Review Explores Advanced Basal Cell Carcinoma Mechanisms and Targeted Therapies

Toshihiko Hoashi, MD, PhD, of the department of dermatology at Nippon Medical School, Bunkyo-Ku, in Tokyo, Japan and colleagues conducted the review. BCC is the most common type of skin cancer, with 2 million Americans diagnosed each year, according to study authors.¹ “BCCs are one of the most common cutaneous malignancies and account for approximately 80% to 90% of skin cancers in Caucasians,” Hoashi and colleagues wrote.¹ They said sun exposure is the most significant risk factor, in addition to age, skin type, and radiation exposure.

Clinical and Histopathological Features of BCC

BCC typically presents as a small, raised lesion on the skin, often with a pearl-like appearance, the authors said. “Clinical manifestations may vary widely in BCCs, and BCC lesions usually grow slowly, are non-healing, and might show bleeding or ulceration.”¹ BCCs are categorized in several ways. Nodular BCCs are firm, raised, and often have a central depression. Researchers said this is the most common type. Superficial BCCs are scaly and flat, and are the second most common. Morpheic BCCs, also called sclerosing BCCs have “poorly defined lesions, scar-like features, infiltrative, or shining plaques, which might be flat or sometimes atrophic including telangiectasias, erosions, or small crusts.”¹ Pigmented BCCs show up as black papules or nodules, sometimes with ulcerations. The authors explained that this type can mimic melanoma and needs a histopathological exam to select the best treatment.¹

Next, researchers reviewed BCC’s histopathology. They said BCC is “generally distinguished by lobules of basaloid cells harboring large and hyperchromatic nuclei as well as scant cytoplasm, which are all accompanied by a fibromyxoid stroma and sometimes by tumor retraction spaces.”¹ They reviewed several subtypes and said pigmented, infundibulocystic, nodular, superficial and fibroepithelial have a low chance of recurring.¹ High-risk BCC subtypes include morpheic/sclerosing, basosquamous, micronodular, infiltrating, and sarcomatous differentiated BCCs, which researchers said are aggressive types.

Other Important Molecules

Study authors reported that other key molecules that have been implicated in BCC development include p53, a tumor suppressor protein, and melanocortin-1 receptor, a protein that regulates pigmentation. Dysregulation of these molecules can lead to the uncontrolled growth of skin cells, leading to BCC.¹

Treatment:

First-line treatment for BCC is usually surgery, with Moh’s micrographic surgery being the method of choice for aggressive and difficult-to-treat types or those in hard-to-reach areas. Other treatments include radiation and topical therapy with 5-fuorouracil or imiquimod. While not approved by the FDA, photodynamic therapy works better with superficial BCCs than nodular ones, the authors said.

Researchers made significant breakthroughs in understanding BCC by identifying a specific gene mutation, patched 1 (PTCH1). Patients with Gorlin syndrome, a rare genetic condition that predisposes individuals to BCC, have this mutation. PTCH1 plays a crucial role in the hedgehog signaling pathway, which is involved in the development of several types of cancer, including sporadic and hereditary BCCs, when it becomes dysregulated according to Hoashi and colleagues.

New treatment strategies have emerged, including targeted therapies such as hedgehog pathway inhibitors vismodegib (GDC-0449) and sonidegib (Erismodegib, NVP-LDE-225, LDE-225). Targeted therapies can be used to inhibit the activity of specific proteins or signaling pathways. Biomarkers can be used to identify patients at high risk of developing BCC or to monitor treatment response.¹

Researchers said no comparative randomized controlled trials of vismodegib and sonidegib have been run. “Vismodegib appears to be the treatment of selection for metastatic BCC, because vismodegib has FDA approval for mBCC and may have superior efficacy to sonidegib in treating mBCC,” the authors said.¹

Clinical trials are in progress for several therapies, including phthalazine-based smoothened inhibitor taladegib, XmAb20717 monoclonal bispecific PD-1 and CTLA-4 antibody, combinations of hedgehog inhibitors with immune checkpoint inhibitors, and several others.

Despite these advances, there are still many unanswered questions about BCC. “The discovery of hedgehog signaling in BCCs is quite striking and targeted therapies have rapidly emerged. However, differences between nodular BCCs and morpheic BCCs, which are quite distinct, have not yet been unveiled. Drug resistances are also a big obstacle. Future investigations are eagerly awaited,” researchers said.¹

Reference

1. Hoashi T, Kanda N, Saeki H. Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma. Int J Mol Sci. 2022;23(19):11968. Published 2022 Oct 8. doi:10.3390/ijms231911968