Basal Cell Carcinoma: Diagnostic and Therapeutic Management – Expert Opinion of the Polish Dermatological Society

Introduction

Recent years have seen a rapid increase in the incidence of all types of non-melanoma skin cancers (NMSC). Basal cell carcinoma (BCC) is the most prevalent skin cancer and the most common malignant tumor among the Caucasian population. BCC is typically characterized by slow progression, localized malignancy, and a low mortality rate. However, it can cause significant destruction of surrounding tissues and organs, as well as infiltration and deformation of cartilage and even bone. Even though BCC rarely causes distant metastases (approximately 0.0027−0.5% of BCC cases [1]), its clinical course often results in tumor formation in areas exposed to ultraviolet radiation (UV), making it a major social concern that significantly affects patients’ quality of life. Given the importance of the issue, the diagnosis and treatment of BCC are critical components of the clinical practice for dermatologists, venereologists, surgeons, clinical oncologists, and family physicians. Determining the appropriate treatment for BCC is a frequently debated and highly relevant topic in medical discussions. This study on the management of patients with suspected and diagnosed BCC, prepared by an interdisciplinary group of experts from the Polish Dermatological Society (PTD), incorporates current literature, the guidelines of the American Academy of Dermatology (AAD, 2018) [2], the latest recommendations from the National Comprehensive Cancer Network (2024) [3], guidelines from the European Academy of Dermatological Oncology (EADO, 2023) [4], and Polish multidisciplinary recommendations [5].

Epidemiology

Skin cancers are the most common malignant tumors in humans [6]. In Caucasians, the lifetime risk of developing skin cancer exceeds 20%, with the risk increasing as age progresses [7]. Basal cell carcinoma and squamous cell carcinoma (SCC) account for up to 99% of all NMSC cases, with BCC being diagnosed three to five times more frequently than SCC [1, 6, 8].
Although the incidence of skin cancer among the Caucasian population is highest in Australia, an increasing number of cases are being reported in Europe and the United States [1]. Based on data from the Polish National Cancer Registry (KRN), it is evident that the incidence rates of NMSC in Poland have grown significantly over the past 20 years. In 2000, there were over 2,700 new cases among women and more than 2,600 among men. By 2010, the number of new cases had risen to 5,300 for women and 4,800 for men, respectively. This reflects nearly a 100% increase in disease incidence over the course of 10 years [9]. According to estimates, this upward trend is expected to continue in the coming years. In 2019 alone, 7,073 cases of NMSC were recorded in men and 7,608 in women in Poland, totaling 14,681 new cases [7]. Only in 2020 was there a slight decrease in the number of new skin cancer cases, likely due to diagnostic delays caused by the COVID-19 outbreak and other restrictions associated with the pandemic. A further increase in the incidence of NMSC is expected in the coming years [4]. It is also important to note that the reported numbers are likely significantly underestimated due to incomplete registration of new cases.

Etiology and risk factors

The etiology of BCC development is multifactorial. The primary etiological factor in the development of BCC is excessive exposure to UV radiation. This is supported by data on BCC incidence rates based on geographical latitude and the typical localization of lesions on sun-exposed skin [3]. Additionally, the rising incidence of BCC in recent years has been linked to lifestyle changes, excessive and improper tanning, clothing choices, and the use of UV-emitting lamps (such as in tanning salons). Individuals who work outdoors and are chronically exposed to UV radiation without using any form of photoprotection are particularly vulnerable to developing skin cancers [10]. Moreover, intense sun exposure during childhood appears to play a crucial role in the development of BCC in adulthood [11]. Other important carcinogens include ionizing radiation and arsenic [4].
Phenotypic characteristics, including a low Fitzpatrick skin phototype, red or blond hair, and light eye color, are also independent risk factors [3]. Fitzpatrick phototypes I and II are particularly associated with a higher predisposition to developing BCC compared to other phototypes. Additional risk factors for skin cancer development include prior radiotherapy, chronic immunosuppression, and infection with human immunodeficiency virus (HIV) and oncogenic human papillomaviruses (HPV) [3, 11, 12].
Genetic factors are also known to play a significant role in the development of BCC [3, 11]. Studies on Gorlin-Goltz syndrome (NBCCS, nevoid BCC syndrome), a genetic disorder inherited in an autosomal dominant manner, caused by a mutation in the PTCH1 gene at locus 9q22.3 and characterized by multiple BCC foci, have confirmed the important contribution of the Hedgehog pathway in the development of BCC [13]. The Hedgehog pathway plays a crucial regulatory role in embryonic development and, in the adult organism, it contributes to the maintenance of healthy tissues. However, its dysregulation has been implicated in the development of certain cancers, including BCC. In most sporadic cases of BCC, the Hedgehog pathway is overactivated, primarily due to inactivation of the PTCH1 (Patched 1) receptor in 90% of cases or, less commonly, oncogenic activation of the SMO (Smoothened) receptor in 10% [14]. Additionally, various genetic syndromes may increase the predisposition to developing NMSC, including xeroderma pigmentosum, epidermolysis bullosa, Ferguson-Smith syndrome, Muir-Torre syndrome, Bazex syndrome, and Rombo syndrome [3, 4].

