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Quinta-feira, 13.08.15

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology (2)

Biomarkers in Hematological Malignancies: A Review of Molecular Testing in Hematopathology


Lymphoblastic Leukemia/Lymphoma

Similar to AML, the detection of certain characteristic translocations further subclassifies cases of B-ALL, including t(12;21)(p12,q22) TEL/AML-1, t(1;19)(q23;p13) PBX/E2A, t(9;22)(q34;q11) ABL/BCR, (5;14)(q31;q32) IL3-IGH, and (V;11)(V;q23) V/MLL. 20 t(9;22)(q34;q11) is seen in 25% of adult cases and 2% to 4% pediatric cases.72

Patients with this Ph+ translocation carry the worst prognosis of all types of lymphoblastic leukemia73; however, these patients can be treated with adjuvant imatinib, which improves complete remission rates.74 The presence of the translocation also serves as a useful marker for minimum residual disease testing.

Molecular methods for detecting the translocation are similar to those used for CML. Notably, when qRT-PCR testing is undertaken, the p190 protein product is typically associated with B-ALL, not the p210 protein typical of CML; in children with ALL, the break point occurs in m-bcr, which generates the p190 protein product in 90% of cases.6

If a p210 protein product is detected, then consideration should be given to a lymphoid blast crisis arising in CML. By contrast to t(9;22), the reverse demographic appears to be true for t(12;21)(p12,q22): It occurs in 25% of pediatric cases but is rare in adults and associated with a favorable prognosis and curative rates of higher than 90% in children.75 MLL can have various translocation partners, the most common of which is AF4 on chromosome 4.

MLL translocations carry a poor prognosis, and this is particularly true in infants.76 The unique characteristic of t(5;14)(q31;q32) IL3/IGH B-ALL, which is rare, is its association with eosinophilia due to the overexpression of IL3.77

t(1;19)+ B-ALL is historically associated with a poor prognosis, but this has changed through the use of intensive chemotherapy regimens.78 Immunophenotypically, the blasts lack CD34 but have aberrant CD9 positivity.79

Based on gene-expression profiling, BCR-ABL1–like B-ALL has been identified as being associated with deletions of IKZF1, CRLF2 rearrangements, and poor outcomes.80 JAK1/2-activating mutations are present in a subset of these patients and may benefit from Janus kinase inhibitor therapy.80

In all children with ALL, cytogenetic testing or flow cytometric analysis of ploidy should be undertaken. Hyperdiploidy (> 50 chromosomes) is associated with a better prognosis, whereas hypodiploidy (< 44 chromosomes) is associated with a poor prognosis.80,81 Translocations in T-cell ALL (T-ALL) commonly involve 1 of the TCR loci (A, B, G, D).

The most common translocation partner includes HOX11 on chromosome 10 (occurring in 10%–30% of cases) or various other transcription factors dysregulated by juxtaposition to 1 of the TCR genes.82 PICALM-MLLT10 and MLL rearrangements are seen in approximately 10% of cases.83

Both B-ALL and mature B-cell non-Hodgkin lymphomas (NHLs) show clonal immunoglobulin (Ig) gene rearrangements, which are helpful in residual disease testing as well as in establishing a malignant diagnosis. For follow-up specimens, screening for clonal peaks identical to those identified at diagnosis can be performed to assess for residual/relapsed minimal residual disease.

B-cell antigen receptors are encoded by IGH (14q32), IGLK (2p11), and IGLL (20q11), coding for the Ig heavy chain, κ light chain, and the λ light chain, respectively. Each contains variable (V), joining (J), and constant regions; IGH contains an additional diversity (D) region.

Multiplex PCR that uses primers to target highly conserved framework regions within the V segment are used to generate PCR products, which can then be separated using capillary electrophoresis, which is preferred to Southern blot analysis.84,85 Monoclonal peaks have heights 2 to 3 times that of the background and can be seen in clonal B-cell neoplasms.

Repeat peaks in duplicate wells raise confidence that clonal peaks do not represent a PCR artifact. Care must be taken because false-positive results can occur in cases of benign lymphoid hyperplasia, which may be present in the setting of immunodeficiency and autoimmune disease.86,87 Furthermore, lineage infidelity is present with BCR gene rearrangement and is similar to that seen in T-cell lymphoma.

