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Clinical and Experimental Ophthalmology 2014; 42: 603–607 doi: 10.1111/ceo.12298
Original Article Histological subtypes of periocular basal cell carcinoma Albert Wu,1 Michelle T Sun MBBS,1 Shyamala C Huilgol MBBS(Hons) FACD,2 Simon Madge FRCOphth1,3 and Dinesh Selva FRANZCO1 1
South Australian Institute of Ophthalmology, and 2Department of Dermatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia; and 3Department of Ophthalmology, Hereford County Hospital, Hereford, UK
ABSTRACT Background: To determine the proportion of different subtypes of periocular BCC in South Australia. Design: Retrospective review. Participants: One thousand seven hundred thirteen consecutive periocular basal cell carcinoma (BCC) excision specimens. Methods: Histological analysis of consecutive periocular BCC specimens. Main Outcome Measures: Date of resection, patient age at resection, gender, tumour location, histological subtype and perineural invasion. Results: From 2006 to 2012, a total of 1713 consecutive periocular BCC excision specimens were analysed. The mean age at resection was 68.8 years (median: 71, range: 21–101). Most specimens (56.4%) were removed from male patients. 52.7% involved the lower eyelid, 29.0% the medial canthus, 10.9% the lateral canthus and 7.5% the upper eyelid. The main histological subtypes identified were nodular (65.7%), infiltrative (17.5%), superficial (12.6%) and micronodular (4.2%). Of the specimens, 25.6% had more than one subtype. The most common subtype combinations were nodular with infiltrative (49.7%), and nodular with superficial (26.0%).
Conclusions: The majority of periocular BCC were located on the lower lid and classified histologically as nodular. Infiltrative BCC occurred more frequently than the superficial subtype. As the proportion of mixed BCC containing aggressive subtypes is high, surgical excision with margin control should be considered for periocular BCC. Key words:
basal cell carcinoma, epidemiology, eyelid.
INTRODUCTION Basal cell carcinoma (BCC) is the most common eyelid cancer in Australia, accounting for up to 90% of all malignant eyelid tumours.1,2 The high incidence of BCC in Australia has been attributed to high levels of sunlight exposure and a fair-skinned population of increasing age.1 The classifications of histological subtypes advocated by the World Health Organisation and the Royal College of Pathologists have been widely used in the recent literature.3,4 The main growth patterns recognized are superficial, nodular, infiltrative and micronodular. The latter two are associated with significantly increased risk of local recurrence and increased morbidity.3–5 It has been found that nodular BCC predominantly occur on the head and neck, and that infiltrative BCC predominate over superficial BCC on the face.6–10 The higher proportion of infiltrative BCC on the face may prompt more aggressive treatment, especially in the periocular region where local invasion can result in significant
■ Correspondence: Mr Albert Wu, South Australian Institute of Ophthalmology, Level 8, East Wing, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Email: [email protected] Received 11 September 2013; accepted 16 January 2014. Albert Wu and Michelle T Sun contributed equally. Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
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morbidity. Few studies have examined the proportion of periocular BCC subtypes.11,12 To aid in the management of periocular BCC, we aimed to investigate the proportion of BCC subtypes occurring in the periocular region.
METHODS A retrospective histological review was conducted of all periocular (upper lid, lower lid, medial canthus or lateral canthus) excision specimens diagnosed as BCC at the Institute of Medical and Veterinary Science (IMVS) Main Laboratory, Adelaide in the 7-year period from 2006 to 2012. Approval was granted from the Ethics Committee of the Royal Adelaide Hospital (RAH). Reports were retrieved from the IMVS Histology database. All specimens were examined with paraffin section and reported by an IMVS pathologist. Tumour resection was performed at the RAH, The Queen Elizabeth Hospital, Port Pirie Hospital, Whyalla Hospital and other smaller medical centres in South Australia. The following data were analysed: date of resection, patient age at resection, gender, tumour location (laterality and periocular region), histological subtype and perineural invasion. The diagnostic criterion of perineural invasion, which was consistent with guidelines,13 was the observation of cytologically malignant cells in the perineural space of nerves. In addition, total or near-total circumferential involvement, presence of perineural tracking in tangential sections and intraneural involvement all supported the diagnosis. Differences in subtype proportion according to tumour location were analysed with chi-square tests. Differences in the laterality of the lesion according to gender were also analysed with chi-square tests. One-way analysis of variance was employed to compare mean age at resection according to subtype with post-hoc Bonferroni testing.
