Background
Giant cell angiofibroma (GCA) was first described by Dei Tos as a rare soft tissue tumor of the orbit [
1]. Since the initial report of the disease in orbital tissue, GCA has been reported in a variety of other extraorbital sites [
2‐
8]. GCA is a benign, mesenchymal lesion showing histological features intermediate between, but distinct from, solitary fibrous tumor (SFT) and giant cell fibroblastoma (GCF) of soft tissue [
5].
In this paper, we report a rare case of a patient with a large GCA extending from the right parotid gland to the homolateral parapharyngeal space that was being treated as a vascular malformation for a year prior to surgical removal. The clinical findings, diagnostic procedure followed, treatment and histopathological/immunohistochemical findings are also outlined in this paper.
Discussion
GCA is a rare tumor of soft tissues. Although it was firstly described as a distinct orbital neoplasm by Dei Tos [
1], until now there are approximately 26 various extraorbital site cases reported in the literature [
2‐
18] (Table
1). By taking into account the orbital GCA cases and extraorbital head and neck cases we could assume that GCA may have a predilection for the head and neck region.
Table 1
Known reported giant cell angiofibroma extraorbital cases
Subcutaneous neck area | 1 | Cutaneous (thigh) | 1 |
Occipital region | 2 | Hip | 1 |
Retroauricular area | 1 | Forearm | 1 |
Parotid | 1 | Vulva | 1 |
Submandibular region | 1 | Retroperitoneum | 1 |
Parapharyngeal space | 1 | Back | 3 |
Oral buccal mucosa | 3 | Mediastinum | 1 |
Tongue | 1 | Axilla | 1 |
Vocal cord | 2 | Groin/Inguinal region | 3 |
The tumor may grow rapidly, simulating malignancy, or may have an indolent course with slow growth over many years. GCA most often occurs in middle-aged adults (median age 45 years). In regard to sex predilection of this tumor, some reports suggest that orbital GCA is more common in men, while extraorbital locations are more common in women [
6].
Gonzalez-Perez
et al. were the first to report a GCA of the parapharyngeal region in a 25-year-old female patient [
6]. Both GCA cases presented with similar clinical characteristics of a benign non-infiltrative slow growing tumor. In both cases a differential diagnosis of parotid gland, fibrous or vascular tumor was made. In our case, the more cystic (pseudocystic) nature of the tumor in addition to the lack of other evidence from the fine needle aspiration biopsy, led to the misdiagnosis of the tumor as a VM. Despite the positive results for CD31 in our case, histological and immunohistochemical findings were also similar in both cases.
The pathogenesis of the tumor remains unclear. There are currently two papers in the literature trying to associate an orbital case of GCA with mutations on chromosome 6q13 [
18] and another extraorbital case with an associated translocation t(12;17) [
14].
In the clinical setting during preoperative management, diagnosis of GCA may be virtually impossible. Besides the fact that GCA is an extremely rare tumor it also shares many clinical and radiological features with other soft tissue tumors of the head and neck. Furthermore the pseudovascular spaces that are present in large GCAs may associate it with tumors of vascular origin, as in our case. The multitude of soft tissue tumors of the region that need to be differentially diagnosed from GCA, can be roughly depicted in an abbreviated summary of the World Health Organization (WHO) system for classifying soft tissue tumors on the basis of tissue type and biologic potential (Table
2) [
19].
Table 2
Summary of World Health Organization (WHO) classification of soft tissue tumors of the neck
Adipocytic | Lipoma and its variants (lipoblastoma, hibernoma, lipomatosis) | Atypical lipomatous tumor, well-differentiated liposarcoma | … | Liposarcoma |
Fibroblastic/myofibroblastic | Fibromatosis colli, myofibroma, giant cell angiofibroma | Desmoid-type fibromatosis | Solitary fibrous tumor hemangio-pericytoma, inflammatory myofibroblastic tumor (inflammatory pseudotumor) | Fibrosarcoma |
So-called fibrohistiocytic | Benign fibrous histiocytoma, diffuse-type giant cell tumor (pigmented villonodular synovitis) | … | Giant cell tumor of soft tissues | Malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma) |
Skeletal muscle | Rhabdomyoma | … | … | Rhabdomyosarcoma |
Smooth muscle | Leiomyoma, angioleiomyoma | … | … | Leiomyosarcoma |
Vascular | Hemangioma, lymphangioma | Kaposiform hemangioendothelioma | Kaposi sarcoma | Angiosarcoma |
Perivascular | Glomus tumor, myopericytoma | … | … | Malignant glomus tumor |
Chondro-osseous | Soft tissue chondroma | … | … | Mesenchymal chondrosarcoma, extraskeletal osteosarcoma |
Uncertain differentiation | Myxoma | … | Ossifying fibro-myxoid tumor | Synovial sarcoma, alveolar soft part sarcoma, primitive neuroectodermal tumor, Ewing sarcoma |
Vascular malformation is a collective term for many different disorders of the vasculature. It can be a disorder of capillaries, arteries, veins and lymphatics or a combination of those. A VM consists of a clew of deformed vessels, due to an error in vascular development. However, endothelial turnover is stable in these defects. Congenital VMs are always present at birth, although they are not always visible. In contrast to vascular tumors, vascular malformations do not have a growth phase, nor an involution phase, they tend to grow proportionately with the child, never regressing and persisting throughout life [
20]. Vascular malformations can be divided in slow-flow VM, fast-flow VM and complex-combined VM. Clinically, diagnosis of superficial VM is not difficult, deep VM should be determined by clinical examination with identification of postural movement and a positive puncture test. Ultrasound and MRI can aid significantly in the diagnosis of VM, while angiography is usually reserved for treatment planning.
