Alveolar soft part sarcoma in buccal mucosa of a young child

Summary

Alveolar soft part sarcoma (ASPS) is a rare malignant tumour that is considered to lack a normal cell counterpart and is commonly associated with a poorer prognosis. Etio-pathologically, it has been associated with alveolar soft part sarcoma critical region-1-transcription factor for immunoglobulin heavy chain enhancer 3 fusion gene. Diagnosis is usually confirmed through histopathology, immunohistochemistry (IHC) and molecular testing. Being chemo-resistant, surgical excision with clear margins is the primary treatment, with radiation therapy considered adjuvant in advanced cases. Deceptively slow growth and potential metastatic potential make its diagnosis, treatment and prognosis challenging for clinicians. We report a case of ASPS in the left buccal mucosa of a young child who was mistaken for a dental infection by a local dentist. Later on, confirmation with histopathology and IHC, the patient underwent complete excision with hemi-mandibulectomy followed by adjuvant radiation therapy. This case emphasises the diagnostic and therapeutic approach for ASPS in the buccal mucosa of a young child.

Background

Alveolar soft part sarcoma (ASPS) is a rare malignant neoplasm of uncertain histogenesis which was first described and coined by Christopher in 1952 by presenting 12 cases.¹ This tumour accounts for less than 1% of all adult soft tissue sarcomas and mainly affects females with a median age of 20 years. In the paediatric population, it is even rarer, comprising approximately only 1–2% of all childhood soft tissue sarcomas.² ASPS has a common predilection for extremities, but develops in the head and neck region that accounts for only 25% of all ASPS.³ However, in children, the head and neck region is a more commonly affected area, particularly the orbit and tongue.⁴ Intraoral involvement, especially the buccal mucosa, is exceedingly rare, posing significant diagnostic challenges. The usual presentation of this tumour is as a painless, soft, slow-growing lesion without functional interference. The pathogenesis of ASPS involves a specific chromosomal translocation t(X;17)(p11;q25) and resultant fusion protein involves the alveolar soft part sarcoma critical region-1 (ASPSCR1) gene located on chromosome 17q25 and the transcription factor for immunoglobulin heavy chain enhancer 3 (TFE3) gene located on chromosome Xp11.22.⁵ This TFE3 fusion protein is a key diagnostic marker and can be detected through immunohistochemistry (IHC) or molecular techniques such as FISH or RT-PCR. TFE3 IHC demonstrates strong nuclear positivity, helpful in diagnosis. Histologically, ASPS exhibits a pseudoalveolar or organoid growth pattern, with uniform nests of large polygonal cells showing abundant eosinophilic granular cytoplasm, vesicular nuclei and prominent nucleoli. The nests may be separated by delicate capillary-sized vascular channels. The pseudoalveolar appearance is attributed to prominent cellular dyscohesion.⁶ Surgical excision with clear margins remains the primary treatment, as ASPS is typically resistant to conventional chemotherapy and radiotherapy. Recently, targeted therapies such as tyrosine kinase inhibitors (eg, sunitinib, pazopanib) and immune checkpoint inhibitors have shown promise, though optimal treatment strategies are still under investigation. Despite its indolent clinical growth, ASPS is known for its high metastatic potential (approximately 20–30%), particularly to the lungs, brain and bone, often occurring years after the initial diagnosis. The prognosis is generally poor, with a 5-year survival rate of 60–80% and a 20-year survival rate dropping below 20% in metastatic cases.⁷ In the paediatric population, ASPS can be mistaken for benign lesions or dental infections due to its indolent nature and non-specific clinical presentation. Therefore, clinicians must maintain a high degree of suspicion and use appropriate diagnostic tools to ensure accurate and timely diagnosis.

Case presentation

A male patient in his first decade presented to the Dental College and Hospital with a painful, lobulated swelling involving the left buccal mucosa. The patient had initially sought care at a local dental surgery (day −7), when the lesion was approximately 3 cm in diameter. An initial aspiration performed on the day of presentation at that facility was inconclusive. However, following this intervention, the patient reported a rapid increase in both the dimensions of the mass and the intensity of the associated pain, prompting referral to our institution (day 0).

On clinical examination at his first visit, a reddish, lobulated swelling was noted in the left buccal mucosa, extending posteriorly to the retromolar area. Due to the clinical appearance and the patient’s age, an incisional biopsy was performed under general anaesthesia (day +5). By the time of the post-biopsy follow-up (day +12), the lesion had demonstrated aggressive clinical progression, measuring 4.5×4.7×3.0 cm, resulting in significant facial asymmetry and functional discomfort (figure 1A,B).