RESULTS From 2006 to 2012, a total of 1713 consecutive periocular BCC excision specimens were analysed.
The mean age at resection was 68.8 ± 14.3 years (median: 71, range: 21–101). Of the specimens, 966 (56.4%) were removed from male patients and 747 (43.6%) from female patients. BCC occurred on the right side in 838 (51.1%) cases and on the left in 801 (48.9%). There was no significant interaction between gender and the side of the lesion (P = ns). Of the specimens, 742 (52.7%) involved the lower eyelid, 409 (29.0%) the medial canthus, 153 (10.9%) the lateral canthus and 105 (7.5%) the upper eyelid. The most common histological subtype was nodular, accounting for 1278 (65.7%) cases. Infiltrative BCC was identified in 341 (17.5%) cases, superficial in 245 (12.6%) cases and micronodular in 81 (4.2%) cases. Subtype was not reported for 195 specimens. Squamous differentiation was identified in 81 (4.7%) specimens. Perineural invasion was identified in 16 (0.9%) cases. Table 1 shows the relationships between subtype and mean age at resection, gender and tumour location. Mean age at resection varied by subtype (P = 0.03), with infiltrative subtypes diagnosed at older age compared with nodular subtypes (P < 0.05). There were significant differences in the proportion of subtypes by tumour location (P = 0.004). Compared with lower lid and medial canthus, lateral canthus had higher proportions of infiltrative and superficial subtypes and upper lid had lower proportions of these subtypes. There were 388 (25.6%) specimens containing more than one subtype. The most common subtype combinations were nodular with infiltrative (193 specimens), and nodular with superficial (101 specimens), accounting for 49.7% and 26.0% of mixed BCC, respectively. Table 2 lists the frequency of occurrence of all the combinations.
DISCUSSION The majority of periocular BCC were located on the lower lid and classified histologically as nodular. Infiltrative BCC occurred more frequently than the superficial subtype, consistent with previous studies of facial and periocular BCC. Additionally, we found that 25.6% of all BCC had mixed histology, of
Table 1. Relationships between basal cell carcinoma subtype and mean age at resection, gender and tumour location
Mean age at resection (years) Gender, % (n) Male Female Periocular region, % (n) Lower lid Medial canthus Lateral canthus Upper lid
Nodular
Infiltrative
Superficial
Micronodular
68.5 ± 14.4
71.0 ± 14.1
69.8 ± 14.7
70.2 ± 14.1
65.3 (740) 66.3 (538)
18.2 (206) 16.6 (135)
12.0 (136) 13.4 (109)
4.6 (52) 3.6 (29)
64.7 (548) 68.1 (322) 56.1 (115) 76.1 (83)
18.5 (157) 15.9 (75) 25.4 (52) 11.0 (12)
13.0 (110) 11.6 (55) 16.6 (34) 7.3 (8)
3.8 (32) 4.4 (21) 2.0 (4) 5.5 (6)
© 2014 Royal Australian and New Zealand College of Ophthalmologists
Periocular basal cell carcinoma subtypes Table 2. Combinations of subtypes in mixed basal cell carcinoma Subtypes N+I N+S N+M N+I+S I+S S+M N+I+M N+S+M I+M I+S+M N+I+S+M
605 Table 3. Comparison of basal cell carcinoma subtypes in the literature
Number of specimens, n (%) 193 (49.7) 101 (26.0) 29 (7.5) 28 (7.2) 21 (5.4) 4 (1.0) 4 (1.0) 3 (0.8) 2 (0.5) 2 (0.5) 1 (0.3)
I, infiltrative; M, micronodular; N, nodular; S, superficial.
