© Borgis - Postępy Nauk Medycznych 9/2009, s. 714-724
Tomasz Dębski, Lubomir Lembas, *Józef Jethon
Basal cell carcinoma. Current views (Part III). Surgical treatment
Rak podstawnokomórkowy skóry. Współczesne poglądy (Część III). Leczenie chirurgiczne
Department of Plastic Surgery, The Medical Centre of Postgraduate Education in Warsaw
Head of the Department: Józef Jethon, MD, PhD, Professor of Plastic Surgery
Basal Cell Carcinoma (BCC) is one of the most common human malignancies. Although it is not directly life-threatening and rarely metastasises, its local malignant features cause significant functional and aesthetic disturbances, what has a profound effect on the quality of life of patients.
The constantly increasing incidence of BCC observed within the last couple of years and the fact that this malignancy tends to occur in younger and younger people prove that BCC is now and will be in the future an important clinical problem. However, this problem is undernoticed and underestimated mainly to its low mortality and the fact that this malignancy is not listed in incidence reports.
Although currently several factors are suspected to be responsible for BCC the most important roles in cancerogenesis are played by UV radiation and advanced age of patients. They account for more than 90% of BCC.
Diagnosis of BCC basing only on the clinical appearance is difficult and depends on physician´s experience to a large extent. Traditionally, several clinical forms of BCC can be distinguished; however, the awareness of their existence may only help distinguish oncologically suspicious lesions, and not diagnose them. A histopathological examination is the only test that can verify and complete the BCC diagnosis.
The clinical course of BCC is not characteristic and cannot be predicted: a lesion may not change for years, it may grow slowly or extremely fast, the infiltration area may enlarge or recede, it may also ulcerate or tend to heal. BCC metastases occur extremely rarely (<0.1% of cases).
Rak podstawnokomórkowy skóry (Basal Cell Carcinoma – BCC) jest najczęściej występującym nowotworem złośliwym człowieka. Chociaż nie zagraża on bezpośrednio życiu i rzadko daje przerzuty, jego miejscowa złośliwość jest przyczyną znacznych zaburzeń funkcjonalnych i estetycznych, co istotnie wpływa na jakość życia pacjentów.
Stały wzrost zachorowań na BCC obserwowany w ciągu ostatnich lat oraz tendencja do występowania tego nowotworu u osób coraz młodszych, świadczą o tym, że BCC stanowi i będzie stanowił istotny problem kliniczny w przyszłości. Problem ten jest jednak niedostrzegany i niedoceniany głównie ze względu na niewielką śmiertelność oraz nieuwzględnianie tego nowotworu w zestawieniach zachorowalności.
Chociaż w chwili obecnej postuluje się kilka czynników odpowiedzialnych za powstawanie BCC, najistotniejszą rolę w kancerogenezie odgrywają promieniowanie UV oraz zaawansowany wiek chorych. Odpowiadają one za ponad 90% zmian nowotworowych.
Rozpoznanie BCC na podstawie samego obrazu klinicznego jest trudne i w dużej mierze zależy od doświadczenia badającego. Tradycyjnie wyróżnia się kilka form klinicznych BCC, których znajomość może pomóc jedynie w wyodrębnieniu zmian podejrzanych onkologicznie, a nie w rozpoznaniu. Jedynym badaniem weryfikującym rozpoznanie wstępne i decydującym o rozpoznaniu BCC jest badanie histopatologiczne.
Przebieg kliniczny BCC jest niecharakterystyczny i nieprzewidywalny: zmiana może nie zmieniać się przez lata, rosnąć powoli lub bardzo szybko, zwiększać obszar nacieku lub ustępować, ulegać owrzodzeniu lub nawet goić się. Przerzuty BCC zdarzają się niezwykle rzadko (<0,1% przypadków).
Surgical excision with a margin of clinically normal surrounding tissues
Surgical treatment is the simplest, the most effective and nowadays the most popular method of treatment. Its efficacy evaluated as the recurrence rate in a 5-year follow-up is 2-10% (1, 2, 3, 4, 5). So far only few prospective studies comparing surgical excision with other methods have been published in the literature.