Figure 1. Intraoral clinical features of the patient. (A) Before biopsy. (B) After biopsy.

Histopathological examination of the biopsy specimen revealed a tumour composed of sheets and nests of polygonal cells with abundant eosinophilic granular cytoplasm and vesicular nuclei. The cells were arranged in clusters and sheets with areas of focal discohesion, strongly suggestive of ASPS.

To establish a definitive diagnosis, immunohistochemical (IHC) analysis was done. The tumour was found to be positive for TFE3 and negative for periodic acid-Schiff (PAS) stain. Following the confirmed diagnosis, the patient was referred to a tertiary care centre, where a multidisciplinary treatment plan was formulated, including hemi-mandibulectomy and radiotherapy.

Investigations

Radiological investigation

CT oral cavity (plain and contrast): contrast-enhanced CT revealed a well-defined, oval, heterogeneously enhancing soft tissue lesion in the left buccal space, measuring approximately 29 × 29 × 24 mm. Central non-enhancing areas suggested necrosis or cystic degeneration. The lesion caused scalloping of the adjacent mandibular alveolar process without cortical erosion. It extended medially into the oral cavity and laterally into the subcutaneous fat, while remaining confined posteriorly by the mandible. No cervical lymphadenopathy was observed (figure 2).

Figure 2. (A) Sagittal CT scan shows a lateral section of the head and upper cervical spine. It includes the nasal cavity, oral cavity, oropharynx and upper airway space. The airway appears partially narrowed at the oropharyngeal level, and the vertebrae of the cervical spine are clearly delineated. (B) This axial CT scan provides a horizontal cross-sectional image through the lower face and upper neck. It shows the dental arch of the mandible, which is disrupted by a tumour (with high-density (white) dental structure).

An NCCT thorax was performed at the tertiary care centre, which ruled out any evidence of pulmonary distant deposit, as lungs remain a primary organ for metastasis of ASPS.

Histopathological examination and immunohistochemistry

Histopathological examination showed hyperplastic squamous mucosa with a subepithelial tumour composed of polygonal cells arranged in sheets and nests. These cells had abundant eosinophilic granular cytoplasm and vesicular nuclei, with focal areas of discohesion, which were suggestive of alveolar soft part sarcoma (figures3 4). IHC analysis was performed for further characterisation. The tumour cells showed nuclear positivity for TFE3, a transcription factor commonly associated with ASPS. The tumour cells were negative for a panel of other markers, including S100, desmin, AE1/AE3, PAX8, MDM2, SOX10, Calretinin and Melan A, helping to exclude melanocytic, epithelial, myogenic and neural crest origin. Periodic acid-Schiff stain with diastase (PAS-D) was also negative (figure 5).

Figure 3. Microscopic imaging of H&E (A and B) demonstrates a multinodular growth pattern of the tumour (4× view).

Figure 4. (A) H&E,10×: tumour cells within nodules are arranged in nests and sheets of polygonal cells (arrow). (B) H&E, 40×: tumour cells of uniform size and shape (round and polygonal) with abundant eosinophilic granular cytoplasm with vesicular nuclei (arrow) are shown in the image. The cells are arranged in clusters and sheets with focal dyscohesion.

Figure 5. Immunohistochemical analysis of the lesion: 10× (A) AE1, (B) calcitonin, (C) Melan A, (D) S100 showing negative immunoreactivity. (E) TFE3 showing positive immunoreactivity. (F) at 40× showing positive results for TFE3 by diffuse strong nuclear staining. TFE3, transcription factor for immunoglobulin heavy chain enhancer 3.

Based on the histological and immunohistochemical findings, the tumour was diagnosed as ASPS.

Differential diagnosis

Histologic overlapping with other aggressive tumours like metastatic renal cell carcinoma, paraganglioma, alveolar rhabdomyosarcoma and malignant melanoma poses a diagnostic challenge. A careful evaluation of clinical imaging features, histopathology and immunohistochemical analysis are crucial for accurate diagnosis.⁸ Among all, renal cell carcinoma shares the closest similarity with ASPS with clear cell change. However, unlike ASPS, renal cell carcinomas immunostaining with AE1/AE3, epithelial membrane antigen and PAX8 are usually reactive; a negative expression of these markers was noted in the present case. Paragangliomas also show ASPS-like alveolar growth pattern and occur in older individuals, but tumour cells of paraganglioma show neuroendocrine differentiation, immunoreactive with anti-S-100 protein, in contrast to ASPS. Similar findings are noted in the present case. Alveolar rhabdomyosarcoma, despite its similar name, is classified as a distinct ‘small

blue round cell tumour’ that shows strong expression of desmin and calretinin, negative in the present case. Metastatic melanoma, which also shares similar tumour cell morphology, that is, round cells with abundant morphology, consistently demonstrates the presence of melanocytic markers, like HMB45 and Melan A, in addition to S100 protein.^{6 9} On the contrary, negative immunoreactivity for the abovementioned markers was observed in ASPS, as in the present case.

