A Primer on the Evolving Basal Cell Carcinoma Landscape

Supplements and Featured Publications, New Horizons in the Treatment of Basal Cell Carcinoma,

Basal cell carcinoma (BCC) is one of the most common forms of cancer.1 Although most cancer registries do not collect BCC data,2 the most recent incidence study estimated that 3.3 million Americans had nonmelanoma skin cancers (NMSCs),3 the majority of which are BCCs.1 The estimated cost of treating NMSC in the United States is more than $1.4 billion annually, making NMSC 1 of the top 5 most expensive cancers.4 Additionally, the overall incidence of BCC continues to increase, which is likely because of improved detection, increased sun exposure, and longer life expectancy.5 BCC occurs most frequently on the head and neck, particularly on the nose and eyelids, and men appear to be more commonly affected than women.6

Basal cell carcinoma can affect patients’ activities of daily living, as well as their physical, psychosocial, and emotional health.7,8 Patients may experience pain, stress, itching, red or bleeding lesions, trouble sleeping, or lack of energy.7

Although most cases of BCC are treatable, a smaller subset of BCCs can become advanced (either locally advanced or metastatic).9 Advanced BCC, compared with noninvasive, nonmetastatic disease, has a poor prognosis.

This article provides an overview of the incidence, diagnosis, and treatment of BCC, including the evolving therapeutic spectrum for advanced BCCs.

Incidence and Risk Factors

Basal cell carcinoma occurs most often in fair-skinned individuals. Other risk factors for BCC include history of sunburn, high cumulative UV exposure, and advanced age.10,11 A personal history of skin cancer or compromised immune system can also increase risk, as can exposure to arsenic or ionizing radiation for treatment of skin diseases or childhood cancer.10,12 Another recognized risk factor is indoor tanning. In a 2014 study, younger patients (aged 25 to 50 years) with a history of indoor tanning had an odds ratio for developing BCC of 1.6 (95% CI, 1.3-2.1) versus controls.13 People who lightly tan or not at all after sun exposure have a lower risk of BCC when compared with those who tan regularly.14

In a 2015 study of patients with BCC diagnoses between 1998 and 2012, female patients 40 years and older and male patients 64 years and older had a higher incidence of BCC.4 The incidence of BCC in other age groups was unchanged or slightly decreased.4 However, increased incidence has been observed among younger age groups, as well.8

People who are immunosuppressed after organ transplantation have a 5 to 10 times greater risk for BCC than the general population.12 Patients with HIV have an adjusted rate ratio of 2.1 (95% CI, 1.8-2.3) for developing BCC versus those without HIV.15 Ionizing radiation, which has been used to treat malignancy and other conditions, is also a risk factor for developing BCC. Patients exposed to 35 Gy or more as children have an odds ratio of 39.8 (95% CI, 8.6-185) for developing BCC later in life.16 Other conditions that have been linked to an increased risk of BCC include the genetic diseases xeroderma pigmentosum and Gorlin syndrome.17

Histological Subtypes

Basal cell carcinoma is characterized by abnormally proliferative keratinocytes derived from the basal cell layer of the epidermis.18 BCC is classified into various pathohistological subtypes based on growth patterns. These subtypes include nodular, superficial, morpheaform, infiltrative, fibroepithelial, micronodular, and basosquamous (also known as metatypical or mixed BCC).10,18

Between 60% and 80% of all BCC is nodular.10 Nodular BCC has a pearly or translucent appearance, sometimes with telangiectatic vessels, and it most often occurs on the head and neck. Ulceration may be present when tumors are large. Approximately 20% of BCC is superficial type and occurs on the trunk and limbs. It appears as well-circumscribed, scaly, red patches or plaques, and it may have central atrophy and a rolled border.10

Morpheaform-type carcinoma (also called sclerosing or desmoplastic type) makes up 5% to 10% of all BCC.10 Morpheaform tumors are often found on the head and neck and are flesh-colored plaques with poorly defined borders. Infiltrative-type BCC usually occurs in the context of preexisting BCC of other types.10 Clinically, these lesions are white or pale pink, poorly defined, indurated, and flat or depressed, and possibly have erosions or ulcerations.10 Fibroepithelial-type BCC commonly occurs on the lower back as skin-colored or erythematous papules or papulonodular lesions.10 Basal cell carcinomas with pigmentation can be seen in any subtype; these lesions are most often seen in patients of Asian or African descent and are rare in patients of Caucasian descent.10

