Basal Cell Carcinoma Multiplicity – a Retrospective Analysis of 899 Biopsy-proven Patients from a Single Institute

Summary

Background:
An interesting clinical feature of basal cell carcinoma (BCC) of the skin is a marked interpatient variation in tumor number, lesion accrual and anatomic distribution. We analyzed a proportion of patients with multiple BCCs in the cohort of pathology report-confirmed cases of BCC and investigated clinicopathological differences between individuals suffering from multiple tumor lesions and patients with a single tumor.

Material and Methods:
All consecutive patients with primary cutaneous BCCs, who were histologically diagnosed at our Department of Pathology during a 10-year period were enrolled into the study.

Results:
A cohort of 899 participants with a total of 1,239 histologically proven primary BCCs were assessed. Of them, 728 (81%) had single BCC and 171 (19%) had multiple BCCs. Multiple lesions occurred more frequently in men than women. Mean number of tumors per patient was 1.5 in males and 1.2 in females. Among participants with multiple BCC manifestation, there was a steady increase of the male-to-female ratio with rising tumor number per individual. In the multiple BCC subgroup, the tumors were found more commonly in the trunk and upper limbs, and less frequently in the face. Histologically, these BCCs much more commonly included superficial subtype. There was a positive correlation between the non-aggressive histologic phenotype of BCC and multiple tumor presentations on the one hand, and the aggressive histologic phenotype of BCC and a single tumor occurrence on the other.

Conclusion:
Our analysis shows that clinicopathological features associated with multiple BCC manifestations include male gender, tumor location in the trunk and upper extremities, and superficial histological subtype. Focus on this risk profile may be beneficial for clinical screening and may help clinicians in the selection of individuals, who should be followed-up more closely.

Key words:
basal cell carcinoma – single and multiple manifestations – clinicopathological differences

Introduction

A striking clinical feature of cutaneous basal cell carcinoma (BCC) is a marked interpatient variation in tumor number, sites and accrual of new lesions [1,2]. While some patients have developed one BCC only, a proportion of patients is affected multiple times by new primary tumor. Further, although most patients demonstrate a single lesion at each presentation, others may suffer from many tumor clusters at different locations [1,2]. The rate and extent to which this occurs is quite unclear. In clinical practice, it would be useful to predict the probability for additional new BCC development in the patients who were affected by a first initial lesion.  Information on the frequency and timing of these subsequent BCCs may be crucial for adequate follow-up care. A recent meta-analysis showed that approximately 29% of patients with a first BCC will develop at least one more lesion in their lifetime [3]. Another previous study estimated that 5-year risk for further BCC development in relation to number of prior BCC is rising as follows: 27% in 1 BCC, 49% in 2 BCCs, 68% in 3 BCCs, 73% in 4–5 BCCs, 78% in 6–9 BCCs, and 90% in ≥ 10 BCCs [4]. However, these data cannot be universally accepted and are insufficient for reliable individual prediction in dermatological practice. The main risk factors for sporadic BCC include excessive exposure to sunlight, age, male gender, phenotypic characteristics and genetic predisposition. In contrast, the risk factor profile of those individuals who develop many subsequent BCCs during their life is less documented [5,6]. Moreover, a recent study gives evidence that the risk factor profile for a second BCC differs from the first BCC [6].

In the current study, we analyzed a proportion of patients with multiple cutaneous BCCs in the cohort of pathology report-confirmed cases of BCC at our institution. Also, we investigated clinicopathological differences between individuals suffering from multiple BCC lesions and patients with only a single tumor.

