AUTHOR AND EDITOR INFORMATION

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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Clinical
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Background

The most common form of skin cancer and the most common epithelial tumor is basal cell carcinoma (BCC), accounting for 80-90% of skin malignancies. Although it is the most common skin cancer, it accounts for fewer than 0.1% of patient deaths due to cancer. BCCs are more likely to occur in white or light-skinned individuals who have had significant unprotected exposure to UV (sunexposed) radiations and are more common in the southern latitudes of the northern hemisphere.

The overall cure rate is directly related to the histologic staging of the disease, time of diagnosis, and treatment modality used. The cure rate is suggested to be approximately 95%. However, since BCC is not a reportable disease, the precise 5-year cure rate (survival rate) is not known.

Pathophysiology

Radiation has proven to be tumorigenic by two mechanisms. The first mechanism entails the initiations of prolonged cellular proliferation, thereby increasing the likelihood of transcription errors that can lead to cellular transformation. The second mechanism is direct damage of DNA replication, leading to cellular mutation that may activate proto-oncogenes or deactivate tumor suppressor genes.

BCC of the eyelid is the most common epithelial tumor, but its molecular-genetic pathogenesis is unclear. Mutation of p53 (in this case, an overexpression of the p53 gene) may form an integral part of the pathogenetic sequence and may attempt to explain the pathogenesis of BCC. A published article by Zhang et al demonstrates that the UV-specific nucleotide changes in 2 tumor suppressor genes, p 53 and PTCH, are both implicated in the development of early-onset BCC.

Immunologically, the mechanism by which prolonged UV radiation exposure leads to the development of BCC includes suppression of the cutaneous immune system and immunologic unresponsiveness to cutaneous tumors. This local effect includes a decrease in Langerhans cells, dendritic epidermal T cells, and Thy1+ cells. Furthermore, systemic proliferation of suppressor T cells and the release of immunosuppressive factors (eg, tumor necrosis factor-a [TNF-a], interleukin 1 [IL-1], prostaglandin [PG], interleukin 10 [IL-10]) are believed to be pathogenic to the development of BCC.

Frequency

United States

Solar radiation exposure is the most important etiologic factor in the genesis of BCC. The tumor most commonly arises in the lower eyelid (48.9-72.1%), followed by the medial canthus (25-30%), the upper eyelid (15%), and the lateral canthus (5%). Review of the literature showed all authors agreed that BCC most commonly occurs in the lower eyelid; however, the remaining anatomical locations and the incidence of occurrence differ among authors.

In the United States, the prevalence of BCC is approximately 1 million with more than 900,000 cases developing in the head or the neck. The age- and sex-adjusted incidence rates for BCC are 14.25 cases per 100,000 individuals per year.

Patients with AIDS are at a greater risk of developing BCC.

Mortality/Morbidity

BCC is slow growing, locally invasive and destructive, and rarely metastasizes (0.0028-0.1%); thus, a metastatic workup often is not indicated. However, cases of metastatic lesions arising from a primary BCC lesion have been reported; Patel et al reported a case of BCC metastasizing to the lung.

• Death from BCC is extremely rare; however, if BCC is allowed to progress, it can result in significant morbidity, and cosmetic disfigurement is not uncommon.
• BCC arising in the medial canthus tends to be deep and invasive and may result perineural extension and loss of nerve function.
• Pieh et al reported a recurrence rate of 5.36% after the first excision of the tumor; the rate increased to 14.7% after the second operation, and the rate reached 50% after the third and fourth operations. The highest recurrence, approximately 60%, was seen with lesions arising from the medial canthus, since these lesions tend to be more invasive and difficult to manage.
• The incidence of BCC increases in patients who are immunocompromised.

Race

BCC occurs more commonly in white or light-skinned individuals than in blacks or in Asians.

Sex

BCC is slightly more common in males than in females with a male-to-female ratio of 3:2.

