Clinicopathological effect of <i>PLAG1</i> fusion genes in pleomorphic adenoma and carcinoma ex pleomorphic adenoma with special emphasis on histological features

Asahina, Miki; Saito, Tsuyoshi; Hayashi, Takuo; Fukumura, Yuki; Mitani, Keiko; Yao, Takashi

doi:10.1111/his.13759

Cited by 38 publications

(32 citation statements)

References 39 publications

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“…Our analyses resulted in the identification of an HMGA2-WIF1 and a CTNNB1-PLAG1 fusion gene in breast PAs, and of a CRTC1-MAML2 fusion gene in a breast MEC. The HMGA2 and PLAG1 rearrangements, and the CRTC1-MAML2 fusion genes identified in the breast PAs and breast MECs of this study, have been reported in PAs and MECs arising in the salivary gland and in other anatomic locations [6][7][8]20,21,23,24 . Moreover, our findings on breast MECs are in agreement with the study by Bean et al 30 , who reported on the presence of the CRTC1-MAML2 fusion gene in two breast MECs.…”

Section: Discussionmentioning

confidence: 98%

“…The CTNNB1-PLAG1 fusion gene was predicted to result in a chimeric transcript encompassing exon 1 of CTNNB1 and exons 4 and 5 of PLAG1 ( Fig. 2d) and has been described in PAs of the salivary glands and of the lacrimal glands 23,24 . The CTNNB1-PLAG1 fusion identified in BPA2 was validated by fluorescence in situ hybridization (FISH) using PLAG1 dual-color break-apart probes ( Fig.…”

Section: Casesmentioning

confidence: 99%

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Pleomorphic adenomas and mucoepidermoid carcinomas of the breast are underpinned by fusion genes

et al. 2020

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Primary pleomorphic adenomas (PAs) and mucoepidermoid carcinomas (MECs) of the breast are vanishingly rare. Here we sought to determine whether breast PAs and MECs would be underpinned by the fusion genes reported to occur in their salivary gland counterparts. Our study included three breast PAs and one breast MEC, which were subjected to RNA sequencing (PAs, n = 2; MEC, n = 1) or to Archer FusionPlex sequencing (PA, n = 1). Our analyses revealed the presence of the HMGA2-WIF1 fusion gene in breast PA3, the CTNNB1-PLAG1 fusion gene in breast PA2, and the CRTC1-MAML2 fusion gene in the breast MEC analyzed (1/1). No oncogenic fusion genes were detected in breast PA1, and no additional oncogenic fusion genes were detected in the cases studied. The presence of the fusion genes identified was validated by fluorescence in situ hybridization (n = 1), reverse transcription-PCR (n = 1), or by both methods (n = 1). Taken together, our findings indicate that PAs and MECs arising in the breast resemble their salivary gland counterparts not only phenotypically but also at the genetic level. Furthermore, our data suggest that the molecular analysis of breast PAs and MECs might constitute a useful tool to aid in their differential diagnosis.

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Section: Discussionmentioning

confidence: 98%

Section: Casesmentioning

confidence: 99%

Pleomorphic adenomas and mucoepidermoid carcinomas of the breast are underpinned by fusion genes

et al. 2020

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“…[ 14 ] An extensive study of 220 PAs found that 50% had normal karyotypes, 25% had 8q12 rearrangements, and 13.2% had 12q13–15 rearrangements. [ 15 ] In 1997, Kas et al [ 1 ] reported PLAG1–CTNNB1 fusion as a critical event in the tumorigenesis of PA and CHCHD7, [ 2 ] LIFR, [ 16 ] and TCEA1 [ 2 , 4 ] as fusion partners of PLAG1 . Subsequently, HMGA2 - NFIB , [ 2 ] HMGA2 - FHIT , [ 3 ] and HMGA2 - WIF1 [ 5 ] in PAs have also been reported.…”

Section: Discussionmentioning

confidence: 99%

“…In the recent report of 105 and 11 cases of PAs and carcinoma ex PA, respectively, approximately 40% of cases harbored PLAG1 fusion genes: CTNNB1-PLAG1 in 22 cases, CHCHD7-PLAG1 in 14 cases, LIFR - PLAG1 in 4 cases, and HMGA2 fusion genes in 2 cases. [ 16 ] Hence, the PLAG1 gene is predicted to play a crucial part in the tumorigenesis of PA. Conversely, approximately half of PAs do not undergo chromosomal rearrangements. [ 17 ] In 1 compelling case of distant metastasis, Akiba et al found that both the primary PA and metastasis sites were positive for PLAG1 protein, but neither tumor harbored the PLAG1 fusion gene.…”

