Cutaneous Basal Cell Carcinoma with Bone Metastases: An Orthopaedic Case Report
Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is increasing. Though metastatic BCC (mBCC) is uncommon, the literature demonstrates a 0.0028%-0.55% rate of metastasis. We report on a patient treated at our institution who was found to have mBCC with osseous metastases. To our knowledge, this is the first report of mBCC in the orthopaedic literature. Orthopaedic oncologists should consider mBCC in patients diagnosed with carcinoma of unknown origin, with a known history of BCC, or individuals with light skin pigmentation and age 50 or greater. This can help clinicians make the correct diagnosis and provide the appropriate treatment.
A recent literature review spanning 1981-2011 identified only 172 cases of primary cutaneous BCC with pathology-confirmed metastasis not resulting from direct tumor spread. When these results are added to the preceding literature, only ~400 cases of metastatic BCC have been reported. Analysis of 100 patients from the 1981-2011 cohort with adequate follow-up showed patients with distant metastases were diagnosed at a younger age (mean 58.0 years) than those with regional metastases (mean 66.3 years) and had shorter interval survival (24 vs. 87 months). Of the 24 identified patients with metastasis to bone, 20 had vertebral lesions and 9 had rib lesions. The patients with bone metastases had median survival of 12 months, significantly shorter than the 26-month mean without bone metastases. Fourteen of the 24 also had metastases to multiple sites. Among those with mBCC, lymphatic spread may predict longer survival times than hematogenous spread.
Here, we have described a case of cutaneous BCC with bony metastasis. To our knowledge, this is the first that such case was described in the orthopaedic literature. Most orthopaedic clinicians are likely not aware that BCC can metastasize to the bone and therefore may not include it on the differential of a metastatic bone lesion, even in a patient with known prior cutaneous BCC. The same can be said of most pathologists, who may not choose stains to identify metastatic cutaneous BCC.
Weissferdt et al. recently reported on the clinicopathological and immunohistochemical findings in 15 cases of mBCC. They suggest that distant metastasis from BCC should be included on the differential for any basaloid carcinoma of the thorax or bone. All but 1 of their patients had a previously diagnosed BCC at the time metastasis was identified. Most () of their patients had metastasis to the lung, with one to the heart and 3 to the bone ( to femur, to iliac crest, and to sacrum). One patient with initial lung metastases later developed bone metastasis as well. Eight of their patients died at a mean of 27 months from mBCC diagnosis, while 7 remained alive at a mean of 29 months after diagnosis. Histologically, 5 were classified as nodular BCC, 3 as basosquamous, 3 mixed, and 1 each morpheaform, micronodular, infiltrative, and superficial. Initially, 8 cases were diagnosed at mBCC, 5 as primary nonsmall cell lung cancer, and 1 as metastatic carcinoma of unknown origin. Two of the bone metastases were initially diagnosed as mBCC and 1 as metastatic carcinoma of unknown origin. Regarding immunohistochemistry, 7/10 cases were positive for bcl-2, 9/11 for BerEP4, and 10/10 negative for EMA (a marker commonly found in SCC). The authors point out that of the primary bone lesions, adamantinoma is histologically similar to mBCC. Clinically, adamantinomas tend to occur in younger patients (generally in their teens and 20s, though they have been reported in 5 year olds to 79 year olds), most commonly in the tibial diaphysis. On radiographs, they appear as expansile lytic lesions commonly with concurrent fibular involvement, and on MRI, they are T1 hypointense and T2 hyperintense lytic intramedullary lesions with cortical involvement. Histologically, they appear less cytologically aggressive and may stain positive for keratin, CK1, CK5, CK14, vimentin, TGF beta, and EMA.
The management of localized BCC is typically straightforward, with most lesions amenable to treatment with cryotherapy, curettage and electrodesiccation, marginal excision, or Mohs micrographic surgery. However, the treatment of locally advanced or metastatic BCC is complex. Historically, patients with more advanced lesions received platinum-based agents with reported favorable responses in 38% of patients. More recent targeted therapy has been developed based on the knowledge that improper signaling within the Hedgehog pathway is present in and contributes to the pathogenesis of a large percentage of localized and metastatic BCCs. Two such Hedgehog pathway inhibitors, vismodegib and sonidegib, have shown promising results in the treatment of locally advanced and metastatic BCC and are now approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA). A recent meta-analysis of eight studies and 704 patients was performed that demonstrated a response range of 28.0% to 100% and a weighted average of 64.7% (95% CI, 63.7%-65.6%) of patients with locally aggressive BCC to vismodegib. The response range of patients with mBCC was 30.8% to 38.0% with a weighted average of 33.6% (95% CI, 33.1%-34.2%). Adverse events have been reported in 30% of patients and include muscle spasms, weight loss, fatigue, alopecia, and dysgeusia. Results for sonidegib have been similarly promising for locally advanced BCC with a response rate of 57.5%, but less promising for mBCC, with a response rate of only 17%. Additionally, basic science suggests vismodegib may sensitize BCC to radiation therapy. Additional targeted Hedgehog pathway therapies are being investigated, as early evidence suggests resistance to vismodegib and sonidegib, both inhibitors of the smoothened (SMO) protein, often develops through SMO mutation or downstream Hedgehog pathway alterations. while rare, metastatic BCC should be considered in the differential for bone lesions in patients with known history of BCC. In patients where histology shows carcinoma of unknown primary, especially with basaloid appearance on histology or in Caucasian patients in their 50s or later, the orthopaedic oncologist should specifically assess for suspicious skin lesions or any known history of cutaneous BCC. Inclusion of this diagnosis on the differential could allow pathologists and medical oncologists to better diagnose and treat these patients, improving morbidity and mortality.
Journal of Orthopedic Oncology.
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