• The lifetime risk for developing BCC approaches 40% in men and 30% in women.
• Cook et al reported the incidence of BCC to be equal for both men and women.
• Also, according to Cook et al, the age-adjusted incidence rates for all malignant tumors of the eyelid in men were 19.6 cases per 100,000 population per year, and, in women, the rates were 13.3 cases per 100,000 population per year. The age-adjusted incidence rates for BCC of the eyelid for men and women were 16.9 and 12.4, respectively, per 100,000 population per year, as reported by Cook et al.

Age

The incidence of BCC increases with advancing age and tends to occur in the seventh decade of life. The median age at diagnosis is 67 ± 2.5 years, and the mean age is 64.4 ± 5.6 years (age range, 20-90 y). Approximately 5-15% of cases of BCC occur in patients aged 20-40 years.

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
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History

• Patients often present complaining of a nonhealing ulcer that often bleeds with mild trauma (eg, wiping or drying after a shower).
• History also may elicit a long history to sun exposure early in life and/or an outdoor occupation.
• Presenting symptoms are often painless.

Physical

Clinically, several variants of BCC exist. However, most tumors present with the following characteristics: painless nodule, shiny and waxy, indurated, firm and immobile, pearly, rolled border, and with fine (small) telangiectatic vessels on the surface.

Clinically, BCC can be grouped into 3 types: nodular, nodulo-ulcerative (rodent ulcer), and morpheaform or sclerosing.

• Nodular
• • Most common
  • Presents as a firm, shiny, pearly nodule with fine telangiectasia
  • Slow growing, 0.5 cm in 1-2 years
  • May become pigmented due to the presence of melanin (secondary melanosis) and can be misinterpreted clinically as malignant melanoma
  • Fine vessels may bleed, resulting in hemosiderin deposition.
  • Tumor may present as a cyst, which can be mistaken for inclusion cysts of the eyelid.
  • Undetected or left untreated, the tumor nodule may undergo central ulceration to become an early form of nodulo-ulcerative BCC.
• Nodulo-ulcerative
• • Characterized by central ulceration, which can be extensive in neglected cases; hence, rodent ulcer, the other name for this type of BCC
  • Tumor margin is raised with rolled pearly borders.
  • Dilated blood vessels course over tumor borders.
  • If left untreated, the tumor can involve and erode a large portion of the eyelid.
• Morpheaform (sclerosing)
• • Least common
  • Tumor appears as a pale, well-defined, indurated plaque.
  • Tumor borders are ill defined.
  • Tumor tends to grow laterally beneath the epidermis; therefore, the lesion may be more extensive on palpation than on inspection.

Causes

The risk factors for developing BCC include the following:

• Prolonged unprotected exposure to the sun
• White race
• Lightly pigmented skin, eyes, and hair
• Increased age (usually seen in the sixth and seventh decades)
• Freckling
• Inability to tan
• Male
• Prolonged redness after exposure to sunlight
• Exposure to ionizing radiation and environmental exposures (eg, hydrocarbons, pesticides)
• Genetic determinants, such as inherited defects in DNA replication and/or repair (eg, xeroderma pigmentosa)

DIFFERENTIALS

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Other Problems to be Considered

Actinic keratosis
Sebaceous hyperplasia
Nevi malignant melanoma
Keratoacanthoma
Seborrheic keratosis
Bowen disease
Cutaneous T-cell lymphoma (mycosis fungoides)
Metastatic malignancies

WORKUP

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• Follow-up
• Miscellaneous
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Imaging Studies

• Radiological imaging of the facial and orbital bones and soft tissues may be helpful for an invading or deep tumor in the medial canthus.
• The use of ultrasonography is currently controversial. High-frequency (20 MHz) and ultra–high-frequency (40-100 MHz) ultrasound systems have been used; however, their accuracy in delineating malignant lesions from benign lesions remains inadequate with a success rate of approximately 20%. Furthermore, the claims of reliable tumor sizing and depth of invasion are promising but still passionately debated.
• Laser Doppler may be a useful tool in delineating the tumor margin. It is reported that cutaneous perfusion to the eyelids is statistically significantly higher than other regions of the body (eg, forearm). Furthermore, the mean perfusion in pretarsal skin was 50% greater than preseptal skin. In histologically documented BCC of the eyelid, cutaneous perfusion was significantly greater. As an adjunct tool, laser Doppler may assist ophthalmologists in distinguishing benign versus malignant adnexal skin lesions and in establishing the tumor margin.

