Real-Life Data on the Management of Incompletely Excised Basal Cell Carcinoma Free

Basal cell carcinoma (BCC) is the most common human malignancy and is estimated to account for 75% of all skin cancers in white populations. For white-skinned patients, the average lifetime risk to develop BCC is approximately 30% (1 in 5 patients) and the major risk factors are related to a combination of sun exposure and skin aging [1‒3].

Staging of BCC can be done using the TNM system or by classifying the tumors according to their risk for local recurrence after surgery [4]. The latter classification might be more relevant from a clinical perspective since it might guide the recommended management. Several factors determine the recurrence risk of a BCC. Tumors developing on head-neck area are at higher risk as compared to other anatomic sites. Histopathologic subtypes with an aggressive growth pattern, including infiltrative, micronodular, morpheaform, and metatypical, are at higher risk to recur as compared to nodular BCC [2, 3, 5]. The recurrence risk increases also with tumor size, history of previous recurrence, poorly defined borders, and perineural involvement [2, 4, 6‒9].

Surgery is the cornerstone of treatment for most BCCs, with recurrence rates ranging from less than 2% up to 8% at 5 years after surgery [2, 6, 10]. To reduce recurrence rates, a peripheral margin of 2–5 mm and 5–15 mm is recommended for low- and high-risk tumors, respectively [2, 4, 7, 10, 11]. Surgery with microscopic margin control is considered ideal for high-risk BCC, but it is not universally available and is also associated with increased cost in time and resources that limit its use. Therefore, standard excision with a pre-determined peripheral margin is probably the most frequently applied treatment for BCC [2, 12].

The term “incomplete” excision is often used when tumor cells are histopathologically found in one or more margins of the excised specimen. Although tumor-positive margins are considered as an evidence of incomplete tumor clearance, residual tumor after re-excision is histopathologically confirmed only in 50% of BCCs re-excised because of positive margins [8, 10]. In addition, clinical recurrence was found to occur in only 26–41% of incompletely excised BCCs after 2–5 years of follow-up and has been associated mainly with the morphoeic histopathologic subtype [6, 13].

Non-surgical modalities such as cryotherapy, photodynamic therapy, imiquimod, and others are frequently used in daily practice to treat superficial BCC or tumors not amendable to surgery or systemic treatment [2, 14‒16]. In a similar off-label context, these modalities are also occasionally used as complementary treatments for incompletely resected BCCs, although data on their efficacy are scarce [2, 6, 7, 14‒16]. In the present study, we report the real-life management of incompletely excised BCC in a tertiary referral center and the recurrence rates at follow-up according to the selected management modality.

This was a retrospective study conducted at a tertiary Dermatology Center in Northern Greece. Our electronic database was scanned over a 5-year period from January 2016 to December 2020 to retrieve eligible cases. Eligible to be considered for the study were all BCCs with available histopathologic assay reporting at least one involved margin (lateral or deep). Finally, only tumors that had been resected with a regular complete surgical excision were included, while those that had been sampled with partial biopsy (punch or shave) for diagnostic purposes were excluded from further analysis. Tumors with incomplete clinical or histopathologic records were also excluded.

Records of included patients were screened to extract data on patient’s age and sex and tumor characteristics. Tumor location was classified in 11 different anatomic sites, namely, scalp, forehead, temporal area, cheeks, ear, periorbital area, nose, perioral area, chin/neck, trunk, and extremities. The maximum tumor diameter was measured using the close-up clinical photograph. Based on the available histopathologic reports, the histopathologic subtype was classified as nodular, superficial, infiltrative, morpheaform, micronodular, or metatypical.

In addition, we extracted information on the selected management after incomplete excision, final outcome, and follow-up period. For further analysis, the included patients were divided into 3 groups according to the selected management after incomplete excision: group 1 included those who underwent immediate re-excision, group 2 those who were followed up without any additional therapy, and group 3 those who were treated with adjuvant/complementary non-surgical treatment. For all patients, we assessed the development and timing of clinical recurrence and the total time of follow-up after the first surgery. Finally, we recorded the presence or absence of residual tumor in the new histopathologic report of those tumors that were selected to be re-excised (group 1).

