Paediatric desmoid tumour of the head and neck: a complete response to chemotherapy and the paradigm shift towards non-surgical management

Abstract

Desmoid tumours are rare locally aggressive mesenchymal tumours with a high local recurrence rate, particularly in the head and neck locations. We present the case of a 5-year-old child with a locally invasive inoperable desmoid tumour of the masticator space who underwent a low-dose chemotherapy regimen for 17 months, obtaining a long-term complete response. Definitive evidenced-based treatment guidelines are lacking. Therefore, paediatric patients should be managed by specialised multidisciplinary teams to try to achieve the best tumour control while minimising treatment associated morbidity and mortality. Available treatment options include surgery, radiotherapy and different systemic medical therapies. Whereas traditionally, surgery was the mainstay of treatment, more conservative options have increasingly shown adequate tumour control with little associated morbidity. In this decision making it is mandatory to take into account the patient’s age, tumour location and extension, and potential short-term and long-term treatment-related sequelae to minimise functional and cosmetic compromise.

Background

To properly diagnose rare disease entities and provide the best medical care to paediatric patients, multidisciplinary cooperation is crucial. We report the case of a 5-year-old child with an infiltrative masticator space desmoid tumour (DT) managed non-surgically, with a favourable long-term outcome.

DT is a distinctly rare entity with an estimated incidence of 5–6 cases/10⁶/year, listed in the WHO classification of soft tissue tumours under the category ‘fibroblastic/myofibroblastic’ tumours. It is characterised by a monoclonal fibroblastic proliferation arising from the deep musculoaponeurotic soft tissues^{1 2} of intermediate/‘borderline’ malignant potential, locally invasive, with high local recurrence rates but incapable to metastasise.³ Whereas most are sporadic and the cause is unknown, some are associated with previous trauma and others with Gardner’s syndrome.³

The peak incidence age is 30–40 years and although rare in children, this tumour appears to be more aggressive in this age group. According to their location, DTs are classified into abdominal and extra-abdominal. Head and neck (H&N) locations are more frequent in paediatric patients comprising 22%–35% of all extra-abdominal locations compared to 12%–15% in adults, with some series showing over 50% of head and neck desmoid tumours (H&NDTs) occurring before the age of 11 years.^{4 5} Surgery, radiotherapy (RT) and chemotherapy (CTX) are the most commonly used and investigated modalities in the treatment of these rare tumours. Surgery was the standard primary treatment, however, recently, there has been a shift towards more conservative approaches, particularly in anatomically challenging H&N locations where a certain degree of functional and cosmetic disability is to be expected,² such as in this case report. This case enlightens a favourable long-term outcome using a non-invasive CTX approach under the close monitoring of a multidisciplinary team.

Case presentation

The patient is a 5-year-old girl, referred to the maxillofacial surgery department due to progressive facial asymmetry and worsening trismus. There were no inflammatory signs and the patient had no constitutional symptoms. Clinical examination was relevant for an asymmetrical bulge of the right cheek effacing the ipsilateral nasolabial fold and widening of the palpebral cleft, limitation of mouth opening with a maximal interincisor distance of 13 mm and limitation on lateral mandibular movements (<8 mm). There was no strabismus or proptosis and ocular movements, facial mimic and sensitivity were preserved. The remainder neurological examination was unremarkable. Neck palpation showed bilateral cervical lymph nodes normal in size and consistency for age. Past medical history was relevant for progressive astigmatism from 8 months of age which required an increasing degree of correction. There was no personal history of previous trauma nor personal or family history of colorectal pathology.

