Basal cell carcinomas are the most common cutaneous tumors, accounting for approximately 70% of all malignant diseases of the skin. They exceed squamous cell carcinomas in frequency by a factor of approximately 5: 1, although this ratio varies from 3:1 to 7:1 in different latitudes. Of course, if solar keratoses are regarded as squamous cell carcinomas then squamous cell carcinoma becomes more common than basal cell carcinoma. The incidence of basal cell carcinomas appears to be increasing.
Basal cell carcinomas are found predominantly on areas of skin exposed to the sun, particularly in fair-skinned individuals. They are rare in black people. Up to 80% of all lesions are found on the head and neck, whereas approximately 15% develop on the shoulders, back or chest. There are isolated reports documenting involvement of the breast, nipple, axilla, perianal region, vulva, penis, scrotum, inguinal region, subungual skin, lower part of the legs, and the palms and soles. Other unusual sites of involvement include piloniclal sinuses, venous ulcers, sternotomy scars, the skin overlying arteriovenous malformations, the nose affected by rhinophyma and the scars that follow thermal burns, radiation, chickenpox, leishmaniasis, smallpox and BCG vaccination. Basal cell carcinomas develop in approximately 20% of organoid nevi and, rarely, in epidermal nevi, fibroepithelial polyps, port wine stains and solar lentigos. Multiple basal cell carcinomas may develop in the basal cell nevus syndrome and in the rare Bazex's syndrome, in which there is also follicular atrophoderma and hypohidrosis. Furthermore, any patient who has had one basal cell carcinoma has a high probability of subsequently developing a further lesion. Patients with truncal lesions represent a high susceptibility group for the development of further lesions. Tumors in this site are commonly of the multifocal superficial type with a male predominance. There appears to be no risk for the development of non‑cutaneous cancers.
Basal cell carcinomas are more common in males, presumably related to occupational and recreational exposure to ultraviolet light. They tend to occur in older people, although they have also been documented in children and young adults. In children there is often a clinical association with the basal cell nevus syndrome, Bazex's syndrome, xeroderma pigmentosum or an organoid nevus.
The clinical presentation of a basal cell carcinoma can be quite variable. It may be a papulonodular lesion with a pearly translucent edge, an ulcerated destructive lesion ('rodent ulcer'), a pale plaque with variable induration, an erythematous plaque with visible telangiectasia, or a partly cystic nodule. Giant lesions up to 20 cm in diameter, and variants with mutilation of the face have also been documented. Rare linear and polypoid forms have been reported. Approximately 2‑5% of lesions are pigmented; basal cell carcinomas in black people and in the Japanese are often pigmented. Rarely, these pigmented variants mimic a malignant melanoma or develop a depigmented halo. The surface microscopy of pigmented basal cell carcinomas is distinctive. Despite the marked variability of their appearance, the accuracy rate in the clinical diagnosis of basal cell carcinomas is still 60‑70%.
Although most basal cell carcinomas are slow‑growing, relatively nonaggressive tumors that are cured by most methods of treatment, a minority have an aggressive behavior with local tissue destruction and, rarely, metastasis. 574 These aspects will be considered in further detail after the histopathology has been discussed.
Although the prime etiological factor in the development of basal cell carcinoma is exposure to ultraviolet light, particularly the UV‑B wavelengths, solar dosimetry studies show a poor correlation between tumor density and ultraviolet dose. Indeed, susceptibility to UV‑B induced inhibition of contact hypersensitivity appears to be a better indicator of cancer risk than cumulative sun exposure, suggesting an important role for immune surveillance in protecting against the development of basal cell carcinoma. Tumor necrosis factor (TNF) may be an important mediator of the immunosuppression produced by UV‑B. Various mediators of UV‑B induced damage are now being reported. Sunlight exposure in adolescence and childhood appears to be a risk factor for the development of basal cell carcinoma. UV‑B radiation produces DNA damage at mutation hot spots on the p53 tumor suppressor gene. Approximately 50% of all basal cell carcinomas studied have mutations of this gene. Whereas squamous cell carcinomas tend to develop at the sites of direct exposure to sunlight (dorsum of hands, ears, bald scalp and lower lip), basal cell carcinomas are more common in sites slightly removed from this, such as the paranasal region and inner canthus. Other predisposing factors include exposure to X‑rays, arsenical intoxication, adjuvant treatment of melanoma with isolated limb perfusion, HPV infection, welding and stasis dermatitis of the legs. In females, the risk of developing a basal cell carcinoma increases with the increasing number of nevocellular nevi. Tumors have also developed following PUVA therapy in patients with psoriasis.
