expression of stem cell or myeloid markers) (2). This immunophenotype correlates well with an ETP-like gene expression signature that also seems to confer genomic instability as indicated by a high burden of DNA copy number alterations (2, 3). In this case, the CD5 negativity as well as expression of HLA-DR and CD11b on a significant subset of blasts is highly suggestive of ETP leukemia. Clinically, several recent studies have confirmed that these patients have aggressive disease and show poor response to therapy, thus highlighting the importance of recognizing this T ALL subgroup (2-5).

Interestingly, whole exome sequencing has revealed that genetic alterations in ETP leukemia tend to involve pathways, such as RAS and JAK-STAT signaling, that are more commonly associated with acute myeloid leukemia (3,5). These findings suggest that targeted therapies or therapies used successfully in myeloid leukemias may be of use in this subgroup of T ALL.

In summary, this case highlights a potential diagnostic pitfall when a child presents with HLH and is not adequately evaluated for an underlying cause. It also reminds the pathologist and the clinician that although infections such as EBV are commonly associated with HLH, lymphomas, including lymphoblastic lymphoma/leukemia, may be associated with HLH either at the time of diagnosis or during treatment.

Finally, this case of T ALL demonstrates the classic immunophenotype of ETP leukemia, a recently defined, and clinically relevant, subgroup of T ALL. Given the distinct gene expression profile of this leukemia, these patients may benefit from targeted therapy in the future and thus further identification and study of this subgroup is critical.

References

1. Jaffe ES, Harris NL, Vardiman JW, Campo E, Arber D. Hematopathology. Philadelphia: Elsevier Saunders; 2011.

2. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. The Lancet Oncology. 2009;10(2):147-56.

3. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157-63.

4. Ma M, Wang X, Tang J, et al. Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia. Front Med. 2012;6(4):416-20.

5. Neumann M, Heesch S, Gokbuget N, et al. Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations. Blood Cancer Journal. 2012;2:e55.

T lymphoblastic leukemia with an early T cell precursor (ETP) phenotype presenting with hemophagocytic lymphohistiocytosis

T-cell neoplasm, with hemophagocytic lymphohistiocytosis

Case 53