Lymphoblastic Lymphoma

Etiology

There is solid evidence that ALL/LBL has a genetic component. This is evidenced by many distinct translocations associated with the disease and a higher prevalence of the disease in monozygotic twins. Research has shown that polymorphic variants in GATA3, CEBPE, ARID5B, IKZF1, and CDKN2A have also been associated with ALL. ALL incidence has also been found to be higher in patients with immunodeficiency disorders such as Down syndrome, neurofibromatosis type 1, Bloom syndrome, and ataxia-telangiectasia.[3][4]

Epidemiology

The estimated number of ALL new cases in the United States is approximately 6000 per year. ALL is primarily a disease of children younger than 6 years with a slight male predominance. About 85% of ALL cases are B-cell in origin, and 15% are T-cell in origin. LBL accounts for approximately 2% of all NHL. B-LBL constitutes approximately 10% of all LBL cases, and the vast majority (90%) are T-LBL. T-cell ALL is more common in males, African Americans, and adolescents. T-ALL accounts for approximately 25% of adults ALL.[1][4]

Pathophysiology

B-ALL arises in either a hematopoietic stem cell or a B-cell progenitor. B-ALL shows various chromosomal abnormalities. Chromosomal abnormalities are thought to be an early initiating event in leukemogenesis and usually involve genes regulating cell signaling, tumor-suppressor functions, and/or lymphoid differentiation. Chromosomal abnormalities encountered include aneuploidy (changes in chromosome number), chromosomal rearrangements/translocations, genetic deletions/gains, and genetic mutations.

Generally, translocations are classified into 2 main classes. The first class involves the translocation of oncogenes to regulatory gene regions. The second class of translocations involves 2 genes and result in a chimeric protein. ALL show many distinct translocations showing both functional classes of translocations.[2]

B-ALL is classified into 2 distinct entities: 

1. B-ALL not otherwise specified (NOS) 
2. B-ALL with recurrent genetic abnormalities

The B-ALL/LBL (NOS) should only be rendered when all other entities have been excluded. B-ALL is classified into multiple entities based on distinct chromosomal abnormalities as follows[5][2]:

B-Lymphoblastic Leukemia/Lymphoma (NOS)

Should only be rendered after the exclusion of all ALL with recurrent genetic abnormalities and Burkitt lymphoma/leukemia.

B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities

This entity is classified into 9 different entities based on distinct chromosomal abnormalities as follows:

B-ALL/LBL with t(9;22)(q34;q 112); BCR;ABL1: This entity is relatively more common in adults than children. The translocation can lead to a p190 BCR-ABL1 fusion protein (common in children) or a p210 BCR-ABL1 fusion protein (common in adults). Overall, t(9;22) B-ALL cases have an unfavorable outcome compared to other ALL entities. Patients who are responsive to tyrosine kinase inhibitors tend to have a more favorable outcome than others.

B-ALL/LBL with t(v;11q23.3); KMT2A rearrangement: This entity shows a translocation between the KMT2A (MLL) gene at band 11q23 and up to 100 different fusion partners. This entity usually presents with a pro-B immunophenotype. ALL with KMT2A rearrangements is by far more common in infants younger than 1 year and tends to present more often with leukocytosis and central nervous system (CNS) involvement compared to other entities. The most common fusion partner gene is AF4 on chromosome 4q21. Overall, B-ALL with KMT2A rearrangements cases has an unfavorable outcome compared to other ALL entities.

B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1: This entity is common and accounts for up to 25% of childhood B-ALL. The entity has a unique immunophenotype that includes positive CD19, CD10, and CD34 and negative CD9, CD20, and CD66c. The ETV6-RUNX1 translocation results in a fusion protein that inhibits RUNX1 function. B-ALL/LBL with t(12;21) also shows a unique genetic signature and overall shows a favorable overall prognosis.

B-lymphoblastic leukemia/lymphoma with hyperdiploidy: Hyperdiploidy in B-ALL/LBL is characterized by more than 50 and fewer than 66 chromosomes without other structural abnormalities. Common chromosomes include 21, X, 14, and 4. This entity is common and accounts for to up to 25% of childhood B-ALL. Lymphoblasts show the following immunophenotype: CD19+, CD10-, CD34+, and CD45-. B-ALL/LBL with hyperdiploidy shows a favorable overall prognosis, although the outcome may vary based on certain trisomies present. For instance, the most favorable outcome is identified in patients with simultaneous trisomies 4, 10, and 17.