Thissen compared cryosurgery (spray technique and double cycle of freezing) with surgical treatment of nodular and superficial BCC of the head and neck with the diameter of <2 cm and observed better therapeutic outcomes in surgically treated patients; however, the differences were not statistically significan (6).
On the other hand, Rhodes compared surgical treatment of nodular BCC located on the face with photodynamic therapy (PDT). He did not observe significant differences in recurrence rates during the first 3 months; however, in 12- and 24-month follow-up he observed a statistically significant increase in the recurrence rate and worse cosmetic results in the case of PDT (7). Taking into account long-term results (after 60 months), recurrence occurred in 14% after PDT and only in 4% after surgical treatment (8).
Moreover, another study where surgical excision of primary BCCs with the diameter below 4 cm was compared with radiation therapy indicated that during a 4-year follow-up a lower recurrence rate was associated with surgical excision (0.7% vs 7.5%.) Moreover, cosmetic results after surgical excision were more acceptable than the ones after radiation therapy (79% vs 40%), which were associated with discolouration and telangiectasia in more than 65% and radiodystrophy in 41% of cases (9, 10).
An important stage in surgical excision of a lesion is the determination of a macroscopic (clinical) lesion border. It can be done using magnification (3x at least), Wood´s lamp or dermatoscope (11). Applying curettage before excision may increase the completeness of a procedure because it may be possible to determine real borders of a tumour more precisely (neoplastic tissues are more curettable) (12, 13). When lesion borders have been precisely determined a margin (range) of clinically normal tissue is planned, and they are removed together with a lesion en-block. The specimen resected in this way is subject to histopathological evaluationduring which a histopathological subtype of BCC is confirmed as well as procedure completeness. The tissue defect formed after lesion excision is closed according to the reconstructive ladder (diagram 1) (fig. 1).
Diagram 1. The reconstructive ladder (14).
Fig. 1. Reconstruction methods in surgical treatment of BCC – examples.
Margin of clinically normal surrounding tissue
It is obvious that the extent of neoplastic infiltration affects the range of a peripheral and deep margin. On the other hand, the infiltration extent correlates with prognostic factors (Part I) (15) e.g. for primary morpheaform BCC resected with a 3-mm margin only 66% of radical excisions observed, with a 5-mm margin – 82% and with a 13-15-mm more than 95%. For that reason, the presence of prognostic factors should determine the extent of a margin. Nonetheless, a precise therapeutic algorithm has so far not been established (15).
The extent of suggested margins ranges from 2 to 15 mm (tab. 1), is established empirically and what is the most important, it does not take prognostic factors into account.
Table 1. Range of excision margin – analysis of selected studies.
||Histological subtype (%)
||3-4 mm - intraperative frozen section control
||medial/lateral canthus - 48.2/17.5 upper/lower lid - 33.4/0.9
||mean 13.3 (2-32)
||infiltrative - 21
others - 79
||4-8 mm - conventional histopathological techniques
||medial/lateral canthus - 35.5/22.6 upper/lower lid - 41.9/0
||mean 12.9 (5-18)
||infiltrative - 22.6 others - 77.4
||0 (10 mm margin)
||cheek - 18.1 lips - 1.1 forehead - 14.5 nose - 20.9 ear - 1.9 neck - 6.4 extremities - 7.5 trunk - 14.1 orbital region - 4.9 scalp - 4.1
||0-5 - 22% 6-10 - 40.3% 11-15 - 20.7% 16-20 - 7.2% >20 - 9.8%
||3-8 mm - nodular 3-10 mm - infiltrative, multifocal, poor-circumscribed >10 mm - recurrence
||head and neck - 75.5% trunk - 8.4% extremities - 16%
||12.7 (primary BCC) 0.7 (recurrent BCC)
||2 mm - size < 10 mm
||mean 8 (3-20)
||nodular - 73 infiltrative - 6 superficial - 21
||6 (1 mm margin) 2 (2 mm margin)
