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Reappraisal of giant basal cell carcinoma: Clinical features and outcomes
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Journal of Plastic, Reconstructive & Aesthetic Surgery (2019) 000, 1–5
Reappraisal of giant basal cell carcinoma: Clinical features and outcomes Deemesh Oudit a,∗, Hoang Pham a, Titus Grecu a, Clare Hodgson a, Megan E. Grant b, Andzhela Abu Rashed b, Donald Allan c, Adele C. Green b,d,e a
The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK c Medical Physics Department, Salford Royal NHS Foundation Trust and University of Manchester, Manchester Academic Health Science Centre, Salford, UK d QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia e Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester b
Received 20 March 2019; accepted 19 June 2019 Available online xxx
KEYWORDS Giant basal cell carcinoma; Surgical treatment; Aggressive BCC; Photodynamic therapy; Radiotherapy
Summary Background: Giant basal cell carcinoma (GBCC) is a rare subgroup of basal cell carcinomas with a diameter of >5 cm. Current evidence about determining factors is conflicting, suggesting patient neglect, on the one hand, and biologically aggressive behaviour, on the other, with outcomes varying from clearance to death. We aimed to clarify the natural history of GBCC and its response to treatment. Methods: We extracted information from clinical records of all patients with GBCC treated from 1998 to 2017 in a tertiary oncology hospital in northwest England. Associations between patient and tumour characteristics were investigated, and modes of treatment and outcomes were assessed. Results: In the 20-year study period, 43 patients (median age 76 years; 23 (53%) female), 3 of whom had Gorlin syndrome, were treated for GBCCs. Median diameter was 6.3 cm, and median time to presentation was 5 years. Seven (16%) GBCCs arose from recurrent BCC, while the majority (84%) presented de novo. The size of GBCC was significantly correlated with delay in presentation (p = 0.03) but not with age or sex. Of 41 patients receiving definitive treatment, 19 GBCCs were treated by excision with ≤1 cm margin and none recurred during follow-up, compared with 10 recurrences of 23 treated with photodynamic therapy (PDT), and 1 of 7 recurred after radiotherapy. Two of 43 patients with GBCC (<5%) presented with extensive local invasion, one of whom also had distant metastases, and both died of the disease.
∗ Corresponding
author. E-mail address: [email protected] (D. Oudit).
https://doi.org/10.1016/j.bjps.2019.06.029 1748-6815/© 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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D. Oudit, H. Pham and T. Grecu et al. Conclusion: The majority of GBCCs are not clinically aggressive and respond to conservative surgical treatment with a low risk of recurrence. © 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Basal cell carcinoma (BCC) is the most common type of skin malignancy affecting mainly the white population worldwide.1 GBCCs comprise a rare subgroup whose diagnosis is based on the longest axis measuring >5 cm, independent of histological subtype, local invasion or metastasis, although each of these has been reported as a potential feature of GBCCs.2 According to the American Joint Cancer Committee classification,3 GBCCs are categorized as T3 tumours. Because of its rarity, GBCC has not been well studied and accounts in the literature have mostly been selected case reports of biologically aggressive variants of BCC at high risk of invading local structures and metastasising4 or small- to moderate-sized case series with similar findings.5 The largest series of 50 GBCC cases collected during a 4-year period at a tertiary centre in the USA suggested that many cases arose from previously treated BCCs and that other factors such as long delay in seeking treatment or high-risk histological subtype were also associated.6 However, in another series of 37 patients with GBCC, no metastases were reported.7 To better understand the presentation, associated factors and clinical course of GBCCs, we carried out a records-based review of all patients treated for GBCC in a tertiary care hospital in northwest England during a 20-year period and documented the features of the patients and their tumours, their clinical management and outcomes on follow-up.
in selected patients). Full clinical details of all GBCC patients were extracted from electronic medical records and patients’ case notes.
Data analysis Patient and tumour data were recorded in a spreadsheet and verified against extraction forms before analysis. MannWhitney tests and Spearman’s rank correlation coefficients were used to test for associations between patient and disease characteristics. Statistical analysis was performed using Stata version 13.
Results A total of 43 patients presented to The Christie with GBCC from 1998 to 2017. One patient (female, aged 85 years) was diagnosed with 3 separate primary GBCCs during the study period, and only features of the first-diagnosed GBCC have been included here. GBCCs presented as de novo lesions in 36 (84%) patients, while 7 (16%) arose in previously treated BCCs (i.e. BCCs that were <5 cm when previously treated). As there was no difference in features and outcomes of these groups when analysed separately, results are presented for all patients who presented with primary GBCC.