Micronodular tumors, which present with smaller tumor nests, have a higher risk of subclinical extension than nodular BCCs.19 However, such a classification has yet to be defined. In the interim, the currently most favored classification is one based predominantly on histological growth pattern. This classification contributes to the useful concept of low- and high-risk histological subtypes of BCC. The latter are characterized by an increased probability of subclinical extension and/or incomplete excision and/or aggressive local invasive behavior and/or local recurrence. The Royal College of Pathologists has published a minimum dataset for the histopathological reporting of BCC and this has been written to be compatible with the British Association of Dermatologists’ management guidelines. Growth patterns to be reported include nodular, superficial, infiltrative/morphoeic, and micronodular types. Basosquamous BCC has mixed histology with features of both basal cell and squamous cell cancer.12 It appears that the risk for metastasis is related to the squamous component of the cancer, and it has a metastatic potential similar to that of pure squamous cancers.12

Morpheaform, infiltrative, and basosquamous types are more likely to be excised incompletely, recur, and metastasize.12,19,20 For the more aggressive subtypes (ie, micronodular, morphoeic, and infiltrative), it is more difficult to define borders clinically; as a result, these types are more often excised with incomplete margins.19

Considerations for Treatment Decision-Making

Biopsy technique should be determined by the characteristics of the tumor. Morphological characteristics to consider include likely histologic subtype and depth, natural history, and anatomic location.1 Patient-specific factors, such as bleeding, wound healing diatheses, and patient preference, should also be considered.1 Punch or shave biopsies are usually able to detect the more aggressive histologic subtypes of BCC. Shave biopsy is likely to make the diagnosis but will not reliably assess depth.1 Excisional biopsy will make the diagnosis and stage the tumor while providing definitive treatment in most cases.1

For nonadvanced disease, local treatment with excision or destruction of the tumor and a small margin of normal skin is usually curative.12 However, in the small portion of BCC cases that are locally aggressive or metastatic, systemic therapy or radiation therapy may be appropriate first-line or adjuvant treatment.12

Though treatment of BCC is usually surgical, multidisciplinary evaluation is crucial to ensure optimal outcomes, especially in patients with advanced disease. Depending on the details of an individual’s tumor, the treatment team may include dermatologists, Mohs surgeons, surgical oncologists, medical oncologists, nurse practitioners, social workers, and nutrition specialists.9,21 In a multidisciplinary evaluation, the stage of the cancer, tumor location, immune health, patient age, comorbidities, lifestyle factors, and risk of recurrence or spread are considered when selecting the approach.9 Depending on the individual and their disease, treatment may include surgical excision, Mohs surgery, curettage and electrosurgery, cryotherapy, radiotherapy, photodynamic therapy, topical therapy, or systemic therapy.12

Surgical excision with adequate margin is the most common therapy, and it is the most effective therapy when it is complete.12 For well-circumscribed BCC lesions less than 2 cm in diameter, excision with 4-mm clinical margins should completely excise the lesion in more than 95% of cases.12 BCC with high-risk features should have larger margins because of the increased likelihood of clinically occult local invasion. In cases with incomplete excision, reexcision is recommended; if reexcision is not possible, then radiation therapy may be appropriate.12

Mohs surgery involves iterative excision and microscopic examination of a tumor specimen until clear margins are obtained, ensuring complete excision while minimizing loss of uninvolved tissue.12,22 Mohs surgery is best suited to areas such as the head and neck, where tissue coverage and cosmetic outcomes are a concern, or in large morphoeic or recurrent lesions when more aggressive tumor infiltration of surrounding tissue is likely.22 The 5-year recurrence rate for primary lesions is 1%, and it is 5.6% for recurrent lesions.12

Curettage and electrosurgery use electrosurgical devices to ablate the tumor with 5-year cure in 92% of patients. This procedure, however, precludes margin assessment and should be used only for low-risk lesions. It should also be avoided in the head and neck region.10