||cheek - 19 nose - 25 forehead - 11 ear - 4 temple - 18 neck - 1 extremities - 10 trunk - 5 orbital region - 12 scalp - 2
||mean 8.9 (1-30)
||nodular - 68 micronodular - 6 superficial - 12 morpheaform - 3 infiltrative - 4 others - 7
||4 mm - poor-circumscribed; 3 mm - well-circumscriced
||head and neck - 51
||mean 12.1 (53% > 10 mm)
||nodular - 63 infiltrative - 10 superficial - 16 morpheaform - 2
||upper/lower lid - 56/11 medial/lateral canthus - 23.6/3.6 forehead - 0.5% cheek - 0.5%
||3 mm - well-circumscribed 10 mm - poor-circumscribed and >10 mm
||cheek - 14.2 ear - 3.2 nose - 21.1 chin - 2.2 forehead - 21.0 neck - 4.9 extremities - 2.9 trunk - 5.5 orbital region - 9 scalp - 6.8
||<5 - 38% 6-10 - 38.2% 11-20 - 17.5% 21-30 - 4.5% >30 - 1.8%
||forehead - 9.6 temple - 9.7 cheek - 10.2 neck - 2.6 nose - 17.1 scalp - 2.6 lower lid - 3.3 ear - 5.4 med./lateral canthus - 5.1 lips - 4.6
||<10 - 48% 10-20 - 30% >20 - 9%
||solidum - 52 morpheaform - 13 superficial - 14 mixed - 20
||46.7 (2 mm margin) 20.7 (4 mm margin) 14.7 (6-8 mm margin)
||4 mm - <2 c well-circumscribed, non-aggressiv growth pattern
||<10 - 62%, 10-20 - 29% >20 - 9%
||5 (4 mm margin) 15 (3 mm margin) 30 (2 mm margin)
||2-3 mm - well-circumscribed 5 mm - poor-circumscribed
||forehead - 10 temple - 14 cheek - 9 ear - 8 nose - 22 lips - 3 orbital region - 9 scalp - 5 neck - 5 trunk - 5 extremities - 10
||Lower/upper lid - 37.6/6.7 medial/lateral canthus - 38.4/7.9
||<5 - 25.2% 5-10 - 33.6% 10-20 -37.6% >25 - 3.6%
|| solidum - >50%
As reports published so far are in the majority retrospective reviews of therapeutic outcomes for different margins, their conclusions should be treated more like advices rather than methodologically proven guidelines.
Although American recommendations of NCCN (National Comprehensive Cancer Network) (Part II) recommend to remove low-risk BCCs with a 4-mm margin it has to be noted that, what is emphasised by the authors of these recommendations, this guideline was based on lower-level evidence (16). It is based on the prospective report by Wolf from 1987 (tab. 1) where 117 primary lesions were resected with a 2-mm margin with subsequent histopathological evaluation according to Mohs. If excision was incomplete, the margin of resected tissues was expanded by 1 mm until the procedure was complete. When lesions were excised with 2-mm margins, completeness of 70% was achieved, with 3-mm margins excisions were complete in 85% of cases and when margins were 4 mm completeness was as high as 95%. Although these results are statistically significant, they are poorly reliable because the study did not take into account prognostic factors that have been identified until now. The study lacks in information regarding the site of a tumour, its histopathological subtype and regards only well-demarcated lesions, and in 91% of cases the tumour diameter was below 2 cm, and the mean was 9 mm. Due to low reliability of studies published so far the need to perform prospective studies according to evidence based medicine (EBM) arises as it is necessary to determine unanimously the range of margins depending on prognostic factors.
It is of special importance when BCCs are located in functionally and aesthetically important face areas such as nose (ala nasi, columella, naso-facial sulcus), eyelids, medial and lateral canthus, ear with preauricular and postauricular region, lips philtrum (17, 18). All anatomical regions mentioned above are associated with a high risk of recurrence (H-area – Part II), and the differences in suggested margin are extremely important although they are as small as several millimetres.
The excision of a lesion with a larger margin may for example result in the removal of lacrimal ducts or cause ectropion. For that reason, during margin selection a surgeon resecting a lesion in these areas (a suggested margin for the face is from 2 to 10 mm) has to take into account such aspects as post-surgical function preservation, possibility of defect closure or, last but not least, achieving acceptable cosmetic results.
