1. Introduction: defining transformation
Lymphoma transformation can be defined as a clonal relationship between an indolent lymphoma and a concurrent or subsequent morphologically distinct aggressive lymphoma. The spectrum includes patients with a history of pre-existing low grade lymphoma and subsequent higher grade lymphoma, and the co-existence of low and high grade lymphoma. By contrast the term composite lymphoma is a purely descriptive term, and is irrespective of clonal relationship ¹. Composite lymphoma may refer to collision between two unrelated processes or clonal transformation, and only in the latter case would be relevant to this discussion. For example low grade NHL with two distinct morphological and immunophenotypic patterns in the same anatomic site are frequently biclonal with sequence analysis revealing unrelated clones ². Also not further considered is the phenomenon of lymphoma 'downgrading' in which a less aggressive component becomes evident during the course of treatment for a higher grade NHL ³. One explanation for this scenario is the therapeutic eradication of the rapidly proliferating high grade component with survival of the less rapidly proliferating low grade lymphoma.

Table 1: Patterns of transformation:

Indolent B-cell lymphoma	Transformed lymphoma
MALT and marginal zone B-cell lymphoma	DLBCL DLBCL Anaplastic Variant Classical Hodgkin Lymphoma Follicular Lymphoma
Mantle cell lymphoma	Blastoid variant of Mantle Cell Lymphoma
Small Lymphocytic Lymphoma	DLBCL (Richter's syndrome) DLBCL Anaplastic Variant Classical Hodgkin lymphoma High grade lymphoma unclassifiable with features resembling Burkitt morphology High grade lymphoma unclassifiable with blastoid morphology
Follicular lymphoma	DLBCL DLBCL Anaplastic Variant High grade lymphoma unclassifiable with features resembling Burkitt morphology High grade lymphoma unclassifiable with blastoid morphology Classical Hodgkin Lymphoma

2. Transformation of MALT and marginal zone B-cell lymphoma:
Extranodal marginal zone lymphomas or MALT as well as splenic marginal zone lymphoma may progress to aggressive B-cell lymphomas⁴. The term 'high grade MALT' lymphoma should be avoided. Gastric MALT with concomitant DLBCL show clonal relationships in many cases ⁵. Primary gastric DLBCL are more heterogeneous, and it is uncertain how many arose in the background of MALT. Rare cases of transformation of MALT to Classical Hodgkin Lymphoma and follicular lymphoma have also been described, as well as a MALT that subsequently developed CD30+ DLBCL ⁶.

3. Blastoid transformation in mantle cell lymphoma (MCL)
Blastoid transformation of MCL may arise de novo or following a history of typical mantle cell lymphoma. Blastoid evolution may arise in lymph nodes, or present with bone marrow and leukemic involvement including high white cell counts (>120x10⁹/L). The phenotype of blastoid MCL is BCL-1+, CD20+, CD5+, CD43+, IgD+, TdT-, CD23-, Ki67 proliferation index >90%.

3.1 Molecular studies in transformation to blastoid variant of MCL (MCL-BV)
Using laser capture microdissection and gene expression profiling we have attempted to delineate genetic events in transformation of normal mantles to MCL and MCL-BV ⁷. Cyclin D1 alone is insufficient to promote the development of MCL in transgenic mice and therefore other oncogenic events are implicated. Additional mutations, deletions, or other abnormalities in negative cell cycle regulatory proteins such as TP53, p16, and p18 are implicated, as are cytogenetic abnormalities and a high incidence of tetraploidy. Uncommon secondary abnormalities involving the c-myc gene on 8q24 have been shown to be associated with blastoid cytologic features and leukemic involvement ^8,9. Our molecular studies in MCL-BV demonstrate clonal evolution, and indicate additional cell cycle anomalies supporting a faster G1/S and G2/M checkpoint transition. Candidate genes associated with transformation include anti-apoptosis genes like DAD1 and other candidate genes such as PIM1/2.

4.0 Transformation of small lymphocytic lymphoma/leukemia(SLL)
About 5% of cases of SLL show transformation to DLBCL, an eponymous observation made by Richter in 1928 ¹⁰. Clinical features of Richter's transformation include abrupt onset of fever, marked asymmetric lymphadenopathy with formation of masses, splenomegaly, and hepatomegaly¹¹. Many studies have demonstrated the clonal relationship between the low and high grade lymphomas, even though there may be disparate immunoglobulin heavy and light chain rearrangements. Chromosomal imbalances in SLL often increase during the progression of the disease and transformation into large cell lymphoma ¹². Most cases of DLBCL arising in SLL retain the characteristic phenotype of SLL (CD19+, CD5+, CD23+, FMC7-), although some are CD5- ^13,14. They may also retain characteristic cytogenetic abnormalities with a high frequency of trisomy 12¹⁵. Surface immunoglobulin is of variable intensity. In addition to abnormalities in p53, P16(INK) deletions are often associated with transformation ^16,17. By comparison de novo CD5+ DLBCL have bcl-6 gene rearrangements and resemble the more common CD5- cases¹⁸. These lymphomas have recently been shown to derive from a somatically mutated CD5+ progenitor B-cell.

