Aggressive basal cell carcinoma: dermatoscopy vascular features as clues to the diagnosis

Background: Basal cell carcinoma (BCC) can present with indolent or aggressive subtypes. These subtypes usually display vascular features, which are often readily identified using dermatoscopy. Objective: Dermatoscopy vascular features of aggressive BCC were compared to superficial, superficial and nodular, and nodular BCC for diagnostic discrimination. Method: Dermatoscopy vascular features were recorded live direct from the patient for 1,098 consecutive BCC. Cases with potential confounding influences were excluded. These tumor vascular features included branching (arborizing), serpentine, dot, coil (glomerular), loop (hairpin) and linear vessels. The proportion of pink within the tumor, central versus peripheral tumor vessel distribution and the presence of large vessels within the tumor boundary were also recorded. Results: Different subtypes of BCC have distinctive vascular features. Aggressive BCC (n=213) displays a tumor area with no pink (12.2%) or less than half the area pink (27.2%) and absent vessels in the central tumor area (22.1%, CI 17.0%–28.1%, P<0.001) compared to other subtypes. Superficial BCC (n=284) have more than half the tumor area pink (84.9%) and absent large vessels (92.6%), CI 89.0%—95.1%. Nodular BCC (n=230) is characterized by larger vessels (45.7%, CI 39.3%–52.1%, P<0.001) as compared to other subtypes, as well as less dot, coil and loop vessels. Kappa values for all recorded features ranged from 0.48 to 1.0. Limitations: Aggressive BCCs within the combined aggressive group were not assessed separately. Conclusions: Diagnostic discrimination between different subtypes of BCC is facilitated by vascular feature assessment. Compared to other subtypes, aggressive BCC displays less or no pink and less or absent central tumor vessels.


Introduction
Basal cell carcinoma (BCC) is a common encounter in practice, presenting as either a whole single subtype or as various subtype combinations within a single lesion. This study focuses on dermatoscopy vascular features of BCC subtypes with the intention of improving subtype diagnostic discrimination and aggressive subtype identification.
Superficial and nodular BCC subtypes behave with relatively indolent malignant behaviour. More aggressive BCC subtypes include micronodular, infiltrating, morphoeic or sclerosing, and BCC with squamous differentiation-these aggressive subtypes were assessed combined as "aggressive subtype," in this study. The distribution of BCC subtypes have anatomical site variation, with nodular and morphoeic BCC being more common on the head and neck and superficial BCC more common on the trunk and limbs [1]. Aggressive BCC subtypes have higher rates of recurrence and excision margin involvement [2]. Infiltrative BCC has the highest representation in perineural invasion, one series reported over 30% of cases of perineural invasion were infiltrating BCC [3]. Squamous differentiation indicates a nonexclusive increased risk for the quite rare event of metastasis in BCC [4]. Optimal management of BCC can be facilitated by early recognition and by priority given to appropriate treatment of aggressive BCC subtypes. There are other rare variants of BCC with differentiation representing various cutaneous structures. These rare variants were not covered in this study.
Most early dermatoscopy studies on BCC focused on pigmented features [5,6,7] with the recurrent purpose of diagnostic separation from melanoma. Only a few studies investigate the dermatoscopy vascular features of individual different BCC subtypes. Superficial [8,9,10] and nodular BCC [11,13]

Methods
This project was prospective and data collection was direct from patients, not from digital photographs. Studies on vessels usually record retrospective data from photographs with a fixed focus. This study recorded data direct from patients using "live" variable focus dermatoscopy. Cases came from primary care and referral patients from two centres in Sydney, Australia. During the project time window, all excisions where BCC was either the obvious diagnosis or in the differential diagnosis, were considered for inclusion. After the application of exclusion criteria, the defined vascular fea-tures of the remaining cases were recorded direct from each patient with a Heine Delta 20 non-polarized dermatoscope (Heine, Optotechnic GmbH, Herrsching, Germany), just prior to anaesthetic injection, excision and submission for routine histopathological examination. Transparent ultrasound gel was applied between the dermatoscope glass plate and the skin in all cases to enhance resolution by maximizing light transmission and reducing compression on vessels. All excised tissue was submitted for histopathological examination. Histopathology determined non-BCC entities were removed from the data resulting in a final total of 1,098 consecutive BCC cases. Each of these 1,098 BCC cases were allocated into one of the following subtype categories: (1) superficial (no other subtype present), (2)

Exclusion criteria
Patient informed consent, conforming to the Ethics Committee requirements, was required-only one case was excluded due to an inability to obtain consent. Other exclusion criteria were carefully selected to exclude cases with potential confounding influences. The intention was to only accept BCCs displaying vascular features due to the tumor presence or influence.
The exclusion criteria included the following: collision situations where a BCC was in combination with a non-BCC entity, in either clinical or dermatoscopy examination or in histopathology sections; tumors where exogenousapplied preparations (for example, "make up" or "fake tan") obscured dermatoscopy detail; residual or recurrent tumors following surgical intervention; tumors that had received previous cryotherapy or other ablative treatments; tumor areas following topical pharmacological treatment, either physician or patient initiated; tumors within fields of previous photodynamic therapy or radiotherapy; and sites juxtaposed to a scar, associated with tattoos or with mucosal involvement.

