Basal-Cell Carcinoma

Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raised area with ulceration. Basal-cell cancer grows slowly and can damage the tissue around it, but it is unlikely to spread to distant areas or result in death.

Risk factors include exposure to ultraviolet light, having lighter skin, radiation therapy, long-term exposure to arsenic and poor immune-system function. Exposure to UV light during childhood is particularly harmful. Tanning beds have become another common source of ultraviolet radiation. Diagnosis often depends on skin examination, confirmed by tissue biopsy.

It remains unclear whether sunscreen affects the risk of basal-cell cancer. Treatment is typically by surgical removal. This can be by simple excision if the cancer is small; otherwise, Mohs surgery is generally recommended. Other options include electrodesiccation and curettage, cryosurgery, topical chemotherapy, photodynamic therapy, laser surgery or the use of imiquimod, a topical immune-activating medication. In the rare cases in which distant spread has occurred, chemotherapy or targeted therapy may be used.

Basal-cell cancer accounts for at least 32% of all cancers globally. Of skin cancers other than melanoma, about 80% are basal-cell cancers. In the United States, about 35% of white males and 25% of white females are affected by BCC at some point in their lives.

Signs and symptoms

Individuals with a basal-cell carcinoma typically present with a shiny, pearly skin nodule. However, superficial basal-cell cancer can present as a red patch similar to eczema. Infiltrative or morpheaform basal-cell cancers can present as a skin thickening or scar tissue – making diagnosis difficult without using tactile sensation and a skin biopsy. It is often difficult to visually distinguish basal-cell cancer from acne scar, actinic elastosis, and recent cryodestruction inflammation.

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  Dermoscopy showing telangiectatic vessels

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  Basal-cell carcinoma

Cause

The majority of basal-cell carcinomas occur on sun-exposed areas of the body.

Pathophysiology

Micrograph of a basal-cell carcinoma, showing the characteristic histomorphologic features (peripheral palisading, myxoid stroma, artefactual clefting). H&E stain

Basal-cell carcinomas are currently considered to have origin from the folliculo-sebaceous-apocrine germ, also known as trichoblast. The differential diagnosis with trichoblastic carcinoma, a rare malignant form of trichoblastoma, can be challenging. Alternatively, one argument is that basal-cell carcinoma is trichoblastic carcinoma. Overexposure to sun leads to the formation of thymine dimers, a form of DNA damage. While DNA repair removes most UV-induced damage, not all crosslinks are excised. There is, therefore, cumulative DNA damage leading to mutations. Apart from the mutagenesis, overexposure to sunlight depresses the local immune system, possibly decreasing immune surveillance for new tumor cells.

Basal-cell carcinomas can often come in association with other lesions of the skin, such as actinic keratosis, seborrheic keratosis, squamous cell carcinoma. In a small proportion of cases, basal-cell carcinoma also develops as a result of basal-cell nevus syndrome, or Gorlin Syndrome, which is also characterized by keratocystic odontogenic tumors of the jaw, palmar or plantar (sole of the foot) pits, calcification of the falx cerebri (in the center line of the brain) and rib abnormalities. The cause of this syndrome is a mutation in the PTCH1 tumor suppressor gene located in chromosome 9q22.3, which inhibits the hedgehog signaling pathway. A mutation in the SMO gene, which is also on the hedgehog pathway, also causes basal-cell carcinoma.

Diagnosis

To diagnose basal-cell carcinomas, a skin biopsy is performed for histopathologic analyses. The most common method is a shave biopsy under local anesthesia. Most nodular basal-cell cancers can be diagnosed clinically; however, other variants can be very difficult to distinguish from benign lesions such as intradermal naevus, sebaceomas, fibrous papules, early acne scars, and hypertrophic scarring. Exfoliative cytology methods have high sensitivity and specificity for confirming the diagnosis of basal cell carcinoma when clinical suspicion is high but unclear usefulness otherwise.

Characteristics

High-magnification micrograph of basal-cell carcinoma.

Basal-cell carcinoma cells appear similar to epidermal basal cells, and are usually well differentiated.