Other Tests

• Cytology
• • To accurately and definitively diagnose BCC of the eyelid, histological confirmation is required and is most commonly obtained through excisional biopsy. However, cytology does provide a rapid alternative that may yield and even help confirm a diagnosis during the initial visit.
  • The accuracy of this technique has been reported to be good, but its sensitivity in diagnosing BCC of the eyelid is unknown. In a paper by Barton et al, patients who underwent cytology followed by excisional biopsy showed that cytology had a sensitivity of 92% in diagnosing BCC with a predictive accuracy of 75%. These values were compared to a second group of patients who had incisional biopsy and histological examination followed by excision with histological confirmation. The second group showed a sensitivity of 100% in diagnosing BCC with a predictive accuracy of 96%.
  • Cytology may play a role in helping to diagnose BCC. It is sufficiently accurate; however, it is not sufficiently sensitive in planning surgical management.

Histologic Findings

Nodular type: The nodular type accounts for more than 70% (73.4%) of the histologic type. Nests of basaloid cells in different sizes are present. Tumor cells show peripheral palisading. Cells have large, oval or elongated nuclei with scant cytoplasm. Cells may be pleomorphic or atypical and may contain mitotic figures. Sharp demarcation between normal cells and neoplastic cells is well visualized on microscopy. Contraction artifact at the periphery of the tumor lobules is seen; this histologic feature results from shrinkage of the mucin-rich stroma during specimen processing. Desmoplasia (pseudocarcinomatous changes) of the surrounding stroma is seen.

Variants of the nodular type include the following:

• Cystic - Cyst fills with blood (hemorrhage) and necrotic tumor cells. This often is seen in a large tumor mass and possible fast-growing tumors.
• Basosquamous - Possesses a basal and squamous component in the tumor
• Sebaceous - Rare; if present, should suspect Muir Torre syndrome
• Keratotic - Nest of keratin
• Adenoidal - Mucin producing (foamy, lucent, slightly basophilic)
• Pigmented - Melanoma versus nevi versus iron deposition (hemosiderin)

Paavilainen et al recently described nodular subtypes, to include micronodular (4.9%) and superficial (1.9%), both with a low incidence of occurrence compared to the nodular form.

Morpheaform (fibrosing) type: Tumor cells grow in thin, elongated strands or cords. Usually, this type is one cell layer thick (Indian file pattern). This type lacks desmoplasia. Proliferation of connective tissue into dense fibrous stroma is seen. Contraction artifact is observed histologically. This type tends to be more aggressive, invades deeper into the underlying tissue, and is likely to recur.

Staging

Unlike other carcinomas (eg, colorectal cancer), BCC is not commonly staged because it rarely metastasizes. Staging BCC often is reserved for large or widespread basal cell cancers. If staging is necessary, the most widely used method is the TNM system.

• TNM classification
• • The primary tumor (T) is classified as follows:
    • TX: The primary tumor cannot be assessed.
    • T0: No evidence of primary tumor is present.
    • T1: Tumor is less than or equal to 2 cm in the greatest dimension.
    • T2: Tumor is greater than 2 cm but less than 5 cm in the greatest dimension.
    • T3: Tumor is greater than 5 cm in the greatest dimension.
    • T4: Tumor invades the deep and/or extradermal structures.
  • The regional lymph nodes (N) are classified clinically into the following:
    • NX: Regional (nearby) lymph nodes cannot be assessed.
    • N0: No metastasis to regional lymph node is present.
    • N1: Regional lymph node metastasis is present.
  • Metastasis (M) is classified as follows:
    • MX: Distant metastasis cannot be assessed.
    • M0: Distant metastasis is not noted.
    • M1: Distant metastasis is present.
• Clinical staging
• • Stage 0 (carcinoma in situ [CIS]): Abnormal cells are found but have not invaded deeper tissue.
  • Stage 1: Tumor cells are found and measure less than 2 cm in greatest dimension and have not spread to regional lymph nodes.
  • Stage 2: Tumor measures greater than 2 cm in greatest dimension and has not spread to regional lymph nodes.
  • Stage 3: Tumor has metastasized to the tissues under the skin (muscle, bone, or cartilage) or to the regional lymph nodes.
  • Stage 4: Tumor (any size) has metastasized to distant organ(s).