which the combination of nodular with infiltrative accounted for close to half of these specimens. The proportion of subtypes in our study was compared with that in five previous studies shown in Table 3. These studies were conducted at different latitudes, with the latitude of Adelaide greater than Queensland but less than Melbourne, the United Kingdom and France. Our study demonstrated higher rates of infiltrative BCC compared with superficial subtype, consistent with previous reports from Townsville, Brisbane and the United Kingdom of facial and periocular BCC.7,11,12 These findings may be attributable to the theory which suggests that superficial BCC results from acute, intense sun exposure to skin that is less exposed to sunlight and thus less tanned.14 As the face and periocular region are chronically exposed to sunlight and more tanned, fewer superficial BCC may develop at these sites.6–8 Another theory suggests that BCC subtype progresses from superficial to nodular to infiltrative, and therefore, if chronic sun exposure triggers progression to infiltrative BCC, more infiltrative BCC may develop in the periocular region.15 In general, infiltrative and superficial subtypes have been shown to occur more frequently in the periocular region and at lower latitudes compared with on the head and neck and at higher latitudes.6– 8,11,12 Thus, these subtypes may be associated with greater sun exposure which occurs at lower latitudes. Additionally, latitude has been shown to influence BCC subtype more than body site, with significantly higher proportions of infiltrative and superficial BCC found on the head and neck in the Townsville study compared with in the periocular region in the United Kingdom study.7,11 Our findings are in keeping with this, as we reported higher proportions of infiltrative and superficial BCC compared with studies of head and neck BCC conducted at higher latitudes. We found that there was mixed histology in 25.6% of our specimens and Ho et al. identified mixed his-
Nodular Infiltrative Superficial Micronodular (%) (%) (%) (%) Periocular region Adelaide (34.9°S) n = 1681 2006–2012 Wong et al.12 Periocular region Brisbane (27.5°S) n = 596 1992–2001 Ho et al.11 Periocular region United Kingdom (52.6°N) n = 338 2000–2006 Raasch et al.7 Face Townsville (19.3°S) n = 3245 1997–1999 McCormack et al.6 Head and neck Melbourne (37.8°S) n = 1982 1991 Scrivener et al.8 Head and neck France (48.5°N) n = 9941 1967–1996
65.7
17.5
12.6
4.2
61.2
21.5
10.9
6.4
82.0
11.5
5.9
0.6
56.9
19.3
12.9
10.9
81.7
10.4
7.9
Not reported
85.6
7.1
7.3
Not reported
n, number of specimens examined.
tology in 17.9% of their periocular BCC.11 Our most common subtype combinations of nodular with infiltrative and nodular with superficial were consistent with previous studies.6 Mixed histology has been reported to occur in up to 38.5% of all BCC and can result in an initial biopsy that misses one or more additional aggressive subtypes.16–23 If an aggressive subtype is missed, initial treatment may be inadequate and BCC may recur. As the proportion of mixed BCC is high and aggressive subtypes require modified treatment, surgical excision with margin control may be favoured over nonsurgical destructive modalities for periocular BCC.1,2,24 Although we found that infiltrative subtypes were diagnosed at older age compared with nodular subtypes, previous studies of BCC from the whole body did not find such a relationship.6–9 Patients with superficial BCC have been found to be markedly younger than those with other subtypes, suggesting that carcinogenesis of superficial BCC requires less sunlight exposure than nodular BCC.5–7,9 It has also been suggested that superficial
© 2014 Royal Australian and New Zealand College of Ophthalmologists
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BCC results from intermittent, intense sun exposure which occurs more frequently at younger ages and decreases with increasing age.6–9 However, we found that the mean age for superficial BCC was not significantly different to that for nodular BCC. Thus, our findings differ from previously proposed pathways of BCC subtype progression of superficial to nodular to micronodular and superficial to nodular to infiltrative.15 The periocular region, which is chronically exposed to sunlight and more tanned, may be less likely to sunburn and develop superficial BCC at a young age when acute, intense sun exposure usually occurs, resulting in the mean age for superficial BCC being similar to nodular BCC. Our findings suggest there may be differences in the pattern of BCC development in the periocular region compared with the rest of the body.5–9 Further studies analysing the relationship between mean age and histological subtype