In uncertain cases, immunohistochemistry using BerEP4 can be used, having a high sensitivity and specificity in detecting only BCC cells.

Main classes

Basal-cell carcinoma can broadly be divided into three groups, based on the growth patterns.

1. Superficial basal-cell carcinoma, formerly referred to in-situ basal-cell carcinoma, is characterized by a superficial proliferation of neoplastic basal-cells. This tumor is generally responsive to topic chemotherapy, such as imiquimod, or fluorouracil.
2. Infiltrative basal-cell carcinoma, which also encompasses morpheaform and micronodular basal-cell cancer, is more difficult to treat with conservative methods, given its tendency to penetrate into deeper layers of the skin.
3. Nodular basal-cell carcinoma includes most of the remaining categories of basal-cell cancer. It is not unusual to encounter heterogeneous morphologic features within the same tumor.

Nodular basal-cell carcinoma

Basal-cell carcinoma with nodular pattern.

Nodular basal-cell carcinoma (also known as "classic basal-cell carcinoma") accounts for 50% of all BCC. It most commonly occurs on the sun-exposed areas of the head and neck.^:748:646 Histopathology shows aggregates of basaloid cells with well-defined borders, showing a peripheral palisading of cells and one or more typical clefts. Such clefts are caused by shrinkage of mucin during tissue fixation and staining. Central necrosis with eosinophilic, granular features may be also present, as well as mucin. The heavy aggregates of mucin determine a cystic structure. Calcification may be also present, especially in long-standing lesions. Mitotic activity is usually not so evident, but a high mitotic rate may be present in more aggressive lesions. Adenoidal BCC can be classified as a variant of NBCC, characterized by basaloid cells with a reticulated configuration extending into the dermis.

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  Palisading

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  Cleft.

Other subtypes

Other more specific subtypes of basal-cell carcinoma include:^:646–50

Type	Histopathology	Other characteristics	Image
Cystic basal-cell carcinoma		Morphologically characterized by dome-shaped, blue-gray cystic nodules.:647
Morpheaform basal-cell carcinoma (also known as "cicatricial basal-cell carcinoma", and "morphoeic basal-cell carcinoma")	Narrow strands and nests of basaloid cells, surrounded by dense sclerotic stroma.	Aggressive:748:647
Infiltrative basal-cell carcinoma	Deep infiltration.:647	Aggressive:647
Micronodular basal-cell carcinoma	Small and closely spaced nests.
Superficial basal-cell carcinoma (also known as "superficial multicentric basal-cell carcinoma")		Occurs most commonly on the trunk and appears as an erythematous patch.:748:647
Pigmented basal-cell carcinoma exhibits increased melanization.:748:647		About 80% of all basal-cell carcinoma in Chinese are pigmented while this subtype is uncommon in white people.
Rodent ulcer (also known as a "Jacob's ulcer")	Nodular, with central necrosis.:748:647	Generally a large skin lesion with central necrosis.:748:647
Fibroepithelioma of Pinkus	Anastomosing epithelial strands in a fenestrated pattern	Most commonly occurs on the lower back.:748:648
Polypoid basal-cell carcinoma	Exophytic nodules (polyp-like structures)	Generally on head and neck.:648
Pore-like basal-cell carcinoma		Resembles an enlarged pore or stellate pit.:648
Aberrant basal-cell carcinoma		Absence of any apparent carcinogenic factor, and occurring in odd sites such as the scrotum, vulva, perineum, nipple, and axilla.:648

Aggressiveness patterns

There are mainly three patterns of aggressiveness, based mainly the cohesion of cancer cells:

Differential diagnoses

Main histological differential diagnoses of basal cell carcinoma:

Differential diagnosis	Pathological Features	Image
Hair follicles	Peripheral sections may look like nests, but do not display atypia, nuclei are smaller, and serial sections will reveal the rest of the hair follicle.
Squamous-cell carcinoma of the skin	Squamous-cell carcinoma of the skin is generally distinguishable by for example relatively more cytoplasm, horn cyst formation and absence of palisading and cleft formations. Yet, a high prevalence means a relatively high incidence of borderline cases, such as basal-cell carcinoma with squamous cell metaplasia (H&E stain at left in image). BerEP4 staining helps in such cases, staining only basal-cell carcinoma cells (right in image).
Trichoblastoma	Absence of cleft, rudimentary hair germs, papillary mesenchymal bodies.
Adenoid cystic carcinoma	Lack of basaloid cells disposed in peripheral palisades; adenoid-cystic lesion without connection to the epidermis; absence of artefactual clefts
Microcystic adnexal carcinoma	Bland keratinocytes, keratin cysts, ductal differentiation. BerEp4- (in 60% of cases), CEA+, EMA+
Trichoepithelioma	Rims of collagen bundles, calcification, follicular/sebaceous/infundibular differentiation and cut artefacts. Cytokeratin (CK)20+, p75+, Pleckstrin homology-like domain family A member 1 + (PHLDA1+), common acute lymphoblastic leukemiaantigen + (CD10+) in tumor stroma, CK 6-, Ki-67- and Androgen Rceptor- (AR-)
Merkel cell carcinoma	Cells arranged in a diffuse, trabecular and/or nested pattern, involving also the subcutis. Mouse Anti-Cytokeratin (CAM) 5.2+, CK20+, S100-, human leukocyte common antigen- ( LCA-), thyroid transcription factor 1- (TTF1-)

Radicality

Comparison H&E stain (left) with BerEP4 immunohistochemistry staining (right) on a pathological section having BCC with squamous cell metaplasia. Only BCC cells are stained with BerEP4.

In suspected but uncertain BCC cells close to the resection margins, immunohistochemistry with BerEp4 can highlight the BCC cells.

Prevention

Basal-cell carcinoma is a common skin cancer and occurs mainly in fair-skinned patients with a family history of this cancer. Sunlight is a factor in about two-thirds of these cancers; therefore, doctors recommend sunscreens with at least SPF 30. However, a Cochrane review examining the effect of solar protection (sunscreen only) in preventing the development of basal-cell carcinoma or cutaneous squamous cell carcinoma found that there was insufficient evidence to demonstrate whether sunscreen was effective for the prevention of either of these keratinocyte-derived cancers. The review did ultimately state that the certainty of these results was low, so future evidence could very well alter this conclusion. One-third occur in non-sun-exposed areas; thus, the pathogenesis is more complex than UV exposure as the cause.

The use of a chemotherapeutic agent such as 5-Fluorouracil or imiquimod can prevent the development of skin cancer. It is usually recommended to individuals with extensive sun damage, history of multiple skin cancers, or rudimentary forms of cancer (i.e., solar keratosis). It is often repeated every 2 to 3 years to further decrease the risk of skin cancer.

Treatment

The following methods are employed in the treatment of basal-cell carcinoma (BCC):

Surgery

Standard surgical excision

Surgery to remove the basal-cell carcinoma affected area and the surrounding skin is thought to be the most effective treatment. A disadvantage with standard surgical excision is a reported higher recurrence rate of basal-cell cancers of the face, especially around the eyelids, nose, and facial structures. There is no clear approach for treating basal-cell carcinoma around the eye.

For ill-defined or recurrent basal-cell cancer on the face after previous surgery, special surgical margin controlled processing (CCPDMA – complete circumferential peripheral and deep margin assessment) using frozen section histology (Mohs surgery is one of the methods) should be considered. The pathologist processing the frozen section specimen should cut multiple sections through the block to minimize the false negative error rate. Or one should simply process the tissue utilizing a method approximating the Mohs method (described in most basic histopathology text books or described in this reference ) during frozen section processing. Unfortunately, these methods are difficult when applied to frozen sections; and they are very tedious to process. When not utilizing frozen section, the surgeon might have to wait a week or more before informing the patient if more tumour is left, or if the surgical margin is too narrow. A second surgery must be performed to remove the residual or potential residual tumour once the surgeon informs the patient of the positive or narrow surgical margin on the surgical pathology report.

