Management of basal cell carcinoma with pulmonary metastasis

Background

Basal cell carcinoma (BCC) is a non-melanocytic skin cancer characterised by uncontrolled proliferation from the basal layer of the epidermis and its surrounding appendages. Most cases are locally invasive and do not behave aggressively. However, although exceptionally rare, metastatic variations also occur.1

Annual incidence of BCC in Australia was approximately 770 per 100 000 from 2011 to 2014 with a low association with morbidity and mortality, although this is thought to be underestimated as non-melanocytic cancers are not included in the cancer registry.2 Furthermore, metastatic BCC has an approximate incidence of 0.0028%–0.5% with a significant association with morbidity and mortality.3

BCC is generally managed with surgical excision, radiotherapy, curettage, photodynamic therapy or topical treatments including imiquimod.4 Metastatic cases require a multidisciplinary approach to management. Management of metastatic or advanced BCC include extensive surgical resections, radiotherapy, chemotherapy, targeted therapy, and more recently, immunotherapy.

This is a case of an undiagnosed BCC that had locally invaded surrounding tissue which progressed to pulmonary metastases over the course of several months. This was initially treated with sonidegib, a hedgehog signalling pathway inhibitor (HPI), before changing to Cemiplimab, a programmed cell death protein 1 inhibitor (PD-1). This case reports the use of PD-1 inhibitors to treat advanced or metastatic BCC.

Case presentation

A previously fit and well man in his 50s was referred to the plastic and reconstruction surgeons with a 10×5 cm non-healing ulcer that was deeply fixed within the left axilla (figure 1). The ulcer had been present for 18 months and was treated with several courses of antibiotics and closures with no successful resolution. Biopsy and CT scans of the thorax revealed an ulcerating BCC with muscle, arterial and venous involvement. This necessitated surgical excision and postoperative radiotherapy. Biopsy-proven pulmonary metastatic BCC 7 months later prompted treatment with sonidegib. Further disease progression 14 months later was managed with cemiplimab.

A previous left shoulder BCC was previously excised. Pathology reports are unavailable.

On examination, there was no cervical or axillary lymphadenopathy, while a neurological examination found normal power and strength with some paraesthesia over the medial aspect of the left forearm.

Investigations

Punch biopsy of the left axillary lesion confirmed a BCC without an associated in situ component. Following this, a neck and chest CT scan revealed a 27×18 mm subcutaneous left axillary ulcer lateral to the left pectoralis major muscle. At the base of the ulcer, a 30×17 mm mass extended to the left axillary artery (figure 2). A left arm CT angiogram revealed a left axillary BCC that extended to the left subscapular artery and left axillary vein.

Histopathology of the resection specimens demonstrated a BCC with perineural invasion, vascular invasion and 1/8 lymph nodes being involved (figure 3A–D). A tumour, nodes and metastases (TNM) status of pT3pN1pM0 was given at this time. This demonstrated that the primary tumour was more than 40 mm in maximum dimension and there was local metastasis in a single ipsilateral lymph node that was less than 30 mm. There was no cited distant metastatic disease.

A CT chest scan 7 months postoperatively demonstrated pulmonary nodules bilaterally. CT-guided lung biopsy confirmed metastatic BCC with pulmonary involvement, with tissue consisting of basaloid cells surrounded by a peripheral palisade of neoplastic cells (figure 4A–F). The TNM status was upgraded to pT3pN1pM1 with new evidence of distant metastatic disease. Any presence of metastatic disease automatically denotes the status of disease as a stage IVB BCC.

Differential diagnoses were considered, such as squamous cell carcinoma (SCC). Macroscopically BCC generally has a pink, pearly and nodular appearance that is associated with telangiectasias, rolled borders and central ulceration. SCC typically have plaque-like appearances that are nodular before becoming ulcerated with everted edges and an appearance that resembles granulation tissue. On pathology, BCC may be represented by discrete nesting of basaloid cells within the dermis with ulceration showing discontinuous epithelium.5 Peripheral palisading may also be seen. In contrast, SCC may show atypical basaloid cells with features of nuclear palisading and cellular apoptosis.5 Keratin pearls (hyperkeratosis), intraepithelial bridges and tumour nesting may also be seen with SCC.5

A repeat CT chest scan was performed 15 months later which revealed mild increase of size in pulmonary nodules. In particular, a 16 mm nodule was noted in the left major fissure, a 15 mm nodule was noted in the anterior segment of the right upper lobe and a 16 mm nodule was noted in the medial basal segment of the left lower lobe (figure 5A).