Vascular features defined
The following defined tumor vascular features and anatomical sites were recorded for each case. Every case was allocated into one of the following categories: (1) head and neck, (2) shoulder, (3) abdomen and back, (4) upper limb, (5) lower limb. The data from all anatomical sites were also combined into one data set per vascular feature.
Pink areas: Pink within the tumor area was categorized into either: (1) no pink present, (2) less than 50% of the tumor pink, or (3) pink present in 50% or more of the tumor area.

Data validation
To assess inter-observer agreement on the vascular features

Inference from proportion
The sample proportion p, of tumors with a certain vascular feature observed in the tumors is calculated by: This is an estimation to the occurrence rate (denoted as π) of a certain vascular feature being seen in a cutaneous tumor. These vascular features include: linear, branching, serpentine, hairpin/loop, dot, large vessels and the proportions of pink in the tumor. The 95% confidence interval of the occurrence rate π is calculated by the Wilson's score method without continuity correction where z .975 1.96 is the 97.5 percentile point of the standard normal distribution [1,2].

Kappa measure of agreement
The Kappa (κ) measure of agreement is used to access the agreement between two clinicians (observers) for the presenting of a certain vascular feature, given the assumption that both clinicians assess n patients independently. If clinicians agree purely by chance, they are not really "agreeing" at all. Only the agreement beyond that expected by chance can be considered as "true" agreement. Kappa is such a measure of "true" agreement. It indicates the proportion of agreement beyond that expected by chance. Its confidence interval takes the form: In practical situations, the value of lower bounds of confidence interval should usually be higher than 0.4 to be considered as clinically acceptable. All statistical analyses were performed using R software [11].

Results
Patient ages ranged from 29 to 98 for the total BCC cases (n=1098), the median age was 64 years, the mean 64.

Proportions of pink in basal cell carcinoma subtypes
Aggressive BCC had a tumor area with no pink or less than 50% pink in 39.4% cases compared to 18

Vessel morphology in basal cell carcinoma subtypes
Examination of the vessel morphology data in Figure

Large vessels in BCC subtypes
Superficial BCCs (n=284) together with superficial and nodular BCCs (n=371) display a relative absence of large vessels compared to nodular together with aggressive BCC subtypes, P< 0.001. Superficial BCC had absent large vessels in 92.6%   Table 1 below sets out the Kappa values for two observers (JP and DS) for BCC (n=108), with 95% confidence inter-

Discussion
Diagnosing BCC utilizing dermatoscopy is facilitated by the recognition of multiple distinctive features, including pigmented structures, shiny white lines (chrysalis [13] in metaphoric terminology), ulceration and vascular features.
Discussion on the practical use of the study of vascular features follows with the intention of assisting in the correct identification of aggressive subtype BCC.

Pink areas
In practice, pink in the tumor area of BCC commonly attracts the clinician's attention during clinical examination.
Aggressive subtypes display absent or less tumor area pink than other subtypes (Figure 1), this may render aggressive subtypes less obvious on clinical examination. Prominent collagen in the tumor stroma of infiltrating ( Figure 4B) and morphoeic BCC may correlate with reduced pink areas identified during dermatoscopy ( Figure 4A). Although not formally recorded in this study, the non-pink tumor areas where observed to be dominated by white structureless areas.
White structureless areas have been reported to be seen more frequently in BCC using contact dermatoscopy compared to polarized non-contact dermatoscopy [14]. Pink represents increased localized vascular perfusion in BCC and is more conspicuous in polarized non-contact dermatoscopy [14].
The finding of 84.9% of superficial BCCs having greater than half the tumor area pink is a useful clue to identifying this tumor (Figure 2A). It is unknown to what extent these pink areas correlate with the commonly associated lichenoid response in the papillary dermis, as shown in Figure 2B, or to more specific tumor factors.

Vessel distribution in central and peripheral tumor areas
Reduced or absent vessels in the central tumor area are also more frequent in aggressive subtypes, particularly the lower limb, where 1 in 3 aggressive BCCs displayed no central vessels ( Figure 3B).

Vessel morphology
The presence or absence of the selected specific vessel morphologies alone were ineffective in subtype discrimination between the BCC subtypes assessed in the anatomical sites selected ( Figure 5). Linear vessels are more frequent in aggressive subtypes, yet the low incidence (23.5%, in all anatomical sites combined) and lack of statistical significance (overlapping confidence intervals) limits practical use.
Dot, loop and glomerular vessels are usually associated with keratinocytic malignancy [14].   BCC recorded vessel morphology profile towards squamous cell carcinoma.

Large diameter vessels
Large diameter vessels were the hallmark of nodular BCC in this study. This is not surprising given the usual larger volume of tumor per unit area observed during dermatoscopy and in histopathology sections. Microvascular studies [16,17] and reflectance confocal microscopy [18,19]