Original article
A closer look at Warthin tumors and the t(11;19)

https://doi.org/10.1016/j.cancergencyto.2007.10.007Get rights and content

Abstract

The translocation t(11;19)(q21;p13) has been described in mucoepidermoid carcinoma (MEC) and rarely in Warthin tumors (WT), both tumors of the salivary gland. The translocation creates a fusion gene in which exon 1 of CRTC1 is linked to exons 2–5 of MAML2. To verify the translocation in WT, we performed nested reverse transcriptase–polymerase chain reaction using RNA from 48 WTs. This revealed the t(11;19)(q21;p13) translocation and expression of the chimeric gene in two metaplastic WT samples, but in none of the remaining ordinary 46 WTs. On review, the two positive cases were classified as tumors highly suspect for MEC. Indeed, our experience and published observations of the t(11;19)(q21;p13) translocation in WT reveal that only a small subset of WTs are positive, and that these tumors are often classified as infarcted or metaplastic WT, known to overlap considerably with MEC on purely morphological grounds. We therefore conclude that the presence of the t(11;19)(q21;p13) rearrangement favors a diagnosis of MEC.

Introduction

Mucoepidermoid carcinoma (MEC) is the most frequent malignant tumor type of the salivary glands and the second most frequent lung tumor of bronchial gland origin [1], [2]. Previous cytogenetic studies on MECs of the salivary and bronchial glands have revealed a t(11;19)(q21;p13) translocation, in some cases as the only chromosomal rearrangement [3], [4], [5]. The translocation was first described by Bullerdiek et al. [6] in a Warthin tumor.

The second most common benign tumor of the salivary glands [7], WT is composed of glandular and often cystic structures, sometimes with a papillary cystic arrangement, lined by characteristic bilayered epithelium comprising inner columnar eosinophilic or oncocytic cells surrounded by smaller basal cells. The stroma contains a variable amount of lymphoid tissue with germinal centers. Most WTs are well circumscribed and partly cystic. The cysts vary from small slits to quite large spaces and contain clear, mucous, creamy white or brown fluid. In the metaplastic variant, solid areas are predominant and often firm and fibrous. The immunoprofile of the lymphocyte subsets is similar to that in normal or reactive lymph nodes [8], [9]. The typical type of WT is usually unmistakable in differential diagnostics. In cases of marked regressive changes and subsequent squamous and mucous metaplasia (the so-called metaplastic variants), however, the differential diagnosis of MEC invariably occurs [10], [11].

Recent studies have shown that the t(11;19)(q21;p13) translocation in MEC and sometimes in WT results in a fusion of the N-terminal domain of the CREB-regulated transcription coactivator 1, CRTC1 (previously MECT1; alias TORC1, WAMTP1), with the Notch coactivator MAML2 (mastermind-like 2) [12], [13], [14]. Exon 1 from CRTC1 at 19p13 fuses with exons 2–5 of MAML2 at 11q21. Full-length MAML2 acts as a CSL-dependent transcriptional coactivator of Notch. In contrast, CRTC1MAML2 activates transcription of the Notch target gene HES1 on 3q28∼q29, independent of Notch ligands and CSL binding sites. In addition, the recent identification of the CRTC1 gene product as a potent coactivator for genes that are regulated by cAMP-responsive elements suggests that CRTC1MAML2 may be disrupting both Notch and CREB signaling pathways to induce tumorigenesis [15], [16], [17].

To check for the t(11;19)(q21;p13) translocation in WT that could result in a CRTC1MAML2 gene fusion, we performed reverse transcriptase–polymerase chain reaction (RT-PCR) using RNA from 48 WTs.

Section snippets

Materials and methods

In this study, 46 snap-frozen WTs, two formalin-fixed, paraffin-embedded (FFPE) metaplastic WTs, and one human MEC cell line (NCI-H292) were used. All tumors were obtained from the Salivary Gland Registry in Hamburg, Germany. All tumors were carefully reexamined, and the diagnosis of WT was confirmed according to the criteria of the World Health Organization [9].

Total RNA from snap-frozen tumors and NCI-H292 was extracted by using TRIzol LS reagent (Invitrogen, Karlsruhe, Germany). For cDNA

Results

As control for intact RNA and cDNA, a RT-PCR for the housekeeping gene GAPDH was performed on all cDNAs used. The 445-bp product for GAPDH was detected in all samples (Fig. 1; not all data shown). To investigate the expression of the chimeric gene in WT specimens, we used RT-PCR to screen a total of 48 WTs and one cell line for presence of the CRTC1MAML2 fusion gene. A fusion transcript was detected in the NCI-H292 cell line and in both metaplastic WTs, but in none of the 46 ordinary WTs (

Discussion

WT and MEC are both salivary gland tumors but do not generally share clinicopathological features, and their accepted histogenesis is also distinct [9], [19]. Metaplastic WT, however, is characterized by replacement of much of the original epithelium by metaplastic squamous cells, along with regressive changes in the stroma areas (Fig. 3). Misinterpretation of metaplastic WT as a malignancy such as squamous epithelium carcinoma (PEC) or MEC presents a serious diagnostic pitfall [10], [11]. The

Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG) (BU 592/5 and RO 2081/1). We thank Dr. med. Thorsten Jäckel (Bremen) for pictures of the metaplastic Warthin tumors.

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    1

    Both authors contributed equally to this work and thus both should be considered first author.

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