Clinical characteristics
Methods This retrospective study was conducted at The Christie NHS Foundation Trust, a large tertiary cancer treatment centre serving a population of more than 3 million people in northwest England. All patients with newly diagnosed GBCCs presenting for treatment from January 1998 to December 2017 were included. We excluded recurrent GBCCs from this series (i.e., lesions that were >5 cm when previously treated) because we could not be certain of the presenting features or treatment history of the original GBCC, and their inclusion may have introduced uncontrolled confounding in our analysis. The study was classified by The Christie Hospital as a clinical service study not requiring research ethics committee approval. Patients were ascertained through several separate treatment registers. Those undergoing surgery were identified through review of all operating diaries in the study period; those undergoing photodynamic therapy (PDT) or radiotherapy were ascertained by searches of the respective oncologists’ registers of all treated patients to identify those with large BCCs (noting that at our institution, a clinical oncologist with a special interest used PDT to treat BCCs
Of the 43 patients, 35 (81%) were aged >60 years and 23 (53%) were female (Tables 1 and 2). GBCCs occurred in similar proportions on the trunk (49%) and head and neck (44%), and 3 (7%) occurred on the lower limb. Median diameter was 6.3 cm, with more than half measuring <7 cm in diameter, while approximately 20% measured ≥9 cm to a maximum of 21 cm (Tables 1 and 2). With regard to histological type, 34 cases (79%) were superficial or nodular (6.7 cm median diameter) and 9 (21%) were reported as micronodular, morphoeic or infiltrative (5.8 cm median diameter). Among the 20 (47%) patients for whom time to clinical presentation was available, median delay was 5 years, ranging from 0.3 to 20 years (Table 1). Time to presentation was not associated with tumour site (p = 0.19). Size of GBCC was associated with increasing time to presentation (Table 1) (Spearman’s rank correlation co-efficient 0.48, p = 0.03) but not with age (p = 0.43) or sex (p = 0. 63).
Treatment and outcomes Of the 43 patients, 19 (44%) were treated by surgery, 5 after failed PDT; 15 (35%) were treated by PDT only and 7 (16%)
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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Giant basal cell carcinoma Table 1
Patient and tumour characteristics of 43 patients with giant basal cell carcinoma.
Characteristics
Age at diagnosis (Years) 35–59 60–79 80+ Sex Female Male Gorlin syndrome Yes No Time to presentationa (yrs) (Median no., range) a
3
Site
Tumour diameter (cm)
Histological type
Head, neck N = 19 (%)
Trunk N = 21 (%)
Lower 5–6.9 7–8.9 limb N = 24 N = 10 N = 3 (%) (%) (%)
9+ N=9 (%)
4 (21) 7 (37) 8 (42)
3 (14) 12 (57) 6 (29)
1 (33) 0 (0) 2 (67)
6 (24) 9 (38) 9 (38)
1 (11) 5 (25) 4 (44) 7 (35) 4 (44) 8 (40)
2 (14) 9 (65) 3 (21)
0 (0) 1 (33) 2 (67)
1 (17) 2 (33) 3 (50)
11 (58) 8 (42)
10 (48) 11 (52)
2 (67) 1 (33)
12 (50) 7 (70) 12 (50) 3 (30)
4 (44) 12 (60) 5 (56) 8 (40)
6 (43) 8 (57)
3 (100) 0 (0)
2 (33) 4 (667
1 (5) 18 (95) 5.6 (3–8)
1 (5) 20 (95) 5 (0.3–20)
1 (33) 2 (67) 1.9 (0.5–4)
2 (8) 22 (92) 2.6 (0.3–5)
1 (11) 8 (89) 9 (4–20)
1 (7) 13 (93) 6.1 (3.7–8.5)
0 (0) 3 (100) –
0 (0) 6 (100) 3 (3)
1 (10) 6 (60) 3 (30)
0 (0) 10 (100) 7 (5–9)
Superficial Nodular MicroMorphoeic/ N = 20 (%) N = 14 (%) nodular infiltrative N = 3 (%) N = 6 (%)
2 (10) 18 (90) 2.7 (2–3)
23 patients had missing data.
by radiotherapy, 3 of whom had first received PDT (Table 2). Among the 19 treated with excision, surgical margins were all ≤1 cm, and after a median follow-up of 1.4 years (range 0.8–6.9), there were no recurrences. Of the 15 treated with PDT alone, after a median follow-up of 3.0 years (range 0.5– 13.3), 2 had recurrent disease at the date of last follow-up (Table 2); both were females with GBCC on the trunk, aged 44 and 77 years, with 6.7 cm and 9.5 cm diameter tumours, respectively. Of the 23 treated by PDT overall, recurrence rate was 43% (10/23). Of the 7 treated with radiotherapy and followed up for a median of 3.3 years (range 0.6–5.9), one female aged 86 years with a 6 cm GBCC on the lower limb had recurrent disease at last recorded follow-up. There were 2 GBCC-related deaths in our series. Although both had extensive local invasion, only one developed metastases: a male aged 53 years, with an extensive GBCC affecting both post-auricular areas and the scalp. Biopsies showed morphoeic subtype with no evidence of basisquamous cells. He was initially treated with multiple PDT courses followed by vismodegib when surgical excision was deemed not feasible. The other patient aged 64 years with Gorlin syndrome had a GBCC of the ear with invasion into the mastoid after a period of neglect. A biopsy showed basisquamous differentiation. A staging CT scan revealed no evidence of metastases, but his tumour was deemed unresectable and he died soon after due to tumour complications.