of BCC in the periocular region and face are required to better characterize this pattern of development. Previous studies have investigated whether greater ultraviolet exposure to one side of the body when driving would result in more BCC occurring on that side.12,25–29 In keeping with this theory, our study demonstrated a slight predilection for BCC to occur on the right side which is exposed to more sunlight when driving in Australia. Additionally, it has previously been proposed that as males drive more than females, more BCC would occur in males than females on the side of the face exposed to more sunlight when driving.27–29 However, with increasing numbers of female drivers over the past few decades, the proportion of male to female drivers in Australia is now very similar.30 In keeping with this, we found that there were no statistically significant differences in laterality of tumours between the two genders. Our study has a number of limitations. The retrospective nature of this study precluded the collection of additional clinical information which may have provided further insights. Additionally, our study is not population based as we included resection specimens examined at a single laboratory in South Australia. Thus, bias could potentially result from tendency to send specimens of certain subtypes to the laboratory and use of destructive treatment modalities which preclude histological examination. Bias could also result because subtype was not reported for a number of specimens. Although IMVS is the main pathology laboratory servicing the public health sector in South Australia, studies including specimens from all pathology laboratories in the region would add to our findings. In conclusion, we found that the most common BCC histological subtype occurring in the periocular region was nodular followed by infiltrative and superficial. Additionally, a quarter of all specimens had mixed histology, with nodular and infiltrative
being the most frequently occurring combination. Given the high proportion of mixed BCC containing aggressive histological subtypes, surgical excision with margin control should be considered for periocular BCC given the morbidity associated with recurrence in the eyelids.
REFERENCES 1. Allali J, D’Hermies F, Renard G. Basal cell carcinomas of the eyelids. Ophthalmologica 2005; 219: 57–71. 2. Margo CE, Waltz K. Basal cell carcinoma of the eyelid and periocular skin. Surv Ophthalmol 1993; 38: 169–92. 3. Kossard S, Epstein EH Jr, Cerio R, Yu LL, Weedon D. Basal cell carcinoma. In: LeBoit PE, Burg G, Weedon D, Sarasin A, eds. Pathology and Genetics of Skin Tumours. Lyon: IARCPress, 2006; 13–19. 4. Slater D, Walsh W. Dataset for the histological reporting of primary cutaneous basal cell carcinoma. In: Dataset for the Histological Reporting of Primary Cutaneous Basal Cell Carcinoma, 2nd edn. London: The Royal College of Pathologists, 2012; 1–27. 5. Cancer Council Australia, Australian Cancer Network. Clinical Practice Guide: Basal Cell Carcinoma, Squamous Cell Carcinoma (and Related Lesions): A Guide to Clinical Management in Australia. Sydney, NSW: Cancer Council Australia, 2008. 6. McCormack CJ, Kelly JW, Dorevitch AP. Differences in age and body site distribution of the histological subtypes of basal cell carcinoma. A possible indicator of differing causes. Arch Dermatol 1997; 133: 593–6. 7. Raasch BA, Buettner PG, Garbe C. Basal cell carcinoma: histological classification and body-site distribution. Br J Dermatol 2006; 155: 401–7. 8. Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br J Dermatol 2002; 147: 41–7. 9. Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bouwes Bavinck JN. Differences in age, site distribution, and sex between nodular and superficial basal cell carcinoma indicate different types of tumors. J Invest Dermatol 1998; 110: 880–4. 10. Pelucchi C, Di Landro A, Naldi L, La Vecchia C. Risk factors for histological types and anatomic sites of cutaneous basal-cell carcinoma: an Italian case-control study. J Invest Dermatol 2007; 127: 935–44. 11. Ho SF, Brown L, Bamford M, Sampath R, Burns J. 5 years review of periocular basal cell carcinoma and proposed follow-up protocol. Eye 2013; 27: 78–83. 12. Wong VA, Marshall JA, Whitehead KJ, Williamson RM, Sullivan TJ. Management of periocular basal cell carcinoma with modified en face frozen section controlled excision. Ophthal Plast Reconstr Surg 2002; 18: 430–5. 13. Dunn M, Morgan MB, Beer TW. Perineural invasion: identification, significance, and a standardized definition. Dermatol Surg 2009; 35: 214–21. 14. Neale RE, Davis M, Pandeya N, Whiteman DC, Green AC. Basal cell carcinoma on the trunk is associated with excessive sun exposure. J Am Acad Dermatol 2007; 56: 380–6.
