Soft tissue

Uncertain differentiation

Keratin positive giant cell tumor / xanthogranulomatous epithelial tumor



Last author update: 2 January 2024
Last staff update: 13 February 2024

Copyright: 2023-2024, PathologyOutlines.com, Inc.

PubMed search: Keratin positive giant cell tumor

Asma K. Abu-salah, M.B.B.S.
Carina Dehner, M.D., Ph.D.
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Cite this page: Abu-salah AK, Dehner C. Keratin positive giant cell tumor / xanthogranulomatous epithelial tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissuekeratinposgiantcell.html. Accessed February 22nd, 2024.
Definition / general
  • Keratin positive giant cell tumor (KPGCT) is a rare, emerging entity with uncertain biologic potential that can affect soft tissue and bone (Mod Pathol 2022;35:1656)
Essential features
  • Keratin positive giant cell tumor can affect soft tissue and bone
  • Tumors with uncertain malignant potential can locally recur but rarely metastasizes
  • Characterized by the presence of keratin positive eosinophilic cells in a background of histiocytes, osteoclast type giant cells, Touton giant cells and mixed inflammatory cells with or without hemorrhage or hemosiderin deposition
  • It has been shown to harbor HMGA2::NCOR2 fusions
Terminology
  • Xanthogranulomatous epithelial tumor
  • Giant cell rich tumors with HMGA2::NCOR2 fusion
Epidemiology
Sites
  • Tumor can affect both soft tissues and bone
  • Soft tissue lesions typically affect the subcutaneous tissue, most commonly in the extremities
  • Other reported sites include the back and the head and neck area
  • When the bone is involved, it most commonly affects the vertebral bodies
  • References: Mod Pathol 2022;35:1656, Mod Pathol 2020;33:1889
Pathophysiology
  • Most of the reported cases have been found to have recurrent HMGA2::NCOR2 fusions
  • Histiocytes, giant cells and inflammatory cells, as well as the hemorrhage / hemosiderin deposition, may represent a reaction to the keratin positive mononuclear neoplastic cells
Etiology
  • Unknown
Clinical features
  • May present as superficial, deep or bone lesion
Diagnosis
  • Patients present with either subcutaneous soft tissue masses or with pathologic fractures
  • Imaging findings are not entirely specific
  • Needle core biopsy or excisional biopsy is diagnostic
  • References: Mod Pathol 2020;33:1889, Mod Pathol 2022;35:1656
Radiology description
  • For soft tissue lesions
    • Subcutaneous lesion, growing along the fascial plane with well circumscribed, slightly lobulated margins, with heterogenous echogenicity and increased internal vascularity (Mod Pathol 2020;33:1889)
  • For osseous lesions
Radiology images

Images hosted on other servers:
Subcutaneous soft tissue lesion

Subcutaneous soft tissue lesion

Prognostic factors
Case reports
Treatment
  • Surgical excision for soft tissue tumors
  • Curettage of primary bone tumors
  • Denosumab: a RANKL inhibitor that causes giant cell depletion and fibrosis
  • Pexidarnitib: CSF1R inhibitor (Am J Surg Pathol 2023;47:801)
Gross description
  • Average size: 4.0 cm
  • Well circumscribed, can be encapsulated or nonencapsulated
  • Can be slightly lobulated
  • Color ranges from tan-yellow to brown (Mod Pathol 2022;35:1656)
Gross images

Images hosted on other servers:
Well circumscribed, subcutaneous

Well circumscribed, subcutaneous

Frozen section description
  • On frozen section, it will show giant cell rich tumor with evenly distributed giant cells
  • Keratin positive giant cells may not be obvious
  • Differentiation of this lesion from other giant cell rich lesions is deferred for permanent section
Microscopic (histologic) description
  • Well circumscribed, encapsulated with associated lymphocytic cuff, arranged in lobes with evenly distributed osteoclast type giant cells and variable Touton giant cells (Mod Pathol 2022;35:1656)
  • Background shows foamy histiocytes, mononuclear inflammatory cells and eosinophils (Mod Pathol 2022;35:1656)
  • Mononuclear cells with round to oval nuclei and prominent nucleoli with brightly eosinophilic cytoplasm, distributed singly or in small clusters or cords (Mod Pathol 2020;33:1889)
  • Morphologic spectrum can range from xanthoma-like, showing hybrid features of xanthoma and giant cell tumor, to giant cell tumor-like
  • Stromal hemorrhage or hemosiderin can be seen
  • Infarct type necrosis can be seen
  • Mitotic count ranges from 1 to 7/high power field (Mod Pathol 2022;35:1656)
Microscopic (histologic) images