B-lymphoblastic leukemia/lymphoma with hypodiploidy: Hypodiploidy with B-ALL/LBL includes the following subtypes: near-haploid ALL (23 to 29 chromosomes), low haploid ALL (33 to 39 chromosomes), high hypodiploid (40 to 43 chromosomes), near-diploid (44 to 45 chromosomes). In addition to the chromosome loss, structural abnormalities can also be identified in B-ALL with hypodiploidy. The entity usually demonstrates a B-cell precursor immunophenotype. Low haploid ALL usually shows a distinctive genetic signature that includes loss of function mutation of TP53 or RB1. Overall, B-ALL with hypodiploidy cases has an unfavorable outcome, with near-haploid ALL having the worst prognosis of the 4 subtypes.

B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH: This entity is a relatively rare ALL entity. The translocation between the IL3 gene and IGH gene results in constitutive overexpression of IL3. Patients can present similar to other patients with ALL; however, presenting with asymptomatic eosinophilia is possible. The unusual increase in eosinophils in ALL with t(5;14) is characteristic of this entity; however, it is not related to the leukemic clone and has no clear cause. The prognosis of ALL with t(5;14) is usually favorable.

B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1: This entity is relatively common in children. There is no unique clinical presentation in these patients. The immunophenotype of lymphoblasts in these patients shows a pre-B with CD19, CD10, and cytoplasmic mu positivity. Although this disease entity shows a distinct genetic and immunophenotypic signature, the management of this entity is not different from other ALL (NOS) patients. Therefore, the identification of this entity is not mandatory.

B-lymphoblastic leukemia/lymphoma with BCR-ABL1-like[6]: This entity has been introduced as a provisional entity in the WHO 2017. It is a relatively common subtype of B-ALL, representing 7% to 25% of patients with B-ALL.

• The entity is more common in patients with Down syndrome and uniquely shows CRLF2 translocation. It is a diagnosis of exclusion after exclusion of distinct entities. Gene expression profiling is the “gold standard” for the diagnosis of BCR-ABL1-like B-ALL. FISH and karyotyping may be helpful in ruling out other entities.
  • Some specialized labs currently offer multiplex FISH testing for some of the common genes.
  • Similar to other ALL with recurrent genetic abnormalities, this entity shows no unique presentation, microscopic presentation, or immunophenotypic profile.
• This entity is characterized by a pattern of gene expression similar to that of B-ALL with the BCR-ABL1 translocation but lacks the BCR-ABL1 fusion protein.
• This entity harbors a large number of kinase-activating gene rearrangements primarily involving the ABL class, JAK/STAT, and/or Ras pathway-associated signaling pathways.
• Common genes involved include ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3 PDGFRb, JAK1/2/3, FLT3, IL7R, and SH2B3, IKZF1.
  • Many cases of B-ALL with BCR-ABL1-like may additionally show other deletions or mutations that have a clear role in leukemogeneses, such as IKZFA and CDKN2A/B.
  • The prognosis of ALL with BCR-ABL1-like is unfavorable.
  • Identifying patients with B-ALL with BCR-ABL1-like can influence the management of the patient. For instance, patients with PDGFFB translocation can benefit from TKI inhibitors, while patients with JAK translocations may benefit from JAK inhibitors. Adult patients tend to have a poor outcome even with high-intensity chemotherapy regimens.

B-lymphoblastic leukemia/lymphoma with iamp21[7]: This is a relatively rare B-ALL entity predominately in older children. B-ALL with iAMP21 is diagnosed by identifying 3 or more RUNX1 signals on one marker chromosome.

• Similar to the majority of B-ALL with recurrent genetic abnormalities, this entity shows no unique presentation, immunophenotypic profile, or microscopic finding. Diagnosis can only be rendered through genetic studies.
  • B-ALL with iAMP21 can show variable cytogenetic features that include gains of an X chromosome, abnormalities of chromosome 7, deletions of RB1 and/or ETV6, and rearrangements of CRLF2 gene.
  • The prognosis of ALL with iAMP21 is unfavorable.
  • Identifying patients with B-ALL[6][1]

History and Physical

Diagnosis of patients with ALL/LBL is generally based on clinical, morphologic, immunophenotyping, molecular features. Molecular studies are essential for diagnosis, prognosis, classification, and treatment. The main challenge in the diagnosis of ALL is that the disease is difficult to distinguish from common, self-limited diseases of childhood. B-ALL usually presents as symptoms of bone marrow (BM) suppression by lymphoblasts. Patients can present with anemia, leucopenia or thrombocytopenia, or a combination of these. Symptoms include bruising or bleeding due to thrombocytopenia, pallor and/or fatigue due to anemia, and recurrent infections caused by neutropenia/leucopenia and/or bone pains. Patients may also frequently present with lymphadenopathy (greater than 10 mm in a single dimension of the lymph node), hepatomegaly, and/or splenomegaly. Patients with relapse usually present with persistent peripheral blood cytopenias. While patients with B-ALL present with symptoms that usually render an investigation work-up, B-LBL patients are usually asymptotic. B-LBL most commonly involves the skin, bone-soft tissue, and lymph nodes. Mediastinal involvement is uncommon.[2]