4.1 SLL with transformation to Classical Hodgkin Lymphoma (HL):
Hodgkin/ Reed Sternberg cells (H-RS cells) are occasionally seen in otherwise typical SLL, and these cases may progress to disseminated HL with an aggressive clinical course^19-21. In some cases of SLL and HL a clonal relationship between the small B-lymphocytes and RS cells has been demonstrated ²². Mature B-cells characteristic of SLL appear to undergo transformation to cells with features of H-RS cells with characteristic phenotype and variable expression of CD20. The H-RS cells in these cases contain EBV, which appears implicated in the pathogenesis²⁰. Rare cases have demonstrated a clonal relationship between SLL and both HL and ALCL²³.

5.0 Transformation in follicular lymphoma (FL):
Transformation in FL should be restricted to circumstances where there is morphologic evidence of simultaneous or past low-grade follicular lymphoma. The presence of a t(14;18) in DLBCL or other high grade lymphoma does not imply transformation from FL, and tumors with this abnormality do not necessarily have a low grade follicular stage. Similarly grade 3 FL does not necessarily arise from low grade FL. The term transform implies a change from a previous form. The mean survival of follicular lymphoma is 8 to 10 years with a continuous pattern of relapse. Progression characteristically occurs in follicular lymphomas from grade 1 to grade 2 or 3 with increased numbers of centroblasts. Although FL most commonly transform to DLBCL, transformation may occur to aggressive B-cell lymphoma with features of Burkitt lymphoma, lymphoblastoid lymphoma, Classical Hodgkin lymphoma, and the Anaplastic Variant of DLBCL.

5.1 Transformation to DLBCL
The risk of transformation to DLBCL is greater than 20% at 5 years, and 30% at 20 years, with a median survival after transformation of only 22 months. Most transformed follicular lymphomas are clonally related. Known molecular events include additional chromosomal abnormalities to t(14;18), most often involving p53, myc, rel, bcl-2, p15(INK4b) and p16 (INK4a)^24-27. Also there may be new mutations in the 5' noncoding regulatory region of the bcl-6 gene ²⁸.

5.2 Transformation of follicular lymphoma (FL) to high grade lymphoma unclassifiable with features resembling Burkitt morphology:
FL occasionally undergoes transformation to lymphoma with histologic features resembling BL. Patients with de novo Burkitt lymphoma (BL) are younger, present with earlier stage disease, and have a better prognosis. De novo Burkitt lymphomas are bcl-2 negative, and have c-myc translocations without t(14;18) or other cytogenetic abnormalities. The term Burkitt, Burkitt-like, and atypical Burkitt lymphoma should be restricted to de novo lymphomas. They are either diffuse or may have a partial follicular pattern attributed to involvement of follicles.

Although c-myc rearrangement is a hallmark for the diagnosis of BL, it is occasionally seen in other B-cell neoplasms including FL, DLBCL, lymphoblastic lymphoma²⁹, and myeloma. Patients with dual t(14;18) and c-myc translocations are older, present in advanced disease, with median survival of 2.5 months, and some of these represent transformation from follicular lymphoma ^29,30. C-myc is a gene encoding a basic helix-loop-helix transcription factor that binds to DNA in a sequence-specific fashion. Presumably as a consequence of translocations the c-myc gene comes under the influence of enhancers of the immunoglobulin loci, resulting in c-myc overexpression. The c-myc gene plays a central role in the transcriptional regulation of downstream genes, including genes that control cell cycle progression and apoptosis³¹. In cases with c-myc amplification without translocations the mechanism of transformation is not certain. Studies for c-myc translocations including cytogenetics, FISH and Southern blots may be helpful in all cases of transformed follicular lymphomas since this abnormality may have adverse clinical significance.

