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2019 NPA-04

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 60-year-old woman presented with chronic headache, right orbital pain, progressively worsening visual loss (right greater than left), and cerebral spinal fluid (CSF) rhinorrhea. On examination, she had a prominent protuberance from the right frontal bone in the forehead region. CT scan (Image A and Image B) showed diffuse cortical thickening of bone with areas of ground-glass appearance involving the right frontal bone, bilateral frontal sinuses, and right ethmoid sinus. The patient underwent an anterior cranial fossa bifrontal craniotomy with transorbital roof resection/debulking of the lesion, excision of the right frontal bony protuberance, and repair of anterior fossa floor CSF leak.

Tissue Site
Skull

Image A: Coronal CT scan.*

Image A: Coronal CT scan.*

Image B: Axial CT scan*

Image B: Axial 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. Aneurysmal bone cyst

    2. Chondroma

    3. Fibrosarcoma

    4. Fibrous dysplasia

    5. Osteosarcoma

  2. Which of the following genetic alterations is associated with this entity?

    1. APC mutations

    2. ETV6-NTRK3 fusion

    3. GNAS1 mutations

    4. KIAA1549-BRAF fusion

    5. TP53 mutations

  3. McCune-Albright syndrome encompasses which of the following set of characteristics?

    1. Cortical dysplasias, cutaneous angiofibromas, subependymal giant cell astrocytoma

    2. Fibrous dysplasia, hyperfunctional endocrinopathies, café-au-lait hyperpigmented macules

    3. Medulloblastoma, colorectal adenomas, APC gene mutations

    4. Osteosarcoma, TP53 germline mutation, breast carcinoma

    5. Plexiform neurofibroma, café-au-lait hyperpigmented macules, Lisch nodules

View Answer Key

Discussion

The diagnosis is fibrous dysplasia (ie, fibrocartilagenous dysplasia), a benign fibro-osseous bone lesion with no age, sex, or racial predilection. It comprises approximately 2.5% of primary bone tumors. Lesions typically develop in childhood but are often not diagnosed until years later. In fibrous dysplasia, normal bone architecture is replaced by poorly-organized fibrous tissue with interspersed immature osseous trabeculae due to defective differentiation and maturation of stromal cells. Long bones are more frequently involved in female patients, while ribs and skull are more frequently involved in male patients. When involving the cranium, the maxilla is the most commonly affected bone. Presentation may be monostotic or polyostotic; the monostotic form is greater than five-fold more common than the polyostotic form.

Sporadic activating mutations in GNAS1 have been linked to monostotic and polyostotic forms of fibrous dysplasia, fibrous dysplasia associated with intramuscular myxomas (Mazabraud syndrome), and polyostotic fibrous dysplasia associated with hyperfunctional endocrinopathies and café-au-lait hyperpigmented macules (McCune-Albright syndrome). Hyperfunctional endocrinopathies in McCune-Albright syndrome may include excesses of growth hormone or thyroid hormones (particularly T3), gonadotropin-independent precocious puberty (the most common abnormality), or Cushing syndrome.

The clinical presentation of fibrous dysplasia is variable and most often includes painless enlargement of a bone but may include bone pain, pathologic fracture, or other signs/symptoms based on location of the lesion(s). Orbital involvement may lead to proptosis or visual field defects, for example, while skull base lesions may present with headache, pain/numbness in the face, and/or sinus pressure. Abnormal bone weakness renders fracture the most common complication of fibrous dysplasia, and fractures are particularly associated with the polyostotic form.

Radiographic imaging typically reveals a focal, homogeneous bone lesion with ground glass matrix and indistinct margins that blend into the normal adjacent bone. There is absence of a periosteal reaction unless the lesion is complicated by an associated fracture, and there is no soft tissue extension. X-ray is the preferred primary modality for evaluation of fibrous dysplasia.

