March 2021 — Hematopathology and Laboratory Genetics and Genomics

The diagnosis in this case is: No evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region; does not exclude a mantle cell lymphoma (MCL) diagnosis.

Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are mature CD5-positive B-cell neoplasms which may have a similar clinical presentation but different prognosis. MCL generally follows a moderately to highly aggressive clinical course, which portends a poor prognosis for most patients, and requires a different therapeutic approach. Therefore, it is critical to distinguish between MCL and CLL/SLL [1,2].

Several features aid in the distinction of MCL from CLL/SLL, such as flow cytometric immunophenotyping and cytogenetic findings. MCL expresses CD5, bright CD20 and normal/bright (restricted) surface immunoglobulin light chains, but not CD23 and CD200, which are typically positive in CLL/SLL [1]. Furthermore, MCL is associated with upregulation of CCND1 due to a t(11;14)(q13;q32) (CCND1/IGH) translocation present in nearly 95% of cases, and therefore the detection of a CCND1/IGH rearrangement is useful in supporting a diagnosis of MCL in the differential diagnosis of CD5-positive, mature B-cell neoplasms [3].

Fluorescence in situ hybridization (FISH) is the current gold standard assay utilized to identify recurrent cytogenetic alterations in mature B-cell neoplasms. 

IGH/CCND1 rearrangements are typically detected by using a dual-color dual-fusion (D-FISH) strategy. D-FISH probes are used to identify specific translocations. The two genes involved in a translocation, in this case CCND1 and IGH, are labeled in different colors, and the detection of a classic 2-fusion signal confirms a rearrangement. 

In addition to the classic t(11;14), variant translocations involving CCND1 and IGK [t(2;11)] or IGL [t(11;22)] have also been reported [4,5]. In this case, a CCND1 break-apart probe set should be considered, to test whether the gene (or any other gene of interest) is involved in a rearrangement. Break-apart probes target two areas of a specific gene sequence. When the gene sequence is intact (not involved in a rearrangement), the green and red signals result in a fusion signal. Conversely, separation of the green and red signals constitutes evidence that the gene of interest is rearranged. 

When there is a strong suspicion of MCL, e.g. based on positive cyclin D1 IHC staining, but no evidence of CCND1 rearrangement by CCND1/IGH  D-FISH or CCND1 BAP FISH probes, a complex or cryptic rearrangement should be suspected [6]. Therefore, lack of evidence of a CCND1/IGH rearrangement or disruption of the CCND1 gene region does not rule out a diagnosis of MCL and may not necessarily confirm a CLL/SLL, especially in the context of clinical, immunophenotypic and immunohistochemical findings highly suggestive of MCL.

References

1. Puente XS, Jares P, Campo E. Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions. Blood. 2018 May 24;131(21):2283-2296. 
2. Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019 Jun;94(6):710-725.
3. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011 Jan 6;117(1):26-38. 
4. Peterson JF, Meyer RG, Smoley SA, Webley M, Smadbeck JB, Vasmatzis G, Pearce K, Greipp PT, Ketterling RP, Craig FE, Stewart AK, Baughn LB. Whole Genome Mate-pair Sequencing of Plasma Cell Neoplasm as a Novel Diagnostic Strategy: A Case of Unrecognized t(2;11) Structural Variation. Clin Lymphoma Myeloma Leuk. 2019 Sep;19(9):598-602. 
5. Fuster C, Martín-Garcia D, Balagué O, Navarro A, Nadeu F, Costa D, Prieto M, Salaverria I, Espinet B, Rivas-Delgado A, Terol MJ, Giné E, Forcada P, Ashton-Key M, Puente XS, Swerdlow SH, Beà S, Campo E. Cryptic insertions of the immunoglobulin light chain enhancer region near CCND1 in t(11;14)-negative mantle cell lymphoma. Haematologica. 2020 Aug;105(8):e408-e411. 
6. Polonis K, Schultz MJ, Olteanu H, Smadbeck JB, Johnson SH, Vasmatzis G, Xu X, Greipp PT, Ketterling RP, Hoppman NL, Baughn LB, Peterson JF. Detection of cryptic CCND1 rearrangements in mantle cell lymphoma by next generation sequencing. Ann Diagn Pathol. 2020 Jun;46:151533.