Endometrial cancer with an EML4-ALK rearrangement

Abstract

An 85-yr-old woman was diagnosed with endometrial adenocarcinoma, endometrioid type. Imaging studies showed a large tumor distending the endometrial canal without evidence of local invasion or extrauterine disease. A hysterectomy was performed, followed by microscopic examination of longitudinal tissue sections. Histopathological review showed only focal myometrial invasion, equivocal lymphovascular invasion, and negative bilateral sentinel lymph nodes (FIGO stage IA). A sample of the tumor was submitted for molecular testing (massively parallel sequencing on OncoPanel) and was found to harbor an inversion on Chromosome 2 resulting in an EML4-ALK gene fusion. Confirmatory immunohistochemistry showed ALK overexpression in just a portion of the tumor. Additional genomic characterization on a region of the tumor lacking ALK overexpression by immunohistochemistry was highly congruous with the genomic profile of the ALK-positive portion, showing similar patterns of copy-number variation and mutations in TP53 and KDM5C, with no evidence for an EML4-ALK gene fusion, confirming that EML4-ALK rearrangement had occurred as a subclonal process. EML4-ALK fusions are driver events in 2%-5% of non-small-cell lung cancers; crizotinib is an approved targeted therapy for these patients. EML4-ALK rearrangements have not previously been reported in endometrial cancer.

Keywords: endometrial carcinoma.

Figure 1.

(A) H&E slide of endometrial cancer specimen. (B) Genomic representation (IGV screenshot) of EML4-ALK fusion. (C) Immunohistochemical staining showing ALK overexpression in part of the specimen (shown boxed in A) only. (D) Plot of copy-number variation for specimen 1 (upper) and specimen 2 (lower) by color-coded chromosomes reveals a very similar pattern of copy-number alterations in the specimens. The vertical axis is the ratio of number of reads for this specimen and a panel of normals in log base 2 scale.