Basal cell carcinomas have occurred in renal transplant recipients and in other circumstances of immunosuppression, such as malignant lymphoma or leukemia and the AIDS‑related complex. Tumors are more aggressive in these circumstances. They are also aggressive in albinos. Basal cell carcinomas are now being seen after prolonged hydroxyurea therapy used in the treatment of myeloproliferative disorders.
There is increasing evidence that genetic factors play a role in the susceptibility of some individuals to basal cell carcinoma. Mutations in the PATCHED gene (ptc, PTCH), which is known to be responsible for the nevoid basal cell carcinoma syndrome, have also been reported in sporadic cases of basal cell carcinoma. There is also an association with HLA‑DR7 and HLA‑DR4 in some populations. Mutations in the ptc gene have downstream effects leading to the accumulation of the transcription factor Gli‑1, which may play a role in the development of basal cell carcinomas. Frameshift mutations in the BAX gene (bcl‑2 associated X protein) have also been found in sporadic cases.
Cell of origin
Basal cell carcinomas usually arise from the lowermost layers of the epidermis, although a small percentage may originate from the outer root sheath of the pilosebaceous unit. Whatever their origin ‑ lower epidermis or follicle ‑the cells in the basal cell carcinoma have many features in common with follicular epithelium, particularly follicular matrix cells, rather than follicular bulge cells as once thought. There is a virtually identical cytokeratin pattern in basal cell carcinomas, trichoblastomas and developing fetal hair follicles, compelling evidence for a common histogenetic pathway. Ackerman now classifies basal cell carcinomas as trichoblastic carcinomas. Further circumstantial evidence of this shared antigenicity is the finding of T lymphocytes in the upper portion of hair follicles, adjacent to a regressing basal cell carcinoma. In contrast to squamous cell carcinomas, basal cell carcinomas are difficult to produce experimentally in animals, although they have been produced in rats using chemical carcinogens. Human lesions can, however, be transplanted to nude mice, but only if the animals are athymic and lacking in natural killer‑cell activity. Basal cell carcinomas are stroma dependent, and autotransplantation is unsuccessful if the stroma is not included. This stromal dependency is the most likely reason for the low incidence of metastasis of these tumors. The cells can be cultured.
Various studies have been published recently relating to the treatment of basal cell carcinoma. They are beyond the scope of this book but are referenced in case they are of interest to readers.
There is considerable variability in the morphology of basal cell carcinomas, and as a consequence a number of histopathological subtypes have been defined. Certain features are shared by more than one of these subtypes, and these will be considered first.
Basal cell carcinomas are composed of islands or nests of basaloid cells, with palisading of the cells at the periphery and a haphazard arrangement of those in the centers of the islands. The tumor cells have a hyperchromatic nucleus with relatively little, poorly defined cytoplasm. The intercellular bridges are invisible on routine light microscopy. There are numerous mitotic figures, sometimes atypical and a correspondingly high number of apoptotic tumor cells. This high rate of cell death accounts for the paradoxically slow growth of basal cell carcinomas which possess numerous mitoses.
The vast majority of cases show some attachment to the undersurface of the epidermis. Ulceration is not infrequent in larger lesions. Lesions of long standing and aggressive tumors usually extend into the lower dermis. Deep extension occurs either diffusely or within the paths of the cutaneous adnexae. Involvement of the subcutis or of the underlying cartilage in lesions of the nose and ear is quite uncommon. Perineural invasion is present in nearly I % of cases, although the incidence is higher in aggressive variants.
