Definition: B-ALL/ B-LBL is a B lymphoblastoid tumor that typically consists of small to moderately large mother cells. They have sparse cytoplasm, moderately dense to sparse chromatin, inconspicuous nuclei, and involve the bone marrow and peripheral blood (B-lymphoblast leukemia) and occasionally originate in lymph nodes or extra-nodal sites (B-lymphoblast lymphoma).
B-ALL and B-LBL are the same biological entity, and there should be some restrictions on which terminology is used. The diagnosis of lymphoma should be made when only a mass is present without or with only mild blood and bone marrow involvement. The term lymphoblastic leukemia is more appropriate when there is extensive bone marrow blood involvement. If the patient has a mass and ≤25% lymphoblastoid cells in the bone marrow, the patient should be considered to have lymphoma. This is a rather arbitrary classification, and therefore exceptions may occur.
Synonym: Acute lymphoblastic leukemia.
Epidemiology.
ALL is primarily a childhood disease, occurring in 75% of children under 6 years of age. approximately 3200 new cases were estimated in the United States in 2000, with approximately 80-85% having a prodromal B-cell phenotype.
B-LBL is an uncommon lymphoma, accounting for approximately 10% of lymphocytic lymphomas (the others are T-lymphoblastic lymphomas). From a literature review, it was reported that about 75% of patients were <18 years old; in one report of 25 cases, 88% of patients were <35 years old, with a mean age of 20 years. One report showed a male predominance.
Etiology.
The etiology is unclear; some cases may have a genetic component.
Site of involvement.
All B-ALL have bone marrow and blood involvement. The most susceptible sites of involvement are the central nervous system, lymph nodes, spleen, liver and gonads. In B-LBL, the most susceptible sites are skin, bone, soft tissue, and lymph nodes. Mediastinal masses are rare.
Clinical features.
Most patients with B-ALL have bone marrow failure: complete cytopenia, anemia/neutropenia. White blood cell counts may be decreased, normal, or markedly increased. Lymph node, liver and spleen enlargement are common. Bone and joint pain can be the main symptom.
A small number of patients with B-ALL initially present with lymphoma with or without bone marrow and blood involvement. b-LBL is most commonly seen in the skin, bone, and lymph nodes; skin involvement often appears as multinodular. Bone marrow and blood may also be involved, but lymphoblastoid cells account for <25% of the disease.
Morphology.
Lymphoblasts are highly variable in smears and prints, ranging from small to large cells, with small cells having little cytoplasm, dense chromatin, and inconspicuous nucleoli; large cells have medium cytoplasm, light blue to blue-gray, occasional vacuoles, diffuse chromatin, and clear nucleoli in high numbers. Asplenophilic granules were seen in 10% of cases. These findings may be associated with t(9;22)(q34;q11.2) cytogenetic abnormalities. In some cases lymphoblasts have pseudopods (hand mirror cells).
In bone marrow biopsies, the lymphoblasts of B-ALL are relatively uniform, with round, oval, indurated, and sometimes curved nuclei. The nucleoli are usually inconspicuous (clear). B-LBL is characterized by diffuse distribution of lesions at the site of involvement; in some cases of lymph node involvement, the lymphoblasts invade the paracortical area and involve the germinal center.
The lymphoblastoid cells have a uniform, round to oval nucleus with varying degrees of nuclear membrane curvature. The chromatin is finely punctate and the nucleoli are usually inconspicuous. The morphological features of B and T lymphoblastoid proliferation are similar and morphology cannot be used to distinguish their immunophenotypes.
Cytochemistry.
Lymphocytes do not express MPO and Sudan Black B (SBB). Lymphoblasts can stain light gray with SBB, but not as strongly as myeloblasts. Lymphoblasts may appear PAS+, and in some cases a PAS+ halo may appear around the nucleus. Lymphoblasts may be NSE dot-positive in the Golgi region.
Immunophenotype.
Lymphocytes in B-ALL/LBL are TdT+, HLA-DR+, CD19+, and CD79a+. Lymphocytes in most cases are also CD10+, CD24+, but in t(4;11)(q21;q13) ALL lymphocytes usually do not express CD10 and CD24. expression of CD22 and CD20 is variable. CD45 may be positive. Cytoplasmic CD22 is thought to be cytologically specific. The myeloid-associated antigens CD13 and CD33 may be expressed, but these expressions do not exclude the diagnosis of B-ALL. The degree of differentiation of progenitor B lymphoblastoid cells has clinical and genetic relevance. In the earliest stage, the so-called early prodromal B-ALL, the mother cells express CD19, cytoplasmic CD79a, cytoplasmic CD22, and nuclear TdT. in the middle stage, the so-called common ALL, the mother cells express CD10. in the most mature stage of prodromal B differentiation, the so-called pre-B-ALL, the mother cells express cytoplasmic mu chains (cyt-mu). Surface Ig negativity is an important feature. However, when positive, B-ALL/LBL cannot be completely excluded.
Genetics.
The cytogenetic abnormalities of B-ALL/LBL can be divided into several groups: hypodiploid (hypodiploid), hyperdiploid (hypodiploid)50 , ectopic and pseudodiploid.
