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Clinical and Experimental Ophthalmology 2014; 42: 603607 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 Conclusions: The majority of periocular BCC were

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 perio-
cular BCC specimens.
Main Outcome Measures: Date of resection, patient
age at resection, gender, tumour location, histologi-
cal subtype and perineural invasion.
Results: From 2006 to 2012, a total of 1713 consecu-
tive periocular BCC excision specimens were
analysed. The mean age at resection was 68.8 years
(median: 71, range: 21101). 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 identi-
fied 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%).
located on the lower lid and classified histologically
as nodular. Infiltrative BCC occurred more fre-
quently than the superficial subtype. As the propor-
tion 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 inci-
dence 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 advo-
cated 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 sig-
nificantly increased risk of local recurrence and
increased morbidity.35 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.610 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: albert.wu3@gmail.com
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
morbidity. Few studies have examined the propor-
tion of periocular BCC subtypes.11,12 To aid in the
management of periocular BCC, we aimed to inves-
tigate 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 per-
formed at the RAH, The Queen Elizabeth Hospital,
Port Pirie Hospital, Whyalla Hospital and other
smaller medical centres in South Australia. The fol-
lowing 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 involve-
ment, 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.
Table 1. Relationships between basal cell carcinoma subtype and mean age at resection, gender and tumour location
Nodular
Mean age at resection (years) 68.5 14.4
Gender, % (n)
Male 65.3 (740)
Female 66.3 (538)
Periocular region, % (n)
Lower lid 64.7 (548)
Medial canthus 68.1 (322)
Lateral canthus 56.1 (115)
Upper lid 76.1 (83)
2014 Royal Australian and New Zealand College of Ophthalmologists
Wu et al.
The mean age at resection was 68.8 14.3 years
(median: 71, range: 21101). 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. Infiltra-
tive BCC was identified in 341 (17.5%) cases, super-
ficial 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 rela-
tionships between subtype and mean age at resec-
tion, gender and tumour location. Mean age at
resection varied by subtype (P = 0.03), with infiltra-
tive 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 propor-
tions 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 speci-
mens), 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
Inltrative Supercial Micronodular
71.0 14.1 69.8 14.7 70.2 14.1
18.2 (206) 12.0 (136) 4.6 (52)
16.6 (135) 13.4 (109) 3.6 (29)
18.5 (157) 13.0 (110) 3.8 (32)
15.9 (75) 11.6 (55) 4.4 (21)
25.4 (52) 16.6 (34) 2.0 (4)
11.0 (12) 7.3 (8) 5.5 (6)
Periocular basal cell carcinoma subtypes 605

Table 2. Combinations of subtypes in mixed basal cell Table 3. Comparison of basal cell carcinoma subtypes in the
carcinoma literature