Contributed by Carina Dehner, M.D., Ph.D.
Well circumscribed

Well circumscribed

Osteoclast type giant cells

Osteoclast type giant cells

Touton giant cells are prominent in the xanthogranulomatous tumors

Prominent Touton giant cells

Epithelioid cells Epithelioid cells Epithelioid cells

Mononuclear epithelioid cells


Keratin AE1 / AE3 IHC

Keratin AE1 / AE3 IHC

CD68 IHC

CD68 IHC

Positive stains
Electron microscopy description
  • Mononuclear cells show
    • Intracytoplasmic thin parallel cytoskeletal filaments
    • Basement membrane deposition
  • Reference: Mod Pathol 2022;35:1656
Electron microscopy images

Contributed by Carina Dehner, M.D., Ph.D.
Ultrastructure of mononuclear cells

Ultrastructure of mononuclear cells

Molecular / cytogenetics description
  • HMGA2::NCOR2 fusion can be detected through next generation sequencing but may be hard to detect given the low number of neoplastic cells that are obscured by a large amount of inflammation
Sample pathology report
  • Skin and subcutaneous tissue, left forearm mass, resection:
    • Keratin positive giant cell rich tumor of soft tissue (see comment)
    • Tumor size: 2.5 cm in greatest dimension
    • Resection margin: free of lesion (0.5 cm from closest deep margin and 0.7 cm from closest peripheral margin)
    • Comment: Genetic testing shows a HMGA2::NCOR2 gene fusion, which confirms the above mentioned diagnosis.
Differential diagnosis
  • Soft tissue lesions:
    • Cutaneous fibrous histiocytomas (dermatofibroma):
      • Dermal based, unencapsulated lesion
      • Composed of spindle cell fibroblasts and histiocytes
      • May show scattered multinucleated giant cells
      • Ischemic type necrosis and mitotic figures can be seen
    • Giant cell tumor of soft tissue:
      • Well demarcated, not encapsulated multinodular proliferation of osteoclast type giant cells and mononuclear stromal cells, separated by fibrous septa and surrounded by a rim of metaplastic bone
      • Foamy macrophages can be seen
      • Lacks H3F3A gene mutation (found in giant cell tumor of bone)
    • Xanthogranuloma:
      • Well demarcated dermal based lesion, composed of foamy histiocytes with scattered Touton giant cells that may extend to the subcutaneous tissue
      • Can show infiltration of lymphocytes, plasma cells or eosinophils
  • Bone lesions (Int J Surg Pathol 2023 Jul 17 [Epub ahead of print]):
    • Giant cell tumor of bone:
      • Involves epiphysis
      • Histologically, it is a giant cell rich lesion with evenly distributed osteoclast type giant cells, admixed with mononuclear stromal cells with oval nuclei
      • Characterized by H3F3A gene mutation (positive for H3G34W IHC)
    • Aneurysmal bone cyst:
      • Involves metaphysis of long bone
      • Radiologically, multiloculated cystic lesion
      • Histologically, composed of multicyclic lesion, separated by fibrous septa with fibroblasts and randomly distributed osteoclast type giant cells
      • Characterized by the presence of USP6 gene mutation
    • Nonossifying fibroma:
      • Involves the metaphysis
      • Histologically, spindle cell proliferation, arranged in storiform pattern, admixed with randomly distributed osteoclast-like giant cells
      • KRAS and FGFR mutations have been reported
Board review style question #1

Keratin positive giant cell rich tumor is characterized by which of the following molecular alterations?

  1. GNAS mutation
  2. H3F3A gene mutation
  3. HMGA2::NCOR2 fusions
  4. USP6 gene alteration
Board review style answer #1
C. HMGA2::NCOR2 fusions. Answer A is incorrect because GNAS mutations are seen in fibrous dysplasia. Answer B is incorrect because H3F3A gene mutations are seen in giant cell tumor of bone. Answer D is incorrect because USP6 gene alteration is seen in aneurysmal bone cyst.

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Reference: Keratin positive giant cell tumor / xanthogranulomatous epithelial tumor
Board review style question #2
What giant cell rich neoplasm is keratin positive?

  1. Aneurysmal bone cyst
  2. Giant cell tumor of bone
  3. Keratin positive giant cell tumor
  4. Tenosynovial giant cell tumor
Board review style answer #2
C. Keratin positive giant cell tumor. Keratin positive giant cell tumor is positive for keratin; the thought about the underlying cause for this concept is that the neoplastic cells are likely of epithelial origin; however, this is still under investigation. Answers A, B and D are incorrect because these tumors do not express keratin.

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Reference: Keratin positive giant cell tumor / xanthogranulomatous epithelial tumor
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