Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

Ahead of print publication  

H3F3A mutation as a marker of malignant giant cell tumor of the bone: A case report and review of literature

1 Department of Surgical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Submission11-Feb-2021
Date of Acceptance06-Sep-2021
Date of Web Publication27-Apr-2022

Correspondence Address:
Ranganath Ratnagiri,
Department of Surgical Oncology, Room No 404, Fourth Floor, Specialty Block, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_247_21

 > Abstract 

Giant cell tumor of the bone (GCTB) is a locally aggressive lesion, which characteristically arises from the epimetaphyseal region of long bones. They occur commonly in the third or fourth decade of life with a slight female preponderance. Various lesions such as chondroblastoma, aneurysmal bone cysts, and nonossifying fibromas can mimic the radiologic appearance of giant cell tumors. However, the greatest challenge is to differentiate between a conventional GCTB, a malignancy arising in a giant cell tumor, and osteoclast-rich osteosarcomas. The presence of a histone gene mutation, H3F3A, involving the substitution of glycine 34 has been reported in more than 95% of GCTB. Immunohistochemical (IHC) analysis of the biopsy specimens for H3.3pG34W expression is a surrogate for gene analysis and can be used to establish the presence of GCTB. Our report is the first in Indian literature to report the use of H3.3pG34W IHC in establishing the diagnosis of a primary malignant GCTB.

Keywords: H3F3A mutation, immunohistochemistry, primary malignant giant cell tumor of the bone, sarcoma

How to cite this URL:
Ratnagiri R, Uppin S. H3F3A mutation as a marker of malignant giant cell tumor of the bone: A case report and review of literature. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=344238

 > Introduction Top

Giant cell tumor of the bone (GCTB) is a locally aggressive lesion, which occurs most commonly in the epimetaphyseal region of the distal femur or proximal tibia. There is a slight female preponderance and these tumors are common in the third and fourth decades of life. GCTB is one of the few “benign” lesions which can also have pulmonary metastases.

The differential diagnosis of GCTB includes aneurysmal bone cysts, nonossifying fibromas, brown tumors, chondroblastomas, and tenosynovial giant cell tumors.[1] The main problem is, however, to differentiate between an osteoclast-rich osteosarcoma and a malignancy in a giant cell tumor.

The presence of a histone gene mutation, H3F3A which involves the substitution of glycine 34 and its demonstration in a biopsy specimen using immunohistochemistry (IHC) (H3.3pG34W) solves this diagnostic dilemma.[2] This IHC is positive only in giant cell tumors and not in any other osteoclast-rich lesions and can therefore, be used as a marker for malignant GCTB.

 > Case Report Top

Ms. R, aged 30 years, presented to our institute with a recurrent tumor arising from the left proximal tibia in June 2018. She had been diagnosed initially as a case of giant cell tumor of the left tibia in June 2017 and had undergone resection of the bone and reconstruction with a modular prosthesis. She developed a local recurrence within 7 months and was treated with external beam radiation (30 Gy in 10 fractions in April 2018). This was done at the behest of the operating surgeon as the patient was unwilling for a redo surgery.

This lady, therefore, presented to our institute after being extensively treated at various centers outside. On examination, there was an 18 cm × 16 cm hard, nodular tumor from the left knee joint distally up to the mid-leg, with ulceration of the overlying skin. The patient could not ambulate due to pain and ulceration and was stretcher bound. We obtained the previous biopsy slides for review at our institute and also performed a staging workup. The slides of the previous surgery were reported by our pathologist as a “Giant cell-rich sarcoma” and a computed tomography scan of the thorax revealed bilateral multiple pulmonary metastases.

The clinical condition and prognosis were explained to the patient and her relatives, and after obtaining due consent, an above knee amputation was performed with the aim of palliating the pain and bleeding and making the patient ambulant [Figure 1]. Postoperative recovery was uneventful, and the patient was discharged on the 5th postoperative day.
Figure 1: Gross photograph showing the necrotic tumor infiltrating the soft tissues

Click here to view

The final histopathology was reported as “osteosarcoma – arising in a giant cell tumor” [Figure 2]. Immunohistochemistry was performed with antihistone H3.3 G34W rabbit monoclonal antibody (Clone RM 263, Medaysis, USA) using a semiautomated (Biogenex, i6000) immunostainer by HRP-polymer technique. Nuclear expression was taken as positive and a case of giant cell tumor was used as a positive control.
Figure 2: (a,b) Increased cellularity, (c,d) brisk atypical mitoses and (e,f) malignant osteoid (H and E, ×10)

Click here to view

[Figure 3] shows the various portions of tumor with focal nuclear positivity for H3.3 G34W.
Figure 3: Tumor with focal nuclear positivity for H3.3 G34W for H3.3

Click here to view


The patient received six cycles of IAC chemotherapy, but unfortunately succumbed to the disease in February 2019, 8 months after the amputation was performed. The cause of death was due to progressive pulmonary metastases.

