Thursday, 14 October 2010

Basal cell carcinoma

Basal cell carcinoma (BCC), also called rodent ulcer, is the commonest malignant tumour of the skin. BCC is commoner in males than females. Although the prevalence of this tumour increases within a population as exposure to sunlight increases, the distribution of the lesions does not correlate well with the area of maximum exposure to UV radiation in that BCCs are common on the eyelids, at the inner canthus and behind the ear, but uncommon on the back of the hand and forearm. Thus, regional factors, perhaps related to the density and type of pilosebaceous follicles are important in determining the distribution of the tumour. By contrast, the prevalence and distribution of squamous cell carcinoma correlates well with exposure to UV radiation. 

The development of BCC in an area devoid of pilosebaceous units and apocrine glands certainly suggests that it does not necessarily arise from such structures alone. Instead it might be due to transformation of the pluripotent cells in the epidermis or the eccrine apparatus.  

Basal cell carcinomas arise from pluripotential immature cells that form continuously during life, due to malfunctioning of the hedgehog-patched pathway (involved in embryonic tissue growth and organisation but when it malfunctions in adults it leads to neoplasia)About 90% of sporadic BCCs have identifiable mutations in the PTCH1 gene, resulting in upregulation of hedgehog signalling. About 10% have activating mutations in the SMO gene, encoding smoothened, another member of the hedgehog pathway. Trichoblastoma is the benign counterpart of basal cell carcinoma. It should be noted that trichoblastoma has been misdiagnosed as basal cell carcinoma, the commonest malignancy reported in naevus sebaceous of Jadassohn. Basal cell carcinoma surely may arise in naevus sebaceous of Jadassohn but the phenomenon is unusual and the vast majority of neoplasms diagnosed as basal cell carcinomas in naevus sebaceous of Jadassohn are trichoblastomas, and they are benign.

Basal cell carcinoma is composed of cells similar to those in the basal area of the epidermis and its appendages (basaloid cells with variable atypia). Mitotic figures may be frequent, and it is speculated that the combination of large numbers of mitoses and a slow growth rate result from a high rate of apoptosis. Data on cell kinetics indicate that a considerable proportion of cells in the tumour die fairly rapidly.

Differentiation in basal cell carcinomas is predominantly towards pilar keratin (thus, a basal cell carcinomas can be regarded as a hair follicle tumour rather than a keratinocyte tumour); the presence of citrulline (amino acid) in keratinized structures indicates that the origin of the keratin is the hair matrix because epidermal keratin contains no citrulline. Basal cell carcinomas showing no differentiation are called solid basal cell carcinomas.

Basal cell carcinomas, when transplanted to the anterior chamber of the rabbit’s eye together with their connective tissue stroma (stromal factor), fail to grow, in contrast to squamous cell carcinomas. Accordingly, absence of autonomy in basal cell carcinoma is consistent with its inability to metastasize in most instances (autonomy of the tumour cell is a prerequisite for the formation of metastases). The stroma (stromal factor) is an essential part of the neoplastic process (autotransplants of BCC survive only when they include connective tissue stroma) and it must also be removed in treatment. Fibroblasts in basal cell carcinomas differ from normal fibroblasts; they appear to have a regulatory role in the biology of basal cell carcinoma.

In Rombo syndrome (named after the oldest family member in the pedigree), an autosomal dominant condition, affected individuals develop vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas and peripheral vasodilatation in addition to BCCs. Gorlin syndrome (naevoid basal cell carcinoma syndrome) is an autosomal dominant condition related to the patched gene on chromosome 9, numerous BCCs may start in childhood, and they may resemble skin tags or brown naevi, with palmoplantar pits, calcifications of the falx cerebri, bifid ribs, frontal bossing, hypertelorism, sometimes mental retardation, odontogenic keratocysts of the jaw and systemic malignancy. Linear basal cell naevus is a linear collection of macules and papules histopathologically similar to basal cell carcinoma. Some cases may reflect mosaicism for Gorlin syndrome. Bazex syndrome is an X-linked dominant condition (males have a uniformly severe disease while females show a range of severity of the disease) with follicular atrophoderma, milia, hypotrichosis (especially in males), hypohidrosis, and facial BCCs. This should not be confused with the completely different paraneoplastic Bazex syndrome (acrokeratosis paraneoplastica) or with Bazex syndrome of childhood (benign circinate pityriasiform erythema of childhood).