Fibrous dysplasia is a well-circumscribed lesion on microscopic examination, comprised of irregular, anastomosing, osseous trabeculae alternating with bland spindled cells in a fibrous matrix with inconspicuous mitotic activity (Image C, Image D, and Image E). Normal bone marrow elements are absent. Osteoclasts may be conspicuous, but osteoblastic rimming is typically scarce. Occasional fluid-filled cystic spaces, foamy histiocytes, and/or multinucleated giant cells may be observed (Image F). Aneurysmal bone cysts may arise in association with fibrous dysplasia.

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 E: H&E stain

Image F: H&E stain

Image F: H&E stain

Although fibrous dysplasia has an exceedingly low risk of malignant transformation (less than 0.5%), cases of osteosarcoma, fibrosarcoma, and undifferentiated pleomorphic sarcoma have been reported in patients with preexisting fibrous dysplasia. McCune-Albright syndrome is the most common setting for development of osteosarcoma in a patient with fibrous dysplasia. Fibrosarcoma and osteosarcoma may also arise from preexisting fibrous dysplasia following radiation therapy.

Complete surgical resection of symptomatic lesions is recommended, particularly when there is visual or hearing impairment indicating cranial nerve impingement. Complete resection proffers a low risk of recurrence compared to debulking surgical procedures. Risk of recurrence is higher in McCune-Albright syndrome patients with elevated growth hormone and when total resection is not achieved; management should therefore include periodic radiographic follow-up.

Fibrous dysplasia

Take Home Points

  • Fibrous dysplasia is a benign bone lesion caused by activating mutations in GNAS1. It commonly affects craniofacial bones, is most often a solitary lesion (monostotic), and carries a low risk for malignant transformation.
  • Clinical presentation of fibrous dysplasia is variable and may include bone pain or deformity, pathologic fracture, or other signs/symptoms based on location of the lesion(s).
  • Abnormal bone weakness renders fracture the most common complication of fibrous dysplasia, and fractures are particularly associated with the polyostotic form.
  • McCune-Albright syndrome is a polyostotic fibrous dysplasia with hyperfunctional endocrinopathies (most commonly precocious puberty) and café-au-lait hyperpigmented macules.

References

  1. Amit M, Fliss DM, Gil Z. Fibrous dysplasia of the sphenoid and skull base. Otolaryngol Clin N Am. 2011;44:891-902.
  2. Bianco P, Riminucci M, Majolagbe A, et al. Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. J Bone Mine Res. 2000;15:120-8.
  3. Boyce AM, Burke A, Peck CC, et al. Surgical management of polyostotic craniofacial fibrous dysplasia: Long-term outcomes and predictors for postoperative regrowth. Plast Reconstr Surg. 2016;137:1833-9.
  4. Yang L, Wu H, Lu J, et al. Prevalence of different forms and involved bones of craniofacial fibrous dysplasia. J Craniofac Surg. 2016;28:21-5.
  5. Zhang Y, Rosenberg AE. Bone-forming tumors. Surg Pathol Clin. 2017;10:513-35.

*Reprinted with permission from Dr. Jeffrey R. DeSanto, MD. University of Illinois College of Medicine at Peoria.

Answer Key

  1. Which of the following is the BEST diagnosis?
    A. Aneurysmal bone cyst
    B. Chondroma
    C. Fibrosarcoma
    D. Fibrous dysplasia
    E. Osteosarcoma
  2. Which of the following genetic alterations is associated with this entity?
    A. APC mutations
    B. ETV6-NTRK3 fusion
    C. GNAS1 mutations
    D. KIAA1549-BRAF fusion
    E. TP53 mutations
  3. McCune-Albright syndrome encompasses which of the following set of characteristics?
    A. Cortical dysplasias, cutaneous angiofibromas, subependymal giant cell astrocytoma
    B. Fibrous dysplasia, hyperfunctional endocrinopathies, café-au-lait hyperpigmented macules
    C. Medulloblastoma, colorectal adenomas, APC gene mutations
    D. Osteosarcoma, TP53 germline mutation, breast carcinoma
    E. Plexiform neurofibroma, café-au-lait hyperpigmented macules, Lisch nodules
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