After commencing cemiplimab, a reduction in cited nodules was noted 6 months into treatment. The nodule in the left major fissure reduced to 6 mm, the nodule in the anterior segment of the right upper lobe reduced to 6 mm and the nodule in the medial basal segment of the left lower lobe had resolution (figure 5B).

Differential diagnosis

Treatment

Multidisciplinary team discussions concluded that a multidisciplinary approach was required. Surgical management would have input by general, vascular and plastic surgery. Postoperative management would require input from dermatology and oncology for regular skin checks and radiation therapy.

The plastic and reconstructive surgical team performed an excision of the left axillary fold with an axillary lymph node dissection. The axillary fold was surgically reconstructed with a serratus perforator flap (figure 6A,B).

Nerve and tendon transfers were performed 2 months later following brachial plexopathy of the left upper limb secondary to the excision. Nerve transfer included the extensor carpi radialis brevis to the anterior interosseous nerve and supinator branches to the flexor carpi radialis. Tendon transfer included the extensor indicis muscle to the extensor pollicis longus tendon.

Occupational therapy for the left hand commenced after the tendon and nerve transfer. Intrinsic muscles were non-functional, which were managed with compression garments and exercises promoting wrist extension with passive digit flexion. Rehabilitation has been ongoing, and the most recent review demonstrated ongoing improvements in motor function of intrinsic muscles.

Postoperative radiation therapy was commenced 3 months postoperatively at a dose of 63 Gy in 30 fractions to the site of positive margins and 60 Gy in 30 fractions to the rest of the operative bed. Radiotherapy was completed in 5 weeks after 30 treatments.

When BCC pulmonary metastases were confirmed, it was decided that sonidegib treatment was appropriate. An application was successfully appointed by oncology. Surgical excision was considered but was ultimately negated as there was no perceived benefit if Sonidegib was to be commenced.

Over the next 14 months, sonidegib (200 mg) was taken once daily as a capsule at night, at least 1 hour before or after food to minimise gastrointestinal side effects. It was initially tolerated well. The patient, however, developed episodes of parageusia that self-resolved, along with facial alopecia. Five months into treatment, the patient developed intermittent muscle cramps. After a year, the patient had ageusia and worsening muscle cramps. When bloods revealed an elevated creatine kinase (CK) level of 795 units/L, it was decided that sonidegib was to cease until CK levels returned to baseline. Muscle cramps resolved with cessation. Fourteen months after the initial CT chest scan and treatment with sonidegib, there was progressive disease with mild increase in size of the pulmonary nodules.

Due to progressive disease, it was decided that cemiplimab was to be used instead via compassionate access. This was because cemiplimab is currently not available on the Australian Pharmaceutical Benefits Scheme. A recent phase 2 trial analysed cemiplimab in those with locally advanced BCC (laBCC) after HPI therapy, which exhibited significant antitumour activity and an adequate safety profile.6 It is important to note that the patient himself was not part of a clinical trial during the time of treatment.

Baseline bloods were completed before commencement of cemiplimab. Serial bloods are done every 3 weeks. Cemiplimab (350 mg) is taken once as an intravenous infusion with sodium chloride 0.9% (50 mL) over a 30 min cycle in the day unit investigation therapy facility. A registered nurse administers the infusion after the infusion is confirmed by the treating doctor. Nine cycles in total were done every 3 weeks over a 6-month period. After 6 months of treatment with cemiplimab, the patient had no adverse effects. A CT chest scan at the end of the 6-month treatment period revealed a decrease in size of several nodules. Due to its clinical effectiveness, it was decided that a further seven cycles were to be done.

Outcome and follow-up

He is continuing to attend dermatology and oncology reviews for regular skin checks and ongoing management of metastatic BCC.

The patient is to continue cemiplimab. The patient has responded to treatment and is continuing to work with no limiting factors, such as dyspnoea or fatigue. Serial radiological scans will continue to evaluate metastatic staging.