Discussion In this series of 43 GBCCs treated over a 20-year period, we found that these giant tumours were generally slow-growing and that the majority presented de novo rather than arising in recurrent BCCs as reported in a US series ascertained over a much shorter 4-year period.6 Our patients had a greater proportion of GBCC on the trunk than that seen for BCCs in general8 but no unusual age or sex predilection. The presence of 3 patients with Gorlin syndrome in the series of 43
reflected the existence of a speciality unit for investigation and treatment of patients with Gorlin syndrome within the study hospital. Gorlin syndrome was not found to be associated with GBCC outcome. Among those with known time to presentation, there were substantial delays in seeking treatment (5 years on average, and up to 20 years) consistent with the slow rate of growth (79% were of superficial or nodular subtype), and time to presentation was correlated with size of GBCC. Others have also noted delays in presentation among patients with GBCC,6,8 but these were often counterbalanced in their series by other cases with aggressive histological features such as squamous metaplasia as opposed to the majority of low-risk histological subtypes that we found, and to infiltration and perineural invasion.6 In our 20-year series, there were 2 cases (<5%) with extensive local invasion beyond the depth of the dermis, both of whom died. Indeed, we found that local recurrence of GBCC was related to modality of treatment rather than to tumour features per se. In this series, none of the 44% of patients who underwent surgery had any recurrence (after 1.4 years of median follow-up) and none had a surgical margin >1 cm. Thus, based on our data, 1 cm is an adequate margin for excision of GBCCs, contrary to other reports that these tumours require wide surgical margins of 2–3 cm, with recurrence/metastasis rate of 38%.4 In contrast, of the 23 patients treated with PDT in this study, 10 had recurrent GBCC, 5 of whom were subsequently treated with surgery, 3 with radiotherapy (none of whom had further recurrence) and 2 received further PDT. In the few reports of treatment of GBCCs with PDT in the literature, PDT was used in combination with other modalities such as cryosurgery, surgery and imiquimod.9 Eibenschutz et al. reported a 66% cure rate at 36 months in a series of 19 cases, but 5 of these cases were not GBCCs.10 In our 20-year series, radiotherapy was favoured in those aged more than 80 years and for lesions of intermediate size and superficial histological type. There was no use of topical imiquimod, cryotherapy and 5-fluorouracil to treat GBCC in our series.
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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D. Oudit, H. Pham and T. Grecu et al.
Table 2
Last mode of treatment and outcome according to features of 43 patients with giant basal cell carcinoma. Excisiona N = 19(%)
PDT N = 15 (%)
Radiotherapyb N = 7 (%)
Otherc N = 2 (%)
Total N = 43 (%)
4 (21) 9 (47) 6 (32)
3 (20) 7 (47) 5 (33)
0 (0) 2 (29) 5 (71)
1 (50) 1 (50) 0 (0)
8 (19) 19 (44) 16 (37)
7 (37) 12 (63)
11 (73) 4 (27)
5 (71) 2 (29)
0 (0) 2 (100)
23 (53) 20 (47)
1 (5) 18 (95)
1 (7) 14(93)
0 (0) 7 (100)
1 (50) 1 (50)
3 (7) 40 (93)
8 (42) 9(47) 2 (11)
5 (33) 10 (67) 0 (0)
4 (57) 2 (29) 1 (14)
2 (100) 0 (0) 0 (0)
19 (44) 21 (49) 3 (7)
8 (42) 7 (37) 4 (21)
11 (73) 3 (20) 1 (7)
1 (14) 4 (57) 2 (29)
0 (0) 0 (0) 2 (100)
20 (46) 14 (33) 9 (21)
3 (16) 10 (53)
12 (80) 2 (13)
5 (72) 0 (0)
0 (0) 2 (100)
20 (46) 14 (33)
Characteristics
Excisiona N = 19 (%)
PDT N = 14 (%)
Radiotherapyb N = 7 (%)
Otherc N = 2 (%)
Total N = 43 (%)
Micronodular Morphoeic/infiltrative Outcome Median follow-up (median no. of years, range) Disease-free Yes No Local invasion Yes No Metastases Yes No Death Yes No
1 (5) 5 (26)
1 (7) 0 (0)
1 (14) 1 (14)
0 (0) 0 (0)
3 (7) 6 (14)
1.4 (0.8–6.9)
3.0 (0.5–13.3)
3.3 (0.6–5.9)
4.5 (3.5–5.5)
2.3 (0.8–13.3)
19(100) 0 (0)
12 (80) 3 (20)
6 (86) 1 (14)
0 (0) 2 (100)
38 (88) 5 (12)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
2(100) 0 (0)
2 (5) 41 (95)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
1 (50) 1 (50)
1 (2.5) 42 (97.5)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
2 (100) 0 (0)
2 (5) 41 (95)
Characteristics Patient Age at diagnosis (Years) 35–59 60–79 80+ Sex Female Male Gorlin syndrome Yes No Tumour site Head and neck Trunk Lower Limb Tumour diameter (cm) 5–6.9 7–8.9 9+ Histological type Superficial Nodular
a b c
5 previously treated by photodynamic therapy (PDT). 3 previously treated by PDT. 1 treated by vismodegib after unsuccessful excision/PDT, died later; 1 died before planned treatment with vismodegib.
