In 2020 Fritchie et al.1 reported “xanthogranulomatous epithelial tumor” (XGET) a distinctive tumor of soft tissue and bone, consisting of small nests of keratin-positive epithelial cells in a xanthogranulomatous background. Shortly thereafter, Agaimy et al2 reported “keratin-positive giant cell tumor” (KPGCT) occurring in similar locations, closely resembling giant cell tumor of bone but containing keratin-positive cells and harboring HMGA2::NCOR2 fusions. Panagopoulos et al3 independently reported “Osteoclastic giant cell-rich tumors of bone” harboring HMGA2::NCOR2 fusions. A subsequent publication by Dehner and colleagues demonstrated overlapping morphological, immunohistochemical and molecular genetic features in XGET and KPGCT, strongly suggesting that they represent slightly different manifestations of a single entity.4 A small number of tumors have been reported as examples of “tenosynovial giant cell tumor” with HMGA2::NCOR2 fusions.5,6 XGET and KPGCT will be considered to represent a single entity in the next WHO classification of tumors of soft tissue and bone (XGET/KPGCT) (personal communication, Dr. Andrew Folpe, Mayo Clinic, Rochester, MN USA).

Of the roughly 61 reported examples of XGET/KPGCT (summarized in Tables 1 and 2), 13 (21.3 %) have involved the soft tissues, bones or mucosa of the head and neck region.2,5,7–10 This review will summarize the known information on these neoplasms across anatomic sites and highlight the distinct challenges this neoplasm presents in the head and neck region.

XGET/KPGCT are considerably more common in women than in men (F:M::4:1) and most often occur in young adults (median age 25 years), although they may occur in infants and in the elderly (age range 10 days-87 years). Fifteen (of 58, 25.9 %) cases with an age reported occurred in patients under 18 years of age.1–4,6–17 XGET/KPGCT are more common in soft tissue (57.6 %, 34/59) than in bone (42.4 %, 25/59) and have been reported in diverse anatomic locations. Two tumors occurring in submucosal locations have been reported.7 Tumors occurring in soft tissue typically are centered in the subcutis, sometimes with deep extension involving skeletal muscle and even bone. In the head and neck region, tumors more often occur in women, involve patients with a median age of 20.5 years, and have been reported in scalp, temporal bone, sinonasal cavity, helix of the ear, external auditory canal of the ear, angle of the jaw, vocal cord, and neck.

Eleven reports included radiographic descriptions of these neoplasms.1,2,4,6,10,11,13–17 Computed tomography (CT) of osseous XGET/KPGCTs has generally revealed lytic lesions with cortical destruction, with a differential diagnosis to include both benign and malignant entities. Soft tissue XGET/KPGCT are slightly hyperintense relative to skeletal muscle on T1-weighted images and display variable heterogeneous signal intensity on T2-weighted images; these findings are indeterminate.

Follow up information is available for 39 reported patients, ranging from 7 days to 21 years (median 10 months).1–4,6–11,13–15,17 Most patients underwent surgical resection and had no evidence of disease at last follow up. Six tumors recurred locally (time to recurrence range 3–46 months) and 2 metastasized.7,14,15,18 A 55-year-old female with a XGET/KPGCT involving the right 2nd metatarsal had a local recurrence followed by subcutaneous metastases in the proximal ipsilateral leg.14 A 10-day-old female with a XGET/KPGCT involving the petrous ridge with posterior fossa extension presented with metastases in the femur, tibia, fibula, ilium, scapula, rib and chest wall soft tissue disease. This patient was treated chemotherapy and the tumor continued to increase in size. Following treatment with imatinib there was significant tumor regression in both the primary and metastatic disease.10

In general, XGET/KPGCT tend to segregate into one of two morphological patterns, although cases with hybrid morphology are also seen. The “XGET pattern”, more often seen in soft tissue locations, consists of a partially encapsulated mass dominated by sheets of xanthomatous histiocytes, Touton-type giant cells, osteoclast-like giant cells and chronic inflammatory cells, including eosinophils (Fig. 1). This appearance closely mimics that of solitary (juvenile) xanthogranuloma, although the subcutaneous (rather than dermal) location should be a clue that one is dealing with something else. Close inspection shows epithelioid cells, often with distinctly eosinophilic, vaguely squamous cytoplasm, arranged singly and in small clusters within this xanthogranulomatous background. These epithelioid cells are positive with broad spectrum keratin antibodies (e.g., AE1/AE3, OSCAR) and to a lesser degree with antibodies to high molecular weight keratins such as 34BE12 or epithelial membrane antigen (Fig. 2, Fig. 3, Fig. 4). Markers of solitary xanthogranuloma, such as Factor XIIIa and CD163, may be positive in the xanthogranulomatous histiocytes, but not in the clusters of epithelioid cells. SMARCB1 (INI1) expression is retained (normal).

In contrast, the “KPGCT pattern” closely mimics a giant cell tumor of bone, with sheets of osteoclast-like giant cells and cytologically bland mononuclear cells (Fig. 1). It is typically very difficult, or even impossible to identify the epithelial cells in these lesions, and immunohistochemistry for keratins is required (Fig. 2, Fig. 3). Often the clue that one is dealing with KPGCT, rather than a conventional giant cell tumor of bone, is the absence of histone G34W expression, and it is prudent to perform keratin immunostains before making the diagnosis of “histone G34W-negative giant cell tumor of bone.” To date, there are no known reports of XGET/KPGCT demonstrating features analogous to malignant giant cell tumor of bone.