The presentation of B- and T-cell LBL is different. T-LBL commonly involves the mediastinum (thymus); other possible sites include skin, tonsils, and spleen. Since T-LBL is more common than T-ALL, presentation with mediastinal masses with rapid growth is common.[1] T-lymphoblasts cannot be differentiated from B-lymphoblasts based on morphology, immunohistochemistry (IHC0, and flow cytometry are essential to render a diagnosis.[1]

Evaluation

The diagnosis of ALL/LBL is based on clinical, morphologic, immunophenotyping, and molecular features. Workup for ALL cases usually includes a complete blood count (CBC) with smear evaluation, PT, PTT, comprehensive metabolic panel (CMP), baseline viral titers for cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and varicella-zoster virus. Peripheral blood smear may show lymphoblasts, especially in ALL cases. Bone marrow involvement with more than 20% blasts is diagnostic and necessary for diagnosis and future follow-up. The lymphoblasts vary in size from small-medium and show scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli. It is crucial not to misinterpret hematogones with lymphoblasts. Some cases may need a flow-cytometry assessment to confirm the preliminary findings. In B-LBL, lymphoblasts may show a diffuse or a paracortical pattern of the lymph node.

The differentiation of B and T lymphoblasts cannot be done based on morphology and is usually rendered based on immunostaining and immunophenotyping. The use of cytochemical staining has significantly decreased as compared to immunostaining. Lymphoblasts can be differentiated from myeloblasts utilizing cytochemical staining. Lymphoblasts are negative on myeloperoxidase and Sudan black stain. Lymphoblasts may show periodic acid-Schiff positivity. Lymphoblasts in B-ALL/LBL are positive for CD19, cytoplasmic CD79a, cytoplasmic CD22, TdT, HLA-DR, PAX5, and CD10; and negative for CD117, T-cell markers, CD15, CD30, myeloid markers (CD13/CD33), CK, S100, and neuroendocrine markers. On tissue sections, CD79a and PAX5 are useful in differentiating B- from T-cell lineage. Immunophenotyping has become a crucial test for diagnosis and follow-up of ALL/LBL patients. For B-cell ALL/LBL, the degree of differentiation can be assessed utilizing a combination of B-cell lineage markers. Early precursor B-ALL or pro-B-ALL express CD19, cytoplasmic C079a, cytoplasmic CD22, and nuclear TdT. The second stage, also called common-ALL, the blasts express CD10. The third stage referred to as mature precursor or pre-B-ALL, the blasts express cytoplasmic mu chains (c-u). Research has demonstrated that mature B-cell ALL has a different biology and a poorer overall prognosis when compared to precursor B-ALL. Molecular studies are essential for diagnosis, prognosis, classification, and treatment. Cytogenetic abnormalities are used to classify B-ALL/LBL into separate entities. Most cases of B-ALL have clonal DJ rearrangements of the IGH gene [2]

Approaches to genetic testing in ALL depend on the national guidelines and are largely based on WHO guidelines and recommendations. In the majority of western and developed countries upfront, broad-based testing is implied. This approach is rapid but is more expensive. A stepwise diagnostic algorithm is implemented in some countries and some hospitals in the United States and offers the advantage of overall cost savings at the expense of potentially longer turn-around times. Finally, a tailored genetic approach has also been proposed and implemented in some health care facilities in the United States. The approach implements genetic testing based on the patient's NCI risk.

T-ALL/LBL can only be differentiated from B-ALL/LBL based on IHC and/or flow cytometry. However, some morphological features are common in T-ALL/LBL, for example, increased mitotic index and capsular involvement of the lymph node. Lymphoblasts in T-ALL/LBL are positive for CD3 , CD99, TdT, CD7 and variable expression of other T cell markers (CD1a, CD2, CD4, CD5, CD8), CD34, CD10, CD4/CD8; and negative for CD19, CD20, HLA-DR, surface immunoglobulin, CD22, CD25. Stages of intrathymic differentiation in T-ALL/LBL is based on the cells immunophenotype and is as follows:

• Pro-T: cCD3+, CD7+, CD2-, CD1a-, CD34+/-, double negative CD4 / CD8
• Pre-T: cCD3+, CD7+, CD2+, CD1a-, CD34+/-, double negative CD4 / CD8 
• Cortical T: cCD3+, CD7+, CD2+, CD1a+, CD34-, double positive CD4 / CD8
• Medullary T: cCD3+, CD7+, CD2+, CD1a-, CD34-, surface CD3+, either CD4+ or CD8+

Genetics studies for T-ALL/LBL show clonal TCR gene rearrangements and abnormal karyotypes in the majority of cases, most commonly involving 14q11.2 (a/d TCR loci), 7q35 (beta) and 7p14-15.

