A comprehensive clinicopathologic and molecular reappraisal of GLI1-altered mesenchymal tumors with pooled outcome analysis showing poor survival in GLI1-amplified versus GLI1-rearranged tumors Journal Article
| Authors: | Saoud, C.; Agaimy, A.; Dermawan, J. K.; Chen, J. F.; Rosenblum, M. K.; Dickson, B. C.; Dashti, N.; Michal, M.; Kosemehmetoglu, K.; Din, N. U.; Albritton, K.; Agaram, N. P.; Antonescu, C. R. |
| Article Title: | A comprehensive clinicopathologic and molecular reappraisal of GLI1-altered mesenchymal tumors with pooled outcome analysis showing poor survival in GLI1-amplified versus GLI1-rearranged tumors |
| Abstract: | GLI1-Altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-Altered mesenchymal neoplasms to date, including 23 GLI1-Amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-Amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-Amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-Amplified tumors. GLI1-Amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-Amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-Amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-Amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-Altered mesenchymal tumors. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. |
| Keywords: | immunohistochemistry; survival; adolescent; adult; cancer survival; child; clinical article; controlled study; human tissue; preschool child; aged; aged, 80 and over; middle aged; young adult; gene mutation; overall survival; genetics; missense mutation; clinical feature; histopathology; mortality; cancer recurrence; doxorubicin; cancer growth; bone metastasis; comparative study; brain tumor; follow up; lymph node metastasis; pelvis lymph node; phenotype; genetic predisposition to disease; progression free survival; gene amplification; tumor volume; etoposide; cyclophosphamide; vincristine; pathology; protein p53; tumor marker; distant metastasis; ifosfamide; time factors; liver metastasis; lung metastasis; fluorescence in situ hybridization; gene rearrangement; temporal lobe; thigh; messenger rna; microsatellite instability; amplicon; cancer size; limb tumor; disease free interval; spindle cell; fluorescence microscopy; protein s 100; retroperitoneal tumor; neoadjuvant chemotherapy; cytokeratin; genetic predisposition; adjuvant radiotherapy; tongue tumor; malignant peripheral nerve sheath tumor; thorax wall tumor; giant cell; life expectancy; transcription factor gli1; local metastasis; soft tissue neoplasms; soft tissue tumor; esophagus tumor; stomach tumor; skull tumor; cyclin dependent kinase 4; hospice care; cranial nerve tumor; spine tumor; common acute lymphoblastic leukemia antigen; smooth muscle actin; surgical margin; finger; tumor necrosis; pooled analysis; mitosis index; hypopharynx tumor; proton therapy; hand tumor; arm; time factor; cd56 antigen; foot disease; dedifferentiated liposarcoma; small intestine tumor; multiplex polymerase chain reaction; mesenchymoma; ileum tumor; pharynx tumor; trigeminal nerve; toe; cancer prognosis; high throughput sequencing; knee disease; infratemporal fossa; stat6 protein; very elderly; high mobility group a2 protein; dna sequencing; humans; human; male; female; article; rna sequencing; median survival time; pharyngolaryngectomy; biomarkers, tumor; oncogenomics; primary tumor site; mesenchymal neoplasms; mrna expression level; skull metastasis; short term survival; mouse double minute 2 homolog; epithelioid histiocyte; gli1 protein, human; zinc finger protein gli1; metastasis site; gli1-altered; gli1-amplified; gli1-rearranged; chest wall metastasis; epiglottis tumor; involved margin |
| Journal Title: | American Journal of Surgical Pathology |
| Volume: | 48 |
| Issue: | 10 |
| ISSN: | 0147-5185 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2024-10-01 |
| Start Page: | 1302 |
| End Page: | 1317 |
| Language: | English |
| DOI: | 10.1097/pas.0000000000002272 |
| PUBMED: | 38934567 |
| PROVIDER: | scopus |
| PMCID: | PMC12150273 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Cristina Antonescu -- Source: Scopus |
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