At the molecular genetic level, XGET/KPGCT harbor rearrangements involving the HMGA2 gene, most often in the form of an HMGA2::NCOR2 fusion.2,3 Alternative HMGA2 partners have been described in a few cases, including COL14A1, SUPT3H, and EP400.6,7,9,11 In limited biopsies, HMGA2 rearrangements can be identified with fluorescence in situ hybridization instead of next generation sequencing.3,7

In general, the differential diagnosis of XGET/KPGCT centers on other tumors that may have a xanthogranulomatous appearance and/or contain large number of osteoclast-like giant cells. Solitary (juvenile) xanthogranuloma typically presents as a small, non-destructive tumor of the dermis, usually consists of both small histiocytes with folded nuclei and xanthomatous histiocytes, displays diffuse Factor XIIIa and CD163 expression in the lesional cells themselves, and lacks keratin-positive cells. Tenosynovial giant cell tumor tends to occur in association with the synovium of joints and tendon sheaths, and is a neoplasm of synoviocytes (large, plasmacytoid mononuclear cells frequently containing intracytoplasmic hemosiderin) in association with a variable number of small histiocytes, foamy macrophages and osteoclast-like giant cells. Synoviocytes express clusterin and CSF1, but not keratins. Older examples of Langerhans histiocytosis may be extensively lipidized, but usually show a more prominent infiltrate of eosinophils, and are positive for S100 protein, CD1a and Langerin, but not keratins. Rosai-Dorfman disease is typified by the presence of very large histiocytic cells with centrally placed, round nuclei having small nucleoli and intracytoplasmic lymphocytes; expression of S100 protein but not keratins is seen.

The differential diagnosis with giant cell tumor of bone is mentioned above, and this distinction depends in large part on the absence of histone G34W expression (reflecting underlying mutations in H3F3A at Gly34 codon) and the presence of keratin-positive mononuclear cells. Soft tissue giant cell tumors typically involve the dermis and subcutis, grow in a distinctly multinodular pattern, and often show metaplastic bone formation. Despite their close resemblance to giant cell tumor of bone, soft tissue giant cell tumors lack histone G34W expression, and thus the absence of this marker is not helpful in the distinction from XGET/KPGCT. Again, keratin-positive cells are not found. The very bland cytology of the keratin-positive cells seen in XGET/KPGCT helps to distinguish them from osteoclast-rich carcinomas or other osteoclast-rich malignancies (e.g., osteoclast-rich osteosarcoma or melanoma). None of the above entities, of course, harbor HMGA2::NCOR2 fusions.

In the head and neck region, other site-specific differential diagnostic considerations include giant cell-rich lesions involving the jaw, infections, inflammatory/immune-mediated conditions, and neoplasms that can have contain multinucleated giant cells (Fig. 5). Central giant cell granuloma, peripheral giant cell granuloma, brown tumor of hyperparathyroidism and cherubism demonstrate similar morphologic features consisting of proliferation of mononuclear spindle-shaped/polygonal cells intermingled with osteoclast multinucleated giant cells in a vascular background. The clinical scenario aids the separation of these entities. Central giant cell granulomas are located within the bone and peripheral giant cell granulomas occur almost exclusively on the gingiva. Brown tumor of hyperparathyroidism develops as a complication of hyperparathyroidism and can be multifocal, while cherubism is an autosomal-dominant hereditary childhood disease that typically affects the jaws bilaterally. These giant cell lesions have a fibrovascular background as opposed to the inflammatory background of XGET/KPGCT. Additionally, these tumors lack keratin expression.

Granulomatosis with polyangiitis can present as a mass. The morphologic findings of any given biopsy can show various amounts of giant cells, granulomatous inflammation, vasculitis, and necrosis. The giant cells are usually scattered or isolated and keratin positive cells are not a feature.

Mycobacterial spindle cell pseudotumor is a spindle cell proliferation caused by Mycobacterium avium-intracellulare and impacts immunocompromised patients. The inflammatory background consists of sheets of foamy histocytes and multinucleated giant cells are typically absent. Acid-fact bacilli or Ziehl-Neelsen stain highlights the mycobacteria and keratins are negative.

Sarcomatoid squamous cell carcinoma can have significant numbers of osteoclast-like giant cells and focal keratin expression. The overtly malignant cytology of sarcomatoid squamous cell carcinoma and the low-grade cytology XGET/KPGCT allows for this distinction. However, sarcomatoid squamous cell carcinoma can display deceptively low-grade cytology and have an inflammatory background. Even so, sarcomatoid squamous cell carcinoma does not harbor HMGA2::NCOR2 fusions.

Xanthogranulomatous epithelial tumors/keratin-positive giant cell-rich tumors can involve the head and neck region and add another challenging entity in to the list of lesions with increased multinucleated giant cells. Understanding the keratin-positive cells may be inconspicuous should allow for careful review of giant cell-rich lesions and deployment of keratin immunostains to aid in the diagnostic evaluation. The presence of high-grade cytology should caution the diagnosis XGET/KPGCT and allow for consideration of giant cell-rich malignancies.