The main limitations of our study were the large amount of missing data on time before presentation and a lack of long-term follow-up data on a proportion of our cases. Further, we lacked a comparison series of patients, but we used the established clinical and epidemiologic features of BCCs in general as reference values.11 In addition, the long duration of our series meant we included GBCCs that were initially treated with PDT on the assumption that they were histologically superficial BCCs, as these tumours were not biopsied before the PDT in earlier years. Thus, although we
have a relatively large series of GBCCs treated with PDT, we are unable to assess the effectiveness of PDT in this group of tumours. Although our case numbers were relatively small for robust statistical analysis, GBCCs are a rare presentation and our sample represents one of the largest GBCC series reported. A major strength of the study was the long period of ascertainment and follow-up of cases in a single oncology hospital. Based on our findings, it appears that the natural history of GBCC is not aligned to its size but is likely to
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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Giant basal cell carcinoma correlate better with tumour factors such as histological subtype and possibly molecular biomarkers. We would therefore recommend future studies comparing molecular factors such as Twist1-induced EMT in tumour cells or αSMA-positive myofibroblasts12 in GBCC with high-risk histological features, e.g. morphoeic/infiltrative subtypes, and in smaller (<5 cm) BCCs of the same subtypes and also in GBCCs with low-risk features. This would enable correlation of molecular factors with aggressive behaviour per se in both GBCC12 and BCC <5 cm (notwithstanding host factors like immunosuppression).
Conclusion In an extensive case series collected over 20 years, we found that GBCCs were generally slow-growing tumours that can be treated adequately by surgery with ≤1 cm margins. The aggressive behaviour of GBCC was likely correlated with high-risk histological subtypes as seen among BCCs in general, irrespective of size.
CRediT authorship contribution statement Deemesh Oudit: Conceptualization, Formal analysis, Writing - original draft, Validation. Hoang Pham: Data curation, Conceptualization, Writing - original draft, Validation. Titus Grecu: Data curation, Validation. Clare Hodgson: Data curation, Formal analysis, Writing - original draft, Validation. Megan E. Grant: Data curation, Writing - original draft, Validation. Andzhela Abu Rashed: Data curation, Validation. Donald Allan: Data curation, Validation. Adele C. Green: Conceptualization, Formal analysis, Writing - original draft, Validation.
Acknowledgements We are grateful for the contributions and assistance of Professor Richard Marais, Professor of Molecular Oncology, CRUK Manchester Institute, University of Manchester; Professor Martin Cook, Consultant Histopathologist, CRUK Manchester Institute, University of Manchester; Mr David Mowatt, Mr. Damir Kosutic and Mr Gerard Lambe, Consultant Plastic Surgeons, Dr Ernest Allan, Dr Andrew Sykes and Dr Agata Rembielak, Consultant Clinical Oncologists, The Christie NHS Foundation Trust.
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Financial disclosure We are grateful to the CRUK Manchester Institute Core Grant (reference: A27412) for funding part of the study.
References 1. Telfer NR, Colver GB, Morton CA. British Association of D. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008;159(1):35–48 PubMed PMID:18593385. 2. Mott SE, Hunter WJ, Silva E, Huerter CJ. Approach to management of giant basal cell carcinomas. Cutis 2017;99(5):356–62 PubMed PMID:28632797. 3. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin 2017;67(2):93–9 PubMed PMID:28094848. 4. Archontaki M, Stavrianos SD, Korkolis DP, Arnogiannaki N, Vassiliadis V, Liapakis IE, et al. Giant Basal cell carcinoma: clinicopathological analysis of 51 cases and review of the literature. Anticancer Res 2009;29(7):2655–63 PubMed PMID:19596942. 5. Maimaiti A, Mijiti A, Yarbag A, Moming A. Giant basal cell carcinoma of the face: surgical management and challenges for reconstruction. J Laryngol Otol 2016;130(2):176–82 PubMed PMID:26676100. 6. Randle HW, Roenigk RK, Brodland DG. Giant basal cell carcinoma (T3). Who is at risk? Cancer 1993;72(5):1624–30 PubMed PMID:8348493. 7. Codazzi D, Bruschi S, Bocchiotti MA, Robotti E. Giant basal cell carcinoma: a series of 37 cases without metastasis. Plast Reconstr Surg 2012;129(6):999e–1000e author reply e-1e. PubMed PMID:22634697. 8. Kokavec R, Fedeles J. Giant basal cell carcinomas: a result of neglect? Acta Chir Plast 2004;46(3):67–9 PubMed PMID:15663105. 9. Requena C, Messeguer F, Llombart B, Serra-Guillen C, Guillen C. Facial extensive recurrent basal cell carcinoma: successful treatment with photodynamic therapy and imiquimod 5% cream. Int J Dermatol 2012;51(4):451–4 PubMed PMID:22435437. 10. Eibenschutz L, Marenda S, Buccini P, et al. Giant and large basal cell carcinoma treated with topical photodynamic therapy. Eur J Dermatol EJD 2008;18(6):663–6 PubMed PMID:18955200. 11. Verkouteren JAC, Ramdas KHR, Wakkee M, Nijsten T. Epidemiology of basal cell carcinoma: scholarly review. Br J Dermatol 2017;177(2):359–72 PubMed PMID:28220485. 12. Motegi S, Yamada K, Ishikawa O. Twist1 in tumour cells and α-smooth muscle actin in stromal cells are possible biomarkers for metastatic giant basal cell carcinomas. J Dermatol 2013;40(8):661–3 Pubmed PMID:23683049.