Subtypes Number of specimens, n (%) Nodular Inltrative Supercial Micronodular

N+I 193 (49.7) (%) (%) (%) (%)
N+S 101 (26.0) Periocular region 65.7 17.5 12.6 4.2
N+M 29 (7.5) Adelaide (34.9S)
N+I+S 28 (7.2) n = 1681
I+S 21 (5.4) 20062012
S+M 4 (1.0) Wong et al.12 61.2 21.5 10.9 6.4
N+I+M 4 (1.0) Periocular region
N+S+M 3 (0.8) Brisbane (27.5S)
I+M 2 (0.5) n = 596
I+S+M 2 (0.5) 19922001
N+I+S+M 1 (0.3) Ho et al.11 82.0 11.5 5.9 0.6
Periocular region
I, inltrative; M, micronodular; N, nodular; S, supercial. United Kingdom
(52.6N)
n = 338
which the combination of nodular with infiltrative 20002006
accounted for close to half of these specimens. Raasch et al.7 56.9 19.3 12.9 10.9
The proportion of subtypes in our study was com- Face
pared with that in five previous studies shown in Townsville (19.3S)
Table 3. These studies were conducted at different n = 3245
latitudes, with the latitude of Adelaide greater than 19971999
McCormack et al.6 81.7 10.4 7.9 Not reported
Queensland but less than Melbourne, the United
Head and neck
Kingdom and France. Our study demonstrated Melbourne (37.8S)
higher rates of infiltrative BCC compared with super- n = 1982
ficial subtype, consistent with previous reports from 1991
Townsville, Brisbane and the United Kingdom of Scrivener et al.8 85.6 7.1 7.3 Not reported
facial and periocular BCC.7,11,12 These findings may Head and neck
be attributable to the theory which suggests that France (48.5N)
superficial BCC results from acute, intense sun expo- n = 9941
sure to skin that is less exposed to sunlight and thus 19671996
less tanned.14 As the face and periocular region are n, number of specimens examined.
chronically exposed to sunlight and more tanned,
fewer superficial BCC may develop at these sites.68
Another theory suggests that BCC subtype pro- tology in 17.9% of their periocular BCC.11 Our most
gresses from superficial to nodular to infiltrative, and common subtype combinations of nodular with
therefore, if chronic sun exposure triggers progres- infiltrative and nodular with superficial were con-
sion to infiltrative BCC, more infiltrative BCC may sistent with previous studies.6 Mixed histology has
develop in the periocular region.15 been reported to occur in up to 38.5% of all BCC and
In general, infiltrative and superficial subtypes can result in an initial biopsy that misses one or more
have been shown to occur more frequently in the additional aggressive subtypes.1623 If an aggressive
periocular region and at lower latitudes compared subtype is missed, initial treatment may be inad-
with on the head and neck and at higher latitudes.6 equate and BCC may recur. As the proportion of
8,11,12 Thus, these subtypes may be associated with mixed BCC is high and aggressive subtypes require
greater sun exposure which occurs at lower latitudes. modified treatment, surgical excision with margin
Additionally, latitude has been shown to influence control may be favoured over nonsurgical destructive
BCC subtype more than body site, with significantly modalities for periocular BCC.1,2,24
higher proportions of infiltrative and superficial BCC Although we found that infiltrative subtypes
found on the head and neck in the Townsville study were diagnosed at older age compared with nodu-
compared with in the periocular region in the United lar subtypes, previous studies of BCC from the
Kingdom study.7,11 Our findings are in keeping with whole body did not find such a relationship.69
this, as we reported higher proportions of infiltrative Patients with superficial BCC have been found
and superficial BCC compared with studies of head to be markedly younger than those with other sub-
and neck BCC conducted at higher latitudes. types, suggesting that carcinogenesis of superficial
We found that there was mixed histology in 25.6% BCC requires less sunlight exposure than nodular
of our specimens and Ho et al. identified mixed his- BCC.57,9 It has also been suggested that superficial
2014 Royal Australian and New Zealand College of Ophthalmologists
606
BCC results from intermittent, intense sun exposure
which occurs more frequently at younger ages and
decreases with increasing age.69 However, we found
that the mean age for superficial BCC was not sig-
nificantly 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 infil-
trative.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 devel-
opment in the periocular region compared with the
rest of the body.59 Further studies analysing the rela-
tionship 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.12,2529 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.2729 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 retro-
spective 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 speci-
mens 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
2014 Royal Australian and New Zealand College of Ophthalmologists
Wu et al.
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 peri-
ocular BCC given the morbidity associated with
recurrence in the eyelids.
REFERENCES
1. Allali J, DHermies F, Renard G. Basal cell carcinomas
of the eyelids. Ophthalmologica 2005; 219: 5771.
2. Margo CE, Waltz K. Basal cell carcinoma of the eyelid
and periocular skin. Surv Ophthalmol 1993; 38: 16992.
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; 1319.
4. Slater D, Walsh W. Dataset for the histological report-
ing 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; 127.
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: 5936.
7. Raasch BA, Buettner PG, Garbe C. Basal cell carci-
noma: histological classification and body-site distri-
bution. Br J Dermatol 2006; 155: 4017.
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:
417.
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: 8804.
10. Pelucchi C, Di Landro A, Naldi L, La Vecchia C. Risk
factors for histological types and anatomic sites of cuta-
neous basal-cell carcinoma: an Italian case-control
study. J Invest Dermatol 2007; 127: 93544.
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: 7883.
12. Wong VA, Marshall JA, Whitehead KJ, Williamson
RM, Sullivan TJ. Management of periocular basal cell
carcinoma with modified en face frozen section control-
led excision. Ophthal Plast Reconstr Surg 2002; 18: 4305.
13. Dunn M, Morgan MB, Beer TW. Perineural invasion:
identification, significance, and a standardized defini-
tion. Dermatol Surg 2009; 35: 21421.
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: 3806.
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: 293307.
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: 111826.
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: 985989.
18. Kamyab-Hesari K, Seirafi H, Naraghi ZS et al. Diagnos-
tic 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: 10611.
20. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma
with mixed histology: a possible pathogenesis for
recurrent skin cancer. Dermatol Surg 2006; 32: 54251.
21. Mosterd K, Thissen MR, van Marion AM et al. Corre-
lation between histologic findings on punch biopsy
specimens and subsequent excision specimens in
recurrent basal cell carcinoma. J Am Acad Dermatol 2011;
64: 3237.
22. Roozeboom MH, Mosterd K, Winnepenninckx VJ,
Nelemans PJ, Kelleners-Smeets NW. Agreement
2014 Royal Australian and New Zealand College of Ophthalmologists
607
between histological subtype on punch biopsy and
surgical excision in primary basal cell carcinoma. J Eur
Acad Dermatol Venereol 2013; 27: 894898.
23. Welsch MJ, Troiani BM, Hale L, DelTondo J, Helm KF,
Clarke LE. Basal cell carcinoma characteristics as pre-
dictors of depth of invasion. J Am Acad Dermatol 2012;
67: 4753.
24. Walling HW, Fosko SW, Geraminejad PA, Whitaker
DC, Arpey CJ. Aggressive basal cell carcinoma: pres-
entation, pathogenesis, and management. Cancer Metas-
tasis Rev 2004; 23: 389402.
25. Butler ST, Fosko SW. Increased prevalence of left-sided
skin cancers. J Am Acad Dermatol 2010; 63: 100610.
26. Bulliard JL, Ess S, Bordoni A, Konzelmann I, Levi F.
Left-sided excess in the laterality of cutaneous mela-
noma. Arch Dermatol 2008; 144: 5568.
27. 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: 2523.
28. 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.
29. 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.
30. Court R, Francis D, Grogan-Jones A et al. eds. RoadFacts
2005. Sydney: Austroads Incorporated, 2005.