© 2014 Royal Australian and New Zealand College of Ophthalmologists
Periocular basal cell carcinoma subtypes 15. Kaur P, Mulvaney M, Carlson JA. Basal cell carcinoma progression correlates with host immune response and stromal alterations: a histologic analysis. Am J Dermatopathol 2006; 28: 293–307. 16. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol 1990; 23: 1118–26. 17. Wolberink EA, Pasch MC, Zeiler M, van Erp PE, Gerritsen MJ. High discordance between punch biopsy and excision in establishing basal cell carcinoma subtype: analysis of 500 cases. J Eur Acad Dermatol Venereol 2013; 27: 985–989. 18. Kamyab-Hesari K, Seirafi H, Naraghi ZS et al. Diagnostic accuracy of punch biopsy in subtyping basal cell carcinoma. J Eur Acad Dermatol Venereol 2014; 28: 250– 253. 19. Haws AL, Rojano R, Tahan SR, Phung TL. Accuracy of biopsy sampling for subtyping basal cell carcinoma. J Am Acad Dermatol 2012; 66: 106–11. 20. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg 2006; 32: 542–51. 21. Mosterd K, Thissen MR, van Marion AM et al. Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma. J Am Acad Dermatol 2011; 64: 323–7. 22. Roozeboom MH, Mosterd K, Winnepenninckx VJ, Nelemans PJ, Kelleners-Smeets NW. Agreement
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25. 26.
27.
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30.
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between histological subtype on punch biopsy and surgical excision in primary basal cell carcinoma. J Eur Acad Dermatol Venereol 2013; 27: 894–898. Welsch MJ, Troiani BM, Hale L, DelTondo J, Helm KF, Clarke LE. Basal cell carcinoma characteristics as predictors of depth of invasion. J Am Acad Dermatol 2012; 67: 47–53. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev 2004; 23: 389–402. Butler ST, Fosko SW. Increased prevalence of left-sided skin cancers. J Am Acad Dermatol 2010; 63: 1006–10. Bulliard JL, Ess S, Bordoni A, Konzelmann I, Levi F. Left-sided excess in the laterality of cutaneous melanoma. Arch Dermatol 2008; 144: 556–8. Jones CA, Adams M. Re: ‘Laterality of periocular basal cell carcinomas in relation to driving practices in Philadelphia, PA, U.S.A.’. Ophthal Plast Reconstr Surg 2007; 23: 252–3. Lim LT, Agarwal PK, Cauchi P, Diaper CJ. Laterality of periocular basal cell carcinomas in relation to driving practices in Scotland, United Kingdom. Ophthal Plast Reconstr Surg 2011; 27: 306. Schrack KE, Youssef OH. Laterality of periocular basal cell carcinomas in relation to driving practices in Philadelphia, PA, U.S.A. Ophthal Plast Reconstr Surg 2007; 23: 252. Court R, Francis D, Grogan-Jones A et al. eds. RoadFacts 2005. Sydney: Austroads Incorporated, 2005.
Clinical and Experimental Ophthalmology 2014; 42: 603–607 doi: 10.1111/ceo.12298
Original Article Histological subtypes of periocular basal cell carcinoma Albert Wu,1 Michelle T Sun MBBS,1 Shyamala C Huilgol MBBS(Hons) FACD,2 Simon Madge FRCOphth1,3 and Dinesh Selva FRANZCO1 1
South Australian Institute of Ophthalmology, and 2Department of Dermatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia; and 3Department of Ophthalmology, Hereford County Hospital, Hereford, UK
ABSTRACT Background: To determine the proportion of different subtypes of periocular BCC in South Australia. Design: Retrospective review. Participants: One thousand seven hundred thirteen consecutive periocular basal cell carcinoma (BCC) excision specimens. Methods: Histological analysis of consecutive periocular BCC specimens. Main Outcome Measures: Date of resection, patient age at resection, gender, tumour location, histological subtype and perineural invasion. Results: From 2006 to 2012, a total of 1713 consecutive periocular BCC excision specimens were analysed. The mean age at resection was 68.8 years (median: 71, range: 21–101). Most specimens (56.4%) were removed from male patients. 52.7% involved the lower eyelid, 29.0% the medial canthus, 10.9% the lateral canthus and 7.5% the upper eyelid. The main histological subtypes identified were nodular (65.7%), infiltrative (17.5%), superficial (12.6%) and micronodular (4.2%). Of the specimens, 25.6% had more than one subtype. The most common subtype combinations were nodular with infiltrative (49.7%), and nodular with superficial (26.0%).
