Page 68 - New epidemiological and PSMA-expression based paradigms in salivary gland tumors

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Chapter 4
mutations in genetically related subsequent recurrent tumors were accompanied histologically by malignancy; thus a driver role seems likely, as TP53 is a well- known tumor suppressor gene [28]. Loss of TP53 function is the most common molecular aberration in human malignancies and is involved in initiation and progression of many malignant disorders. Based on results from DNA mutation, single nucleotide polymorphism (SNP) and DNA amplicon coverage analyses, all three lesions are probably bi-allelic for the TP53 locus (supplementary material, Figure S3), and therefore have one functional intact TP53 allele. The identified TP53 mutations p.R248Q and p.Y220C, however, are known to exert a dominant- negative effect leading to complete inactivation of TP53 without a second hit mutation (e.g. loss of the wild type TP53 allele)[29].
In this case, the first recurrence was not originally recognized as malignant although the proliferation rate of 15% was relatively high [30]. In the second recurrence, morphology and proliferation rate were obvious clues for malignancy. In retrospect, p53 and Ki-67 IHC might have raised the suspicion of malignancy, warranting molecular analysis.
Several aspects complicate salivary gland tumor diagnosis in general, like the rare nature and the wide morphological spectrum. Although SGPA is the most frequent primary salivary gland tumor, it is still a rare tumor (European Standardized Rate: 4.5/100,000; as opposed to 62/100,000 for breast cancer)[31]. Some of its characteristics can make correct diagnosis challenging, like the morphological overlap with features of some of the 22 salivary gland carcinomas[20,32]. Furthermore, malignant transformation of SGPA occurs only occasionally, at a frequency of 6% of first RPAs [1]. And as shown in this case, malignant transformation can be difficult to recognize as the first recurrence already harboured a TP53 mutation but was not identified as malignant morphologically. This shows that, in the rare case of a RPA, molecular analysis can be of value in recognizing early malignant transformation.
Clinically, the risks of infiltrative growth and malignant transformation have been important arguments for aggressive surgical treatment of RPA, which warrants the sacrifice of vital structures in selected cases. This case for the first time illustrates that malignant transformation of SGPA occurs and that molecular analysis can help to recognize malignancy. The combination of histology and molecular analysis