Islands of tumor cells are surrounded by a stroma, which is newly formed and different from the adjacent dermis. This stroma contains variable amounts of acid mucopolysaccharicles. Laminin and types IV, V and VII collagen are present in the basement membrane, which separates the tumor cells from the stroma. However, there is decreased expression of some other basement membrane components, which may facilitate their ability to invade. Aggressive basal cell carcinomas show discontinuous staining for laminin and type IV collagen, but a marked stromal myofilbroblastic response with an increase in stromal fibronectin. They are also more likely to express p53 protein. Amyloid, which is formed by the tumor cells, is present in the stroma in up to 50% of cases. It is less common in aggressive variants. The adjacent dermis shows solar elastosis in over 90% of cases, although its degree is sometimes mild. The overlying epidermis may show the changes of a solar keratosis, although this is only rarely the precursor of a basal cell carcinoma.
A variable inflammatory cell infiltrate is usually present, although there is a paucity of cells in some recurrences. The presence of plasma cells in the infiltrate correlates with ulceration. The infiltrate is usually composed mainly of T cells, the majority of which are CD4. Natural killer cells, mast cells and Langerhans cells are also present. Cell‑mediated immunity appears to play a role in the focal regression seen in up to 20% of tumors. The expression of interleukin‑2 receptor is increased in regressing lesions. Active regression is characterized by the presence of a lymphocytic infiltrate which surrounds and penetrates tumor nests, with disruption of the normal palisaded outline and the formation of numerous apoptotic tumor cells. Both C4+ and CD8+ cells are present in regressing lesions. Past regression can be recognized by finding areas of eosinophilic new collagen within a tumor, associated with absence of tumor nests, an increase in small blood vessels, loss of appendages and a variable inflammatory cell infiltrate. Prominent central regression with the formation of scar tissue is a feature of the so‑called 'field fire' type of basal cell carcinoma.
Calcification may be present in the center of the keratin cysts that form in several of the histological subtypes. Ossification is an exceedingly rare event. Another rare finding is the presence of transepidermal elimination of tumor nests. Also rare is the development of pseudoepitheliomatous hyperplasia or keratoacanthoma‑like changes in the epidermis following irradiation or excision of a basal cell carcinoma: this is known as pseudorecidivism.
Basal cell carcinomas or closely related changes may overlie a dermatofibroma. Basal cell carcinomas have also been reported in association with seborrheic keratoses, intradermal nevi, porokeratosis, Darier's disease, lupus vulgaris, keratoacanthoma, desmoplastic tricholemmoma, neurofibromas and, as already mentioned, organoid nevi.
Sometimes no tumor can be found in a biopsy specimen despite a strong clinical suspicion that basal cell carcinoma is present. This is particularly so with the multifocal superficial basal cell carcinoma where nests can be widely spaced or undergo regression. It is good practice to order, routinely, three levels of all punch and shave biopsies to prevent sampling errors. Clues in an initial non‑diagnostic slide that suggest that deeper sections may yield basal cell carcinoma include focal basal atypia, stromal or superficial fibrosis, empty dermal spaces, equivocal adnexae and microcalcifications.
The tumor cells in basal cell carcinoma resemble epidermal basal cells, both in their glycoconjugate pattern, their keratin expression and the presence of bcl‑2. Clinically aggressive basal cell carcinomas have low labeling with bcl‑2. However, the cells also express cytokeratins, which are found only in follicular epithelium. Tumor cells stain with the murine monoclonal antibody VM‑1; they usually do not stain for involucrin, epithelial membrane antigen or CD44, as occurs in squamous cell carcinomas, although CD44has been found in infiltrative tumor strands. However they do stain diffusely for Ber EP4, unlike squamous cell carcinomas, which are always negative; basaloid carcinoma of the anus is also negative. A band‑like peritumorous reaction with peanut agglutinin has been reported in most basal cell carcinomas but not in trichoepitheliomas. Other features that can be used to distinguish these two tumors are the staining pattern for bcl‑2 (expressed in virtually all cells in most basal cell carcinomas, but only weakly in some aggressive variants, and only in the basal layer of trichoepitheliomas) and CD34 (found in the peritumoral fibroblasts around trichoepitheliomas but not in those around sclerosing basal cell carcinomas), in contrast, stromelysin‑3 is expressed by the fibroblastic cells of nearly 70% of morpheic basal cell carcinomas, but not by fibroblasts in desmoplastic trichoepithelioma. Light microscopy is still the most reliable method of distinguishing these two tumors, although the diffuse staining of basal cell carcinomas with bcl‑2 is of some value.