Investigations

To assess the nature and extent of the lesion, maxillofacial CT (figure 1) and MRI (figure 2) were performed showing a 50×40×36 mm, expansile, soft tissue mass in the right masticator space extending from the central skull base to the mandibular angle. There was involvement of adjacent structures (parapharyngeal and retromaxillary fat, pterygopalatine fossa and inferior orbital fissure), smooth remodelling of adjacent bones (posterolateral wall of the maxillary sinus, mandibular ramus, base of the pterygoid plate, medial aspect of the greater sphenoid wing and lateral orbital wall) and enlargement of the foramen ovale and mandibular foramen (without signs of perineural extent to Meckel’s cave or along the inferior alveolar nerve). No epidural component was seen in the intracranial compartment. The lesion was isodense to muscle on plain CT images and, on MRI, isointense on T1W and slightly hyperintense on T2W images with no restricted diffusion. Vivid and homogeneous contrast enhancement was seen with a few non-enhancing linear strands. The tumour was lobulated with well-defined borders with neighbouring structures.

Figure 1.

CT of the neck axial images on soft tissue (A) and bone windows (B) and coronal images on soft tissue (C) and bone windows (D) show a 50×40×36 mm expansile soft tissue mass in the right masticator space extending craniocaudally from the central skull base to the mandibular angle. The lesion effaces the parapharyngeal fat and displaces posterior and laterally the deep lobe of the parotid gland. Also note the effacement of the retromaxillary fat with tumour abutting the pterygopalatine fossa and extending into the inferior orbital fissure (solid arrow). There is smooth bone remodelling of the greater sphenoid wing, posterolateral wall of the maxillary sinus, mandibular ramus and pterygoid plate and smooth enlargement of the right foramen ovale compared with the contralateral side (dashed arrows). The lesion is mostly isodense to the muscles of mastication with a more hypodense inferior component (asterixis).

Figure 2.

MRI of the neck (A) coronal T2W and pregadolinium (B) and postgadolinium fat-suppressed (C) T1W images: On MRI the lesion is isointense on T1W, slightly hyperintense on T2W and shows vivid and homogeneous contrast enhancement with a few intermingled strands of non-enhancing tissue (solid arrows). The mass has a lobulated contour but shows well-defined borders with neighbouring structures. In spite of the enlarged foramen ovale there is no evidence of perineural spread along V3 and Meckel’s cave is free of tumour (dashed arrows).

These imaging features suggested a locally invasive, slowly growing tumour, probably of mesenchymal origin.

Routine laboratory findings were unremarkable.

For definitive diagnosis a surgical biopsy was performed revealing a uniform proliferation of spindle-shaped cells, separated by bands of dense collagenous stroma with slit-like, thin-walled vessels, without aggressive cytological features or necrosis, presenting a low mitotic rate. Immunohistochemistry showed multifocal positivity for β-catenin and negative staining for desmin, myogenin and oestrogen receptors (figure 3). These histopathological findings were consistent with DT. Tumour cells also expressed P53, a feature associated with a more aggressive behaviour and higher recurrence rates.

Figure 3.

Pathology slides stained with H&E (A) low and (B) medium power show a uniform proliferation of spindle-shaped myofibroblasts arranged in a loose fascicular pattern immersed in a collagenous stroma (A) with areas of keloidal hyalinisation (B). Tumour cells have bland and regular nuclei with a fibrillary eosinophilic cytoplasm. β-catenin staining (C) shows strong nuclear staining. Immunohistochemistry for desmin, myogenin and oestrogen receptors was negative (not shown).

After the surgical biopsy the patient symptoms improved and a follow-up MRI (figure 4) showed an 80% decrease in tumour size with a 42×26×13 mm residual mass in the infratemporal fossa and central skull base.

Figure 4.

MRI of the neck: coronal T2W (A) and contrast-enhanced T1W images (B) before and after (C and D) surgical biopsy showing a decrease in tumour size estimated at 80% according to RECIST criteria.

Differential diagnosis

The differential diagnosis of masticator space masses is challenging as clinical inspection of this deep-seated space is limited and the imaging features of different entities may overlap. In paediatric patients, even when lesions have a ‘benign-looking’ appearance, rhabdomyosarcoma should always be included in the differential diagnosis as this is the second most common paediatric H&N tumour.⁶ This malignant tumour can occasionally appear misleadingly benign with well-defined borders and leading to smooth remodelling of adjacent structures. MRI signal intensity and enhancement pattern are variable depending on tumour composition (eg, cellularity, matrix, necrosis, haemorrhage), lacking diagnostic specificity.⁶ Perineural spread and cervical lymphadenopathy are helpful clues in the differential diagnosis with benign tumours.