Clinical presentation and clinical types of basal cell carcinoma

The typical clinical appearance of BCC is a pink plaque, papule, or nodule with a raised pearly border or, in the case of a nodule, an opalescent, translucent surface. As the disease advances, small erosions, crusts, or ulcerations may develop on the lesion surface. BCC presents in several clinical forms: superficial, nodular, pigmented, morpheaform, and ulcerative. Among these, ulcerative BCC is the most destructive to surrounding tissues. The clinical differential diagnosis of BCC encompasses several disease entities, including actinic keratosis, Bowen’s disease, seborrheic keratosis, dermomycosis, nummular eczema, psoriatic lesions, chronic discoid lupus erythematosus (DLE), scar tissue, lupus vulgaris, cutaneous adnexal neoplasms, and amelanotic melanoma. Differential diagnosis is facilitated by dermoscopy, which reveals characteristic features of BCC (figs. 1–3).
The most common clinical types of BCC, listed in descending order of prevalence, are nodular (21%), superficial (17%), micronodular (14%), infiltrative (7.5%), and morpheaform (1%). Approximately one-third of BCCs, particularly recurrent ones, exhibit a mixed histological type.
The morpheaform type of BCC requires differential diagnosis to distinguish it from desmoplastic adnexal tumors, desmoplastic melanoma, and microcystic adnexal carcinoma.
Ulcerative BCC always requires histopathological diagnosis, as other malignant skin tumors or metastases may present similarly, such as SCC, Merkel cell carcinoma, porocarcinoma, sebaceous carcinoma, or metastases of thyroid cancer or kidney cancer.
The diagnosis of BCC, irrespective of the planned treatment approach, should be based on clinical and dermoscopic examinations and confirmed through histological analysis of a diagnostic or excision biopsy to identify the BCC type. The histological type of BCC plays a key role in determining the most appropriate therapeutic approach.

Histological types of basal cell carcinoma

Transformed BCC cells originate from basal epithelial cells of hair follicles in the bulge region of anagen hair, hair matrix cells, or pluripotent epidermal cells. For this reason, these cells may exhibit diverse differentiation into hair follicle structures, sebaceous glands, eccrine glands, or apocrine glands. There are many histological types of BCC, depending on the cytological features and differentiation of tumor cells (BCC adnexogenes). However, they are distinguished by the dark purple coloration of the cells at the nodule’s rim and their palisade-like arrangement (fig. 4). Nevertheless, the most significant classification is based on the growth pattern of the BCC tumor, which determines how it infiltrates the dermis tumor. From the perspective of biology and prognosis, the architecture of tumor growth plays a crucial role in determining its clinical course. Consequently, the following histological types of BCC are distinguished: nodular (fig. 4 A), superficial (fig. 4 B), micronodular (fig. 4 C) and infundibulocystic which represent a slow-progressing group. The aggressive growth group includes infiltrative (fig. 4 D), basosquamous, metatypical (fig. 4 E), and morpheaform BCC (fig. 4 F). Pigmented BCC is typically either nodular (fig. 4 G) or superficial (fig. 4 H) in type, characterized by the presence of melanocytes within its structure and melanophages in the stroma. Histological types define the size of cancer cell tumors (nodular, micronodular), their position relative to the epidermis (superficial, infiltrative), and their relationship to the connective tissue stroma (infiltrative, morpheaform). Nodular BCC foci are surrounded by mucopolysaccharides, which form empty clefts around them during tissue processing (fig. 4 I). In contrast, infiltrative BCCs (fig. 4 D) and, even more so, morpheaform BCCs (fig. 4 F) create narrow geometric shapes or thin streaks that closely adhere to the surrounding collagen fibers. BCCs with aggressive growth cause deep infiltration of the dermis, requiring broad excision margins of clinically unaffected skin, performed under microscopic supervision. Excision biopsy results should detail the histological type of BCC, lesion size, depth of infiltration, and margin dimensions.
In histologically uncertain cases, microscopic examination should be complemented by BCC-characteristic immunohistochemical staining using the Ber-EP4 monoclonal antibody, which detects the specific epithelial cell adhesion molecule (EpCAM) expressed in BCC cells.

