Basal cell carcinoma

Basal cell carcinoma (BCC) (also known as basalioma or basal cell cancer), is the most common skin cancer, and one of the most common cancers in the United States.[1] While BCC has a very low metastatic risk, this tumor can cause significant disfigurement by invading surrounding tissues.
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.
Cause
About two thirds of basal-cell carcinomas occur on sun-exposed areas of the body. One-third occur on areas of the body that are not exposed to sunlight, emphasizing the genetic susceptibility of basal-cell cancer.
Classification
Basal cell carcinoma can be divided into three groups, based on the growth patterns.

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 Aldara (Imiquimod), or Fluorouracil.
Infiltrative basal cell carcinoma, that 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.
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.
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.
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.[7] Alternatively, one argument is that basal call carcinoma is trichoblastic carcinoma.[8] 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.
Pathophysiology
Basal cell carcinomas can often come in association with other lesions of the skin, such as actinic keratosis, seborrheic keratosis, squamous cell carcinoma.[9] 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.
Standard surgical excision
This can be with either frozen section histology, or paraffin-embedded fixed-tissue pathology. It is the preferred method for removal of most BCCs. A dermatoscope can help an experienced surgeon accurately identify the visible tumour that the naked eye can not see.[11][12]

The cure rate for this method, whether performed by a General Surgeon, Otolaryngologist, Head & Neck Surgeon, Plastic Surgeon, Maxillofacial Surgeon or dermatologist is totally dependent on the surgical margin. The narrower the free surgical margin (skin removed that is free of visible tumor) the higher the recurrence rate.[13][14][15][16] If a 4 mm free surgical margin is obtained around a small tumor (less than 6mm), or a wider 6 mm free surgical margin is obtained around a larger tumor (greater than 6mm), the cure rate is very high—95% or better.[17][18][19][20][21][22] However, for cosmetic reasons, many doctors take only very small surgical margins 1–2 mm,[23] especially when operating on the face. In such a case, a pathology report indicating the margins are free of residual tumour is often inaccurate, and recurrence rates are much higher (up to 38%).[19][23][24][25]

A weakness with standard surgical excision is the high recurrence rate of basal-cell cancers of the face, especially around eyelids,[24] nose, and facial structures.[26] A diagram on page 38 of the National Comprehensive Cancer Network publication demonstrate the area of high risk of recurrence as most the face with the exception of the central cheek and upper forehead.[17][27] On the face, or on recurrent basal-cell cancer after previous surgery, special surgical margin controlled processing (CCPDMA—complete circumferential peripheral and deep margin assessment[27][28])[29] using frozen section histology (Mohs surgery is one of the methods) is required.[30][31]

With surgical margin controlled frozen section histology, a surgeon can achieve a high cure rate and low recurrence rate on the same day of the excision.[32] 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.[33] 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 (see figure 2 of reference[34]).

When in doubt,[clarification needed] a patient should demand that either Mohs surgery or frozen section histology with either margin control (ccpdma) or thin serial bread-loafing is utilized when dealing with a tumour on the face.[17] 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 [30]) 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.[35] And 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.

A 2008 meta-study of the literature around management of BCCs suggested that excision is a good treatment for primary tumors.
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.[36] 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.[40] 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.[41] 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[who?] advocate the use of curettage (see EDC below) first, followed by chemotherapy. These experimental procedures are not standard care. The 2008 study reported that topical IMQ appears effective in the treatment of primary small superficial BCCs, but only 'may possibly' have a role in the treatment of primary nodular BCC.[36]

Approved in 2012, vismodegib is used to treat an advanced form of basal-cell carcinoma.
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[46] new cases yearly in the United States alone. Up to 30% of Caucasians develop basal-cell carcinomas in their lifetime.[47] 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.[48][49]

In the United States approximately 3 out of 10 caucasians develop a basal cell carcinoma during their lifetime.[47] 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.[47] Furthermore, there appears to be an increase in the incidence of basal-cell cancer of the trunk in recent years.[47]

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's Syndrome.

Tweet