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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Journal of Plastic, Reconstructive & Aesthetic Surgery (2019) 000, 1–5
Reappraisal of giant basal cell carcinoma: Clinical features and outcomes Deemesh Oudit a,∗, Hoang Pham a, Titus Grecu a, Clare Hodgson a, Megan E. Grant b, Andzhela Abu Rashed b, Donald Allan c, Adele C. Green b,d,e a
The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK c Medical Physics Department, Salford Royal NHS Foundation Trust and University of Manchester, Manchester Academic Health Science Centre, Salford, UK d QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia e Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester b
Received 20 March 2019; accepted 19 June 2019 Available online xxx
KEYWORDS Giant basal cell carcinoma; Surgical treatment; Aggressive BCC; Photodynamic therapy; Radiotherapy
Summary Background: Giant basal cell carcinoma (GBCC) is a rare subgroup of basal cell carcinomas with a diameter of >5 cm. Current evidence about determining factors is conflicting, suggesting patient neglect, on the one hand, and biologically aggressive behaviour, on the other, with outcomes varying from clearance to death. We aimed to clarify the natural history of GBCC and its response to treatment. Methods: We extracted information from clinical records of all patients with GBCC treated from 1998 to 2017 in a tertiary oncology hospital in northwest England. Associations between patient and tumour characteristics were investigated, and modes of treatment and outcomes were assessed. Results: In the 20-year study period, 43 patients (median age 76 years; 23 (53%) female), 3 of whom had Gorlin syndrome, were treated for GBCCs. Median diameter was 6.3 cm, and median time to presentation was 5 years. Seven (16%) GBCCs arose from recurrent BCC, while the majority (84%) presented de novo. The size of GBCC was significantly correlated with delay in presentation (p = 0.03) but not with age or sex. Of 41 patients receiving definitive treatment, 19 GBCCs were treated by excision with ≤1 cm margin and none recurred during follow-up, compared with 10 recurrences of 23 treated with photodynamic therapy (PDT), and 1 of 7 recurred after radiotherapy. Two of 43 patients with GBCC (<5%) presented with extensive local invasion, one of whom also had distant metastases, and both died of the disease.
∗ Corresponding
author. E-mail address: [email protected] (D. Oudit).
https://doi.org/10.1016/j.bjps.2019.06.029 1748-6815/© 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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D. Oudit, H. Pham and T. Grecu et al. Conclusion: The majority of GBCCs are not clinically aggressive and respond to conservative surgical treatment with a low risk of recurrence. © 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Basal cell carcinoma (BCC) is the most common type of skin malignancy affecting mainly the white population worldwide.1 GBCCs comprise a rare subgroup whose diagnosis is based on the longest axis measuring >5 cm, independent of histological subtype, local invasion or metastasis, although each of these has been reported as a potential feature of GBCCs.2 According to the American Joint Cancer Committee classification,3 GBCCs are categorized as T3 tumours. Because of its rarity, GBCC has not been well studied and accounts in the literature have mostly been selected case reports of biologically aggressive variants of BCC at high risk of invading local structures and metastasising4 or small- to moderate-sized case series with similar findings.5 The largest series of 50 GBCC cases collected during a 4-year period at a tertiary centre in the USA suggested that many cases arose from previously treated BCCs and that other factors such as long delay in seeking treatment or high-risk histological subtype were also associated.6 However, in another series of 37 patients with GBCC, no metastases were reported.7 To better understand the presentation, associated factors and clinical course of GBCCs, we carried out a records-based review of all patients treated for GBCC in a tertiary care hospital in northwest England during a 20-year period and documented the features of the patients and their tumours, their clinical management and outcomes on follow-up.
in selected patients). Full clinical details of all GBCC patients were extracted from electronic medical records and patients’ case notes.