Diagnostic procedure

Familiarity with the typical clinical features of BCC and its common locations, as well as thorough patient history, are essential for making an initial diagnosis. The majority (up to 80%) of BCC lesions develop on the skin of the head and neck, with 90% of these appearing on the face [15, 16]. BCC often coexists with conditions associated with excessive UV radiation exposure, such as lentigines, telangiectasias, and actinic keratosis. In many cases, the typical patient history and the macroscopic appearance of the lesion enable a correct initial diagnosis of BCC. Dermoscopy is also a valuable tool in diagnosing BCCs. This specialized, non-invasive method allows for rapid examination and – in many atypical clinical presentations – can help establish an early, tentative cancer diagnosis [17–19]. Additionally, dermoscopy is recommended to assess the extent of the neoplastic lesion before surgical excision. In selected cases, dermoscopy may also be employed for ex vivo examination of excised foci with appropriate marking for histopathological analysis, as well as for monitoring postoperative scars to facilitate early detection of potential recurrence.
The presence of certain dermoscopic structures of BCCs correlates with the histopathological subtype of BCC [20–22]. Dermoscopy results showing palmate or maple leaf-like areas and fine telangiectasias, along with the absence of blue-gray ovoid nests, ulcerations, and arborizing vessels, suggests a superficial BCC form. The algorithm has a sensitivity of 81.9% and specificity of 81.8% (figs. 1 A, B) [20]. Furthermore, the presence of numerous small erosions and white-pink homogeneous areas increases the likelihood of a dermoscopic diagnosis of superficial BCC (figs. 1 C, D) [20, 21]. Arborizing vessels are the most characteristic dermoscopic feature of nodular BCC (figs. 2 A, B) [21], with additional blue-grey ovoid nests present in pigmented BCC (figs. 2 C, D) [21]. The infiltrative type is distinguished by the presence of scattered, fine telangiectasias that tend to form smaller branches set against a yellow-red background (figs. 3 A, B) [22]. The morpheaform type is characterized dermoscopically by a white background with individual thin arborizing vessels, and numerous brown granules (figs. 3 C, D) [22]. Basosquamous cell carcinoma exhibits dermoscopic features characteristic of both BCC (blue-grey ovoid nests, ulcerations, blue-grey areas) and SCC (hyperkeratosis, white homogeneous areas, spoke-wheel pattern, and keratin masses with ecchymoses (figs. 3 E, F) [22, 23]. Polarized light dermoscopy, especially in cases of non-pigmented BCC, also reveals the presence of shiny white lamellae and streaks, which occur in the superficial (figs. 1 C, D), nodular (figs. 2 A, B), and morpheaform types of BCC [24]. Determining the histopathological subtype guides the selection of the treatment method. Dermoscopic detection of pigmented structures characteristic of BCC lesions, clinically defined as pigmented (figs. 2 C, D), but also occurring in non-pigmented lesions, may indicate a poor response to treatment methods other than surgical excision [25].
In diagnostically challenging cases of BCC, particularly those with small-diameter foci, reflectance confocal microscopy (RCM) can be used to identify structures characteristic of BCC [26]. In recent years, in vivo vertical skin imaging using line-field confocal optical coherence tomography (LC-OCT) has proven helpful in the early diagnosis of BCC tumors [27] and in determining excision margins in Mohs microsurgery [28].
Another effective imaging tool for BCC is high-frequency ultrasonography (HF-USG), based on frequencies of 20 MHz or higher. It is important to note that HF-USG cannot reliably differentiate the BCC type; however, a strong correlation has been demonstrated between histological examination and HF-USG in assessing the depth of tumor infiltration [27]. Histopathological examination remains the gold standard for diagnosing BCC. However, according to the latest consensus statement by the EADO [4], for low-risk BCC subtypes, non-invasive imaging techniques may suffice to confirm the diagnosis, particularly before planned topical or destructive therapies [4].
Selecting the appropriate treatment method requires determining the histopathological type of the tumor, assessing the stage of lesion advancement, and evaluating the patient’s overall condition. When deeper tissue infiltration by the tumor is suspected, extending the diagnostic work-up to include imaging tests is recommended. When lymph node involvement is suspected, it is essential to perform a fine-needle aspiration biopsy or excise an entire lymph node for microscopic assessment [2, 3].