Haematolymphoid malignancies (lymphoma and chloroma) are the most common paediatric H&N tumours.⁶ These small round cell hypercellular tumours are featured by intermediate signal intensity on both T1W and T2W MR images and restrict diffusion with very low ADC values being its hallmark.

Osteosarcoma and peripheral neuroectodermal tumour (PNET)/Ewing’s sarcoma are less common in the H&N region. Osteosarcomas tend to occur in older children (second decade) and are often associated with previous irradiation or syndromic conditions. Specific imaging features include osteoid or chondroid matrix and aggressive periosteal reaction.⁷ Primitive PNET/Ewing’s sarcoma can affect bone and soft tissues but is exceedingly rare in the H&N with only a few cases described in the literature. Imaging features are similar to that of other small cell hypercellular malignancies.⁶ Metastatic disease, particularly from neuroblastoma, should also be considered and can rarely be the first presentation of a primary malignancy located elsewhere.

A malignant peripheral nerve sheath tumour originating from the trigeminal nerve was another possible diagnosis. However, only 10%–20% of these tumours occur in the first two decades of life and imaging features tend to be more aggressive (ill-defined infiltrative margins and heterogeneous signal intensity).

Only a few benign masticator space tumours have specific clinical/imaging features allowing the diagnosis with a high likelihood. This is the case of adipose tumours due to their intrinsic fat density/intensity; lymphangiomas, presenting as multiloculated cystic lesions; and slow-flow vascular malformations due to their typical pattern of centripetal, cotton-like, contrast enhancement and the presence of phleboliths.

Infantile haemangioma is a common paediatric vascular H&N neoplasm. It affects infants and is characterised by a proliferative phase followed by spontaneous involution.⁸ They present as lobulated lesions with intermediate signal intensity on T1W (between that of muscle and fat), high signal intensity on T2W, homogeneous contrast enhancement and, occasionally, internal flow voids.⁷

Nerve sheath tumours can also present as painless, expansile, slow-growing soft tissue masses causing smooth remodelling of neighbouring osseous structures. In the masticator space they most often originate from the trigeminal nerve and are more commonly encountered in the setting of neurofibromatosis. Imaging features are non-specific showing isointensity or hypointensity to muscle on T1W images and heterogeneous hyperintensity on T2W images. Target and fascicular signs, when present, may suggest the diagnosis.^{9 10}

Rhabdomyoma is a benign muscle tumour affecting the myocardium in children, frequently associated with tuberous sclerosis. They are rare in the H&N region, arising in skeletal muscles derived from the third and fourth branchial arches.¹¹ As DTs, rhabdomyomas present as hard, usually painless, lobulated and well-defined solitary masses which follow the density/signal intensity of skeletal muscle in all pulse sequences.⁷

Although rare, 50% of granular cell tumours (GCTs) occur in the H&N and may affect children. They usually present as painless, slowly growing masses but, like DT, they can have a more aggressive behaviour and recur locally after excision.¹² Malignant transformation is a concern and, as opposed to DT, GCTs can metastasise.

There is a wide range of paediatric fibroblastic-myofibroblastic tumours categorised into benign, low-grade tumours (myofibroma, fibrous hamartoma of infancy and fibromatosis colli), intermediate-grade, locally aggressive (DT and lipofibromatosis), intermediate-grade rarely metastasising (inflammatory myofibroblastic, infantile fibrosarcoma and low-grade myofibroblastic sarcoma) and malignant (fibromyxoid sarcoma).⁷ These tumours share similar imaging features that may vary according to tumour composition. Among this group, DTs account for 60% of all the fibrous tumours seen in children.¹³

On pathology, the main differential diagnoses include reactive fibrosis, hypertrophic scars, nodular fasciitis and fibrosarcoma and this distinction requires a representative tissue biopsy.⁷

As clinical and imaging features of H&NDT overlap with those of other benign and malignant tumours with different prognosis, histopathology is mandatory to achieve a final diagnosis and to offer patients appropriate management. The rare incidence, structural complexity and infiltrating growth makes H&NDTs difficult to diagnose on clinical grounds.