For poorly defined or recurrent tumours on the face, Mohs surgery or frozen section histology with either margin control (ccpdma) or thin serial bread-loafing should be considered. However, most standard excisions done in a plastic surgeon or dermatologist's office are sent to an outside laboratory for standard bread loafing method of processing. With this method, it is likely that less than 5% of the surgical margin is examined, as each slice of tissue is only 6 micrometres thick, about 3 to 4 serial slices are obtained per section, and only about 3 to 4 sections are obtained per specimen. There is no clear research comparing the effectiveness of Mohs micrographic surgery versus surgical excision for BCC of the eye.

For basal cell carcinoma excisions on the lower lip the wound can be covered with a keystone flap. A keystone flap is achieved by creating a flap below the defect and pulling it superiorly to cover the wound. This can be performed if there is enough skin laxity to cover the defect and adequate blood supply to the flap.

Mohs surgery

Mohs surgery (or Mohs micrographic surgery) is an outpatient procedure, which was developed by Frederic E. Mohs in the 1940s, in which the tumor is surgically excised and then immediately examined under a microscope. It is a form of pathology processing called CCPDMA. The base and edges are microscopically examined to verify sufficient margins before the surgical repair of the site. If the margins are insufficient, more is removed from the patient until the margins are sufficient. It is also used for squamous-cell carcinoma; however, the cure rate is not as high as Mohs surgery for basal-cell carcinoma. The 2008 study found Mohs surgery to be a good option for both primary and high-risk recurrent BCCs.

Cryosurgery

Cryosurgery is an old modality for the treatment of many skin cancers. When accurately utilized with a temperature probe and cryotherapy instruments, it can result in very good cure rate. Disadvantages include lack of margin control, tissue necrosis, over or under treatment of the tumor, and long recovery time. Overall, there are sufficient data to consider cryosurgery as a reasonable treatment for BCC. There are no good studies, however, comparing cryosurgery with other modalities, particularly with Mohs surgery, excision, or electrodesiccation and curettage so that no conclusion can be made whether cryosurgery is as efficacious as other methods. Also, there is no evidence on whether curetting the lesions before cryosurgery affects the efficacy of treatment. Several textbooks are published on the therapy, and a few physicians still apply the treatment to selected patients.

Electrodesiccation and curettage

Electrodesiccation and curettage (EDC, also known as curettage and cautery, simply curettage) is accomplished by using a round knife, or curette, to scrape away the soft cancer. The skin is then burned with an electric current. This further softens the skin, allowing for the knife to cut more deeply with the next layer of curettage. The cycle is repeated, with a safety margin of curettage of normal skin around the visible tumor. This cycle is repeated 3 to 5 times, and the free skin margin treated is usually 4 to 6 mm. Cure rate is very much user-dependent and depends also on the size and type of tumor. Infiltrative or morpheaform BCCs can be difficult to eradicate with EDC. Generally, this method is used on cosmetically unimportant areas like the trunk (torso). Some physicians believe that it is acceptable to utilize EDC on the face of elderly patients over the age of 70. However, with increasing life expectancy, such an objective criterion cannot be supported. The cure rate can vary, depending on the aggressiveness of the EDC and the free margin treated. Some advocate curettage alone without electrodesiccation, and with the same cure rate.

Chemotherapy

Some superficial cancers respond to local therapy with 5-fluorouracil, a chemotherapy agent. Topical treatment with 5% imiquimod cream, with five applications per week for six weeks has a reported 70–90% success rate at reducing, even removing, the BCC [basal-cell carcinoma]. Both Imiquimod and 5-fluorouracil have received FDA approval, and topical IMQ is approved by the European Medicines Agency for treatment of small superficial basal-cell carcinoma. Off label use of imiquimod on invasive basal-cell carcinoma has been reported. Imiquimod may be used prior to surgery in order to reduce the size of the carcinoma. One can expect a great deal of inflammation with this treatment. Chemotherapy often follows Mohs surgery to eliminate the residual superficial basal-cell carcinoma after the invasive portion is removed. Some advocate the use of imiquimod prior to Mohs surgery to remove the superficial component of the cancer.