New EADO classification and stages of basal cell carcinoma: common (easy-to-treat) and difficult-to-treat

According to the new EADO clinical classification, BCCs are divided into easy-to-treat (common) and difficult to treat (DTT-BCC). The former group encompasses over 90% of BCCs which can be effectively treated with standard surgery or various alternative therapies. The latter group, difficult-to-treat BCCs, encompasses all locally advanced BCCs (laBCCs) and common BCCs that present unique treatment challenges for various reasons, including:
1) technical difficulty of maintaining function and aesthetics due to the size or location (eyes, nose, lips, and ears);
2) poorly defined borders often associated with morpheic subtype or recurrence;
3) multiple recurrences on the face (often requiring much larger excision);
4) prior radiotherapy;
5) patient’s reluctance to accept the consequences of surgery;
6) patient’s comorbidities interfering with surgery.
In addition, the EADO classification divides DTT-BCCs into five groups based on different clinical variants (table 1).

Clinical staging

For the staging of skin cancers, the classification developed by the American Cancer Society (AJCC, 2009 and 2017 revisions) is recommended, which is based on the standard TNM staging system (T – tumor, N – node, M – metastasis). Since BCCs rarely metastasize to regional lymph nodes and distant organs, this classification is seldom applied and is therefore not included in this paper. A clinically more significant method for stratifying patients with diagnosed locally advanced BCC is determining the risk of cancer recurrence. In such cases, the preferred method of risk assessment is that proposed by the National Comprehensive Cancer Network (NCCN, 2.2024) [3]. It considers both clinical and pathological parameters (table 2) to classify the lesion as high or low risk for recurrence.
The latest EADO classification (2023) identifies stage I as including most BCCs which are easy-to-treat and low-risk. EADO stage II comprises common BCC considered difficult-to-treat for any reasons linked to the patient or tumor (stage IIA) and BCCs considered difficult-to-treat due to their number (stage IIB). Stage III encompasses laBCCs out of (stage IIIA) or on (stage IIIB) critical/functional areas and extremely large tumors infiltrating extracutaneous tissue and often involving muscles and bones (stage IIIC). Stage IV refers to metastatic BCCs (table 1).

High-risk basal cell carcinoma and recurrence of basal cell carcinoma

High-risk BCCs are most commonly located in the “H” area of the face and are characterized by aggressive histopathological subtypes, including perineural and perivascular invasion [4]. BCCs with a high risk of recurrence, classified as stage II according to the latest EADO therapeutic algorithm [4] (nodular subtypes in critical locations, as well as aggressive histopathological subtypes, i.e. micronodular, morpheaform, infiltrative, and meta-typical) always require surgical treatment or a therapeutic decision made by a multidisciplinary team, especially in cases of multiple BCCs, NBCCS, or existing contraindications to surgical excision [4]. Furthermore, the latest EADO classification for BCC (I, IIA-B, IIIA-C, IV) is based not only on BCC subtypes with a high risk of recurrence (stages IIA to IV) but also on DTT-BCC variants (table 1) [4].
BCC carries a recurrence risk of 10%, and it increases significantly with the use of inappropriate topical therapies and the lack of control over excision margins, particularly for aggressively growing BCC variants. It is 26% for the infiltrative type, compared to 6% for the nodular type and 3.6% for the superficial type. The anatomical regions with the highest risk of recurrence include the nose and ears. Recurrences most commonly occur within 3 years of the removal of the primary tumor [29, 30].
Familiarity with BCC types is essential for clinical diagnosis, dermoscopy, and the interpretation of pathological consultations. This knowledge should significantly influence the selection of appropriate therapeutic management and guide patient monitoring.

