GCTs most commonly occur between the ages of 40 and 60, but they have been documented across all age groups, including rare congenital cases11. Reported incidence rates highlight variability, with some studies indicating a higher prevalence in women, whereas others report that up to 68% of cases occur in men10. These tumors present significant diagnostic and therapeutic challenges because of their rarity and biological variability14.
Approximately 1,000 cases involving a wide range of organs and tissues have been reported in the literature. Commonly affected sites include the head and neck region (particularly the tongue and oral mucosa), skin, subcutaneous tissue, and soft tissues, as well as the breast, thyroid, mediastinum, respiratory tract, gastrointestinal tract, and nervous system8.
The clinical presentation of GCTs is highly variable, with fewer than 10% being asymptomatic and incidentally discovered22. Ultrasonography typically reveals a solid, round, hypoechoic lesion lacking distinctive features, frequently leading to misdiagnoses as lipomas or reactive lymph nodes19. In our case, the lesion exhibited these same ultrasonographic features, closely mimicking a range of other pathological conditions—both neoplastic and inflammatory—thereby further complicating the diagnostic process.
Microscopically, GCTs are composed of large, ovoid or polygonal cells with abundant eosinophilic cytoplasmic granules20. Benign lesions exhibit low mitotic activity and lack cellular atypia. However, features such as a Ki-67 proliferation index above 10%, the presence of mitotic figures, or necrosis may suggest aggressive behavior, although these findings alone are insufficient to confirm malignancy; metastasis remains the definitive criterion for malignancy7.
The histogenesis of GCT has been debated for many years. While Abrikossoff initially proposed a muscular origin, immunohistochemical studies have conclusively supported a neural origin, specifically from Schwann cells17. This hypothesis is reinforced by tumor positivity for the S-100 protein and neuron-specific enolase (NSE), as well as electron microscopy findings of lamellar structures resembling myelin. Its neural origin is supported by tumor positivity for S-100 protein and neuron-specific enolase (NSE), as well as electron microscopy findings showing lamellar structures resembling myelin16.
While most GCTs exhibit benign behavior, even in the presence of atypical morphology, atypical lesions rarely metastasize and are generally confined locally, resembling incompletely excised benign lesions9. Consequently, atypical GCTs are considered part of a spectrum with classical GCTs. Lesions with unfavorable parameters are described as being "at increased risk for metastasis" rather than outright malignant. Malignant GCTs are exceedingly rare, accounting for less than 2% of cases. These tumors are characterized by rapid growth, large size, and high mitotic indices20. Metastases, although uncommon, have been documented in regional lymph nodes, lungs, liver, and bones24. Unlike benign GCTs, which predominantly affect premenopausal women, malignant GCTs lack estrogen receptor expression, excluding hormonal involvement in their pathogenesis21.
Variants of GCTs that do not express the S-100 protein are classified as "nonneural GCTs”12. Typically, of cutaneous origin, these variants often present as polypoid masses. Despite the absence of S-100 expression, they demonstrate reactivity for markers such as CD68, NKIC3, CD10, and α1-antitrypsin13. This classification remains controversial, as some nonneural GCTs exhibit NSE and PGP9.5 positivity, suggesting neural differentiation. These are sometimes referred to as "primitive GCTs."
Macroscopically, GCTs vary in consistency, ranging from soft to firm, and in color, from gray‒white to pale yellow. Larger tumors are often associated with poorer clinical outcomes2. Histologically, GCTs are characterized by large, polygonal, round, or elongated cells arranged in sheets or cords. The cytoplasm contains abundant eosinophilic granules that are PAS positive and diastase resistant12. Subepidermal or submucosal GCTs, particularly in locations such as the esophagus, vagina, or bladder, may induce pseudoepitheliomatous hyperplasia, mimicking well-differentiated squamous carcinoma18. However, invasive features such as vascular or perineural infiltration, commonly observed in benign cutaneous GCTs, should not be considered indicators of poor prognosis23.
A distinctive histological feature of GCTs is the presence of “Milian pustulo-ovoid bodies,” which are eosinophilic granules surrounded by a clear halo5. These structures aid in differentiating true GCTs from other neoplasms with similar characteristics, such as melanocytic or fibrohistiocytic tumors.
MRI is the preferred imaging modality for evaluating and characterizing GCTs because of its superior soft-tissue resolution22. Benign GCTs typically appear iso- or slightly hyperintense relative to muscle on T1-weighted MR images. On T2-weighted sequences, the lesions may exhibit central isointensity and peripheral signal enhancement. In contrast, malignant GCTs demonstrate invasive features, such as vascular or perineural invasion, and may present with central necrosis or diffuse signal alterations13.
In this clinical case, differential diagnosis proved crucial in guiding the diagnostic process, particularly in light of the heterogeneous radiological findings. The comparison between different imaging modalities, including ultrasound and MRI, yielded inconclusive results, with no definitive features able to reliably support a specific diagnosis. In particular, the historadiological mimicry of the lesion with various other pathological conditions—both neoplastic and nonneoplastic—made the radiological interpretation of the differential diagnosis ambiguous, thus making direct assessment indispensable. The primary treatment for GCTs is complete surgical excision with clear margins (R0). Open excisional biopsy is the preferred method, as it minimizes the risk of recurrence—even years later—and provides a definitive histological diagnosis.