Cryotherapy uses liquid nitrogen or frozen carbon dioxideto destroy tumor tissue and is best used in low-risk lesions.12 Ideally, the lesion should be biopsied prior to treatment to rule out more aggressive tumor types. According to retrospective reviews, 5-year recurrence is seen in up to 13% of cases, but in prospective trials, recurrence has been as high as 39%.10,12 Cryotherapy outcomes may vary in part because no standard protocol exists regarding the number and duration of freeze-thaw cycles. Another factor to consider with cryotherapy is that it can potentially result in permanent hypopigmentation, and margins cannot be assessed.10,23

Radiotherapy is appropriate for patients for whom surgical excision is inappropriate because of comorbidity, extensive local invasion, or patient preference.1 In some reviews, long-term cure rates are reported to be 93% to 96%.12 However, in a prospective randomized study of surgery versus radiotherapy as primary treatment, radiation therapy was associated with a higher recurrence rate (7.5% vs 0.7%; P = .003), worse cosmetic result, and more complications.12

Finally, topical treatments such as 5% imiquimod or 5-fluorouracil can be used to treat multiple low-risk lesions. In one phase 3 trial, there were no signs of recurrence 3 years after imiquimod treatment in 84% of patients.12 Surgical treatment was 98% successful in this study (P<.001), but imiquimod provided better cosmetic outcomes.12 5-fluorouracil has similar outcomes based on limited literature.12

Recurring and Advanced BCC

Although most BCC cases are unlikely to shorten life, metastasize, invade deeply into tissues, or recur, a small percentage become locally advanced or metastasize and become a significant burden for patients.7,8,18 Of recurrent cases, 90% are in the head and neck, and the rate of recurrence increases with tumor size and location on the face.18 As much as 65% of recurrent tumors have aggressive histological features, and such tumors tend to recur without early symptoms, which can delay diagnosis and treatment.18

Larger lesions can penetrate deeply into the skin or surrounding tissue, destroying tissue and forming difficult-to-treat, locally advanced disease. Multiple factors are associated with locally advanced BCC, including tumor size, location in the mask area of the face, presence of multiple lesions, aggressive histology, and likelihood of incomplete treatment of the disease (eg, with recurrent tumors).9

Metastatic basal cell cancer is rare, occurring in less than 1% of cases.22 Risk factors for occult metastatic disease include a tumor diameter less than 2 cm, location on the central part of the face or ears, long-standing presence of the lesion, incomplete excision, aggressive histologic pattern, and perineural or perivascular involvement.18,22 Basal cell carcinoma most often spreads to regional lymph nodes, but bone, lung, and liver metastasis can occur less commonly.1,18 Metastatic BCC can involve large areas of soft tissue, cartilage, and bone, and it can lead to substantial disfigurement.20,24,25 Metastatic BCC has historically been associated with a very poor prognosis: There are few treatment options, and the mean survival ranges from 8 months to 3.6 years.1,22

Patients with advanced BCC likely have significant personal burdens associated with disease and treatment. These can include pain, blood loss, anemia and fatigue, open wounds, and limitations in function due to tumor location. Patients may also experience adverse effects from surgery, radiation, or chemotherapy.7,8

Guidelines for treatment for advanced BCCs are lacking, and treatment strategies vary widely.20 Complete excision with negative margins can be effective, but aggressive surgery may be disfiguring or impair function.24 In some cases, radiotherapy is used to treat patients who are not surgical candidates; it may also be used as adjuvant therapy in patients who have incomplete resections.10 Systemic chemotherapy has been used to treat advanced disease, but no standard regimen exists, and response to traditional chemotherapy in advanced BCC has been limited.9

Recently developed medications are changing the treatment landscape for advanced BCC.12 Several Hedgehog pathway inhibitors have been developed and show promise in clinical trials.12,24 During embryogenesis, Hedgehog signaling guides differentiation, proliferation, and tissue patterning.9 In adults, Hedgehog signaling maintains stem cells and certain tissues.9 Hedgehog mutations are found in most BCC tumors and are thought to lead to the cancer phenotype. This led researchers to investigate Hedgehog pathway inhibitors for efficacy in BCC.9

Vismodegib is a Hedgehog pathway inhibitor that showed efficacy in metastatic and locally advanced BCC. In a 2012 phase 2 study of patients with advanced BCC, for whom surgery was inappropriate, the response rate was 30% (95% CI, 16%-48%; P=.001) in the 33 patients with metastatic BCC, and 43% (95% CI, 31%-56%; P<.001) in the 63 patients with locally advanced BCC.26 There were complete responses in 21% of patients.26 Response to treatment lasted for a median of 7.6 months.26 More than 30% of patients experienced muscle spasms, alopecia, disturbance in taste, or weight loss and/or fatigue.26 Seven deaths occurred because of adverse events.26