Premalignant fibroepithelial tumour of Pinkus (most likely to be diagnosed as a fibroma on the trunk) is composed of cells resembling those of BCC arranged in a thin honeycomb around a prominent, overgrown papillary stroma. Small buds of cells may arise from the strands and enlarge to form BCC, replacing part or the entire tumour. Based on clinicopathological features and the presence of Merkel cells (basal cell carcinoma lacks these cells) in the neoplasm it has been proposed that fibroepithelioma of Pinkus is a variant of trichoblastoma rather than a variant of basal cell carcinoma.

The early basal cell carcinomas are commonly small, translucent or pearly, raised and rounded areas covered by thin epidermis through which a few dilated, superficial vessels show (tiny flecks of pigment may be seen with a hand lens). The common nodular type of tumour has a distinctive appearance when it is more than a few millimetres in diameter. In the initial stages it may be hard to separate from a melanocytic naevus, molluscum contagiosum or senile sebaceous hyperplasia without the aid of a biopsy. Naevi can be distinguished if hairs grow from the surface, and in molluscum contagiosum and sebaceous hyperplasia there is a central keratin-filled pit. Scaling or crusting on the surface can cause confusion with warts, keratoacanthoma, squamous cell carcinoma or molluscum contagiosum. In all cases, the debris should be removed, and this is easily done in BCC. The friable, relatively avascular tissue beneath is characteristic, and if fragments are removed and smeared on a slide the diagnosis can be confirmed by cytology.

Darkly pigmented and ulcerated tumours are occasionally confused with malignant melanoma. The margin of BCC is usually rolled, telangiectatic and multinodular, and there is no pigmented halo. The colour tends to be more definitely brown, in contrast with the dusky greyish brown of malignant melanoma.

Other modes of presentation are a small, pearly, erythematous, lichenoid papule or plaque, as a keratotic and slightly indurated area, or as a small and superficial ulcer resembling an excoriation. It may occasionally be pedunculated and telangiectatic, resembling a pyogenic granuloma. The more advanced tumours have as wide a variety of forms as the early lesions and tend to maintain the same pattern of growth throughout their course.

Less commonly, the tumour spreads only superficially. It is bounded by a slightly raised thread-like margin, which is irregular in outline and may be deficient at part of the circumference. Perhaps the most difficult problems (although least crucial from the patient’s viewpoint) are found with these superficial BCCs. Casual inspection may suggest that these are patches of eczema, psoriasis or Bowen’s disease. When the scale is removed and the edge stretched, the thread-like margin will reveal the true diagnosis. Careful inspection will almost always rule out eczema or psoriasis, which the patient’s history will have also made unlikely. There are some cases, however, where distinction from Bowen’s disease can be made only after biopsy. The superficial type is found mainly on the trunk.

The atypical rodent ulcer has an indurated edge and base, but no thread-like margin. The morphoeic BCC is uncommon, and is so named because dense fibrosis of the stroma produces a thickened plaque rather than a tumour. The consistency of a morphoeic BCC may resemble morphoea (palpation reveals a firm skin texture); the outline is usually less sharp and the evolution more gradual and relentless (can produce a sizeable lesion). The morphoeic type occurs almost exclusively on the face. Solitary desmoplastic [sclerosing] trichoepithelioma (much commoner than multiple desmoplastic trichoepitheliomas) can be easily misinterpreted as sclerosing (morphoeic) BCC. Small incomplete biopsies may cause uncertainty about excluding sclerosing BCC or microcystic adnexal carcinoma, and re-excision or resampling may be necessary for a definitive diagnosis or complete eradication in uncertain cases. Merkel cells are present in desmoplastic trichoepithelioma and absent in microcystic adnexal carcinoma and in most cases of morphoeic basal cell carcinoma. Immunostaining with cytokeratin 20, to identify Merkel cells, is therefore useful in the differential diagnosis of these neoplasms.

The typical BCC runs a slow progressive course of peripheral extension, which produces the thread-like margin, the nodule with a central depression or the expanding rodent ulcer. In rare cases, the tumour may disseminate.