A descriptive analysis with mean and standard deviation for continuous and frequencies for categorical variables was conducted. Mann-Whitney t test for non-normally distributed continuous variables (ANOVA Kruskal-Wallis for variables with 3 or more categories) was used for the comparison among age or size and different parameters, such as treatment selection and clinical recurrence. Possible associations among categorical variables were searched for using Pearson χ² test (Fisher’s exact test was preferred for variables with less than 5 observations). All statistical tests were two-sided, and p value <0.05 was considered statistically significant. Statistical analysis was conducted using IBM SPSS v.28.

Of 1689 BCCs recorded in our database, 99 were eligible for this study. However, 15 patients had incomplete records or reports and only 84 met all the inclusion criteria and were finally included in the analysis. Of them, 50 were men and 34 women and the mean age was 72.1 years.

The main characteristics of the incompletely excised BCCs included in this study are analytically shown in Table 1. Most of them were located on the face (76%), with the nose being the most frequent subsite of the facial skin (19%). The most common histopathologic subtype was nodular (56/84, 66.7%) followed by infiltrative (12/84, 14.3%).

In terms of management decision, re-excision had been selected in 26 of 84 patients (group 1), watchful waiting in 40 (group 2), and non-surgical treatments in 18 (group 3). The latter group consisted of 7 patients treated with imiquimod, 6 with cryotherapy, and 5 with combination of imiquimod and cryotherapy (immunocryosurgery). Although the criterion guiding treatment selection was not recorded, we investigated possible associations between treatment selection and tumor’s location, initial size, subtype, and patient’s age. We found a statistically significant association between tumor location and treatment decision (χ² test, p = 0.003). High-risk histopathologic subtypes were re-excised more frequently compared to low-risk subtypes. We also found a trend for re-excision being selected for younger patients (mean age 67.5 years) and non-surgical treatments in older ones (mean age 75.4 years) (Table 2). Although not recorded in our data, we assume that patients' comorbidities also influence the treatment selection, especially for those that watchful waiting was chosen.

The histopathologic reports of the 26 tumors of group 1 that were re-excised revealed residual tumor in 14 (53.8%) and absence of residual tumor in 12 (46.2%) cases. None of the investigated factors (tumor size, location, subtype, or patient’s age) was associated with the histopathological presence of residual disease (Table 3).

Overall, a clinical recurrence occurred in 14 of 84 patients (16.7%) after a mean follow-up of 17 months. The median time to recurrence was 14 months, and the maximum follow-up period was 60 months.

Of 26 patients that underwent re-excision, only 2 recurred (7.7%). Of 40 patients without any treatment, recurrence developed in 10 (25%), while only 2 of 18 patients treated with non-surgical treatments recurred (11.1%). Despite these differences, there was no statistical association between the type of management and the appearance or recurrence.

We investigated whether the appearance of recurrence is associated with the initial size of the BCC, the anatomic site, histopathologic subtype, or patient’s age. Although none of these associations was statistically significant, a noteworthy finding was that 7 of 14 recurrent BCCs were located on the nose (Table 4) [17].

Our study provides real-world data on the management of incompletely excised BCC. The main finding of our study was that only 14 of 84 (16.7%) BCCs with positive histopathologic margins did recur clinically. Even among 40 patients that did not receive any treatment after the initial surgery, only 10 (25%) experienced a recurrence. In addition, residual BCC was found only in half of the re-excised tumors.

Surgery of BCC should ideally combine adequate tumor eradication with minimal defects and scars. Incomplete excisions would be easy to avoid by using wide margins [18], but this is undesirable especially on the face. Therefore, the need for the smallest possible cosmetic impairment drives more conservative surgical approaches that increase the risk of incomplete excision. Dermoscopy may improve the clinical margin assessment and minimize the risk of incomplete excisions [19]. The most effective method to combine a high likelihood of complete tumor eradication with sparing of healthy skin is surgery with microscopic margin assessment. However, these techniques are not available in all settings and they are associated with increased requirements in time, resources, and costs. Therefore, even when available, they are indicated for high-risk tumors only [2, 4, 10, 20, 21].