Various morphological subtypes have been defined. These include solid (nodular), micronodular, cystic, multifocal superficial (superficial multifocal), pigmented, adenoid, infiltrating, sclerosing, keratotic, infundibulocystic, metatypical, basosquamous and fibroepitheliomatous. Mixed patterns are quite common. Several other rare variants have also been described. It should be remembered that punch and shave biopsy techniques provide approximately 80% accuracy in the diagnosis of the various subtypes of basal cell carcinoma.
Solid (nodular) type
The solid variant, also known as the large nest type, accounts for approximately 70% of all cases. It is composed of islands of cells with peripheral palisading and a haphazard arrangement of the more central cells. Retraction spaces sometimes form between the tumor islands and the surrounding stroma. Ulceration may be present in larger lesions.
The micronodular variant resembles the solid type, but the nests are much smaller and the peripheral palisading is not always as well developed. The micronodular type has a much greater propensity for local recurrence than the solid type. Sometimes it infiltrates quite widely through the dermis and extends into the subcutis. The micronodular type is often included incorrectly with the infiltrating or solid types.
One or more cystic spaces are present toward the center of some or all of the tumor islands. This results from the degeneration of tumor cells centrally, and it may be associated with increased mucin between the tumor cells adjacent to the cyst.
Multifocal superficial (superficial multifocal) type
Although a three dimensional reconstruction study has shown that the apparently discrete nests of tumor cells are interconnected, suggesting a unicentric origin, inclusion of the word 'multifocal' in the title is still recommended for the full characterization of this variant. The author has difficulty in accepting the concept of a unicentric origin for all such cases, given the wide separation of nests that is sometimes found. The multifocal superficial basal cell carcinoma is composed of multiple small islands of basaloid cells attached to the undersurface of the epidermis, and usually confined to the papillary dermis. Acantholysis has been reported in a few cases. A narrow zone of fibrous stroma may surround the nests. There is usually a patchy band‑like lymphocytic infiltrate and an increase in thin walled vessels. This pattern accounts for 10‑ 15% of all tumors, and is the usual pattern seen in lesions removed from the shoulder region. The age of patients with this subtype is lower than for other types.
Melanin pigment is usually formed in solid, micronodular, multifocal superficial or follicular variants. Functional melanocytes are scattered through the tumor islands and there are numerous melanophages in the stroma. There are few melanosomes within the tumor cells. Melanosome complexes form in tumor cells as a consequence of repeated cycles of phagocytosis of melanosome‑containing tumor cells that have undergone apoptosis. Basal cell carcinomas of the usual type are also populated by some melanocytes. Other pigmented phenomena in basal cell carcinomas are the colonization one by a melanoma in situ, the metastasis of a melanoma to one, and the presence of a combined melanoma and basal cell carcinoma.
The adenoid variant consists of thin strands of basaloid cells in a reticulate pattern. Stromal mucin is often quite prominent. The adenoid type is quite uncommon in a pure form. It may occur in association with the solid type.
This non‑sclerosing variant has an infiltrative rather than an expansile pattern of growth. It accounts for approximately 5% of all tumors, although this figure is higher in some patient groups. The histological features are distinctive, with elongated strands of basaloid cells, cells thick, infiltrating between collagen bundles. Sometimes, even narrower strands are present, with spiking projections. There may be a slight increase in fibroblasts, but there is no significant fibrosis. Often there is a solid pattern superficially with the infiltrating nests at the periphery or base of the lesion. Sometimes a focal infiltrative pattern is seen in the re‑excision specimen of a biopsy proven solid (nodular) basal cell carcinoma. These changes are limited to the region of the biopsy scar and appear to represent a scar induced phenomenon without any sinister connotations. Like the sclerosing variant, it has a clinically indistinct border, but it differs from that variant in its opaque, yellow‑white color. Metallothionein, a presumptive marker of aggressive clinical behavior, is increased in the infiltrative variant.