Treatment

The patient underwent left segmental mandibulectomy with neck dissection and reconstruction using a left fibula free osteocutaneous flap. A 6×5cm cutaneous paddle with a 5cm fibula was harvested. Microvascular anastomosis was performed. Final histopathology confirmed the diagnosis of ASPS. All bony and soft tissue margins were free of tumour involvement. All 46 lymph nodes harvested were found to be tumour-free. Following surgical recovery, the patient was referred for post-operative oncology care. In view of the aggressive nature of the tumour, adjuvant radiotherapy was administered, which comprised a total dose of 59.4 Gy delivered in 33 fractions over 7 weeks using a conformal technique, following complete wound healing. No systemic therapy was considered or administered to the patient.

Outcome and follow-up

A 6-month follow-up was carried out. The patient had undergone surgical resection and radiotherapy successfully (figure 6). The patient is currently under follow-up with no evidence of recurrences (12-month post-treatment). Thus, the patient has been strictly instructed to be under follow-up for the next 5 years.

Figure 6. (A) Six-month follow-up and (B) 12-month follow-up after surgery and radiotherapy.

Discussion

ASPS is a rare, slow-growing malignant tumour with a predilection for deep soft tissues of the extremities, particularly the thigh region in adults. In children, its occurrence in the buccal mucosa is exceedingly rare, as depicted in table 1. An uncommon presentation, along with the deceptive slow growth of ASPS, poses significant diagnostic challenges. Clinical presentation of ASPS as a polypoidal growth with prominent vascularity, mainly in childhood, is often misinterpreted as a polyp, hamartoma, arteriovenous malformation or benign neoplasms such as haemangioma, lymphangioma or rhabdomyoma.¹⁰ In the present case, the lesion was misdiagnosed as a dental infection and hence subjected to unwanted aspiration, which led to an increase in the size and patient’s discomfort. Further on biopsy, an apparent exacerbation of the lesion’s clinical severity was also observed. This could be attributed to marked propensity for intratumoral haemorrhage and inflammatory changes, caused by invasive procedures (aspiration and biopsy) as this tumour is characterised by rich vascular network.²

Table 1. Clinicopathological details of ASPS affecting the buccal mucosa region of children.

Author/year	Age/sex	Location	Clinical presentation	Max dimension (cm)	Tumour duration (months)	PAS	IHC (positive)	IHC (negative)	Treatment
Argyris et al (2012)4	13 /M	Buccal mucosa	A rapidly enlarging mass of the left posterior buccal mucosa, at the occlusal line, with popping and bleeding of the lesion.	3.2	2	Positive	TFE3	Cytokeratin AE1/AE3, vimentin, smooth muscle actin, smooth muscle myosin heavy chain, S-100, HMB45, Melan A, and synaptophysin and chromogranin	Surgery
Wang et al (2015)15	5 /M	Cheek	Lobulated appearance with yellowish-white mucosa Lobulated multiple nodules	5.5	–	Positive	Not performed	Not performed	Surgery
Asano et al (2019)16	11 /F	Cheek	Pain in the right jaw after becoming aware of a mass in her right cheek	–	–	Negative	TFE3	AE1/AE3, CAM 5.2, vimentin, S-100, α-actin, desmin and HMB 45	–
Present case	4 /M	Buccal mucosa	Earlier, a small lobulated growth in the left buccal mucosa, but after aspiration aggressive growth of the same lesion	3.0	2	Negative	TFE3	S100, desmin, AE1/AE3, PAX8, MDM2, SOX10, calretinin and Melan A	Surgery, radiotherapy

IHC, immunohistochemistry; PAS, periodic acid-Schiff; TFE3, transcription factor for immunoglobulin heavy chain enhancer 3.