Treatment

After the wide surgical biopsy provided the diagnosis, the multidisciplinary board of soft tissue tumours (composed of a paediatrician, H&N and plastic surgeon, radiologist, radiation oncologist, medical oncologist and pathologist) thoroughly discussed possible treatment options in conjunction with the child’s parents. As β-catenin mutation was present a search for familial adenomatous polyposis was waived (β-catenin and adenomatous polyposis coli (APC) mutations are mutually exclusive).^{2 14 15}

There are different options to manage solitary DT and the choice depends on the patient’s age, potential cosmetic concerns, functional disability, tumour size, location, growth rate and biology (eg, mitotic rate and molecular markers of prognosis and/or treatment response). Unfortunately, evidence-based guidelines are lacking, as DTs are quite rare and the few existing clinical trials include a limited number of patients.

Available treatments comprise active surveillance (watch-and-wait), surgical excision, RT and medical therapy. These may be used as primary or adjuvant therapies.

In our case, active surveillance was not deemed appropriate due to the large size of the residual tumour, proximity to crucial neurovascular structures (particularly V2 and V3) with impending aggravation of functional prognosis and the presence of P53 mutation, a molecular marker of more aggressive behaviour with higher recurrence rates.

Further surgery, aiming for free surgical margins, was considered but would require an extensive craniofacial resection, likely with poor functional and cosmetic outcomes and the need for several reconstructive steps. The child’s parents were not comfortable with this treatment option.

RT was waived due to its lower efficacy in children and the risk of long-term sequelae including impairment of craniofacial growth and radiation-induced second neoplasms.

Medical therapy is generally considered the first-line option for inoperable H&NDT and includes CTX, hormonal treatment with antioestrogens, cyclooxygenase-2 (COX-2) and tyrosine kinase inhibitors (TKIs), and interferon-α. As the tumour was negative for oestrogen receptors hormonal therapy was not an option. Systemic and/or local treatments with COX-2 inhibitors is based on the fact that DTs are known to overexpress cyclo-oxygenase 2 and β-catenin. Evidence of efficacy comes from anecdotal case reports and retrospective studies including limited numbers of patients.^16–19 Experience in paediatric patients is even more scarce and refers to a second-line or third-line option after conventional treatments have failed or to combined treatments, particularly with TKIs.²⁰ Therefore, due to the lack of evidence-based efficacy and previous experience with such therapy in paediatric H&NDTs this treatment was not considered a first-line option for our patient.

The experience with TKIs (imatinib, nilotinib, sorafenib and pazopanib) also comes from limited phase II multicentre, non-randomised clinical trials including limited numbers of paediatric patients.^{2 21} In these trials overall response rates were limited, ranging from 6% to 11% with imatinib and 25% to 33% with sorafenib and pazopanib, but disease stabilisation could be achieved in 80% of patients showing a clear clinical benefit of TKIs in DTs. Side effects of TKIs are not negligible and due to the limited experience on paediatric H&NDTs this treatment was not considered a primary option.

While DTs express interferon-α and interferon-β receptors in the majority of fibroblasts, the mechanism of action of interferon-α in the treatment of these tumours remains not fully understood. Prolonged disease stabilisation has been reported in a limited number of cases after failure of other treatments but evidence-based efficacy of these drugs is lacking.^{22 23}

Although associated to various side effects, different CTX regimens have been used achieving variable rates of local tumour control. These include hydroxyurea, vincristine, actinomycin-D and cyclophosphamide and, most recently, the association of methotrexate (MTX) and an alkylating agent such as vinblastine or vinorelbine. Reported response rates are within 35%–40%, long-term disease control is achieved in up to 50%–70% of patients, there is tumour reduction even after treatment withdrawal and the treatment can be repeated with substantial benefit on recurrence (especially in previous responders).²

