Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy

Cancer Cytopathol. 2018 Aug;126(8):552-566. doi: 10.1002/cncy.22000. Epub 2018 May 14.


Background: Diagnosing giant cell-rich bone tumors can be challenging on limited biopsies. H3 histone family member 3A (H3F3A) (G34W/V/R/L) mutations are present in the majority of giant cell tumors (GCTs) of bone and H3 histone family member 3B (H3F3B) (K36M) mutations are present in nearly all chondroblastomas, but are absent in histologic mimics. Mutation-specific immunohistochemistry (IHC) is highly specific for GCT and chondroblastoma in surgical excisions. The objective of the current study was to validate H3G34W and H3K36M IHC in the diagnosis of giant cell-rich bone tumors on fine-needle aspiration and core needle biopsy specimens.

Methods: IHC was performed using monoclonal antibodies against histone H3.3 G34W and K36M in GCTs of bone (26 cases, including 2 malignant cases), GCT of Paget disease (1 case), chondroblastoma (8 cases), aneurysmal bone cyst (7 cases), and osteosarcoma (13 cases) with available fine-needle aspiration and/or core needle biopsy specimens from 2 institutions. H3F3A and H3F3B Sanger sequencing was performed on all 4 H3G34W IHC-negative GCTs.

Results: IHC for H3G34W was positive in 22 of 26 GCTs (85%) and negative in all histologic mimics. IHC for H3K36M was positive in all 8 chondroblastomas and negative in all histologic mimics. IHC results were concordant between biopsy and surgical specimens in 152 of 158 samples (96%). Sequencing identified alternate H3F3A G34L and G34V mutations in 1 IHC-negative GCT each, but no mutation was found in the remaining 2 cases.

Conclusions: H3G34W and H3K36M IHC is highly specific for GCT and chondroblastoma, respectively, among giant cell-rich bone tumors, and is useful for confirming the diagnosis in limited biopsies. The presence of alternate H3F3A mutations accounts for the H3G34W IHC negativity in a subset of GCT of bone cases. Cancer Cytopathol 2018. © 2018 American Cancer Society.

Keywords: H3 histone family member 3A (H3F3A); H3 histone family member 3B (H3F3B); H3G34W; H3K36M; chondroblastoma; core needle biopsy; fine-needle aspiration; giant cell tumor of bone; giant cell-rich; immunohistochemistry.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / immunology
  • Biomarkers, Tumor / analysis*
  • Biopsy, Fine-Needle
  • Biopsy, Large-Core Needle
  • Bone Neoplasms / diagnosis*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / metabolism
  • Chondroblastoma / diagnosis*
  • Chondroblastoma / immunology
  • Chondroblastoma / metabolism
  • DNA Mutational Analysis
  • Female
  • Follow-Up Studies
  • Giant Cell Tumor of Bone / diagnosis*
  • Giant Cell Tumor of Bone / immunology
  • Giant Cell Tumor of Bone / metabolism
  • Histones / genetics
  • Histones / immunology
  • Histones / metabolism*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Young Adult


  • Antibodies, Monoclonal
  • Biomarkers, Tumor
  • Histones