As it can be seen, due to varied and often not very reliable recommendations, the decision to choose an oncologically radical margin is extremely difficult and in most cases made based on operator´s experience (his knowledge and skills).
Prospective trials taking into account all factors affecting the range of a margin (including prognostic factors) would systematise the current state of knowledge and contribute to establishing consensus regarding the excision margins, what is indispensable in order to prepare a consistent algorithm for BCC treatment.
The deep margin range is less controversial. The majority of authors recommend to resect BCCs at the depth reaching the fat tissue (15). In BCCs where the skin is directly above deep tissues (cartilages, bones) it is obligatory to perform imaging tests and if necessary, increase the depth of a margin (19).
In order to determine the location of a resected tumour with relation to the adjacent tissues, each specimen indicated for a histopathological examination should be equipped with a surgical marker (suture, cut, dye mark) and a precise diagram presenting its location with relation to the adjacent tissues. As a result, it will be possible to identify sites where excision was incomplete. Moreover, information regarding previous treatment and results of a biopsy are also necessary (19).
The aim of a histopathological examination is to determine a histological subtype of BCC and excision completeness.
From a histopathological point of view BCC is similar to the basement membrane cells but differs in that the nucleus/cytoplasm ratio is higher.
Moreover, BCC cells do not have intercellular bridges and mitotic figures (20).
According to the latest WHO classification there are several clinical-pathological types of BCC. It includes criteria of a clinical and histopathological picture of different subtypes of BCC (21).
From a clinical point of view it is important to distinguish histopathological subtypes with a aggressive growth pattern, what is of importance when a surgical procedure is planned (tab. 2). In addition, infiltration along vessels and nerves is dangerous, and associated with a high risk of recurrence (11).
Table 2. Clinical-pathological classification of BCC (WHO 2006) and classification based on the recurrence risk (21, 22).
|Non-aggressive growth pattern (well circumscribed, low recurrence rate)
||Aggressive growth pattern (poor circumscribed, high recurrence rate)
|Nodular forms (approx. 50%):
- nodular-solid (nodularis-solidum)
- nodular-adenoid (nodularis adenoides, nodularis cribriforme)
- nodular-cystic (nodularis - cysticum)
|Infiltrating (5-20%) (infiltrativu infiltrative non-sclerosing, styloides)
Morpheaform (approx. 5%) (sclerodermiforme, morpheiforme, morphea-like, sclerosans, sclerotic, cicatrisans, infiltrative sclerosing)
||Metatypic (matatypicu baso-spinocellulare)
|Fibroepithelial (fibroepithelioma, Pinkus tumour)
||Superficial multifocal (15%) (superficiale multicentricu Arning)
The literature also describes undifferentiated and differentiated BCC. Little or no differentiation is reffered to as a solid BCC and includes pigmented, superficial, morpheaform and infiltrative subtypes. Differentiated BCC is mainly nodular BCC which often differentiates into cutaneous appendages, including hair, sebaceous or tubular glands (20). For statistical purposes the classification including three types is often used: nodular (solid), fibrosing (desmoplastic) and metatypic (baso-spinocellular) (22).
Based on precise histopathological evaluation it was determined that neoplastic infiltration is irregular and unpredictable; however, it is usually present to a limited extent (23).
The margin of clinically normal surrounding tissues viewed under a microscope is on average smaller by 24% from a macroscopic in vivo margin as a result of shrinking and fixing (24).
Hendrix et al. proved that infiltration in the case of infiltrating BCC is on average 7.2 mm, whereas for nodular BCC it is 4.7 mm (primary /recurrent 5.6/10.4 vs 4.3/5.7 respectively) (25). On the other hand, according to Salasche primary morpheaform BCC can infiltrate tissues even up to the width of 7 mm beyond macroscopic borders of a lesion (26). Based on Burg´s studies microscopic borders of primary BCC infiltration are estimated to be 3-6 mm, and 5-9 mm in the case of recurrent disease (23).