Removing the residual superficial tumor with surgery alone can result in large and difficult to repair surgical defects. One often waits a month or more after surgery before starting the Imiquimod or 5-fluorouracil to make sure the surgical wound has adequately healed. Some people advocate the use of curettage (see EDC below) first, followed by chemotherapy. These experimental procedures are not standard care.

Vismodegib and sonidegib are drugs approved for specially treating BCC, but are expensive and cannot be used in pregnant women.

Immunotherapy

Immunotherapy research suggests that treatment using Euphorbia peplus, a common garden weed, may be effective. Australian biopharmaceutical company Peplin is developing this as topical treatment for BCC. Imiquimod is an immunotherapy but is listed here under chemotherapy.

Radiation

Radiation therapy can be delivered either as external beam radiotherapy or as brachytherapy (mostly internal radiotherapy). Although radiotherapy is generally used in older patients who are not candidates for surgery, it is also used in cases where surgical excision will be disfiguring or difficult to reconstruct (especially on the tip of the nose, and the nostril rims). Radiation treatment with external radiation often takes as few as 5 visits to as many as 25 visits. Usually, the more visits scheduled for therapy, the less complication or damage is done to the normal tissue supporting the tumor. Radiotherapy can also be useful if surgical excision has been done incompletely or if the pathology report following surgery suggests a high risk of recurrence, for example if nerve involvement has been demonstrated. Cure rate can be as high as 95% for small tumor, or as low as 80% for large tumors. A variation of an external brachytherapy is the epidermal radioisotope therapy (e.g. with ¹⁸⁸Re in form of the Rhenium-SCT). It is used in accordance to the general indications for brachytherapy and especially complex localisations or structures (e.g. earlobe) as well as the genitals.

Usually, recurrent tumors after radiation are treated with surgery, and not with radiation. Further radiation treatment will further damage normal tissue, and the tumor might be resistant to further radiation. Radiation therapy may be contraindicated for treatment of nevoid basal-cell carcinoma syndrome. A 2008 study reported that radiation therapy is appropriate for primary BCCs and recurrent BCCs, but not for BCCs that have recurred following previous radiation treatment.

Photodynamic therapy

Photodynamic therapy (PDT) is a new modality for treatment of basal-cell carcinoma, which is administrated by application of photosensitizers to the target area. When these molecules are activated by light, they become toxic, therefore destroy the target cells. Methyl aminolevulinate is approved by EU as a photosensitizer since 2001. This therapy is also used in other skin cancer types. The 2008 study reported that PDT was a good treatment option for primary superficial BCCs and reasonable for primary low-risk nodular BCCs but a "relatively poor" option for high-risk lesions.

Prognosis

Prognosis is excellent if the appropriate method of treatment is used in early primary basal-cell cancers. Recurrent cancers are much harder to cure, with a higher recurrent rate with any methods of treatment. Although basal-cell carcinoma rarely metastasizes, it grows locally with invasion and destruction of local tissues. The cancer can impinge on vital structures like nerves and result in loss of sensation or loss of function or rarely death. The vast majority of cases can be successfully treated before serious complications occur. The recurrence rate for the above treatment options ranges from 50 percent to 1 percent or less.

Epidemiology

Basal-cell cancer is a very common skin cancer. It is much more common in fair-skinned individuals with a family history of basal-cell cancer and increases in incidence closer to the equator or at higher altitude. There are approximately 800,000 new cases yearly in the United States alone. Up to 30% of White people develop basal-cell carcinomas in their lifetime. In Canada, the most common skin cancer is basal-cell carcinoma (as much as one third of all cancer diagnoses), affecting 1 in 7 individuals over a lifetime.

In the United States approximately 3 out of 10 White people develop a basal-cell carcinoma during their lifetime. This tumor accounts for approximately 70% of non-melanoma skin cancers. In 80 percent of all cases, basal-cell carcinoma affects the skin of head and neck. Furthermore, there appears to be an increase in the incidence of basal-cell cancer of the trunk in recent years.

Most sporadic BCC arises in small numbers on sun-exposed skin of people over age 50, although younger people may also be affected. The development of multiple basal-cell cancer at an early age could be indicative of nevoid basal-cell carcinoma syndrome, also known as Gorlin Syndrome.

Notes