Conclusions: The majority of periocular BCC were located on the lower lid and classified histologically as nodular. Infiltrative BCC occurred more frequently than the superficial subtype. As the proportion of mixed BCC containing aggressive subtypes is high, surgical excision with margin control should be considered for periocular BCC. Key words:
basal cell carcinoma, epidemiology, eyelid.
INTRODUCTION Basal cell carcinoma (BCC) is the most common eyelid cancer in Australia, accounting for up to 90% of all malignant eyelid tumours.1,2 The high incidence of BCC in Australia has been attributed to high levels of sunlight exposure and a fair-skinned population of increasing age.1 The classifications of histological subtypes advocated by the World Health Organisation and the Royal College of Pathologists have been widely used in the recent literature.3,4 The main growth patterns recognized are superficial, nodular, infiltrative and micronodular. The latter two are associated with significantly increased risk of local recurrence and increased morbidity.3–5 It has been found that nodular BCC predominantly occur on the head and neck, and that infiltrative BCC predominate over superficial BCC on the face.6–10 The higher proportion of infiltrative BCC on the face may prompt more aggressive treatment, especially in the periocular region where local invasion can result in significant
■ Correspondence: Mr Albert Wu, South Australian Institute of Ophthalmology, Level 8, East Wing, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Email: [email protected] Received 11 September 2013; accepted 16 January 2014. Albert Wu and Michelle T Sun contributed equally. Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
604
Wu et al.
morbidity. Few studies have examined the proportion of periocular BCC subtypes.11,12 To aid in the management of periocular BCC, we aimed to investigate the proportion of BCC subtypes occurring in the periocular region.
METHODS A retrospective histological review was conducted of all periocular (upper lid, lower lid, medial canthus or lateral canthus) excision specimens diagnosed as BCC at the Institute of Medical and Veterinary Science (IMVS) Main Laboratory, Adelaide in the 7-year period from 2006 to 2012. Approval was granted from the Ethics Committee of the Royal Adelaide Hospital (RAH). Reports were retrieved from the IMVS Histology database. All specimens were examined with paraffin section and reported by an IMVS pathologist. Tumour resection was performed at the RAH, The Queen Elizabeth Hospital, Port Pirie Hospital, Whyalla Hospital and other smaller medical centres in South Australia. The following data were analysed: date of resection, patient age at resection, gender, tumour location (laterality and periocular region), histological subtype and perineural invasion. The diagnostic criterion of perineural invasion, which was consistent with guidelines,13 was the observation of cytologically malignant cells in the perineural space of nerves. In addition, total or near-total circumferential involvement, presence of perineural tracking in tangential sections and intraneural involvement all supported the diagnosis. Differences in subtype proportion according to tumour location were analysed with chi-square tests. Differences in the laterality of the lesion according to gender were also analysed with chi-square tests. One-way analysis of variance was employed to compare mean age at resection according to subtype with post-hoc Bonferroni testing.
RESULTS From 2006 to 2012, a total of 1713 consecutive periocular BCC excision specimens were analysed.
The mean age at resection was 68.8 ± 14.3 years (median: 71, range: 21–101). Of the specimens, 966 (56.4%) were removed from male patients and 747 (43.6%) from female patients. BCC occurred on the right side in 838 (51.1%) cases and on the left in 801 (48.9%). There was no significant interaction between gender and the side of the lesion (P = ns). Of the specimens, 742 (52.7%) involved the lower eyelid, 409 (29.0%) the medial canthus, 153 (10.9%) the lateral canthus and 105 (7.5%) the upper eyelid. The most common histological subtype was nodular, accounting for 1278 (65.7%) cases. Infiltrative BCC was identified in 341 (17.5%) cases, superficial in 245 (12.6%) cases and micronodular in 81 (4.2%) cases. Subtype was not reported for 195 specimens. Squamous differentiation was identified in 81 (4.7%) specimens. Perineural invasion was identified in 16 (0.9%) cases. Table 1 shows the relationships between subtype and mean age at resection, gender and tumour location. Mean age at resection varied by subtype (P = 0.03), with infiltrative subtypes diagnosed at older age compared with nodular subtypes (P < 0.05). There were significant differences in the proportion of subtypes by tumour location (P = 0.004). Compared with lower lid and medial canthus, lateral canthus had higher proportions of infiltrative and superficial subtypes and upper lid had lower proportions of these subtypes. There were 388 (25.6%) specimens containing more than one subtype. The most common subtype combinations were nodular with infiltrative (193 specimens), and nodular with superficial (101 specimens), accounting for 49.7% and 26.0% of mixed BCC, respectively. Table 2 lists the frequency of occurrence of all the combinations.