Treatment / Management

Combination chemotherapy has been an effective treatment modality for ALL since the 1950s. Combination chemotherapy is usually administered in distinct three phases (induction, consolidation, and maintenance) and should include intrathecal treatment, which is directed to the central nervous system (CNS). Chemotherapy protocols vary; however, the multi-drug induction phase (8 weeks) and the consolidation phase (4 to 8 months) have become the standard of care for most patients. Therapeutic drugs used in Induction therapy include glucocorticoid, vincristine, an asparaginase preparation, anthracycline, and intrathecal chemotherapy. Therapeutic drugs used in the consolidation phase include cytarabine, methotrexate, anthracycline (daunorubicin, doxorubicin), alkylating agents (cyclophosphamide, ifosfamide), and epipodophyllotoxins (etoposide, etopophosphamide). The maintenance phase usually lasts 30 to 42 months; therapeutic drugs used include mercaptopurine (6-MP), methotrexate, vincristine, and prednisone. Despite the favorable outcome of management in the majority of ALL/LBL patients, major life-threatening adverse events are possible and include tumor lysis syndrome, thrombosis, major bleeding, and sepsis. The management of patients with ALL should include antibiotics, BM stimulants, and antiemetics, among others, based on the side effects that the patients endure.[8][9][10](A1)

Risk stratification of patients with ALL classifies patients into low 15, average 36, high 25, very high 24, and special groups. There are guidelines for the management of each group, and the guidelines differ based on the national recommendations. ALL distinct entities such as t(9;22)/BCR-ABL1 translocation will require the addition of tyrosine kinase inhibitors to the standard regimens. Patients with ALL relapse require aggressive reinduction therapy and intensification depending on the risk stratification. Induction failure is a form of treatment resistance and is defined as the persistence of lymphoblasts post the induction phase and is generally considered as an indication for allogeneic hematopoietic-cell transplantation. Allogeneic, hematopoietic cell transplantation is the preferred mode of treatment for patients who relapse or who are resistant to therapy.[8][9][5][11](A1)

Differential Diagnosis

• Myeloid leukemia
• Diffuse large B-cell lymphoma
• Burkitt lymphoma
• Neuroblastoma: rosettes and neuroendocrine marker positivity
• Ewing Sarcoma: CD99 positivity
• Osteosarcoma, small cell variant: osteoid
• Mesenchymal chondrosarcoma: chondroid differentiation, S100+
• Juvenile idiopathic arthritis
• Osteomyelitis
• Epstein-Barr virus infection
• Immune thrombocytopenia (ITP)
• Pertussis, parapertussis infection
• Aplastic anemia
• Acute infectious lymphocytosis
• Hypereosinophilic syndrome

Prognosis

B-ALL has a favorable overall prognosis in children but a less favorable outcome in adults. The rate of complete remission rate in children is more than 95% and in adults is 75%. The following factors are associated with a poor prognosis in ALL/LBL: infancy, age (older than 10 years), leukocytosis, inadequate, slow response to initial therapy, the presence of minimal residual disease, and CNS involvement.

There are a number of stratification schemes that are used to assess risk in ALL/LBL patients. One of the stratification schemes utilized in ALL stratifies patients into "standard risk" and "high risk." The stratification is based on age (younger than 10 years standard and older than 10 years high risk) and white blood cell (WBC) count (fewer than 50,000 per cubic millimeter-standard, greater than 50,000 per cubic millimeter-high). Another useful tool in assessing prognosis in B-ALL is genetic studies. The following genetic abnormalities are associated with a favorable outcome: high hyperdiploidy and the t(12;21) ETV6-RUNX1.

On the other hand, the following genetic abnormalities are associated with an unfavorable outcome: 

• Hypodiploidy (fewer than 44 chromosomes)
• MLL rearrangement
• BCR-ABL1 Ph-like ALL
• CRLF2 rearrangement
• Intrachromosomal amplification of chromosome 21[1]

T-ALL shows an unfavorable prognosis compared to B-ALL. Early T-cell precursor ALL, a rare subtype of T-ALL/LBL, is particularly associated with an unfavorable outcome. Overall, T-LBL prognosis depends on age, disease stage, and LDH levels.