 > Discussion Top

The definition of a primary malignant GCTB (PMGCTB) is of utmost importance when discussing about the treatment options and prognosis. According to Hutter et al.[3] and Dahlin et al.,[4] a primary malignancy in a giant cell tumor is a lesion, in which there are areas of synchronous high-grade sarcoma adjacent to the areas of benign giant cell tumor. A secondary malignancy is defined as a metachronous sarcoma developing in a previously treated benign giant cell tumor. The treatment modality could be either surgery or radiation therapy. The minimum latent period between the treatment and the development of a secondary malignancy is 1.7–2 years in most reports in the literature. Dahlin et al. have also postulated that if a malignancy is detected within a year of treatment of a giant cell tumor, it has to be considered a PMGCTB and hypothesized that the malignancy would have been detected by thorough sectioning of the original tumor.[4]

Previous reports suggest that the patients with PMGCTB are older on average when compared to patients with benign giant cell tumors. Furthermore, those patients with Secondary Malignant Giant Cell Tumor of Bone (SMGCTB) after radiotherapy were younger than those who had undergone surgery alone.[2] The clinical features of PMGCTB and SMGCTB were similar to those of benign giant cell tumors, but postradiation tumors were more common in the pelvic bones. The radiological features of malignant giant cell tumors were identical to those of benign ones.[4] The occurrence of pulmonary metastases in a few cases of benign giant cell tumors confounds the issue further.

High-grade sarcomas – osteosarcoma, fibro sarcomas, and pleomorphic undifferentiated sarcomas – are the most common malignancies diagnosed histologically in giant cell tumors.[5] It becomes difficult sometimes to differentiate between giant cell-rich osteosarcoma and a PMGCTB pathologically, though clinically the management does not differ. Reports of osteosarcoma in a giant cell tumor give credence to the hypothesis that there is a mesenchymal cell line in giant cell tumors which gives rise to sarcomas.[3] There is also a theory that p53 plays an important role in the malignant transformation of giant cell tumors.[6] The presence of a high-grade sarcomatous component portends a poorer prognosis and is a marker of dedifferentiation.

The monoclonal antibody against the G34W-mutated site of H3F3A is a specific biomarker and is useful in differentiating malignant giant cell tumors from other giant cell-rich tumors of the bone.[2] These mutations have been detected by exome-wide and genome-wide sequencing and are tumor specific.[7] Furthermore, with the availability of denosumab for the treatment of unresectable giant cell tumors, H3F3A mutations act as a biomarker for tumor susceptibility and response.[8]

Different time intervals have been reported in the literature for the development of SMGCTB. Malignant transformation has been seen to occur 2–36 years postsurgery and 4–42 years after radiation for a benign giant cell tumor.[3] In cases where there is only a short interval between the treatment of a giant cell tumor and diagnosis of malignancy, it is possible that the original tumor was already malignant.[4] This fact is very important to ensure appropriate therapy at the right time. Irrespective of the primary or secondary nature of malignancy, the prognosis of these tumors is uniformly poor.

 > Conclusion Top

Malignancy in giant cell tumors occurs only in 1.8%, but due to the poor prognosis, it is necessary to identify them early and treat them with appropriate surgery and chemotherapy. The clinical and radiologic features mimic benign giant cell tumors, and hence a thorough histopathologic examination is the only means of establishing a diagnosis. The use of H3.3pG34W as an immunohistochemical marker is therefore strongly recommended in all cases of malignant giant cell tumors of the bone.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

Nascimento AG, Huvos AG, Marcove RC. Primary malignant giant cell tumor of bone: A study of eight cases and review of the literature. Cancer 1979;44:1393-402.  Back to cited text no. 1
Bai YQ, Yang TT, Zhang HZ. The study of the value of H3F3A G34W immunohistochemical staining in the diagnosis of giant cell tumor of bone. Zhonghua Bing Li Xue Za Zhi 2019;48:531-6.  Back to cited text no. 2
Hutter RV, Worcester JN Jr., Francis KC, Foote FW Jr., Stewart FW. Benign and malignant giant cell tumors of bone. A clinicopathological analysis of the natural history of the disease. Cancer 1962;15:653-90.  Back to cited text no. 3
Dahlin DC, Cupps RE, Johnson EW Jr. Giant-cell tumor: A study of 195 cases. Cancer 1970;25:1061-70.  Back to cited text no. 4
Unni KK. Dahlin's Bone Tumors – General Aspects and Data on 11,087 Cases. 5th ed. Philadelphia, USA: Lippincott-Raven Publishers; 1996. p. 263-87.  Back to cited text no. 5
Amary F, Berisha F, Ye H, Gupta M, Gutteridge A, Baumhoer D, et al. H3F3A (histone 3.3) G34W immunohistochemistry: A reliable marker defining benign and malignant giant cell tumor of bone. Am J Surg Pathol 2017;41:1059-68.  Back to cited text no. 6
Baumhoer D, Höller S. Molekulare Pathologie in der Diagnostik der Knochentumoren: Aktueller Stand [Molecular pathology in the diagnosis of bone tumors: Current concepts]. Pathologe 2020;41:106-15.  Back to cited text no. 7
van der Heijden L, Dijkstra S, van de Sande M, Gelderblom H. Current concepts in the treatment of giant cell tumour of bone. Curr Opin Oncol 2020;32:332-8.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3]


     Search Pubmed for
    -  Ratnagiri R
    -  Uppin S
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Case Report>Discussion>Conclusion>Article Figures
  In this article

 Article Access Statistics
    PDF Downloaded7    

Recommend this journal