For all the aforementioned reasons, incompletely excised BCCs are not rare in the real clinical setting. The risk of incomplete excision of BCC has been estimated to range from 2 to 20.4%, depending on several factors including the anatomic site, tumor subtype, intended width of clinical margins, type of operation (microscopically controlled or not), experience and skills of the surgeon [6‒8, 13, 19]. In our database, of 1689 BCCs with available histopathologic reports, positive margins were found in 99 (5.8%). Most of the 84 tumors that were finally included in the analysis were located on the H area of the face (47%), while 29% were located in area M and 24% in area L. Most incompletely excised BCCs were nodular, and only 25% of them belonged to one of the high-risk histopathologic subtypes.

Our results highlight that, in clinical practice, management of incompletely excised BCC is individualized and might differ case by case. Although not investigated by the present study, we assume that factors influencing the decision include patients’ age and general status, history of previous BCCs, anatomic location, tumor subtype, other histopathologic characteristics, and others [9, 22, 23]. Our analysis suggests that a high-risk histopathologic subtype is the strongest factor driving the decision to re-excise and that younger patients are more likely to be managed with surgical re-excision in case of histopathologically positive margins. Notably, the fact that post-surgery radiotherapy was not selected for any of the incompletely excised tumors is related to the fact that it is not internally available in our setting and access to it is limited.

In our sample, re-excision was performed in 26 patients and residual BCC was found in only 14 of them, which is in line with previous evidence. This paradoxical finding might be explained by the tissue shrinkage occurring at the periphery of the specimen after surgical excision, or by the inflammatory host response scattered by the used diathermocoagulation/surgical treatment, or by post-surgery activation of the immune system and cytotoxic activity of T cells targeting the remaining neoplastic cells. The methodology that pathologists used to detect residual tumors by performing normal conventional vertical sessions and not by horizontal sections might be another reason, since in that case, the results depend on the number of vertical sections performed per tumor. Whichever the explanation might be, our findings suggest that positive margins do not equal to residual tumor [6‒8, 24].

The approach of watchful waiting for tumor recurrence was selected in 40 patients. The tumor recurred in only 10 of them (25%), at a mean follow-up period of 17 months, but we cannot exclude that some additional BCCs might recur later. This finding is consistent with previous evidence suggesting that only 26–41% of BCCs with involved margins recur clinically [6, 7, 15, 20].

Finally, imiquimod, cryosurgery, or their combination was applied in 18 patients and only 2 of them (11.1%) experienced a recurrence. The efficacy of these modalities for treatment of the primary BCC is well known, with clinical and histopathologic cure rates ranging from 60% to 80% in well-designed RCTs [2, 6, 14‒16, 25]. Although scarce evidence exists on their efficacy for treatment of incompletely excised BCC, in our study they were associated with the lowest recurrence rate as compared to all other options [7, 10].

Our study has several limitations. First, it was a retrospective collection of individually treated patients and not a prospective study with different therapeutic arms. Therefore, all conclusions are based on grouping cases managed in a similar way, without taking into consideration all the individualized parameters that guided each one of these management decisions. Second, our routine histopathologic assays are based on traverse sections rather than the en face technique with horizontal sections. This has known limitations regarding the proportion of tissue visualized and, therefore, puts in doubt the accuracy of margin assessments [4, 10, 11, 26]. Finally, since none of the incompletely excised tumors was treated with post-surgery radiotherapy, no conclusions can be extracted for the use of this modality.

In conclusion, our study suggests that positive histopathologic margins after BCC excision result in a clinical recurrence only in a proportion of patients. This percentage is higher when no further treatment is applied and lower when the area is re-excised or treated with imiquimod alone or combined with cryotherapy.

The aim of the study was to report real-life management of incompletely excised BCC comparison of recurrence rates according to the selected treatment.

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent from participants was not required in accordance with local/national guidelines.

The authors have no conflicts of interest to declare.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

M.D., K.L., and A.L.: conception and design; A.M., V.E, P.E., M.B, I.P., and E.St.: surgical procedure; M.D., C.D., T.G., and K.L: data acquisition and analysis; E.So., E.V., D.I., and A.L.: supervision; all authors: critical revision and final approval of the version to be published.

All data needed to evaluate the conclusions in the paper are presented in the paper. Additional data related to this paper may be requested from the authors.