Treatment methods

The primary goal of therapeutic management for skin cancer is the complete removal of neoplastic tissue, which reduces the risk of local recurrence while ensuring the best possible cosmetic outcomes for patients.
When selecting the most appropriate treatment modality for BCC, the following factors should also be considered:
1) number and size of lesions,
2) histopathological type,
3) possibility to preserve organ functions and aesthetic outcome,
4) efficacy of therapy,
5) treatment tolerance (including pain, treatment duration, adverse reactions, and risk of complications),
6) availability of specific therapeutic modalities,
7) the patient’s immunological status
8) the patient’s preferences and expectations.
Available methods of skin cancer treatment include:
1) surgical treatment:
a) with possibility to evaluate treatment margins (FIRST-LINE THERAPIES):
classic radical excision of lesion,
Mohs micrographic surgery,
b) without possibility to evaluate treatment margins:
cryosurgery,
electrotherapy,
laser therapy;
2) non-surgical treatment:
a) radiation therapy,
b) superficial treatment using:
5-fluorouracil,
imiquimod,
photodynamic therapy;
3) treatment of advanced disease:
a) first-line treatment:
vismodegib,
sonidegib,
b) second-line treatment:
cemiplimab.
The recommended therapeutic approach for suspected BCC is shown in figure 5.

Surgical methods

The recommendations from all global societies are consistent: surgery remains the ‘gold standard’ for treating BCC (except in cases of inoperable lesions), regardless of the risk of potential recurrence. This method is often the quickest and most effective way to obtain a complete histological diagnosis of the excised lesion. For BCCs with a low risk of recurrence, a standard excision with a 4-mm margin of healthy tissue is recommended. In cases where cosmetic concerns are significant, excision with a smaller margin may be performed, provided the margin is free of neoplastic cells (R0).
For high-recurrence-risk cancers, it is recommended, where possible, to perform an intraoperative analysis to confirm the radicality of the procedure. The treatment of skin BCCs using Mohs micrographic surgery (MMS) – a method involving staged surgical excision of the tumor followed by intraoperative histological assessment of margins to ensure radicality (subsequent sections from the tumor bed margin are examined for the presence of tumor cells) – is becoming increasingly common in Poland. This approach offers the highest cure rates while minimizing damage to healthy tissue, thereby preserving the aesthetic appearance for the patient. When excision of a high-recurrence-risk lesion using MMS is not feasible, excision margins greater than 5 mm are recommended [4]. However, there is currently no data supporting the need for re-excision in cases of complete excision with histologically narrow margins [4].

Cryosurgery and laser ablation therapy

Cryosurgery is an ablative technique that uses liquid nitrogen or nitrous oxide to induce thermal necrosis of tumor cells by creating a low temperature, ranging from –50 to –60°C, at the base of the tumor tissue. This method is employed for treating superficial BCC types with a low risk of recurrence and lesions up to 2 cm in size. To ensure the highest possible radicality, both neoplastic tissue and a healthy skin margin should be destroyed. Wound healing following the procedure is typically normal, resulting in the formation of small, discolored scars [3].
Due to insufficient data on its effectiveness, laser therapy is not recommended for the treatment of skin cancers.

Radiation therapy

Radiation therapy (RT) serves as an alternative treatment option for patients who are either ineligible for surgery or do not consent to the procedure. Long-term outcomes of BCC treatment with radiation therapy are highly favorable. Analysis of retrospective studies on patients with BCC treated with RT indicates a 5-year cure rate ranging from 93% to 96% [3, 31–34], with a 5-year recurrence risk between 4% and 16% [3, 31–34]. RT is slightly more effective for primary BCCs than for recurrent ones. It also exhibits higher efficacy in lesions with smaller diameters and those of the nodular type [3, 31–34].
RT also plays an important role as an adjunctive therapy for patients who have undergone non-radical excision or cytoreductive surgery, particularly when the procedure was incomplete due to neoplastic infiltration of vital structures. It is also indicated following lymphadenectomy for metastases to regional lymph nodes.