Histopathology shows islands of basaloid cells with peripheral palisading of nuclei (in places continuous with the epidermis). There is often retraction artefact (stroma separates from tumour islands). There is often mucin in the stroma or within basaloid aggregates. A common site of origin is the junction between a pilosebaceous duct and the epidermis. From here the tumour may extend along the epidermis and down the duct. It is difficult to prove a purely adnexal origin for BCC, but some lesions behave as though this were so. In all considerations about the origin of the tumour, one must remember that the tumour can either sever its connection with epithelial structures or establish a secondary connection to structures to which it has grown close. At times differentiating between trichoepithelioma and basal cell carcinoma can be difficult. The separation (retraction) artefact, where dermal connective tissue (surrounding stroma) separates away from islands of basal cell carcinoma cells, helps in differentiating a basal cell carcinoma from a trichoepithelioma (retraction artefact between tumour cells and the surrounding stroma is absent). Distinction between trichoblastoma and basal cell carcinoma may be difficult too, particularly in small biopsies. Mitotic figures can be frequent in trichoblastomas. Hence the need to see the low-power view (in trichoblastomas the tumour is not usually connected to the epidermis and a deep infiltrative pattern is noticed in basal cell carcinoma), to search for Merkel cells by immunohistochemical markers (Merkel cells are quite common in trichoblastomas, while basal cell carcinomas generally lack these cells) and to test for the immunohistochemical expression of androgen receptor (usually negative in trichoblastomas and positive in basal cell carcinomas). Trichoblastomas are found — as is common with follicular tumours — on the head and neck (often within naevus sebaceous). Complete excision is often desirable as exclusion of a basal cell carcinoma may be difficult in small biopsies. Neither trichoblastomas nor basal cell carcinomas express hair keratins but citrulline can be demonstrated histochemically in some cases.

Baso(i)squamous cell carcinoma is also called “metatypical basal cell carcinoma”. The biological significance is that this pathological pattern is associated with a significantly higher incidence of metastatic spread. Having said so, its existence has been questioned by many; the entirely different genesis of squamous cell carcinoma, an anaplastic carcinoma of the keratinocyte and BCC, a tumour composed of immature cells, make the occurrence of transitional forms unlikely. It should be noted however that in “collision tumour” there is a squamous cell carcinoma contiguous to a basal cell carcinoma [like other chronic ulcerative lesions, BCC may stimulate the development of a squamous cell carcinoma] after ruling out that possibility of pseudocarcinomatous hyperplasia occurring in a basal cell carcinoma.

The aim of any therapy selected for BCC is to ensure complete removal or destruction of the primary tumour to prevent local recurrence and the need for further therapeutic intervention whilst exposing the patient to the least risk of complications and producing an acceptable cosmetic result. In most cases, treatment selection is usually based on a clinical assessment which considers a number of factors that are known to influence tumour prognosis. These factors include tumour size, location, clinical subtype and defined margin. In addition to the tumour characteristics, other factors such as the patient’s age, adequacy and success of previous treatments and coexisting medical conditions that influence tumour biology or treatment tolerability need to be considered. Conventional surgical excision with predetermined margins based on the clinical characteristics of the tumour is regarded by many as the most appropriate therapy for most nodular BCCs and provides a specimen for histopathological examination and assessment of the lateral and deep margins. Mohs’ surgery is an important treatment option for the treatment of high-risk BCCs as it offers consistent high cure rates for even the most difficult BCCs. Studies of Mohs' surgical specimens have provided useful information about the probability of achieving complete excision in tumours with predetermined margins in different sized BCCs. For BCCs less than 20 mm in diameter with well-defined clinical margins, a 3-mm margin will clear the tumour in 85% of cases and a 4–5-mm margin in 95% of cases. Liquid nitrogen can be used to destroy basal cell carcinomas; best results are achieved by selecting only small (less than 10 mm in diameter), well defined, previously untreated, tumour at non-critical sites. A 3-mm margin of normal skin should be included in the area treated. The tumour must be treated for two 30-second freeze times with a 2-minute thaw time in-between. Imiquimod 5% activates Toll-like receptors, causing an immune reaction that destroys cells of superficial BCC. Photodynamic therapy has been approved for the treatment of superficial and nodular BCC. Radiation therapy is now used sparingly. 

Vismodegib is a hedgehog signalling pathway inhibitor used in the treatment of basal cell carcinoma (symptomatic metastatic basal cell carcinoma; locally advanced basal cell carcinoma not appropriate for surgery or radiotherapy). Vismodegib may cause severe birth defects and embryo-foetal death. For women of child-bearing potential, pregnancy must be excluded before initiation of treatment, and monthly during treatment. Women must use two contraceptive methods (including one highly effective method and one barrier method) during treatment and for 24 months after the final dose of vismodegib; men must use a condom during treatment and for 2 months after the final dose. Sonidegib is another hedgehog signalling pathway inhibitor used in the treatment of locally advanced basal cell carcinoma not appropriate for surgery or radiotherapy.

This page was last updated in October 2018.

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Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • Weedon's Skin Pathology
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Oxford Textbook of Medicine
  • Practical Dermatopathology (R Rapini)
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Yen & Jaffe's Reproductive Endocrinology