In summary high grade transformation of FL with morphologic resemblance to Burkitt or lymphoblastic lymphoma should be termed as high grade lymphoma unclassifiable with features resembling Burkitt or blastoid morphology respectively. The terms Burkitt lymphoma, atypical Burkitt and Burkitt-like lymphoma should be used for de novo predominantly diffuse lymphomas, not for lymphomas developing secondary to FL or purely follicular lymphomas. The gold standard for diagnosis of Burkitt is c-myc translocation as the sole abnormality. t(8;14) and its variants is not specific for Burkitt lymphoma since it may be present in DLBCL. Whenever possible transformed FL with variant morphology should be investigated for translocations involving c-myc.

5.3 Blastoid transformation of FL (High grade lymphomas unclassifiable with blastoid morphology)
Lymphomas with cells resembling lymphoblasts can arise in patients with follicular lymphoma. The term lymphoblastic lymphoma should be restricted to true precursor neoplasms which are TdT+. In cases of FL with lymphoblastoid transformation, sequencing has revealed a clonal relationship between cases of follicular lymphoma and precursor B-lymphoblastic leukemia/lymphoma ^32-35. Characteristic findings include presence of t(14;18) and bcl-2 protein, p53 point mutations, activation of c-myc, and absence of staining for bcl-1, and myeloperoxidase³⁶. TdT may be variably present. Clinical features for this entity are not well defined, but reported cases have shown increased involvement of bone marrow and blood, and an aggressive clinical course.

5.4 Transformation to Anaplastic Variant of Diffuse Large B-Cell lymphoma (ALCL)
Rare cases have been reported with transformation to morphologically typical ALCL. Unlike most ALCL these cases are negative for T/NK cell markers, express CD20, reveal monotypic SIg, and are positive for bcl-2, and negative for t(14;18). One case reportedly revealed t(2;5) by PCR³⁷.

5.5 Classical Hodgkin lymphoma (CHL) and FL
CHL may precede, follow, or present simultaneously with FL. For this diagnosis one needs typical features of CHL distinct from FL. RS cells should exhibit the typical phenotype, and Oct2 and Bob.1 can be helpful since B-cell lymphomas are positive and HL is often negative for one of the other. The presence of RS cells by themselves in FL does not warrant a diagnosis of HL.

5.6 Molecular events in transformation of FL – a tale of genetic instability
Transformation is associated with genomic wide instability at nucleic acid and chromosomal levels ³⁸. The karyotypes of transformed lymphomas are variable and frequently complex, with possibly the most frequent secondary event a duplication of the der (18)t(14;18) ³⁹. One of the most commonly implicated genes in lymphoma transformation involves alterations in c-myc which occurs in about 8% of transformed lymphomas ⁴⁰. About one third of cases with Burkitt morphology have double transformations t(14;18) and t(8). Activation of c-myc in association with deregulation of bcl-2 (and/or bcl-6) is associated with a grave prognosis ⁴¹. Other abnormalities described include genetic loss of 9p21 targeting p15 and/or p16 ⁴², gains on 2q, 6p, 7p, 12q, 17q and losses on 5p and 8q ⁴³, and deletion of 6q27. Alterations in p53 occur in about 30% ²⁴. There is a high conservation of the bcl-2 gene, and somatic point mutations with transformation may result in alteration of the p26-bcl-2 gene product ⁴⁴. In addition there may be new mutations in the 5' noncoding regulatory region of bcl-6 ^28,45. There is a high degree of intraclonal diversification with highly divergent V(H)DJ gene sequences with transformation ¹⁴. Also described are p16 mutations, deletions, and hyper methylation with loss of protein expression ¹⁷.

Our laboratory and others have used matched microdissected samples of transformed lymphoma and high throughput gene chips to identify other possible molecular culprits ^46,47. Low grade follicular lymphomas are always in close conjunction with follicular dendritic cells and germinal center type T-cells, indicating a dependence on the germinal center microenvironment for survival and growth. The transformed lymphomas by contrast reveal expansion outside of the microenvironment with loss of the dendritic cell component and a more homogeneous population of neoplastic cells. In general transformed follicular lymphomas retain their germinal center signature, but may reveal increased expression of genes such as IRF4 associated with an activated phenotype⁴⁶. Genes we have identified to be associated with transformation include IRF4 (MUM1), ABL2, NEK2, VDUP1, and anti-apoptotic genes such as PDCD1 (programmed cell death 1) ⁴⁶.

6.0 Summary:
Transformation of lymphomas to aggressive variants is an important endpoint for patients with indolent lymphomas. The clonal relationship between MALT, SLL, follicular lymphoma, and Hodgkin lymphoma, DLBCL, Burkitt lymphoma, blastoid mantle cell lymphoma, lymphoblastic lymphoma, and anaplastic variant of large cell lymphoma are described. Transformation is a multistep heterogeneous process, and some of the molecular events implicated in lymphoma progression are highlighted.

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