Most precursor and 5% to 10% of mature B-cell neoplasms will harbor clonal T-cell gene rearrangements.6 Other various factors may result in false-negative results, including primer failure due to somatic hypermutation (which can occur at a rate of > 50% in certain lymphoid neoplasms [eg, follicular lymphoma]), complex IGH rearrangements, or DNA of poor quality.6,88

Mature B-Cell Neoplasms

Various translocations are associated with B-cell NHLs and their detection helps to establish a diagnosis in these entities. t(14;18) involves BCL2 on chromosome 18 and IGH on chromosome 14. BCL2 is juxtaposed to the J region of the heavy chain.

Given that the IGH enhancer element is highly active, bcl2 can become overexpressed. Because bcl2 has antiapoptotic properties, its overexpression will result in neoplasia.

This translocation is found in 85% to 90% of cases of follicular lymphoma (a lower percentage occurs in cases of high-grade follicular lymphoma) and 25% of cases of diffuse large B-cell lymphoma (DLBCL).20 Because follicular lymphomas may lack demonstrable Ig clonality due to ongoing somatic hypermutation, the use of FISH or PCR for the translocation offers alternative markers to assess for clonality, establish a diagnosis, or both; however, FISH is preferred to PCR as it is more sensitive and specific.89

DLBCL, in addition to BCL2, can have translocations of BCL6 and MYC (10% of cases).90 When a MYC translocation is detected along with other specific translocations (usually BCL2 and BCL6) in an intermediate to large B-cell lymphoma, its presence qualifies as a “double hit” lymphoma, which may be categorized under the rubric of large B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma.91

Typically, MYC gene rearrangements are associated with Burkitt lymphoma, but they can also be present in plasmablastic lymphomas (50% of the time) and, rarely, in follicular lymphoma and primary central nervous system DLBCL.92,93

Burkitt lymphoma is characterized by t(8;14) involving MYC and IGH and will less commonly show translocations involving light chain loci (κ or λ).94-96 BCL6 translocations can be seen in follicular lymphoma, DLBCL, and are frequently identified in primary cutaneous leg-type DLBCL.97

Nearly all cases of mantle cell lymphoma carry t(11;14)(q13;q32) CCND1-IGH, which can be assessed by FISH, and is preferred over PCR-based methodologies that demonstrate lower sensitivity rates (50%–60%); this is because of the large number of dispersed break points at 11q13.98 Translocation of CCND1 with light chain has also been reported; rarely, cyclin D2 may be translocated, which should be a consideration in cyclin D1– tumors otherwise characteristic of mantle cell lymphoma.99

Various translocations have also been described in lymphoma involving the mucosa-associated lymphoid tissue. Of these, MALT1 and BCL10 translocations are worthy of mention (t[14;18][q32;q21], t[11;18] [q21;q21], t[1;14][p22;q32]) because they represent mucosa-associated lymphoid tissue that usually does not respond to Helicobacter pylori eradication.100-102

Although multitudinous, single nucleotide variants and copy number changes have been found in B-cell NHL, sometimes even with reported prognostic significance (eg, NOTCH1 mutations in chronic lymphocytic leukemia [CLL]), in clinical practice testing for these in B-cell NHL has a limited role.103

A limited 7-gene CLL panel with targets that carry prognostic implications has been launched by Cancer Genetics (Rutherford, New Jersey).

Commonly, when molecular testing is indicated in B-NHL, the genetic aberrations are usually of diagnostic importance. BRAF V600E mutation was originally found in 100% patients with hairy cell leukemia compared with none of the 195 other peripheral B-cell lymphoma/leukemias.104-106 The results of subsequent studies have confirmed that the mutation is present in all cases of hairy cell leukemia and is rare in other chronic lymphoproliferative disorders.104-106

In lymphoplasmacytic lymphoma, MYD88 mutation has been detected with high frequency (> 90%),107 and detecting the mutation may be diagnostically useful given the overlap with lymphoplasmacytic lymphoma and other low-grade B-cell lymphomas that may be associated with plasmacytic differentiation, including marginal zone lymphoma, multiple myeloma, and CLL.

In these other conditions, the prevalence of the mutation is 3% to 9%.108 Of note, nearly one-third of activated B-cell-like DLBLC harbors the mutation, and its presence is not useful in the differential with IgM monoclonal gammopathy of undetermined significance.108 Thus, a correlation with morphology and other ancillary studies is needed.

