综述：GLI1基因改变的头颈部间叶源性肿瘤

《Seminars in Diagnostic Pathology》：GLI1-altered Mesenchymal Tumors of the Head and Neck

本综述系统阐述了GLI1基因改变（融合/扩增）的头颈部间叶源性肿瘤这一新兴实体，重点介绍其临床病理特征、分子机制（Hedgehog信号通路）及诊断策略（NGS、FISH、GLI1免疫组化）。文章强调该类肿瘤具有独特形态学（单形卵圆形细胞巢状排列伴丰富血管网）及转移潜能（25%），为病理医师提供了从形态学到分子检测的完整诊断路径。

　　

Abstract

GLI1-altered mesenchymal tumors represent a novel category of soft tissue neoplasms primarily identified through advanced molecular techniques like next-generation sequencing (NGS). This review concentrates on those occurring in the head and neck region, detailing their clinicopathological characteristics, molecular underpinnings, and diagnostic methodologies.

Introduction

The emergence of NGS has facilitated the discovery of tumors with specific genetic alterations, such as gene fusions and amplifications. GLI1-altered mesenchymal tumors are one such entity, unified by alterations in the GLI1 gene and distinctive morphological features. Initially reported under various names like "pericytoma," they are now recognized as a distinct group involving diverse anatomical sites, with the head and neck being a common location.

Historical Context and Molecular Evolution

The first documented cases of GLI1-altered tumors were reported in 2004, describing neoplasms with a specific translocation t(7;12) leading to an ACTB::GLI1 fusion. These tumors exhibited a characteristic morphology: multilobulated, infiltrative growth composed of uniform spindle cells with minimal cytoplasm, arranged around delicate branching blood vessels. Since then, numerous fusion partners for GLI1 have been identified, including MALAT1, PTCH1, and others, found in locations spanning the head and neck, soft tissues, and viscera.

Notably, distinct gastric tumors—plexiform fibromyxoma and gastroblastoma—also harbor MALAT1::GLI1 fusions but display unique morphologies separate from the classic GLI1-altered mesenchymal tumors.

In 2019, the molecular spectrum expanded with the report of mesenchymal tumors exhibiting GLI1 gene amplification rather than fusion. These amplified cases often co-amplify nearby oncogenes like CDK4 and MDM2, genes typically associated with other sarcoma types. The current terminology, "GLI1-altered mesenchymal tumor," inclusively covers both fusion-positive and amplified cases.

Clinicopathological Features

These tumors predominantly affect adults, with a median age of 40-46 years, and show no sex preference. They typically present as well-circumscribed, multinodular masses, with sizes ranging from under 1 cm to 20 cm. The head and neck and extremities are frequent sites.

Histologically, the tumors are characterized by lobules of monomorphic ovoid to spindle cells separated by fibrous septa. A key feature is the rich capillary network surrounding nests of tumor cells. Nuclear atypia is generally absent, and mitotic activity is low. Uncommon morphological variations include cytoplasmic vacuolization, granular cell change, and myxoid stroma.

Immunohistochemically, the profile is nonspecific, with variable expression of CD56, SMA, and S100. Importantly, GLI1-amplified tumors often overexpress CDK4, MDM2, and sometimes STAT6. A GLI1 antibody demonstrates high sensitivity and specificity (91% and 98%, respectively) for identifying these tumors.

Molecular Mechanisms

The GLI1 gene, located on chromosome 12q13.3, encodes a transcription factor crucial for the Hedgehog signaling pathway. GLI1 alterations lead to its constitutive activation, driving tumorigenesis. Gene fusions often involve promoter-swapping, placing GLI1 under the control of a highly active partner promoter, resulting in aberrant expression. The fusion proteins retain functional domains necessary for transcriptional activation.

GLI1 amplification, initially identified in gliomas, is also observed in various sarcomas. The GLI1 locus resides in an oncogene-rich region (12q13-15), frequently leading to co-amplification of neighboring genes like DDIT3, CDK4, and MDM2. Detection methods include FISH using probes for GLI1 or the surrogate marker DDIT3.

Clinical Behavior and Prognosis

Initially considered indolent, GLI1-altered tumors are now known to possess metastatic potential, observed in approximately 25% of cases. Features potentially associated with higher risk of metastasis include tumor size ≥6 cm and mitotic rate ≥5 per 10 high-power fields. Studies suggest that GLI1-amplified cases may have a worse prognosis compared to fusion-positive ones.

GLI1-Altered Tumors in the Head and Neck

The head and neck is a common site for these tumors, accounting for 25-30% of reported cases. Within this region, the tongue is the most frequently involved site (62% of head and neck cases). Patients range widely in age (1-82 years), with a median of 35 years and a male predominance (2:1 ratio).

Among head and neck cases, GLI1 fusions (62%) are slightly more common than amplifications (38%). The ACTB::GLI1 fusion is the predominant type. Available follow-up data indicates that most patients (76%) remain disease-free, though a subset experiences metastasis (22%).

Diagnostic Approach

A systematic diagnostic approach is recommended. For tumors with suggestive morphology, the initial immunohistochemical panel should include GLI1, CDK4, MDM2, and STAT6. Positivity for CDK4/MDM2/STAT6 suggests GLI1 amplification, warranting confirmation by FISH or sequencing for GLI1, DDIT3, CDK4, and MDM2. If GLI1 is positive but CDK4/MDM2/STAT6 are negative, RNA sequencing to detect a GLI1 fusion should be pursued.

Summary

GLI1-altered mesenchymal tumors of the head and neck are rare neoplasms defined by GLI1 gene fusions or amplifications. They exhibit distinctive morphological patterns and variable clinical behavior. Accurate diagnosis relies on integrating histology, immunohistochemistry, and molecular testing, which is essential for prognostication and clinical management.