Data analysis Patient and tumour data were recorded in a spreadsheet and verified against extraction forms before analysis. MannWhitney tests and Spearman’s rank correlation coefficients were used to test for associations between patient and disease characteristics. Statistical analysis was performed using Stata version 13.
Results A total of 43 patients presented to The Christie with GBCC from 1998 to 2017. One patient (female, aged 85 years) was diagnosed with 3 separate primary GBCCs during the study period, and only features of the first-diagnosed GBCC have been included here. GBCCs presented as de novo lesions in 36 (84%) patients, while 7 (16%) arose in previously treated BCCs (i.e. BCCs that were <5 cm when previously treated). As there was no difference in features and outcomes of these groups when analysed separately, results are presented for all patients who presented with primary GBCC.
Clinical characteristics
Methods This retrospective study was conducted at The Christie NHS Foundation Trust, a large tertiary cancer treatment centre serving a population of more than 3 million people in northwest England. All patients with newly diagnosed GBCCs presenting for treatment from January 1998 to December 2017 were included. We excluded recurrent GBCCs from this series (i.e., lesions that were >5 cm when previously treated) because we could not be certain of the presenting features or treatment history of the original GBCC, and their inclusion may have introduced uncontrolled confounding in our analysis. The study was classified by The Christie Hospital as a clinical service study not requiring research ethics committee approval. Patients were ascertained through several separate treatment registers. Those undergoing surgery were identified through review of all operating diaries in the study period; those undergoing photodynamic therapy (PDT) or radiotherapy were ascertained by searches of the respective oncologists’ registers of all treated patients to identify those with large BCCs (noting that at our institution, a clinical oncologist with a special interest used PDT to treat BCCs
Of the 43 patients, 35 (81%) were aged >60 years and 23 (53%) were female (Tables 1 and 2). GBCCs occurred in similar proportions on the trunk (49%) and head and neck (44%), and 3 (7%) occurred on the lower limb. Median diameter was 6.3 cm, with more than half measuring <7 cm in diameter, while approximately 20% measured ≥9 cm to a maximum of 21 cm (Tables 1 and 2). With regard to histological type, 34 cases (79%) were superficial or nodular (6.7 cm median diameter) and 9 (21%) were reported as micronodular, morphoeic or infiltrative (5.8 cm median diameter). Among the 20 (47%) patients for whom time to clinical presentation was available, median delay was 5 years, ranging from 0.3 to 20 years (Table 1). Time to presentation was not associated with tumour site (p = 0.19). Size of GBCC was associated with increasing time to presentation (Table 1) (Spearman’s rank correlation co-efficient 0.48, p = 0.03) but not with age (p = 0.43) or sex (p = 0. 63).
Treatment and outcomes Of the 43 patients, 19 (44%) were treated by surgery, 5 after failed PDT; 15 (35%) were treated by PDT only and 7 (16%)
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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Giant basal cell carcinoma Table 1
Patient and tumour characteristics of 43 patients with giant basal cell carcinoma.
Characteristics
Age at diagnosis (Years) 35–59 60–79 80+ Sex Female Male Gorlin syndrome Yes No Time to presentationa (yrs) (Median no., range) a
3
Site
Tumour diameter (cm)
Histological type
Head, neck N = 19 (%)
Trunk N = 21 (%)
Lower 5–6.9 7–8.9 limb N = 24 N = 10 N = 3 (%) (%) (%)
9+ N=9 (%)
4 (21) 7 (37) 8 (42)
3 (14) 12 (57) 6 (29)
1 (33) 0 (0) 2 (67)
6 (24) 9 (38) 9 (38)
1 (11) 5 (25) 4 (44) 7 (35) 4 (44) 8 (40)
2 (14) 9 (65) 3 (21)
0 (0) 1 (33) 2 (67)
1 (17) 2 (33) 3 (50)
11 (58) 8 (42)
10 (48) 11 (52)
2 (67) 1 (33)
12 (50) 7 (70) 12 (50) 3 (30)
4 (44) 12 (60) 5 (56) 8 (40)
6 (43) 8 (57)
3 (100) 0 (0)
2 (33) 4 (667
1 (5) 18 (95) 5.6 (3–8)
1 (5) 20 (95) 5 (0.3–20)
1 (33) 2 (67) 1.9 (0.5–4)
2 (8) 22 (92) 2.6 (0.3–5)
1 (11) 8 (89) 9 (4–20)
1 (7) 13 (93) 6.1 (3.7–8.5)
0 (0) 3 (100) –
0 (0) 6 (100) 3 (3)
1 (10) 6 (60) 3 (30)
0 (0) 10 (100) 7 (5–9)
Superficial Nodular MicroMorphoeic/ N = 20 (%) N = 14 (%) nodular infiltrative N = 3 (%) N = 6 (%)
2 (10) 18 (90) 2.7 (2–3)
23 patients had missing data.
