Cutaneous Tumours With Perineural Involvement in a 42-Year-Old Woman

A 42-year-old Caucasian woman presented to us with a 1-year history of lesion on right cheek and a 1-month history of lesion on her nose. Her right cheek lesion initially appeared red and raised before becoming crusty. A similar lesion emerged on her nasal dorsum without any associated trauma. Examination revealed a 10 mm indurated plaque with a central pitted scar on her right cheek, and a 20 mm erythematous plaque with yellow crust on the dorsum of her nose (Figure 1a). Her medical history includes right vestibular schwannoma (which was removed with ventriculoperitoneal shunt in situ), postneurosurgical trigeminal neuralgia, a congenital blind right eye and psoriasis. She was initially diagnosed with a keratoacanthomas (KAs) and referred to maxillofacial team for a surgical excision. While awaiting surgery, her right cheek lesion regressed, and her nasal lesion quadrupled in size within weeks (Figure 1b). Surgical excision was abandoned in favour of multiple nasal biopsies and an MRI of her neck. Histology confirmed a well-differentiated squamous cell carcinomas (SCCs) (Figure 2a,b) and her MRI showed no lymphadenopathy. The patient family history revealed that her sister and two aunts had similar recurrent cutaneous tumours that self-regressed, leaving pitted scars.

Further questioning revealed a family history of FSD in her sister and two aunts. Genetic testing subsequently confirmed FSD with a pathogenic variant of the TGFBR1 gene designated c.1059_1062delinsCAATAAp.(Leu354AsnfsTer4), whereas no variants in the NF1 gene were found. Following a multidisciplinary team (MDT) discussion, her condition was stabilised with a treatment regime with cryotherapy, imiquimod cream and oral acitretin.

Her acitretin dose was increased to 40 mg/day, and prednisolone was initiated when she developed right infra-orbital swelling and reduced sensation on the right side of her face (Figure 3a). A MRI of her neck (Figure 3b) and biopsy demonstrated soft tissue inflammation. Despite treatment, she continued developing similar lesions on her lips, left upper eyelid and right cheek, which were treated with cryotherapy.

A month later, she developed severe neuropathic pain on the left side of her face and swelling in her cheek (Figure 3c), requiring referral to the pain clinic. Prednisolone was continued, however her Acitretin dose was reduced to 30 mg due to dry lips. An MRI of her neck showed perineural enhancement along her left infraorbital nerve (Figure 3d). The persistent pain and evolving nasal tumour caused significant psychosocial distress. Multiple MDT discussions led to a decision for nonsurgical management with Imiquimod cream which was discontinued shortly after due to intolerance and cryotherapy for active lesions. Radiotherapy was not recommended for treating FSD. Serial MRI scans showed stable progress of the infra-orbital nerve distribution and eventual resolution over a 2-year period. To date, she continues treatment with cryotherapy for new lesions (Figure 3e).

FSD manifests in an autosomal dominant manner and is prevalent in families of Scottish descent [2]. It arises from loss of function mutations in the transforming growth factor beta receptor 1 gene (TGF-BR1), a tumour suppressor gene [3]. Defects in this gene lead to uncontrolled cell growth, increasing the risk of carcinogenesis. The onset of FSD varies, with lesions typically appearing between second and third decades of life, although the age range can span from 8 to 70 years [4]. Our patient, of Scottish descent, carried a pathogenic variant of TGFBR1 and developed the skin lesions in her forties.

Differential diagnoses for FSD include nonfamiliar cutaneous SCCs and KAs, SCCs and KAs in Muir-Torre syndrome, generalised eruptive KAs of Grzybowski syndrome and KAs in xeroderma pigmentosum [5].

To the best of our knowledge, perineural involvement in FSD has never been reported in literature [6, 7]. Perineural involvement can lead to perineural spread, affecting the facial and trigeminal nerves, causing significant pain, dysesthesia, and radiologically detectable infiltration. Perineural invasion, where cancer infiltrates nerves, is associated with a higher risk of locoregional and distant metastasis [8]. Perineural invasion is typically identified through histologic examination, in our case no biopsy was performed. The perineural involvement was evidenced by radiological imaging.

Although FSD tumours often regress spontaneously, they can leave unsightly scars and cause disfigurement, making surgical excision a preferred option for cosmetic improvement. However, managing FSD poses challenges, as repeated surgery in this case would have involved nasal resection. Systemic treatment, such as retinoids (isotretinoin and Acitretin) have shown effectiveness [3] in other FSD cases and provided benefits for our patient. Other treatment options include intralesional methotrexate, 5-fluorouracil (5-FU) or triamcinolone, topical imiquimod, cetuximab and cisplatin [9]. The optimal treatment regime for FSD requires further evaluation as current options in the literature are primarily based on small case reports [9].

In summary, we described a complex case of FSD with perineural involvement, requiring multiple national and regional MDT meetings for treatment planning (Figure 4). This case emphasizes the psychological effects of FSD and highlights the need for a psychological assessment tool in future research to better address the emotional burden of this disease.

T.Y. was responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and critical revision for important intellectual content. C.B., D.F., M.E., D.T., W.H., S.D., R.S. and P.N.W. were responsible for critical revision for important intellectual content. R.S. and P.N.W. gave final approval of the manuscript.

All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical approval: Not applicable.

The authors declare no conflicts of interest.