DISCUSSION The majority of periocular BCC were located on the lower lid and classified histologically as nodular. Infiltrative BCC occurred more frequently than the superficial subtype, consistent with previous studies of facial and periocular BCC. Additionally, we found that 25.6% of all BCC had mixed histology, of
Table 1. Relationships between basal cell carcinoma subtype and mean age at resection, gender and tumour location
Mean age at resection (years) Gender, % (n) Male Female Periocular region, % (n) Lower lid Medial canthus Lateral canthus Upper lid
Nodular
Infiltrative
Superficial
Micronodular
68.5 ± 14.4
71.0 ± 14.1
69.8 ± 14.7
70.2 ± 14.1
65.3 (740) 66.3 (538)
18.2 (206) 16.6 (135)
12.0 (136) 13.4 (109)
4.6 (52) 3.6 (29)
64.7 (548) 68.1 (322) 56.1 (115) 76.1 (83)
18.5 (157) 15.9 (75) 25.4 (52) 11.0 (12)
13.0 (110) 11.6 (55) 16.6 (34) 7.3 (8)
3.8 (32) 4.4 (21) 2.0 (4) 5.5 (6)
© 2014 Royal Australian and New Zealand College of Ophthalmologists
Periocular basal cell carcinoma subtypes Table 2. Combinations of subtypes in mixed basal cell carcinoma Subtypes N+I N+S N+M N+I+S I+S S+M N+I+M N+S+M I+M I+S+M N+I+S+M
605 Table 3. Comparison of basal cell carcinoma subtypes in the literature
Number of specimens, n (%) 193 (49.7) 101 (26.0) 29 (7.5) 28 (7.2) 21 (5.4) 4 (1.0) 4 (1.0) 3 (0.8) 2 (0.5) 2 (0.5) 1 (0.3)
I, infiltrative; M, micronodular; N, nodular; S, superficial.
which the combination of nodular with infiltrative accounted for close to half of these specimens. The proportion of subtypes in our study was compared with that in five previous studies shown in Table 3. These studies were conducted at different latitudes, with the latitude of Adelaide greater than Queensland but less than Melbourne, the United Kingdom and France. Our study demonstrated higher rates of infiltrative BCC compared with superficial subtype, consistent with previous reports from Townsville, Brisbane and the United Kingdom of facial and periocular BCC.7,11,12 These findings may be attributable to the theory which suggests that superficial BCC results from acute, intense sun exposure to skin that is less exposed to sunlight and thus less tanned.14 As the face and periocular region are chronically exposed to sunlight and more tanned, fewer superficial BCC may develop at these sites.6–8 Another theory suggests that BCC subtype progresses from superficial to nodular to infiltrative, and therefore, if chronic sun exposure triggers progression to infiltrative BCC, more infiltrative BCC may develop in the periocular region.15 In general, infiltrative and superficial subtypes have been shown to occur more frequently in the periocular region and at lower latitudes compared with on the head and neck and at higher latitudes.6– 8,11,12 Thus, these subtypes may be associated with greater sun exposure which occurs at lower latitudes. Additionally, latitude has been shown to influence BCC subtype more than body site, with significantly higher proportions of infiltrative and superficial BCC found on the head and neck in the Townsville study compared with in the periocular region in the United Kingdom study.7,11 Our findings are in keeping with this, as we reported higher proportions of infiltrative and superficial BCC compared with studies of head and neck BCC conducted at higher latitudes. We found that there was mixed histology in 25.6% of our specimens and Ho et al. identified mixed his-
Nodular Infiltrative Superficial Micronodular (%) (%) (%) (%) Periocular region Adelaide (34.9°S) n = 1681 2006–2012 Wong et al.12 Periocular region Brisbane (27.5°S) n = 596 1992–2001 Ho et al.11 Periocular region United Kingdom (52.6°N) n = 338 2000–2006 Raasch et al.7 Face Townsville (19.3°S) n = 3245 1997–1999 McCormack et al.6 Head and neck Melbourne (37.8°S) n = 1982 1991 Scrivener et al.8 Head and neck France (48.5°N) n = 9941 1967–1996
65.7
17.5
12.6
4.2
61.2
21.5
10.9
6.4
82.0
11.5
5.9
0.6
56.9
19.3
12.9
10.9
81.7
10.4
7.9
Not reported
85.6
7.1
7.3
Not reported
n, number of specimens examined.
