The (11;14)(q13;q32) Translocation in Multiple Myeloma

Abstract & Commentary

Synopsis: In this retrospective study, 24 cases of multiple myeloma associated with an (11;14)(q13;q32) translocation were identified. Most of these were associated with overexpression of cyclin D1, which can be detected by immunohistochemistry. In addition, six of 30 myeloma cases without the (11;14)(q13;q32) translocation were found to have cyclin D1 overexpression. The presence of the (11;14)(q13;q32) translocation was associated with lymphoplasmacytoid changes as well as plasma cell leukemia.

Source: Hoyer JD, et al. Am J Clin Pathol 2000;113:831-837.

Cytogenetic studies in hematologic malignancies can provide important diagnostic and prognostic information. In multiple myeloma, the (11;14)(q13;q32) translocation is the most common translocation, consisting of 10-25% of all cases with abnormal cytogenetics but only 2-4% of all myeloma cases.1 This translocation, usually associated with mantle cell lymphoma, results in overexpression of the gene called PRAD1. The product of this gene, called cyclin D1, is normally not expressed in lymphoid cells,2 but can be detected in tumors by immunohistochemistry. The purpose of the study by Hoyer and colleagues was to investigate the relationships between cytogenetic analysis, cyclin D1 overexpression, and clinical features in multiple myeloma.

By searching the pathology files at the Mayo Clinic in Rochester, Minn., 24 cases of multiple myeloma where cytogenetics showed an (11;14)(q13;q32) translocation were found over an 11-year period beginning in 1988. Immunohistochemical analysis for cyclin D1 was then performed on the paraffin-embedded bone marrow biopsy specimens. Of these 24 patients, the (11;14)(q13;q32) translocation was found to be part of a complex karyotype in all but two patients. For comparison, 30 cases of multiple myeloma without the (11;14)(q13;q32) translocation were also evaluated for the presence of cyclin D1.

The morphologic appearance of the 24 cases with the (11;14)(q13;q32) translocation was reviewed. Although immunoglobulin M (IgM) was not detected either in the serum or by immunohistochemical staining, 10 of these myeloma cases had a lymphoplasmacytoid appearance. In addition, four of the 24 cases (17%) with the t(11;14)(q13;q32) met criteria for plasma cell leukemia. The rest had typical myeloma features except for one biopsy showing plasmablastic morphology. Thus, just over half the cases with the t(11;14)(q13;q32) had unusual morphologic or clinical features.

The relationship between the cytogenetic results and strong nuclear cyclin D1 positivity was interesting. First, of 30 multiple myeloma cases not containing an (11;14)(q13;q32) translocation, six were still found to be cyclin D1 positive. Second, only 19 of the 24 patients with the (11;14)(q13;q32) were positive for cyclin D1. Positive controls (mantle cell lymphoma) and negative controls stained appropriately.

COMMENT by Kenneth W. Kotz, MD

In this study, the relationship between t(11;14)(q13;q32) and multiple myeloma was examined. Hoyer et al pursued this evaluation because of a previous report showing cyclin D1 overexpression in multiple myeloma.3 The t(11;14)(q13;q32), best recognized for its diagnostic value, occurs in the majority of cases of mantle cell lymphoma.2 However, overexpression of cyclin D1 has actually been reported in other malignancies including head and neck, hepatocellular, esophageal, breast, and bladder cancer, as well as B-chronic lymphocytic leukemia, splenic marginal zone lymphoma, and hairy cell leukemia,4,5 although some of these hematologic cancers may have been misdiagnosed.6 One group has recently reported on 151 patients with mantle cell lymphoma (MCL), identified by histologic and immunophenotypic features, in whom an improved survival was seen if they had "cyclin D1-positive MCL" compared with "cyclin D1-negative MCL-like B-cell lymphoma."4 However, one might call into question the diagnosis of MCL if the manifestations of the typical gene rearrangement are absent at the molecular level.7

It is interesting that strong nuclear staining for cyclin D1 was found in several patients despite the absence of the t(11;14)(q13;q32). Hoyer et al hypothesize that the slow growth that is characteristic of many myeloma clones might not allow representative cells to be cultured during routine karyotypic analysis. Also, although not observed in this study, other translocations can result in PRAD1 overexpression, such as the t(11;22)(q13;q11) in mantle cell lymphoma.8 Hoyer et al suggest that other methods of detecting the t(11;14)(q13;q32), such as fluorescent in-situ hybridization, may further characterize these cyclin D1-positive, karyotype-normal myelomas.

Five of the 24 patients with the (11;14)(q13;q32) translocation did not overexpress cyclin D1. The majority of the cells in these cases had multiple chromosomal abnormalities. It is probable that the acquired genetic changes that characterize neoplastic progression impart a growth advantage to the cells, at the same time resulting in loss of cyclin D1 expression.

An important clinical observation is the increased frequency of lymphoplasmacytoid features and plasma cell leukemia in association with t(11;14)(q13;q32). Plasma cell leukemia has been associated with this translocation in other studies as well.1 Even though lymphoplasmacytoid features were identified, there was no evidence for IgM production in these patients in whom both the clinical and laboratory data supported the diagnosis of multiple myeloma.

The molecular events resulting from the (11;14)(q13;q32) translocation have been extensively evaluated.7 PRAD1, also called bcl-1, is the gene that resides on chromosome 11 at the translocation breakpoint. When juxtaposed to the enhancer element of the immunoglobulin heavy chain region on chromosome 14, the PRAD1 oncogene becomes dysregulated and overexpresses its product, cyclin D1. The uncontrolled cyclin D1 levels that normally vary throughout the cell cycle promote progression of cells from the G1 phase to the S phase, resulting in excessive proliferation.7

There are a number of questions for future studies to evaluate. What is the exact incidence of cyclin D1 overexpression in multiple myeloma? Does cyclin D1 overexpression have any prognostic value in multiple myeloma? Is the (11;14)(q13;q32) translocation a primary or secondary event? What are the diagnostic implications? The interesting study by Hoyer et al is another step in the attempt to understand malignancies at the molecular level and to use this information for diagnostic and prognostic purposes.

References

1. Hoyer JD, et al. Am J Clin Pathol 2000;113:831-837.

2. Harris NL, et al. Blood 1994;84:1361-1392.

3. Vasef MA, et al. Mod Pathol 1997;10:927-932.

4. Yatabe Y, et al. Blood 2000;95:2253-2261.

5. Heerema NA. Cancer Invest 1998;16:183-187.

6. Jaffe E, et al. ASH Educ Book 1999;319-325.

7. Scheuermann R. Monographs in Lymphoma 1999;1:1-14.

8. Komatsu H, et al. Br J Haematol 1993;85:427-429.