Material and methods

We retrospectively reviewed all consecutive patients with BCCs of the skin whowere histologically diagnosed at the Department of Pathology at the Faculty Hospital in Žilina from January 2007 through December 2016. All participants were registered in the Pathology Archive Computer Program (PACP), from which required histopathological data were extracted. Baseline clinical data needed for the study were obtained from the medical records. To our knowledge, one man suffered from genetically verified Gorlin-Goltz syndrome, that is well-known for its susceptibility to multiple BCCs development [7,8].  Relapsing tumors, as well as subsequent re-excisions after inadequate tumor removal, were excluded from the study because they did not represent a primary lesions. A presence of ≥ 2 primary tumors in a single patient already included in the file was considered BCC multiplicity (multiple BCC subgroup). When a patient had only one primary BCC registered in the PACP, the case was assigned to single BCC subgroup. Biopsy samples were obtained from a variety of clinical departments (mostly surgery, dermatology, otorhinolaryngology and ophthalmology) at our hospital.  Biopsy material was fixed in buffered formalin, embedded in paraffin blocks and stained with hematoxylin and eosin. If necessary, immunohistochemical staining methods were also applied. The histopathological classification of BCC subtypes was done using the latest World Health Organization classification system of skin cancers [9]. Further, all the cases were simply categorized into non-aggressive and aggressive histologic phenotypes, according to our previous paper [10]. Briefly, while the infiltrative (morpheaform), micronodular and metatypical BCC subtypes were classified as aggressive-growth phenotypes, all others were considered to be indolent. Data were collected in a databank, using the SPSS Statistics software. For the statistical analysis, chi-square test was employed and p < 0.05 was considered significant.

Results

Study population and histopathological data

A cohort of 899 patients with a total of 1,239 histologically proven primary BCCs were assessed. Among them, 467 (51.9%) were females and 432 (48.1%) were males resulting in male/female ratio of 1: 1.08. The average age of participants was 70.4 years without an apparent difference between males (69.8 years) and females (70.4 years). Age ranged from 27 to 97 years and most cases (969; 78.2%) involved patients older than 60 years. The number of pathology report-confirmed lesions per patient ranged from 1 to 17, with a mean of 1.3 and a median of 1. Topographic distribution of BCCs was as follows: head and neck (852 cases; 68.8%), trunk (268 cases; 21.6%), upper extremities (86 cases; 6.9%) and lower extremities (33 cases; 2.7%). The three most frequent histologic subtypes present were nodular (500 cases; 40.3%), mixed nodular-infiltrative (244 cases; 19.7%) and superficial (164 cases; 13.2%). Infiltrative BCC comprised 99 cases (8.0%).

Single vs. multiple BCC presentation

Of all the 899 patients who entered the study, 728 (81.0%) had single BCC and 171 (19.0%) had multiple BCCs. In the second subgroup, 84 people (49.1%) were diagnosed with at least two or more BCCs on the same date. A man suffering from Gorlin-Goltz syndrome was found to have a total of 11 primary lesions. He was 35 years old at the time of the last BCC diagnosis. We have confirmed apparent differences in several clinicopathological parameters between the single and multiple BCC subgroups, summarized in Tab. 1. Multiple BCCs occurred more frequently in men than women (p = 0.01) attaining a statistical significance. Mean number of tumors per patient was 1.5 in males and 1.2 in females. Among participants with multiple BCC manifestation, we found a steady increase of the male-to-female ratio with rising tumor number per individual (Tab. 2). While this ratio was nearly equal in the set of patients having two lesions, it reached value of 7: 1 in the set of members manifesting ≥ 7 primary tumors. There was a strong correlation regarding tumor topographic distribution. Compared to single BCC patient cohort, in the multiple BCC subgroup, the tumors were found more commonly in the trunk (p < 0.0001) and upper limbs (p = 0.02) and vice versa, much less frequently in the face (p < 0.0001). Among 171 patients having ≥ 2 BCCs, 29 subjects (17.0%) had truncal lesions only and 100 (58.4%) subjects had all lesions present explicitly in the extratruncal sites. Within these two subsets, male gender was more prone to have solely truncal tumors (Tab. 3). Histologically, in multiple BCC subgroup, tumors included the superficial subtype much more commonly (p < 0.0001). Although no statistical significance was found among all other histologic subtypes, there was a positive correlation (p < 0.02) between the non-aggressive histologic phenotype of BCC and multiple tumor presentation on the one hand, and the aggressive histologic phenotype of BCC and a single tumor occurrence on the other.