tology in 17.9% of their periocular BCC.11 Our most common subtype combinations of nodular with infiltrative and nodular with superficial were consistent with previous studies.6 Mixed histology has been reported to occur in up to 38.5% of all BCC and can result in an initial biopsy that misses one or more additional aggressive subtypes.16–23 If an aggressive subtype is missed, initial treatment may be inadequate and BCC may recur. As the proportion of mixed BCC is high and aggressive subtypes require modified treatment, surgical excision with margin control may be favoured over nonsurgical destructive modalities for periocular BCC.1,2,24 Although we found that infiltrative subtypes were diagnosed at older age compared with nodular subtypes, previous studies of BCC from the whole body did not find such a relationship.6–9 Patients with superficial BCC have been found to be markedly younger than those with other subtypes, suggesting that carcinogenesis of superficial BCC requires less sunlight exposure than nodular BCC.5–7,9 It has also been suggested that superficial
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BCC results from intermittent, intense sun exposure which occurs more frequently at younger ages and decreases with increasing age.6–9 However, we found that the mean age for superficial BCC was not significantly different to that for nodular BCC. Thus, our findings differ from previously proposed pathways of BCC subtype progression of superficial to nodular to micronodular and superficial to nodular to infiltrative.15 The periocular region, which is chronically exposed to sunlight and more tanned, may be less likely to sunburn and develop superficial BCC at a young age when acute, intense sun exposure usually occurs, resulting in the mean age for superficial BCC being similar to nodular BCC. Our findings suggest there may be differences in the pattern of BCC development in the periocular region compared with the rest of the body.5–9 Further studies analysing the relationship between mean age and histological subtype of BCC in the periocular region and face are required to better characterize this pattern of development. Previous studies have investigated whether greater ultraviolet exposure to one side of the body when driving would result in more BCC occurring on that side.12,25–29 In keeping with this theory, our study demonstrated a slight predilection for BCC to occur on the right side which is exposed to more sunlight when driving in Australia. Additionally, it has previously been proposed that as males drive more than females, more BCC would occur in males than females on the side of the face exposed to more sunlight when driving.27–29 However, with increasing numbers of female drivers over the past few decades, the proportion of male to female drivers in Australia is now very similar.30 In keeping with this, we found that there were no statistically significant differences in laterality of tumours between the two genders. Our study has a number of limitations. The retrospective nature of this study precluded the collection of additional clinical information which may have provided further insights. Additionally, our study is not population based as we included resection specimens examined at a single laboratory in South Australia. Thus, bias could potentially result from tendency to send specimens of certain subtypes to the laboratory and use of destructive treatment modalities which preclude histological examination. Bias could also result because subtype was not reported for a number of specimens. Although IMVS is the main pathology laboratory servicing the public health sector in South Australia, studies including specimens from all pathology laboratories in the region would add to our findings. In conclusion, we found that the most common BCC histological subtype occurring in the periocular region was nodular followed by infiltrative and superficial. Additionally, a quarter of all specimens had mixed histology, with nodular and infiltrative
being the most frequently occurring combination. Given the high proportion of mixed BCC containing aggressive histological subtypes, surgical excision with margin control should be considered for periocular BCC given the morbidity associated with recurrence in the eyelids.
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