by radiotherapy, 3 of whom had first received PDT (Table 2). Among the 19 treated with excision, surgical margins were all ≤1 cm, and after a median follow-up of 1.4 years (range 0.8–6.9), there were no recurrences. Of the 15 treated with PDT alone, after a median follow-up of 3.0 years (range 0.5– 13.3), 2 had recurrent disease at the date of last follow-up (Table 2); both were females with GBCC on the trunk, aged 44 and 77 years, with 6.7 cm and 9.5 cm diameter tumours, respectively. Of the 23 treated by PDT overall, recurrence rate was 43% (10/23). Of the 7 treated with radiotherapy and followed up for a median of 3.3 years (range 0.6–5.9), one female aged 86 years with a 6 cm GBCC on the lower limb had recurrent disease at last recorded follow-up. There were 2 GBCC-related deaths in our series. Although both had extensive local invasion, only one developed metastases: a male aged 53 years, with an extensive GBCC affecting both post-auricular areas and the scalp. Biopsies showed morphoeic subtype with no evidence of basisquamous cells. He was initially treated with multiple PDT courses followed by vismodegib when surgical excision was deemed not feasible. The other patient aged 64 years with Gorlin syndrome had a GBCC of the ear with invasion into the mastoid after a period of neglect. A biopsy showed basisquamous differentiation. A staging CT scan revealed no evidence of metastases, but his tumour was deemed unresectable and he died soon after due to tumour complications.
Discussion In this series of 43 GBCCs treated over a 20-year period, we found that these giant tumours were generally slow-growing and that the majority presented de novo rather than arising in recurrent BCCs as reported in a US series ascertained over a much shorter 4-year period.6 Our patients had a greater proportion of GBCC on the trunk than that seen for BCCs in general8 but no unusual age or sex predilection. The presence of 3 patients with Gorlin syndrome in the series of 43
reflected the existence of a speciality unit for investigation and treatment of patients with Gorlin syndrome within the study hospital. Gorlin syndrome was not found to be associated with GBCC outcome. Among those with known time to presentation, there were substantial delays in seeking treatment (5 years on average, and up to 20 years) consistent with the slow rate of growth (79% were of superficial or nodular subtype), and time to presentation was correlated with size of GBCC. Others have also noted delays in presentation among patients with GBCC,6,8 but these were often counterbalanced in their series by other cases with aggressive histological features such as squamous metaplasia as opposed to the majority of low-risk histological subtypes that we found, and to infiltration and perineural invasion.6 In our 20-year series, there were 2 cases (<5%) with extensive local invasion beyond the depth of the dermis, both of whom died. Indeed, we found that local recurrence of GBCC was related to modality of treatment rather than to tumour features per se. In this series, none of the 44% of patients who underwent surgery had any recurrence (after 1.4 years of median follow-up) and none had a surgical margin >1 cm. Thus, based on our data, 1 cm is an adequate margin for excision of GBCCs, contrary to other reports that these tumours require wide surgical margins of 2–3 cm, with recurrence/metastasis rate of 38%.4 In contrast, of the 23 patients treated with PDT in this study, 10 had recurrent GBCC, 5 of whom were subsequently treated with surgery, 3 with radiotherapy (none of whom had further recurrence) and 2 received further PDT. In the few reports of treatment of GBCCs with PDT in the literature, PDT was used in combination with other modalities such as cryosurgery, surgery and imiquimod.9 Eibenschutz et al. reported a 66% cure rate at 36 months in a series of 19 cases, but 5 of these cases were not GBCCs.10 In our 20-year series, radiotherapy was favoured in those aged more than 80 years and for lesions of intermediate size and superficial histological type. There was no use of topical imiquimod, cryotherapy and 5-fluorouracil to treat GBCC in our series.
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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D. Oudit, H. Pham and T. Grecu et al.