The sclerosing category includes lesions which have also been referred to as fibrosing, scirrhous, desmoplastic and morpheic. The uncommon 'field fire' type with central fibrosis resulting from regression should not be included in this category. Up to 5% of all basal cell carcinomas are of the sclerosing type. The tumor presents as an indurated, pale plaque with a slightly shiny surface and clinically indistinct margins. There are narrow elongated strands and small islands of tumor cells embedded in a dense fibrous stroma. If the stroma has dense, eosinophilic areas resembling a keloid, then the term 'morpheic' has traditionally been used, although at other times this term has been used interchangeably with 'sclerosing'. The term 'keloidal' has been applied to basal cell carcinomas with thick sclerotic keloidal collagen bundles in the stroma. A selectively enhanced procollagen gene expression has been found in the sclerosing variant. Also, large defects have been found in the basal lamina that surrounds the tumor nests. Smooth muscle (x‑actin and myosin) are often present in the stroma.
The keratotic variant is similar to the solid type, with nests and islands of basaloid cells with peripheral palisading. It differs in the presence of squamous differentiation and keratinization in the centers of the islands. There is usually very little stroma, and no lobular arrangement or follicular differentiation.
The uncommon infundibulocystic variant, found most often on the face, is often confused with the keratotic type. It is small, well circumscribed, and composed of nests of cells arranged in an anastomosing fashion with little stroma. There are numerous small infundibular cyst‑like structures containing keratinous material and sometimes melanin. The stroma may contain amyloid and/or melanin. Multiple lesions are sometimes present.
Although the term 'metatypical' is sometimes applied to tumors with mixed basaloid and squamous features, it should be reserved for the rare basal cell carcinoma composed of nests and strands of cells maturing into larger and paler cells. Peripheral palisading is often lost. The cells express much less keratin 17 and keratin 8 than do the cells in the more usual types of basal cell carcinoma. Peripheral palisading is less obvious than usual, and the stroma is often prominent. This variant is regarded by some as having metastatic potential.
Basosquamous carcinoma is a controversial entity which can be defined as a basal cell carcinoma differentiating into a squamous cell carcinoma. It is composed of three types of cell: basaloid cells, which are slightly larger, paler and more rounded than the cells of a solid basal cell carcinoma; squamoid cells with copious eosinophilic cytoplasm; and an intermediate cell which resembles that seen in metatypical tumors. Accordingly, the basosquamous carcinoma is sometimes confused with metatypical and keratotic basal cell carcinomas. It is an aggressive lesion with metastatic potential. This tumor shows some areas of Ber EP4 positivity, in contrast to squamous cell carcinoma which is always negative.
Fibroepithelioma presents as a soft nodular lesion resembling a fibroma or papilloma, often on the lower part of the back. It is composed of thin anastomosing strands of basaloid cells set in a prominent loose stroma. The stroma has no elastic tissue. Merkel cells are quite prominent. It has been suggested, and subsequently disputed, that this variant derives its histological pattern from the spread of basal cell carcinoma down eccrine ducts, eventually replacing them with solid strands of tumor. A rare cystic variant of fibroepithelioma has been reported.
Appendageal differentiation is sometimes present in basal cell carcinomas. Follicular (pilar) variants have already been mentioned (see above). Matrical and tricholemmal differentiation may also occur: basal cell carcinomas that show this feature require differentiation from matrical carcinomas. Sebaceous differentiation is sometimes seen in areas of an otherwise typical basal cell carcinoma: such lesions require differentiation from other sebaceous tumors. A rare variant with histochemical and ultra structural features of apocrine differentiation has been reported. Tumors with eccrine differentiation also occur, and these shade into lesions best classified with eccrine carcinomas. Other variants include the exceedingly rare granular cell, clear cell and 'signet‑ring' cell (hyaline inclusion) types. Lesions with giant tumor cells and large nuclei have been variously reported as 'basal cell epithelioma with giant tumor cells, 'basal cell carcinoma with monster‑cells' and 'pleomorphic basal cell carcinoma'. The giant cells do not appear to represent a senescent change. There is a report of this variant in which there were stromal giant cells as well.
Adamantinoid, schwannoid and neuroendocrine differentiation are further variants. It has been suggested that the tumor reported as a basal cell carcinoma with thickened basement membrane was really a trichilemmal carcinoma. The rare lesion showing myoepithelial differentiation needs to be distinguished from a carcinosarcoma.