From an etio-pathological perspective, the ASPSCR1:TFE3 fusion gene is considered a principal driver of tumourigenesis in ASPS, resulting from the chromosomal translocation t(X;17) (p11.2; q25). This fusion gene functions aberrantly as a member of the MiT/TFE3 transcription factor family, thereby influencing various cellular processes, including cell proliferation, lysosomal activity, autophagy and angiogenesis (figure 7). Recent studies have indicated that, in addition to ASPSCR1, other TFE3 fusion partners such as HNRNPH3, DVL2 and PRCC also contribute to the progression of ASPS. These discoveries not only underscore the genetic heterogeneity of ASPS but also aid in identifying cases of ASPS that lack the ASPSCR1-TFE3 fusion.¹¹ Histopathologically, the arrangement of large polygonal cells with abundant eosinophilic granular cytoplasm, nests or alveolar patterns and their separation by delicate fibrovascular septa is the hallmark of ASPS. In addition, the presence of PAS-positive and diastase-resistant, rhomboid or rod-shaped crystalline inclusions in the tumour cell cytoplasm is considered to be of diagnostic importance as it detects glycogen, mucins and certain glycoproteins. However, the present case was PAS negative. The reasons for the PAS negativity in our case could be due to the absence of fully mature crystals or the presence of their precursor granules. Other factors, like improper tissue fixation or abnormalities in the formation of PAS-positive crystals due to TFE3 gene translocation, could have contributed to this difference in PAS staining.¹²

Figure 7. Schematic representation of cellular pathway of the gene ASPSCR1:TFE3. ASPSCR1, alveolar soft part sarcoma critical region-1; TFE3, transcription factor for immunoglobulin heavy chain enhancer 3.

Immunohistochemical analysis shows consistent nuclear TFE3 immunoreactivity (sensitivity of 95%) with variable expression of myogenic, neuroendocrine and epithelial markers. However, the specificity of TFE3 is challenged as its positive expression is detected in other tumours, such as granular cell tumour, a few neuroendocrine cell tumours and translocation pheochromocytoma. This necessitates correlation of both histological features and relevant immunohistochemical features for confirmatory diagnosis.^{2 13}

Complete resection is the mainstay treatment of ASPS. The role of adjuvant radiotherapy or chemotherapy in preventing recurrence needs further exploration.^{13 14} As the tumour is believed to be insensitive to chemotherapy, surgical excision of metastatic deposits is also advised to be surgically removed.

Although the 5-year disease-specific survival (DSSue) of ASPS was documented as 68% for all patients with or without metastases, metastasis at presentation was considered an adverse prognostic factor for DSS. Older age, deep-seated tumours and large tumours (size > 5 cm) are considered to be unfavourable indicators of metastases at presentation.^{7 15} Even in children, ASPS is often metastatic at diagnosis as reported in 42% of paediatric cases.^{14 16} Because of its rich vascular nature, ASPS is known for early haematogenous spread, particularly to the lungs, brain and bone. In the present case, no metastasis is evident to date. The review literature and past literature indicated about the shorter follow-up period in the majority of cases (table 1). However, our limitation in this case is that the sarcoma with propensity for late metastasis has a short follow-up to date. Thus, the patient has been strictly instructed to be under follow-up for the next 5 years.

Patient’s perspective.

We noticed a swelling on the left cheek region of my son a few months back, with a sudden complaint of discomfort. We got worried and terrified as the colour of the lesion was red, and rushed to the local dentist without any delay. The dentist told us that the lesion seems to be related to dental infection and suggested for aspiration as he thought it as an abscess. Following his intervention, the swelling further increased in size, which worried us more, and we came to this hospital at the suggestion of one of my relatives. The doctors of this hospital did a series of investigations and performed a small operation to determine the exact identity of the lesion. We just followed the instructions of the doctors and did whatever they asked us to do. The report revealed our son has a rare cancer that needs to be operated on as soon as possible. The world collapsed for us suddenly, but we gathered our courage for the sake of our son. The doctors of the institution quickly connected to another big hospital that deals with these types of diseases. Now, my son has undergone surgery followed by radiation. He is doing well now. One thing I can say here is that if at all, the local dentist could have diagnosed the disease, treatment could have started early, and things could have been different.

Learning points.

• Alveolar soft part sarcoma (ASPS) is extremely rare in the buccal mucosa of young children. Its indolent slow growth and its clinical presentation in the oral cavity may pose a diagnostic challenge to clinicians, which can lead to its delayed treatment and poor prognosis (prone to metastasis).

• Diagnostic accuracy relies on the correlation of histopathological and immunohistochemical features of ASPS.

• Multidisciplinary case review with specialists is recommended for treatment planning and optimal management of ASPS.