In CLL, hypermutation status is assessed by comparing each IGH clonally rearranged gene sequence with a database of germline V-region sequences to determine the expressed V-region gene and the extent and position of somatic mutations. If a difference exists of more than 2%, then the tumor is considered hypermutated and confers a better prognosis.109

Mature T-Cell Lymphoproliferative Disorders

A total of 95% of T cells express the a-b receptor and a smaller proportion express the γ-δ receptor; both of these receptors contain heterodimer proteins encoded by TCR genes located on chromosomes 7 and 14.6,110 Early in development, the TCR genes undergo somatic rearrangement involving V, D, and J regions (TCRB and TCRD) or V–J rearrangements alone (TCRA and TCRG).

Unlike in B cells, in which Ig light chains (κ and λ) can be assessed for clonality by flow cytometry or immunohistochemistry, establishing the clonal nature of T cells using these techniques is difficult, thus making TCR gene rearrangement studies valuable.111

Each T cell bears a unique, rearranged sequence. Under normal circumstances, a range of gene products can be seen given the gamut of polyclonal T cells present.

However, if a clonal process is present, then a particular gene rearrangement product should predominate,112 and it can be detected using Southern blot analysis as a single clonal band. Although Southern blot analysis is considered the gold standard, it is inefficient and seldom used in modern clinical laboratories for T-cell clonality detection.

Drawbacks of Southern blot analysis include its high cost, increased time, large sample requirements, and low sensitivity rates compared with PCR (5%–10% vs 1%).112,113 PCR amplification of TCRG and TCRB gene products followed by gel separation or capillary electrophoresis is employed in the clinical laboratory.

PCR testing demonstrates a clonal peak 2 to 3 times larger than the background peaks in T-cell lymphomas. In certain cases, false-negative results may occur if the rearrangement involves the primer site or too few T cells are present for analysis. Positive cases of gene arrangements should not be taken to mean that T-cell lymphoma is present.

Such positivity can be seen in cases of B-cell lymphoblastic leukemia (approximately 50% of cases), mature B-cell lymphomas (5%–10%), AML (10%), and non-neoplastic conditions such as autoimmune disorders, certain infectious diseases (Epstein–Barr virus–induced oligoclonal processes), and certain cutaneous lesions (eg, lymphomatoid papulosis).6

In ALK-positive anaplastic large cell lymphoma, t(2;5)(p23;q35) juxtaposing ALK and NPM, respectively, is the most frequent genetic translocation (83% of pediatric and 31% of adult cases) present; however, various, less frequently seen partners have also been described, including TPM3 (13%), ATIC, TGS, CLTC, MSN, TPM4, MYH9, and ALO17 (all < 1%).20,114

The translocation can be assayed using RT-PCR or break-apart FISH probes.6,20,114,115 In T-cell prolymphocytic leukemia, the most common genetic aberration (80%) involves inv(14) juxtaposing the TRA locus at 14q11 to the TCL1A and TCL1B oncogenes.20

In a subset of cases, a reciprocal tandem t(14;14) is present; t(X;14)(q28;q11) has also been described but is less common. Both can be assayed using FISH. Cytogenetics can be used to detect chromosome 8 abnormalities (70%–80%), ATM deletions, as well as del(12p13), all of which can be seen in the setting of T-cell prolymphocytic leukemia.116,117

Hepatosplenic T-cell lymphoma is associated with numerical abnormalities of chromosome 7, and most cases will demonstrate i(7q). As the disease progresses, 2 to 5 copies of i(7)(q10) or derangements in the second chromosome 7 may be present. i(7)(q10) can be detected using FISH.118

In adult T-cell leukemia, clonal integration of the human T-lymphotropic virus type 1 viral DNA can be seen. Although it is conceivable to perform testing via Sanger sequencing, it is typically easier to perform serum studies for human T-lymphotropic virus type 1.119 In enteropathy-associated T-cell lymphoma, amplification of 19q31.3, del(16q12.1), or both have been reported.20


Molecular testing is well entrenched in the workup and management of hematological malignancies. As sequencing technologies become both more powerful and affordable, they will take on an even larger role in the molecular diagnostics of hematopathology and in the era of precision medicine.


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Agosto 2015