The most important factor determining the recurrence is to determine the extent of neoplastic infiltration and its relation to the edge of resection (19). It regards cases where tumor was identified at peripheral edge of resection and deep edge of resection what is associated with a more than a double risk of recurrence (17% peripheral vs 35% deep surgical edge in a 5-year follow-up period) (27).
In order to evaluate the risk of recurrence Pascal (28) made the following classification:
? incomplete excision – a tumor is identified at a surgical edge. It is associated with a 33% risk of recurrence within 5 years follow-up.
? suboptimal excision – tumor is visible at the distance smaller than 0.5 mm from a surgical edge, what microscopically corresponds to one high-power field (400x). In such cases there is a 12% risk of recurrence within 5 years follow-up.
? complete excision – tumor is visible at the distance larger than 0.5 mm, namely it is not present in one high-power field (400x) involving a surgical edge.
Although resecting a tumor in these cases is described as complete excision it is associated with a 1.2% risk of recurrence within 5 years follow-up.
It is mainly associated with the fact that histopathological techniques are not perfect. Conventional microscoping processing involves vertical sectioning at every 2-4 ?m, perpendicular to the tumor surface (breadloaf sectioning -recommended for lesions <16 mm) (29), when specimens from all four lesion quadrants are resected (cross sectioning – recommended>16 mm) (29) or from its peripheral parts (peripheral sectioning) (17) (fig. 2A, B, C). Consequently, only representative vertical sections are evaluated and it is not possible to evaluate the whole tumor margin. It is claimed that using conventional methods it is possible to evaluate only from 0.01% to 44% of tumor margins (17, 30).
Fig. 2. Methods of microscopic processing: cross sectioning (A), peripheral sectioning (B), breadloaf sectioning (C), Mohs method (D).
The basic drawback of this method is an assumption that when a tissue margin in representative sections is considered as tumor-free, the whole lesion is considered to be excised completely. The method suggested by Mohs is significantly more precise than conventional techniques as it allows for collecting sections which are horizontal to the tumor surface, namely it is possible to evaluate the whole margin (fig. 2D).
Incomplete excision of BCC is a situation when a tumor is identified at surgical edge or is at the distance of <0.5 mm from it (one high-power field at 400x magnification). On average 4.7%-7% (31, 32) of cases in the UK and 6.3% in Australia (33, 34) are excised incompletely. These numbers prove that a problem is huge and although factors responsible for an increased risk of incomplete excision have already been identified (Part II) until now it has not been possible to create a consistent algorithm of BCC management.
The necessity to improve procedure completeness is undeniable; however, management following incomplete excision (follow-up, reexcision, radiation therapy) raises many controversies.
Followers of follow-up base their opinions on numerous studies proving that recurrent disease will occur only in 30-41% of cases (34, 35, 36) out of all incompletely excised lesions, so as many as 2/3 of tumor tissue left in the skin will not recur.
In addition, prospective studies where incompletely
excised BCCs were reexcised showed the presence of tumor tissue only in 45% (37) and 54% (32) using conventional histopathological evaluation and 55% using the Mohs method (38). It means that in almost half of cases the tumor tissue which was left regresses, possibly with the help of the immune system (38).
Is a reexcision of an incompletely excised tumor justified?
Richmond et al. included in their study 92% patients who underwent reexcision of an incompletely excised tumors and 90% patients who were only observed (until recurrence occur, then it was excised immediately). After a 10-year follow-up period recurrence occurred only in 9% of patients in the first group and in as many as 60% of patients in the other (39).
Koplin recommends reexcision only in two cases: when a tumor is identified at surgical edge and when a tumor was excised suboptimally; however, only when expected life-time is long (40).
On the other hand, Robinson recommends only follow-up in the case of incomplete excision of an aggressive histopathological subtypes of BCC located on the nose, cheeks, around the lips, in men>65 years and in the case when a flap or split-thickness skin graft was used to cover a defect. His stand is based on the observation that in cases mentioned above significantly longer time is required for recurrence development (>5 years) than in other cases of BCC excised incompletely (41).
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