The tumor cells have a large nucleus and cytoplasm containing a few tonofilaments. There are a small number of desmosomes and some thin processes on the cell surface. The appearances resemble those of the primary epithelial germ. Stromal amyloid is sometimes present, and this appears to be formed in the cytoplasm of tumor cells. Myofibroblasts have been found in the stroma.
The cytological diagnosis of basal cell carcinoma is made by finding large clusters of cells with crowded nuclei. Peripheral palisading can seldom be appreciated in cytological preparations.
The 5‑year recurrence rate for basal cell carcinomas is approximately 5%, although this varies with the type of treatment. The figure rises to 9% with long‑term follow-up. Although one study found almost no difference in the recurrence rate of completely excised tumors and those with tumor at one excision margin, this is contrary to most reports, which have found that the distance to the closest resection margin is an important predictor of recurrence. In another report the recurrence rate was noted to be 1.2% in cases of adequately excised lesions, 12% if tumor was present within one high‑power field of a margin and 33% if tumor was present at the excision margin. Residual tumor is found in only 60% of re‑excision specimens following a report of tumor at an excision margin. Failure to find tumor in all such re‑excisions may result from an insufficient amount of tumor surviving to be detected, or because the residual cells spontaneously die or are destroyed by a local inflammatory reaction. Another possibility is that the incompleteness of the initial excision was more apparent than real. Failure to detect tumor in re‑excision specimens, combined with a recurrence rate thought to be 30‑50%, has resulted in a view that additional resection is not always necessary when margins are positive. However, if recurrence does occur, subsequent recurrences are sometimes difficult to control. Patients with small primary basal cell carcinomas that appear to have been completely removed after a biopsy procedure are at risk for recurrence without further treatment.
Recurrences are more common in lesions on the nose and nasolabial fold, but this may in part be related to a difficulty in achieving adequate margins in these sites. Infiltrative, micronodular and multifocal types of basal cell carcinoma are more likely to recur than nodular types. Metatypical and sclerosing variants may also be associated with more aggressive behavior. Recurrences are also more likely in patients who have multiple skin cancers. It is now generally accepted that the majority of recurrent basal cell carcinomas are aggressive from the onset, and that in many cases this can be predicted from the histological appearances of the original tumor. Notwithstanding these studies, tumors recurring after previous radiotherapy are usually aggressive and infiltrative. It is unlikely that all such lesions were of an aggressive type initially. It should be noted that some studies have shown no correlation between the histological type and the recurrence rate, although a lack of uniformity in the histological classification of basal cell carcinomas makes the comparison of some series almost meaningless. Basal cell carcinomas in young adults are not more aggressive than those occurring in older patients, as once thought. Numerous reports document changes in the cells and stroma of basal cell carcinoma, some of which appear to provide explanations for the aggressiveness or otherwise of particular variants of basal cell carcinoma. Tumors showing aneuploidy and hyperexpression of cyclin D I are more likely to have an unfavorable outcome. Angiogenesis may be an important step in the acquisition of an aggressive phenotype. Acquisition of trisomy 6 by tumor cells may lead to the emergence of metastatic potential.
The usual criteria used for the acceptance of metastatic basal cell carcinoma are a previous or present primary lesion in the skin and a metastatic lesion that has a histological picture similar to that of the primary, and which could not have arisen by direct extension from the primary lesion. Metastases are rare, occurring in approximately 0.05% of cases. This low incidence is probably related to the stromal dependence of basal cell carcinomas, which presupposes that only large tumor emboli with attached stroma are successful in implanting. Accordingly, it is not surprising that lesions that give origin to metastases are large, ulcerated and neglected. Metatypical features and/or squamous differentiation have also been regarded as important, although these changes were present in only 15% of the primary lesions in one review of metastasizing basal cell carcinomas.
Metastases occur most commonly in the regional lymph nodes; bones, lungs and liver are less frequent sites of involvement. Other organs and the subcutis are rarely affected. Aspiration metastasis to the lung has been recorded. The median interval between the diagnosis of the primary lesion and signs of metastasis is approximately 9 years, whereas the interval between the appearance of the metastases and the death of the patient is approximately I year. Long survivals have occasionally been reported. Systemic amyloidosis and a myelophthisic anemia secondary to marrow infiltration have been documented in patients with metastatic basal cell carcinomas.