In 2005, the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) for non-rhabdomyosarcoma soft tissue sarcomas proposed a low-dose CTX protocol consisting of weekly intravenous administration of MTX and vinblastine/vinorelbine during 26 weeks and every 2 weeks for another 26 weeks. This regimen is usually well tolerated and has shown a 48% rate of tumour response and a 60% rate of prolonged stable disease in children.^{24 25} In agreement with the child’s parents and with the large institutional experience with the use of these CTX agents this CTX regimen was started according to protocol. Treatment was well tolerated with no complications or significant side effects and the patient resumed normal schooling and daily activities. Significant clinical improvement was noted after 7 weeks with complete resolution of trismus and reduction of the facial asymmetry. Quarterly follow-up MRIs showed partial response with a 30% decrease in tumour size at 3 months and complete response at 9 months after CTX initiation, according to RECIST criteria (figure 5). CTX was continued for another 6 months with no change in clinical/radiological features. At this point it was felt that the maximum therapeutic effect had been reached and that there was no additional benefit of pursuing further treatment. An international DT board consultation was undertaken supporting this decision together with the parents’ agreement. Therefore, after 12 months of weekly CTX and 5 months of CTX every 2 weeks it was decided to suspend further treatment, maintaining active clinical-radiological surveillance.

Figure 5.

MRI of the neck: contrast-enhanced coronal T1W images before chemotherapy (CTX) (A) and after 9 months of CTX (B) showing complete macroscopic tumour resolution.

Outcome and follow-up

The patient maintained quarterly clinical and MRI follow-up and, 3 years after the completion of the CTX regimen, remains asymptomatic with no evidence of tumour recurrence. She has a normal psychomotor development for age and follows regular schooling. Increasing the interval of radiological surveillance to every 6 months was decided on the last consultation.

Discussion

DTs are rare fibroblastic/myofibroblastic neoplasms categorised as intermediate grade, locally aggressive, non-metastatic tumours according to the fourth edition of the WHO classification. The cause is unknown and can occur at any age, being less common in children. However, in this age group the percentage of extra-abdominal locations is higher with H&N sites comprising 25%–35% of cases.⁴ In the H&N most occur in the anterolateral neck, followed by the face, oral cavity, scalp and paranasal sinuses⁴ with only a few case reports of masticator space paediatric DTs.²⁶ In this specific location, differential diagnosis is with other much more common benign and malignant neoplasms. Imaging diagnosis can be suspected in the presence of a well-defined soft tissue tumour, isointense to muscle on T1W, with intermediate signal intensity on T2W, and intense enhancement after contrast administration with intervening non-enhancing bands corresponding, on pathology, to dense, acellular collagenous stroma. However, due to overlapping clinicoradiological appearances, histopathology is required for definitive diagnosis. Paediatric H&NDTs tend to behave more aggressively having a more invasive appearance, faster growth and higher recurrence rates. In addition, the H&N dense intrinsic anatomy, with heavily packed neurovascular structures, carries a higher risk of significant surgical morbidity and mortality and complete resection with negative margins can be challenging and not always possible.⁴

For these reasons, different multimodality strategies have been attempted to overcome these limitations. General guidelines are difficult to establish due to the rarity of this tumour precluding large prospective clinical trials. Those reported in the literature are based on relatively small retrospective series and are phase II clinical trials. On a literature overview of paediatric H&NDT we could only find nine cases located in the masticator space/mandible/infratemporal fossa/parapharyngeal space4 9 26 27 and full information on treatment and prognosis was only present in two of these cases (table 1). Interestingly, a very similar case in terms of tumour location, size and extension recently described²⁷ showed failure of the same CTX regimen used in our case, with rapid symptomatic tumour progression requiring a wide surgical resection.

Table 1.