Superficial therapies

Surgery is the most effective treatment for BCC-type lesions. However, when this method cannot be used, alternative therapeutic options should be considered, including topical therapies such as imiquimod or 5-fluorouracil, or photodynamic therapy with delta-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL). However, it is essential to recognize that these methods have significantly lower treatment success rates compared to surgical modalities. Therefore, they should only be considered for cancers with a low recurrence risk, a non-aggressive growth pattern confirmed histologically, in patients with small tumors who are unable to undergo radical treatment for various reasons [2, 3]. It is also important to note that BCCs occurring in individuals under 35 years of age often exhibit an aggressive clinical course. Consequently, regardless of patient preferences or aesthetic considerations, surgical excision should be prioritized due to the high risk of recurrence.

Imiquimod (5%)
Imiquimod is a local immunomodulator with anti-neoplastic properties, employed in the treatment of superficial BCC. Imiquimod is a cream applied once daily in the evening, five times a week for 6 weeks. It should ideally be left on for 8 h. A prospective study of patients with superficial BCC demonstrated that 85% of those treated with imiquimod did not experience disease recurrence within 5 years [3, 35].
Adverse reactions associated with topical imiquimod treatment may include skin redness, swelling, vesicle formation, itching, and occasionally a tingling sensation [35].

5-Fluorouracil (0.5%)
Another topical cream preparation used in the treatment of superficial BCC is 5-fluorouracil (5-FU). In a randomized study, this agent demonstrated comparable results to imiquimod in terms of efficacy, safety, and cosmetic outcomes [2, 36]. Standard treatment regimens recommend applying the medication twice daily for a minimum of 3–6 weeks, though treatment may extend to 10–12 weeks in some cases.

Photodynamic therapy
Photodynamic therapy (PDT) is recommended for the treatment of superficial and low-risk nodular BCC, particularly for small lesions less than 2 mm in thickness [4]. However, it is not suitable for less common histopathological subtypes, such as morpheaform, pigmented, or micronodular BCC, nor for BCC located in high-recurrence-risk areas, such as the “H” area of the face.
This method involves using light (emitted from SoLux bulbs, LEDs, or lasers) to activate a photosensitizer applied to the affected tissue, leading to the formation of cytotoxic reactive singlet oxygen species [36]. Photosensitizers used for photodynamic therapy include ALA or MAL. Clinical study data indicate that the cure rate for patients diagnosed with BCC and treated with PDT ranges from 70% to 90% [3, 37, 38], with higher success rates observed in superficial BCC compared to nodular types [3, 39]. Furthermore, substantial lesion thickness and the presence of ulceration can negatively impact the effectiveness of PDT [3, 39]. A 2012 meta-analysis of 23 randomized and non-randomized studies found no significant difference in the efficacy of PDT compared to imiquimod in treating superficial BCC [3, 40]. A 2013 randomized trial assessed the effects of treatment in over 600 patients with this type of BCC. Remission of neoplastic lesions was observed in 73% of patients treated with MAL-PDT (two sessions 1 week apart), compared to 83% of patients treated with imiquimod (five times a week for 6 weeks) and 80% of patients treated with 5-FU (twice daily for 4 weeks). Subgroup analyses revealed that treatment success rates were significantly higher with imiquimod compared to PDT for large tumors on the trunk. Conversely, PDT yielded better results than imiquimod in elderly patients with smaller lesions on the lower extremities [3, 41].