Table 2
Last mode of treatment and outcome according to features of 43 patients with giant basal cell carcinoma. Excisiona N = 19(%)
PDT N = 15 (%)
Radiotherapyb N = 7 (%)
Otherc N = 2 (%)
Total N = 43 (%)
4 (21) 9 (47) 6 (32)
3 (20) 7 (47) 5 (33)
0 (0) 2 (29) 5 (71)
1 (50) 1 (50) 0 (0)
8 (19) 19 (44) 16 (37)
7 (37) 12 (63)
11 (73) 4 (27)
5 (71) 2 (29)
0 (0) 2 (100)
23 (53) 20 (47)
1 (5) 18 (95)
1 (7) 14(93)
0 (0) 7 (100)
1 (50) 1 (50)
3 (7) 40 (93)
8 (42) 9(47) 2 (11)
5 (33) 10 (67) 0 (0)
4 (57) 2 (29) 1 (14)
2 (100) 0 (0) 0 (0)
19 (44) 21 (49) 3 (7)
8 (42) 7 (37) 4 (21)
11 (73) 3 (20) 1 (7)
1 (14) 4 (57) 2 (29)
0 (0) 0 (0) 2 (100)
20 (46) 14 (33) 9 (21)
3 (16) 10 (53)
12 (80) 2 (13)
5 (72) 0 (0)
0 (0) 2 (100)
20 (46) 14 (33)
Characteristics
Excisiona N = 19 (%)
PDT N = 14 (%)
Radiotherapyb N = 7 (%)
Otherc N = 2 (%)
Total N = 43 (%)
Micronodular Morphoeic/infiltrative Outcome Median follow-up (median no. of years, range) Disease-free Yes No Local invasion Yes No Metastases Yes No Death Yes No
1 (5) 5 (26)
1 (7) 0 (0)
1 (14) 1 (14)
0 (0) 0 (0)
3 (7) 6 (14)
1.4 (0.8–6.9)
3.0 (0.5–13.3)
3.3 (0.6–5.9)
4.5 (3.5–5.5)
2.3 (0.8–13.3)
19(100) 0 (0)
12 (80) 3 (20)
6 (86) 1 (14)
0 (0) 2 (100)
38 (88) 5 (12)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
2(100) 0 (0)
2 (5) 41 (95)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
1 (50) 1 (50)
1 (2.5) 42 (97.5)
0 (0) 19(100)
0 (0) 15 (100)
0 (0) 7(100)
2 (100) 0 (0)
2 (5) 41 (95)
Characteristics Patient Age at diagnosis (Years) 35–59 60–79 80+ Sex Female Male Gorlin syndrome Yes No Tumour site Head and neck Trunk Lower Limb Tumour diameter (cm) 5–6.9 7–8.9 9+ Histological type Superficial Nodular
a b c
5 previously treated by photodynamic therapy (PDT). 3 previously treated by PDT. 1 treated by vismodegib after unsuccessful excision/PDT, died later; 1 died before planned treatment with vismodegib.
The main limitations of our study were the large amount of missing data on time before presentation and a lack of long-term follow-up data on a proportion of our cases. Further, we lacked a comparison series of patients, but we used the established clinical and epidemiologic features of BCCs in general as reference values.11 In addition, the long duration of our series meant we included GBCCs that were initially treated with PDT on the assumption that they were histologically superficial BCCs, as these tumours were not biopsied before the PDT in earlier years. Thus, although we
have a relatively large series of GBCCs treated with PDT, we are unable to assess the effectiveness of PDT in this group of tumours. Although our case numbers were relatively small for robust statistical analysis, GBCCs are a rare presentation and our sample represents one of the largest GBCC series reported. A major strength of the study was the long period of ascertainment and follow-up of cases in a single oncology hospital. Based on our findings, it appears that the natural history of GBCC is not aligned to its size but is likely to
Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029
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Giant basal cell carcinoma correlate better with tumour factors such as histological subtype and possibly molecular biomarkers. We would therefore recommend future studies comparing molecular factors such as Twist1-induced EMT in tumour cells or αSMA-positive myofibroblasts12 in GBCC with high-risk histological features, e.g. morphoeic/infiltrative subtypes, and in smaller (<5 cm) BCCs of the same subtypes and also in GBCCs with low-risk features. This would enable correlation of molecular factors with aggressive behaviour per se in both GBCC12 and BCC <5 cm (notwithstanding host factors like immunosuppression).
Conclusion In an extensive case series collected over 20 years, we found that GBCCs were generally slow-growing tumours that can be treated adequately by surgery with ≤1 cm margins. The aggressive behaviour of GBCC was likely correlated with high-risk histological subtypes as seen among BCCs in general, irrespective of size.
CRediT authorship contribution statement Deemesh Oudit: Conceptualization, Formal analysis, Writing - original draft, Validation. Hoang Pham: Data curation, Conceptualization, Writing - original draft, Validation. Titus Grecu: Data curation, Validation. Clare Hodgson: Data curation, Formal analysis, Writing - original draft, Validation. Megan E. Grant: Data curation, Writing - original draft, Validation. Andzhela Abu Rashed: Data curation, Validation. Donald Allan: Data curation, Validation. Adele C. Green: Conceptualization, Formal analysis, Writing - original draft, Validation.
Acknowledgements We are grateful for the contributions and assistance of Professor Richard Marais, Professor of Molecular Oncology, CRUK Manchester Institute, University of Manchester; Professor Martin Cook, Consultant Histopathologist, CRUK Manchester Institute, University of Manchester; Mr David Mowatt, Mr. Damir Kosutic and Mr Gerard Lambe, Consultant Plastic Surgeons, Dr Ernest Allan, Dr Andrew Sykes and Dr Agata Rembielak, Consultant Clinical Oncologists, The Christie NHS Foundation Trust.
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Financial disclosure We are grateful to the CRUK Manchester Institute Core Grant (reference: A27412) for funding part of the study.
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Please cite this article as: D. Oudit, H. Pham and T. Grecu et al., Reappraisal of giant basal cell carcinoma: Clinical features and outcomes, Journal of Plastic, Reconstructive & Aesthetic Surgery, https://doi.org/10.1016/j.bjps.2019.06.029