Date of Award

January 2026

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Francis Y. Lee

Abstract

Chondroblastoma is a benign primary bone tumor with controversial cellular origin. Although bearing the name “chondroblastoma”, this musculoskeletal tumor has faced controversy as to whether chondroblasts are chondrocytes. Moreover, its cellular composition can make it difficult to distinguish amongst its mimics including giant cell tumor of bone, chondrosarcoma, and chondromyxoid fibromas.

This thesis aims to characterize the transcriptomic expression atlas of human chondroblastoma to better define the gene expression profile and diagnostic expression markers of chondroblastoma. Secondarily, this thesis aims to identify the lineage progression and cellular composition of chondroblastoma using spatial and temporal patterning analysis.

Histologically confirmed samples of human chondroblastoma samples arising from the long bone epiphysis from 2014 to 2024 were identified and retrieved from the hospital’s pathology archive. RNA quality checks were performed, and representative histology sections were sent for processing using the Visium High-Definition spatial transcriptomics platform. Downstream analysis was subsequently performed after data processing through Space Ranger (10x Genomics) and included spatial clustering, marker gene expression, morphology analysis, and comparison with published single-cell RNA sequencing derived datasets.

A total of 197,142 barcoded genes was included in final downstream analysis. First, established chondroblastoma markers (S100, DOG1, p63) were used to verify chondroblastoma diagnosis. Next, clustering analysis identified unique cellular subsets including CCN2-giant cells, fibroblast stromal cells, and early chondrogenic genes. High CCN2 expression in the absence of CALM1 expression uniquely distinguishes chondroblastoma from osteosarcoma, giant cell tumor of bone, enchondroma, chondrosarcoma, and chondroblastic osteosarcoma. Lineage-based analysis identified distinctive cell-fate commitment markers (COL10A1) that favored hypertrophic chondrocyte phenotypes and suggests a skipping of orderly developmental chondrocyte differentiation.

Accurate diagnosis of chondroblastoma is critical in differentiating against other primary benign and malignant bone tumors including giant cell tumor of bone and chondrosarcoma which directly impact surgical planning and clinical treatment. This study provides the most comprehensive transcriptomic delineation of chondroblastoma expression markers and identifies new cellular and lineage-based markers to enhance future diagnostic accuracy.

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This is an Open Access Thesis.

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