Systemic treatment of advanced basal cell carcinoma

The approval of vismodegib, the first small-molecule Hedgehog pathway inhibitor (HHI), in the US and Europe marked a significant milestone in the treatment of patients with locally advanced BCC (laBCC) and metastatic BCC (mBCC) who had exhausted other treatment options, including surgery and radiation therapy, as well as in those with genetically determined Gorlin-Goltz syndrome [3]. Vismodegib is an oral medication administered at a standard dose of 150 mg/day. Therapy is continued until disease progression or the onset of treatment-limiting toxicity.
The first study confirming the efficacy of vismodegib was the international, multicenter phase II ERIVANCE trial, which included 104 patients with histopathologically confirmed advanced BCC (71 patients with locally advanced BCC (laBCC) and 33 patients with metastatic BCC (mBCC)). Treatment with vismodegib was continued until disease progression, the occurrence of unacceptable toxicity, or the patient’s withdrawal of consent. Data analysis conducted after 39 months of follow-up, once all participants were included, revealed that the median duration of response to treatment in the entire group was 12.9 months (0.7–47.8 months), while in the laBCC and mBCC groups, it was 12.7 months (1.1–47.8 months) and 13.3 months (0.7–39.1 months), respectively [42, 43]. The key results of the study are presented in table 3.
In patients with Gorlin-Goltz syndrome, the drug significantly reduced the occurrence of new BCCs in the vismodegib group compared to the placebo group. The most common adverse events associated with vismodegib therapy include muscle spasms, taste disturbances, alopecia, weight loss, nausea, and diarrhea [3, 42, 43]. Clinical trials have also evaluated the preoperative use of vismodegib and modifications to its dosage regimens. The VISMONEO trial demonstrated that vismodegib treatment might effectively reduce tumor mass, thereby minimizing the extent of required surgical resection [44]. An analysis of the MIKIE trial outcomes indicated that intermittent vismodegib treatment could be a viable management option for patients with multiple BCCs [45].
Since January 2017, vismodegib has been available in Poland as a therapeutic option under the National Health Fund (NFZ) drug program for patients with metastatic or locally advanced BCC who are ineligible for surgical treatment or radiation therapy. Another small-molecule inhibitor of the Hedgehog pathway, approved in the United States and Europe, but not reimbursed in Poland, is sonidegib.
Most patients treated with HHI develop resistance or intolerance to treatment. Following initial data suggesting a positive effect of immunotherapy in patients with advanced BCC who had failed treatment with vismodegib or sonidegib, several studies were conducted that definitively confirmed the efficacy of cemiplimab in this indication. Cemiplimab is a human IgG4 monoclonal antibody that targets the programmed death receptor 1. It was approved by the US Food and Drug Administration in February 2021 and subsequently authorized for regular marketing in Europe as well. In May 2023, cemiplimab was approved in Poland for the treatment of locally advanced or metastatic BCC under the NFZ drug program, specifically for patients who have progressed after HHI treatment or experienced unacceptable toxicity from this therapy.
The study validating the efficacy and safety of cemiplimab for this indication ultimately involved 119 patients with advanced BCC who experienced disease progression during HHI treatment, failed to achieve an objective response within 9 months of therapy, or encountered unacceptable toxicity. All patients enrolled in the study received cemiplimab at a standard dose of 350 mg every 3 weeks until disease progression, unacceptable toxicity, or completion of the planned treatment regimen (93 weeks). After 15 months of follow-up, the objective response rate (ORR) in patients with laBCC was 32.1% and 28.6% in patients with mBCC [46, 47]. The detailed results of cemiplimab efficacy in patients with advanced BCC are presented in table 4.
Table 5 summarizes the therapeutic options available and reimbursed in Poland (as of 1 February 2024).

Current research

At present, there is extensive research into the mechanisms of resistance to Hedgehog pathway inhibitors. Studies are also being conducted to evaluate the efficacy of new-generation HHIs. Research is increasingly focused on identifying predictive factors for response to HHI treatment and immunotherapy in advanced BCC cases. Advancements are being made in the development of topical therapies for BCC. Currently, studies are underway to evaluate the efficacy of patidegib, the only available topical Hedgehog pathway inhibitor administered as a 2% gel for previously untreated BCC and in the course of Gorlin-Goltz syndrome [48].

Follow-up after completed cancer treatment

Long-term post-treatment follow-up is recommended for patients with BCC. This is especially relevant for patients with lesions that are at high risk of recurrence. A key aspect of post-cancer therapy care for BCC patients is educating them about year-round sun protection (using SPF 30-50+ products) and highlighting the importance of secondary prevention, which includes conducting regular self-examinations of the skin at least once a month [4].
The first 2 years of follow-up are the most critical; therefore, patients should undergo regular dermatological examinations, including dermoscopy, during this period (table 6).

Conclusions

The guidelines presented above are designed to assist clinicians in the management of patients with BCC. In each case, diagnostic and therapeutic decisions should be made collaboratively by the physician and patient, guided by current medical knowledge and the potential therapeutic efficacy and safety profile of the selected treatment option for the specific clinical situation. The treatment methods outlined in this study are intended as general recommendations only. This article does not serve as an endorsement by the Polish Dermatological Society for any particular medicinal product, medical device, or manufacturer.

Funding

This work was supported by Medical University of Lodz (503/5-064-01/503-1); and the National Centre of Science (2017/27/B/NZ5/02011).

Conflict of interest

The authors declare no conflict of interest.

References