Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation

Abstract

A subset of cutaneous and superficial soft tissue myoepithelial (ME) tumors displays a distinct ductal component and closely resembles mixed tumors/pleomorphic adenomas of salivary gland. As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions. In contrast, half of the deep-seated soft tissue ME tumors lacking ductal differentiation are known to be genetically unrelated, showing EWSR1 rearrangements. FISH analysis to detect PLAG1 and HMGA2 abnormalities was performed in 35 ME tumors, nine skin and 26 soft tissue, lacking EWSR1 and FUS rearrangements. For the PLAG1-rearranged tumors, FISH and RACE were performed to identify potential fusion partners, including CTNNB1 (beta-catenin) on 3p21 and LIFR (leukemia inhibitory factor receptor) on 5p13. Recurrent PLAG1 rearrangement by FISH was detected in 13 (37%) lesions, including three (33%) in the skin and 10 (38%) in the soft tissue. All were classified as benign and all except one showed abundant tubulo-ductal differentiation (comprising 12/24 [50%] of all tumors with ductal structures). A LIFR-PLAG1 fusion was detected by RACE and then confirmed by FISH in one soft tissue ME tumor with tubular formation. No CTNNB1 or LIFR abnormalities were detected in any of the remaining PLAG1-rearranged tumors. No structural HMGA2 abnormalities were detected in any of the 22 ME lesions tested. A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion.

Figure 1

Morphologic spectrum of PLAG1-rearranged skin and soft tissue myoepithelial tumors is quite variable, but resembling the salivary gland pleomorphic adenoma phenotype. (A) Ductal structure lined by bland cuboidal epithelial cells with moderate amount of pale, eosinophilic cytoplasm embedded in a myxoid background (ME5, subcutaneous soft tissue, left 5^th toe, 53 year old female). (B) Cribriform arrangement of tubulo-ductal structures adjacent to areas of more solid squamoid appearance as well as chondroid matrix differentiation (ME6, subcutaneous soft tissue, right foot, 52 year old female). C. Diffuse solid sheets of myoepithelial cells with a distinctive plasmacytoid appearance (ME9, skin, left hand, 37 year old female). (D) PLAG1 gene rearrangement by FISH showing break-apart signals (telomeric probe, green; centromeric probe, orange; ME9).

Figure 2

LIFR-PLAG1 gene fusion in a soft tissue myoepithelial tumor (ME4). (A) Gross appearance of this well-circumscribed, yellow-tan, firm, hand subcutaneous lesion, arising in a 64 year-old female. The histologic spectrum of this tumor is quite broad, including: (B) ducts lined by columnar cells with abundant mucin-containing cytoplasm and basally-located nuclei; C. tubular structures lined by bland cuboidal epithelial cells; (D) Sheets of myoepithelial cells, with a distinctive rhabdoid or plasma-cell phenotype, showing densely eosinophilic cytoplasm and eccentric round nuclei. E.ABI sequence of 5’RACE product showed the presence of a fusion between LIFR exon 1 to PLAG1 exon 2; F. FISH showing a LIFR gene break-apart signal (telomeric probe , green; centromeric probe, orange).

Figure 3

Myoepithelial carcinoma ex-pleomorphic adenoma. A. Morphologic appearance showing cords and nests of epithelial cells with an infiltrative pattern within a myxoid stroma (ME41). B. Small component of benign pleomorphic adenoma seen adjacent to the malignant myoepithelial component (ME41). C. FISH showing break-apart PLAG1 signals, associated with amplification of the centromeric portion (red); D. similar finding for FGFR1 which show rearrangement and centromeric portion amplification (orange), while the telomeric part is not (green).