Treatment and prognosis of DT in the masticator space (including the present case)

Patient’s age	11 months	2 years	Present case (5 years)
Gender	Male	Female	Female
Primary treatment	Radical resection (R1)	CTX (weekly vinblastine and MTX)	CTX (weekly vinblastine and MTX)
Treatment sequela	Sacrifice of ECA	No	No
Recurrence	Yes	Treatment failure with <25% tumour growth	No
Time to recurrence	35 months	4 weeks	No
Secondary treatment	Surgery	Surgery	No
Treatment sequela	Sacrifice of CN XII	No	No
Outcome	Alive without tumour	Alive without tumour	Alive without tumour
Follow-up time	101 months	12 months	36 months

CN, cranial nerve; CTX, chemotherapy; ECA, external carotid artery; MTX, methotrexate.

Reported recurrence rates of paediatric H&NDT are around 20%–30%, with 89% of cases occurring within the first 3 years.²⁸

The impact of positive microscopic tumour margins on local recurrence is still a matter of debate, although most studies report a negative impact.4 27 29 30 In fact, the main risk factors for local recurrence include incomplete resection with positive surgical margins, young age, large tumours and H&N sites. Adjuvant RT is not recommended as it carries long-term functional and cosmetic sequelae in paediatric patients and is less effective in ensuring local control compared with adults.^{24 25 31}

The EpSSG CTX protocol demonstrated consistent and long-term response rates (40% partial response and 60% prolonged stable disease) in several prior retrospective reviews and complete and sustained long-term responses in inoperable paediatric H&NDTs.⁴

Good results have also been reported with TKIs, with a phase II clinical trial demonstrating a 55% 2-year progression-free survival rate and a recurrence rate below 2% with little adverse effects.²⁹

According to the last joint global consensus-based guideline approach of the DT Working Group, published November 2019,² H&NDTs when asymptomatic or pauci-symptomatic can be managed by active surveillance. If they show interval growth, increasing symptoms or are close to vital structures, patients should receive some form of medical treatment. If it fails, surgery should follow with RT reserved for ‘older’ paediatric patients (figure 6).

Figure 6.

Proposed treatment algorithm (according to the DT Working Group (DTWG)). *In desmoid tumour of the head and neck (H&NDT) medical treatment might be initiated early because of the critical areas involved. **Other treatment modalities include radiotherapy (RT) or surgery (if limited morbidity) plus RT.

Newly emerging minimally invasive image-guided therapies such as ultrasound-guided cryoablation, radiofrequency ablation³² and MRI-guided high-intensity focused ultrasound (MRIgHIFUS) ablation have been attempted in DTs. These techniques have shown promising results in symptomatic relief and tumour reduction and allow for repeated treatments. Some reported results include 63% of mean tumour volume reduction and 64% decline in pain scores (with MRIgHIFUS) and 50% complete or partial response and 67% stable disease in complete or partial cryoablation, respectively. However, the proximity of critical structures in difficult, densely packed anatomical areas such as the H&N are relative contraindications and there is limited experience with the use of these modalities in very young patients,^{33 34} leaving these techniques as second-line or third-line options, when conventional treatments fail.

As the natural history of the disease is largely unknown, close observation and long-term follow-up are required.

This case highlights the need for a dedicated multidisciplinary approach to diagnose and manage these rare and complex tumours and to achieve the best possible outcomes while minimising morbidity and potential long-term sequelae, particularly in this age group. We report another case of a complete response to medical treatment using a low-dose weekly CTX regimen with MTX and vinblastine.²

Learning points.

• Desmoid tumour of the head and neck (H&NDT) although rare is a differential diagnosis to take into account in paediatric patients when dealing with a neck mass.

• The chosen treatment modality should take into account the patient’s symptoms, age, anatomical site, tumour biology and treatment-related morbidity.

• MRI imaging is a valuable tool to monitor treatment response.

• Conservative treatment modalities may provide favourable outcomes in paediatric H&NDT.

• Management of paediatric H&NDT requires a dedicated multidisciplinary team to achieve the best possible outcomes with the least possible morbidity.