Section: Discussionmentioning

confidence: 99%

Molecular profile of a pleomorphic adenoma of the hard palate

Iida¹,

Serizawa

Mukaigawa

et al. 2020

Medicine

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Rationale: Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. PAs have the potential for regional and distant metastases that preserve their benign phenotype; they also have the potential for malignant transformation. The molecular pathogenesis of malignant neoplasms has been studied extensively in recent years, unlike that of benign tumors, such as PA. Patient concerns: In this case report, we identified the molecular signatures of a 57-year-old Japanese woman. Our patient presented with a swelling of the hard palate with an erosive appearance. Diagnoses: The patient was diagnosed with a right hard palate tumor suspected to be a malignant neoplasm. Interventions: Partial maxillary resection and reconstruction were performed. Outcomes: There was no obstacle to swallowing or dysarthria after surgery. There was no sign of recurrent palatal tumor 4 years after the operation. Using next generation sequencing, 5 nonsynonymous mutations and CHCHD7-PLAG1 fusion genes were detected. Moreover, gene expression profiling indicated the possibility of the activation of several cancer-related signaling pathways. Although the PLAG1 gene is predicted to play a crucial role in PA tumorigenesis, its over-expression is reported to mediate multiple downstream factors. In this case, various up- and downregulated RNA signaling pathways, including MAP kinase signaling, PI3K/AKT1/MTOR signaling, JAK/STAT signaling, and PD-L1 signaling, were revealed. Lessons: These molecular profiles of PA may elucidate the mechanism of metastasis, preserving its benign phenotype and carcinoma ex PA.

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“…In terms of histology, cellular atypia and stromal hyalinization have been regarded as the key delineating features of CA-ExPA from benign PA [ 36 , 38 ]. Based on immunohistochemistry (IHC), loss of expression of PLAG-1 (pleomorphic adenoma gene-1) protein and overexpression of Ki-67, p53, and HER-2 (human epidermal growth factor receptor-2) are considered suggestive of malignant transformation in otherwise benign PA [ 38 , 39 ]. At a molecular genetic level, malignant transformation of PA is further characterized by PLAG-1/HMGA-2 (High Mobility Group AT-Hook 2) fusion and rearrangement, p53 mutation, and HER-2 amplification [ 36 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Giant Parotid Pleomorphic Adenoma with Atypical Histological Presentation and Long-Term Recurrence-Free Follow-Up after Surgery: A Case Report and Review of the Literature

Alkindi

Ramalingam

Hakeem

et al. 2020

Case Reports in Dentistry

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Salivary gland tumors (SGT) comprise 3% of all head and neck tumors, are mostly benign, and arise frequently in the parotid gland. Pleomorphic adenoma (PA) is the commonest SGT, representing 60-70% of all benign parotid tumors. Clinically, parotid PA presents as irregular, lobulated, asymptomatic, slow-growing preauricular mass, involving both superficial and deep lobes, and could grow to gigantic proportions. Histologically, PA has epithelial and mesenchymal elements in chondromyxoid matrix and is managed surgically. Based on a review of 43 cases reported in English literature since 1995, giant parotid PA is reported as large as 35 cm (diameter) and 7.3 kg (resected weight). Although rare, 10 cases of malignant transformation were reported in the review. Surgical management included extracapsular dissection (ECD), superficial parotidectomy, and total parotidectomy for benign tumors, and adjuvant radiation or chemotherapy for malignant tumors. We further present the case of a 36-year-old healthy male with slow-growing and asymptomatic giant parotid PA, of 4-year duration. The patient presented with firm, lobulated preauricular swelling, provisionally diagnosed as PA based on radiographic and cytological findings. The tumor was resected through ECD, and the patient had uneventful postoperative recovery and a 7-year recurrence-free follow-up period. Histological examination revealed epimyoepithelial proliferation punctuated by chondromyxoid areas, with extensive squamous metaplasia and keratin cysts. To the best of knowledge from indexed literature, giant parotid PA is rarely reported in Saudi Arabia. In addition to its rarity, this case is reported for its benign nature despite atypical histological presentation, successful surgical management without complications, and long-term recurrence-free follow-up. Based on this report, clinicians must be aware of atypical histological presentations associated with PA and plan suitable surgical management and follow-up to avoid morbidity. Nevertheless, attempts must be made to diagnose and manage these lesions at an early stage and before they reach gigantic proportions.

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Clinicopathological effect of PLAG1 fusion genes in pleomorphic adenoma and carcinoma ex pleomorphic adenoma with special emphasis on histological features

Cited by 38 publications

References 39 publications

Pleomorphic adenomas and mucoepidermoid carcinomas of the breast are underpinned by fusion genes

Pleomorphic adenomas and mucoepidermoid carcinomas of the breast are underpinned by fusion genes

Molecular profile of a pleomorphic adenoma of the hard palate

Giant Parotid Pleomorphic Adenoma with Atypical Histological Presentation and Long-Term Recurrence-Free Follow-Up after Surgery: A Case Report and Review of the Literature

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