This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 24-year-old man with HIV complained of new onset headaches for three months with subsequent development of night sweats, decreased facial hair and body hair, decreased muscle mass, and decreased libido. He then developed binocular diplopia and sought medical attention. MRI demonstrated a large, centrally-necrotic, enhancing mass filling the sphenoid sinus with remodeling of the skull base. The mass extended into the prepontine cistern, right middle cranial fossa, right cavernous sinus, and displaced the pituitary gland superiorly (Image A). The patient underwent surgery for resection, and the surgeon noted the mass to be eroding into adjacent bone.

Tissue Site
Base of skull, sphenoid sinus

Image A: T1-weighted MRI

Image A: T1-weighted MRI

The whole slide image provided is an H&E-stained slide of the skull from a resection.

  1. Which of the following is the best diagnosis?

    1. Germ cell tumor

    2. Giant cell glioblastoma

    3. Giant cell tumor of bone

    4. Giant cell reparative granuloma

    5. Pituitary adenoma

  2. Which of the following is the most common anatomical site of involvement?

    1. Bones of hands and feet

    2. Craniofacial bones

    3. Ends of long bones

    4. Flat bones

    5. Vertebral bodies

  3. Which of the following stains is helpful in identifying the mononuclear cell population?

    1. Cathepsin K

    2. GFAP

    3. P63

    4. S100

    5. Tartrate-resistant acid phosphatase

View Answer Key

The diagnosis is giant cell tumor (GCT) of bone, a benign, locally-aggressive neoplasm characterized by a mixture of mononuclear cells and osteoclast-like giant cells.

This primary bone tumor was formerly known as “osteoclastoma” due to the expression of enzymes and receptors attributed to osteoclasts (tartrate-resistant acid phosphatase, cathepsin K, receptor activator of nuclear factor-κβ (RANK), and calcitonin receptor). These osteoclast-like giant cells are now considered to represent a reactive process rather than a neoplastic component. The mononuclear cell population is considered neoplastic, and these cells are thought to be either macrophage-like osteoclast precursors or mesenchymal cells. Due to reported stem cell-like properties and the expression of proteins suggesting a mesenchymal lineage or pre-osteoblast phenotype, their heterogeneity may, in fact, indicate multiple stages of differentiation. Giant cell formation is a result of RANK pathway activation by the proliferating mononuclear cells, a key signaling pathway for bone remodeling.

The reported incidence of GCT of bone ranges from 4% to 6% of all primary bone tumors with peak ages of 20 to 45 years. Patients can experience pain and swelling at the affected site and possible pathologic fracture. GCT of bone typically involves the ends of long bones (distal femur, proximal tibia, distal radius, proximal humerus) but has been reported to arise in the skull. Although benign, GCT of bone can be locally aggressive and can develop metastasis, most commonly to the lung (1% to 6%). High-grade malignant transformation is exceedingly rare (<1%). Treatment is primarily focused on surgical approaches. Local recurrence rate after intralesional curettage ranges from 15% to 20% and usually occurs within two to three years. En bloc or wide resection is generally associated with a lower recurrence rate. Incompletely resected tumors or tumors located at unresectable sites can be treated with radiotherapy or with the anti-RANKL antibody, denosumab.

Radiographically, GCT of bone is osteolytic, expansile, frequently eccentric, and can elevate the periosteum and form a sclerotic border with cortical thinning (Image A). Secondary cystic degeneration resembling aneurysmal bone cyst-like changes can also be present. MR shows low to intermediate signal on T1 and intermediate to high signal onT2 weighted images.

Image A: T1-weighted MRI

Image A: T1-weighted MRI

Macroscopically, GCT of bone typically erodes and expands the involved bone, is red-brown or white with possible areas of hemorrhage, and is firm to friable in texture. Microscopically, it characteristically displays multinucleated, osteoclast-like giant cells scattered evenly amongst a dense population of mononuclear cells. The osteoclast-like giant cells have abundant eosinophilic cytoplasm, prominent nucleoli, and vesicular nuclei reaching upwards of 50 in number (Image B, Image C, and Image D). The mononuclear cells have ill-defined cell borders and exhibit a syncytial or storiform arrangement. The mononuclear cells range from spindled to round or oval in shape with open chromatin and variably prominent nucleoli. Mitotic figures may be present within the mononuclear cell component but should not be atypical and can number up to 20 per 10 high power fields. Necrosis, hemorrhage, and reactive/woven bone with osteoblastic rimming are also common (Image D). The osteoclast-like giant cells express markers of osteoclast differentiation (CD51, RANK, tartrate-resistant acid phosphatase, cathepsin K, carbonic anhydrase), as well as macrophage markers CD68 (Image E), CD45, and CD33. The mononuclear cells immunolabel with p63 (Image F) and RANKL.

Image B: Intraoperative smear, H&E stain

Image B: Intraoperative smear, H&E stain

Image C: H&E stain

Image C: H&E stain

Image D: H&E stain

Image D: H&E stain

Giant cell tumor (GCT) of bone

Take Home Points

  • Giant cell tumor (GCT) of bone most frequently occurs in long bones (distal femur, proximal tibia, distal radius).
  • GCT of bone is composed of two cell types: nonneoplastic osteoclast-like giant cells and neoplastic mononuclear cells. The mononuclear cells are the neoplastic cell population and induce giant cell production through the RANK/RANKL pathway.
  • GCT of bone is treated using surgical curettage/resection, radiotherapy, and RANK ligand inhibition (denosumab).
  • Although benign, local recurrence, pulmonary metastasis, and malignant transformation can occur.


  1. Bertoni F, Unni KK, Beabout JW, et al. Giant cell tumor of the skull. Cancer. 1992;70(5):1124-32.
  2. Cowan RW, Singh G. Giant cell tumor of bone: A basic science perspective. Bone. 2013;52(1):238-46.
  3. Mendenhall WM, Zlotecki RA, Scarborough MT, et al. Giant cell tumor of bone. Am J Clin Oncol. 2006;29(1):96-9.
  4. Nielsen GP, Rosenberg AE. Giant cell tumor. In: Nielsen GP, Rosenberg AE, eds. Diagnostic Pathology: Bone. 2nd ed. Elsevier; 2017.
  5. Fletcher CDM, Unni KK, Mertens F, eds. WHO Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2013:10-12.
  6. Wu PF, Tang JY, Li KH. RANK pathway in giant cell tumor of bone: pathogenesis and therapeutic aspects. Tumor Biol. 2015;36(2):495-501.

Answer Key

  1. Which of the following is the best diagnosis?
    A. Germ cell tumor
    B. Giant cell glioblastoma
    C. Giant cell tumor of bone
    D. Giant cell reparative granuloma
    E. Pituitary adenoma
  2. Which of the following is the most common anatomical site of involvement?
    A. Bones of hands and feet
    B. Craniofacial bones
    C. Ends of long bones
    D. Flat bones
    E. Vertebral bodies
  3. Which of the following stains is helpful in identifying the mononuclear cell population?
    A. Cathepsin K
    B. GFAP
    C. P63
    D. S100
    E. Tartrate-resistant acid phosphatase