1. Home
  2. Member Resources
  3. Pathology Case Library
  4. Case Library Listing
  5. 2019 NPA-03

2019 NPA-03

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.

Clinical History

A previously healthy 37-year-old woman presented to urgent care with two weeks of headaches localizing to the left side of her cranium. There was a tender spot on the top of her head. Imaging revealed a 1.3 cm soft tissue mass centered in the left posterior parietal calvarium, extending to the dura and peripherally tenting the periosteum, without further intracranial extension (Image A and Image B). The patient underwent a craniotomy with complete excision and subsequent cranioplasty.

Tissue Site
Bone (left parietal calvarium)

Image A: T1-weighted and T2-weighted MRI.

Image A: T1-weighted and T2-weighted MRI.

Image B: CT scan.

Image B: CT scan.

Whole Slide Image

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

Questions

  1. Which of the following is the BEST diagnosis?

    1. Erdheim-Chester disease

    2. Histiocytic sarcoma

    3. IgG4-related disease

    4. Langerhans cell histiocytosis

    5. Rosai-Dorfman disease

  2. Which of the following antigens is MOST useful for establishing this diagnosis?

    1. CD1a

    2. CD35

    3. CD68

    4. CD123

    5. CD208

  3. Which of the following molecular alterations is MOST frequently seen in this disorder?

    1. BRAF V600E

    2. CDKN2A deletion

    3. c-myc amplification

    4. EWSR1 rearrangement

    5. IDH2 R172H

View Answer Key

Discussion

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

Image E: H&E stain

Image F: CD1a, IHC 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.

References

  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. Erdheim-Chester disease
    B. Histiocytic sarcoma
    C. IgG4-related disease
    D. Langerhans cell histiocytosis
    E. Rosai-Dorfman disease
  2. Which of the following antigens is MOST useful for establishing this diagnosis?
    A. CD1a
    B. CD35
    C. CD68
    D. CD123
    E. CD208
  3. Which of the following molecular alterations is MOST frequently seen in this disorder?
    A. BRAF V600E
    B. CDKN2A deletion
    C. c-myc amplification
    D. EWSR1 rearrangement
    E. IDH2 R172H
Back to Case Library
To Top