In our case, the patient had a slow growing tumor in the head and neck region over a period of more than two years. MRI findings were suggestive of a benign non-infiltrating tumor with heterogeneous signal intensity extending from the parotid to the parapharyngeal space which demonstrated intense enhancement after the administration of contrast material. Overall, the cystic nature of the tumor in conjunction with excess blood material in the fine needle aspirate led to the misdiagnosis of this GCA case as a vascular malformation. Sclerotherapy, as expected, had no effect on the lesion which in fact continued to slowly grow. Final diagnosis was only feasible after referral of the patient for surgical removal and subsequent histopathological and immunohistochemical testing of the tumor.
GCA is typically regarded as a non-invasive neoplasm with no potential for metastatic disease compared to solitary fibrous tumor which may rarely metastasize [
19]. There is controversy regarding the potential of the tumor for recurrence. Since there have not been enough reports of GCA to allow us to come to any definitive conclusions regarding its long-term behavior, complete surgical removal and long-term follow up was considered the optimal treatment option.
Diagnosis of GCA is usually made after resection and immunohistochemical analysis. Histological characteristics of GCA include: (1) the presence of homogenous irregularly organized proliferating cells that are round or oval shaped (2) the stromal region that is often collagenized or myxoid and (3) the tumor is richly vascularized and contains pseudovascular spaces in the presence of interstitial hemorrhage. The pseudovascular spaces are lined with multinucleated giant cells [
11].
The immunohistochemical features of GCA include positive staining for CD34, CD99, vimentin, variable bcl2 and negative staining for CD31, CD68, c-kit/CD117, muscle specific actin, S100, desmin [
7,
21].
In our case, positive staining for CD34 in combination with the presence of giant cells and pseudovascular spaces confirmed the diagnosis of GCA. A controversial finding was the unexpected positivity of CD31 in the majority of cells compared to previous reports [
7,
21]. Clinically, this immunohistochemical finding may be interpreted by the more vascular nature of the tumor and it may provide a tool for differential diagnosis of GCA from SFT in the future. Nevertheless several other soft tissue tumors may present with similar findings. For example, GCA might be closely related to GCF, multinucleate cell angiohistiocytoma (MCA), SFT and VM.
GCF is usually differentially diagnosed from GCA by the fact that it is usually a poorly circumscribed lesion invading the dermis and subcutis of somatic soft tissues. The tumor, which typically occurs within the first decades of life, is rarely described in middle-aged and older patients. It most commonly affects the trunk [
22]. Although GCF is composed of CD34 positive spindle and stellate shaped cells including multinucleated floret-like giant cells and tumor cell-lined pseudovascular spaces, it has infiltrative margins and has less conspicuous cellularity and vasculature. Clinically, GCF appears to be a more aggressive lesion than GCA in that up to 50% of cases locally recur [
3].
MCA is a rare benign proliferation of the skin of unknown etiology. Clinically, MCA shows a predilection for adult women (F:M ratio 3:1) and manifests as a single or multiple firm, red-brown or violaceous papules with a smooth, or occasionally, scaly surface [
23]. Histological examination shows a vascular proliferation predominantly of capillaries and veins in the upper and mid dermis with lymphohistiocyte infiltration. Multinucleate giant cells are arranged in a ring-like or overlapping pattern, with a positive staining for factor XIIIa [
24].
The CD34-positive cell neoplasm most closely aligned to GCA is the SFT, which was first described in the pleura but has since been reported in many locations. In approximately half of all described cases it is located in the subcutaneous tissue, but also in deep soft tissue of the extremities, or in the head and neck region, the thoracic wall, mediastinum and abdominal cavity. SFTs on CT scans show moderate to intense enhancement in a well circumscribed mass. Histologically, SFTs show a patternless spindle cell proliferation in a collagenous stroma, although myxoid areas are not uncommon, and a hemangiopericytomatous vascular pattern that is not seen in GCA. Giant cells and pseudovascular spaces are infrequent and serve to distinguish this tumor type from GCA. Both are immunoreactive for CD34 and CD99 [
16,
25,
26].
There is a lot of debate in the literature concerning the classification of GCA. Although many authors believe GCA to be a distinct tumor with distinct histological and immunohistochemical characteristics, others support the opinion that this may be a variant of either SFT or GCA. In fact, the idea that GCA may be a variant of SFT is further supported by WHO’s latest reclassification (2013) [
27], where GCA is considered a synonym for extrapleural SFT rather than being a separate entity. In this reclassification GCA, SFT, hemangiopericytoma and lipomatous hemangiopericytoma are all interconnected and are included under the same category of ‘extrapleural SFT’.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
YH and EK wrote the paper. LW carried out the histological and immunohistochemical studies of the surgical specimens. GL and ZT were involved in collecting the clinical, imaging and laboratory data of the patient. CZ edited and modified the paper. All authors read and approved the final manuscript.