Another Hedgehog pathway inhibitor, sonidegib, was studied in 230 patients at 2 different doses. At 13.9 months, 36% of patients (20 of 55 patients) receiving 200 mg of sonidegib had a response (95% CI, 24%-50%), and 34% of patients (39 of 116 patients) receiving 800 mg of sonidegib had a response (95% CI, 25%-43%).24 Serious adverse events occurred in 14% of patients (11 of 79 patients) in the 200-mg group and in 30% of patients (45 of 150 patients) in the 800-mg group.24 Several other Hedgehog pathway inhibitors are under investigation.27

In addition to Hedgehog pathway inhibitors, the BCC treatment spectrum now also encompasses immunotherapy. Cemiplimab-rwlc is a monoclonal antibody that inhibits PD-1 activity.28 In 2021, the FDA approved cemiplimab-rwlc for patients with locally advanced BCC previously treated with a Hedgehog pathway inhibitor or for patients with locally advanced BCC for whom a Hedgehog pathway inhibitor is inappropriate.28 It was also approved for patients with metastatic BCC previously treated with a Hedgehog pathway inhibitor or for patients with metastatic BCC for whom a Hedgehog pathway inhibitor is inappropriate.28

Given the challenges of treating advanced BCCs, the addition of options with new mechanisms may provide new ways of optimizing care and improving outcomes.

References

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  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654
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  14. Shashank A, Guminski AD, Abu Alrub NKA, Scolyer RA, Damian DL, Thompson JF. Basal Cell Carcinoma. In: Morita SY, Balch CM, Klimberg VS, Pawlik TM, Posner MC, Tanabe KK, eds. Textbook of Complex General Surgical Oncology. 1st ed. McGraw-Hill Medical; 2017:219-228. Accessed May 16, 2021. https://accesssurgery.mhmedical.com/book.aspx?bookid=2209
  15. Silverberg MJ, Leyden W, Warton EM, Quesenberry CP Jr, Engels EA, Asgari MM. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst. 2013;105(5):350-360. doi:10.1093/jnci/djs529
  16. Watt TC, Inskip PD, Stratton K, et al. Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2012;104(16):1240-1250. doi:10.1093/jnci/djs298
  17. Schierbeck J, Vestergaard T, Bygum A. Skin cancer associated genodermatoses: a literature review. Acta Derm Venereol. 2019;99(4):360-369. doi:10.2340/00015555-3123
  18. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 2004;23(3-4):389-402. doi:10.1023/B:CANC.0000031775.04618.30
  19. Saldanha G, Fletcher A, Slater DN. Basal cell carcinoma: a dermatopathological and molecular biological update. Br J Dermatol. 2003;148(2):195-202. doi:10.1046/j.1365-2133.2003.05151.x
  20. McCusker M, Basset-Seguin N, Dummer R, et al. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014;50(4):774-783. doi:10.1016/j.ejca.2013.12.013
  21. Peris K, Fargnoli MC, Garbe C, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines. Eur J Cancer. 2019;118:10-34. doi:10.1016/j.ejca.2019.06.003
  22. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353(21):2262-2269. doi:10.1056/NEJMra044151
  23. Tchanque-Fossuo CN, Eisen DB. A systematic review on the use of cryotherapy versus other treatments for basal cell carcinoma. Dermatol Online J. 2018;24(11):13030/qt49k1c38t.
  24. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716-728. doi:10.1016/S1470-2045(15)70100-2
  25. Puig S, Berrocal A. Management of high-risk and advanced basal cell carcinoma. Clin Transl Oncol. 2015;17(7):497-503. doi:10.1007/s12094-014-1272-9
  26. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179. doi:10.1056/NEJMoa1113713
  27. Leavitt E, Lask G, Martin S. Sonic Hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. Curr Treat Options Oncol. 2019;20(11):84. doi:10.1007/s11864-019-0683-9
  28. Libtayo. Package insert. Regeneron Pharmaceuticals Inc; 2018.

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