Discussion

Currently, BCC of the skin is the most common malignancy in humans. In fact, it represents a heterogeneous group of tumors with variable clinical behavior and histomorphology [11]. Many patients are prone to developing multiple primary lesions at different body sites. As a result, the incidence of persons affected by BCC probably underestimates the true incidence of this neoplasia due to the common occurrence of multiple primary lesions within individuals [12]. In the literature, the percentage of patients with more than one primary BCC varied from 12% to 46% [2,5,6,12–16] and mean number of tumors per individual ranged from 1.5 to 1.9 [15,17]. This variability is due to several factors, such as the total number of participants, follow-up periods and active surveillance. In our retrospective analysis, 19% of all 899 patients with biopsy report-confirmed cutaneous BCC registered in our pathology database had ≥ primary lesions, and the mean number of tumors per individual was 1.3. These values seems to be slightly lower compared with the studies mentioned above. However, we only aimed to determine a proportion of the individuals with multiple BCCs in defined cohorts of patients without their precise follow-up. We realize that it is a crucial limitation of the study, since we could assess only data that were available  within our pathology database. Further, we may have missed BCC diagnoses that were not made based on histopathology, leading to misclassification bias, although we suppose that such cases comprised a very small percentage.

The risk factor profile of the individuals who develop repeated new BCCs during their life is relatively poorly elucidated. The results of several previous studies suggested that the key predisposing factors for multiple BCC development include younger age and superficial BCC subtype at the time of the first diagnosis [5,6,18], red hair phenotype [5], initial or frequent tumor location in the trunk [1,4,5,6,18] or the upper extremities [5] and clinical manifestation with tumor clusters [2]. Further, some studies [12,16,17] have shown that men have higher risk of developing multiple BCCs than women. On contrary, Mantese et al. did not find statistically significant difference between genders regarding the number of lesions [15].

It seems very unlikely that the differences between single vs multiple BCC development result from different UVR exposure patterns solely. Some authorities [1,2] believe that this reflects the heterogeneity of the BCC case group, faster tumor accrual and initial cluster presentation may suggest reduced effectiveness in immune surveillance. However, the genetic factors and individual characteristics associated with susceptibility to this cancer are still unclear. Even the question on clonality of neoplastic cells in persons suffering from multiple BCC has not been clarified until now. The results of some authors [19] suggested that their origin is polyclonal and may not arise from the same progenitor cell. However, another molecular study [20] contradicts such hypothesis.

Several clinicopathological differences exist depending on whether the patients have single or multiple BCCs during their lifetime. We have found that patients with multiple BCC lesions showed a higher prevalence of male gender. In addition, while there was nearly an equal proportion of men and women in the subset of members with two BCCs, the male-to-female ratio continuously increased with the number of additional lesions. These findings suggest that men are more prone to develop a larger number of BCCs than women, corroborating observations from some previous studies [12,16,17]. Further, we confirmed that in the subgroup of patients with multiple BCCs, the tumors developed more frequently in the back and upper limbs and vice versa, much less frequently in the face. Histologically, these BCCs more commonly consisted of the superficial subtype and less commonly of the nodular and the infiltrative ones. These data are consistent with the results published by Kiiski et al. [5]. Of note, Kiiski et al. [5] observed no associations between both, single vs multiple BCC subgroups and cumulative UVR exposure during one’s lifetime. Another recent study [6] demonstrated that no significant influence was found for phenotype status and UVR-related characteristic on the development of a second BCC after a prior one. We are not able to comment on those findings, since we do not have sufficient information on phenotype and lifetime behavior of the patients and our work has not been focused on this topic.

In conclusion, BCC multiplicity is a frequent finding in a routine dermatological practice. Our analysis shows that clinicopathological features associated with multiple BCC manifestations include male gender, tumor location in the trunk and upper extremities and superficial histologic subtype. Since identifying which patients will most probably manifest multiple lesions throughout life allows earlier removal of new lesions with reduced morbidity, focusing on this risk profile may be beneficial for clinical screening and may help clinicians in the selection of individuals, who should be followed-up more closely.

Acknowledgments

The authors wish to thank MUDr. Zacharová Oľga and MUDr. Pokorný Dušan for their educational support.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Vladimir Bartos, MD, PhD., MSc.

Department of Pathology Faculty Hospital in Žilina

Vojtecha Spanyola 43

012 07 Žilina

Slovak Republic

e-mail: vladim.bartos@gmail.com

Submitted: 21. 12. 2016

Accepted: 17. 2. 2017