ALL-t(9;22)(q34;q11.2); BCR/ABLALL-(v;11q23); MLL rearranged ALL-t(12;21)(p13;q22); TEL/AML1ALL -t(1;19)(q23;p13.3); PBX/E2AALL-low diploidy ALL-high diploidy >50 These findings are important to understand the prognosis and are used to adjust the treatment regimen in pediatric cases. The current groups with better prognosis for treatment are.
(i) high diploids between 51 and 65, consistent with flow cytology DI 1.16 to 1.6; and (ii) t(12;21)(p13;q22). The latter is a fusion of the TEL gene at position 12 p13 with the AML1 gene encoded by the transcription factor at position 21q22; since standard cytogenetic methods cannot detect this abnormality, molecular techniques are used to identify it.
The genotypes with a poor treatment prognosis are.
(1) t(9;22), which is the result of fusion of the BCR gene at 22 q11.2 with the ABL gene at 9 q34 and is mostly seen in adults. A P190kdBCR/ABL fusion protein is present in most pediatric cases of t(9;22) ALL. About 1/2 of adult cases of t(9;22) ALL produce the P210kd fusion protein, which is seen in CML. the remaining cases have the P190 protein. There is no absolute difference between the two from a clinical point of view.
(ii) B-ALL at early differentiation stage can have t(4;11), where the MLL gene at 11q23 is fused to the AF4 gene at 4q21. other ectopic positions at 11q23 are due to MLL fusion with other partner genes. 11q23 abnormalities can also occur in ALL. (iii) t(1;19) is seen in 25% of children with B-ALL with cytoplasmic mu expression and fusion of E2A at 19p13.3 with PBX at 1q23, which is associated with poor prognosis with certain treatments.
④High diploidy was associated with poor prognosis. Other abnormalities (deletion of 6q, 9p, 12p, high diploidy with less than 50, near triploidy and near tetraploidy) are associated with moderate prognosis.
Some of the above genetic entities (ENTITY) have characteristic immunophenotypes. leukemias with MLL rearrangements have a CD10- profile and are commonly CD24-, CD15+. t(1;19) B-ALL is CD10+, CD34-, CD20- or unclear and cytosolic. CD20- or unclear and cytoplasmic type mu+. t(12;21) B-ALL is strongly positive for CD10 and HLA-DR, while CD19 and CD20 are usually negative.
Cellular origin.
Probably precursor B lymphoblastoid cells.
Differential diagnosis.
Diseases that should be differentiated in B-ALL are T-ALL, acute myeloid leukemia (AML) with mild differentiation, and reactive myeloid with primitive hematopoietic cellularity. T-ALL, B-ALL, and AML with mild differentiation can be distinguished by immunophenotype alone.
Primitive hematopoietic cytosis is seen in young children and adults with a variety of diseases including: iron deficiency anemia, neuroblastoma, thrombocytopenic purpura, and reactions to cytotoxic therapy. These cells have a high nucleoplasmic ratio, consistent chromatin, and the nuclei may be depressed or fissured. Nucleoli are usually indistinct; even when present, they are not easily identified. Primitive hematopoietic cells are usually absent from peripheral blood. In bone marrow biopsies, primitive hematopoietic cells are evenly distributed in the interstitium. The chromatin is very coarse, and nucleoli and nuclear schizotypes are rare.
It is difficult to distinguish primitive hematopoietic cells from leukemic B lymphoblastoid cells by their immunophenotype. Both types of cells express TdT and CD10; however, multiparametric flow cytometry is different, and primitive hematopoietic cells are characterized by the expression of CD10, CD19, CD20, CD34, CD45. These serial expressions indicate some differentiation and maturation of primitive hematopoietic cells. There are two phenotypes with predominantly mid-stage (CD10+, CD19+, TdT-, SIg-) and late stage (CD19+, CD20+, SIg+) immunophenotypes. In contrast, lymphoblastoid cells in B-ALL differ from the normal situation and show a predominance of immature cells (TdT+, CD19+, SIg-, CD20-) as well as a small number of mature cells. Lymphoblastoma in children should be distinguished primarily from Burkitt’s lymphoma. The differentiation of lymphoblastoid tumors in adults also includes the maternal cell variant of MCL. tdT easily distinguishes these lymphomas.
Lymphoblastoma is the only lymphoma that expresses TdT, and the medulloblast infiltrate is positive for chloroacetate, MPO (myeloperoxidase), and lysozyme.
Prognosis and predictive factors.
In general, this is the leukemia with a relatively good prognosis. In the pediatric group, the complete remission rate is nearly 95% and in the adult group it reaches 60-85%, and the disease-free survival rate in children is 70%. Approximately 80% of childhood B-ALL appears to be curable. The pediatric risk group for B-ALL is determined by cytogenetic profile, age, white blood cell count, sex, and response to initial treatment. Infant cases often have MLL gene ectopic at 11q23 and their prognosis is poor. In children, more than 50% of patients with hyperdiploid karyotype or t(12;21) abnormalities have a better prognosis, with 85-90% of patients surviving long term.
Factors for long-term remission or survival include: age 4-10 years, high diploidy, especially 54-62 containing triple T4 and/or 10 and/or 17, t(12;21) (p13;q22) and low or normal white blood cell count at diagnosis.