TREATMENT

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Medical Care

• Radiation therapy
• • In the past, radiation therapy was a common treatment modality. With the advancement in surgical techniques and other treatment modalities, radiation therapy is a reasonable treatment choice for recurring tumors. It may be reserved for primary lesions requiring difficult or extensive oculoplastic surgery. It also eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good to excellent with a small amount of hypopigmentation or telangiectasia in the treatment port.
  • Radiation adverse effects include dermatitis, keratinization of the conjunctiva, and chronic keratitis.
  • Radiation therapy is contraindicated for patients with xeroderma pigmentosum, epidermodysplasia verruciformis, and basal cell nevus syndrome (this histologic type in conjunction with radiation therapy may induce more tumors in the treated area).
• Chemotherapy: Literature has reported success in treating BCC of the eyelid with chemotherapeutic agents (eg, 5-fluorouracil, cisplatin, doxorubicin). Although not curative, this treatment modality may be helpful in managing selected superficial lesions, lesions located in the medial canthus, recurrent and invasive BCC, and large tumors where surgical resection may result in cosmetic deformity and functional defect. Furthermore, a 5-year follow-up study has shown the tumor to be in complete remission when treated with cisplatin and doxorubicin simultaneously.
• Photodynamic therapy (PDT) with photosensitizers may be an effective treatment of superficial epithelial skin tumors. PDT yielded only a 50% cure rate against superficial BCC versus an 83% cure rate against nodular BCC in one study by Calzavara-Pinton. At present, PDT has no distinct advantage over other well-established therapies for BCC of the eyelid. PDT in adjunct with d-aminolevulinic acid is a viable option in the following cases:
  • Tumor recurrence with tissue atrophy and scar formation
  • Elderly patients or patients with medical conditions preventing extensive oculoplastic reconstructive surgery
  • Tumor with poorly defined borders based on clinical examination
  • Tumor requiring difficult or extensive oculoplastic surgery
• Systemic retinoids
  • Although several clinical trials have shown some efficacy for currently available systemic retinoids in both chemotherapy and chemoprevention, the long-term toxicity of these agents generally excludes them as treatment choices for most patients. Studies are exploring their value as cancer preventive agents in patients at high risk for developing multiple tumors.
  • In a published article by Wilson, tazarotene (Tazorac) gel, a receptor-selective acetylenic retinoid, used topically, has been shown to decrease tumor size in 47% of cases, and, in 53% of cases, the tumor was eliminated completely. A drawback to topical tazarotene is that it requires long-term therapy for 5-8 months. The only reported adverse effect is dry/irritating skin that was relieved after discontinuation of tazarotene.
• Alpha interferon: Several early studies have shown variable responses of BCC to intralesional alpha interferon. However, further data are needed before this treatment modality is recommended for routine ophthalmic practice.

Surgical Care

Histologic type, size, and location are important factors that must be taken into account when treating BCC. Traditionally, treatment modalities have included cryosurgery, radiation therapy, electrodesiccation and curettage, and surgical excision. Each method is useful in specific clinical situations, and depending on the preference and/or expertise (familiarity) of the ophthalmologist, these methods have cure rates ranging from 85-95%.

Mohs micrographic surgery has the highest 5-year cure rates for surgical treatment of both primary BCC (96%) and recurrent BCC (90%). This method uses microscopic control to evaluate the extent of tumor invasion. The 5-year recurrence rates for treated BCC after Mohs micrographic surgery was 1%, 7.5% after cryosurgery, 7.7% after desiccation and curettage, 8.7% after radiotherapy, and 10.1% after surgical excision.

A published paper in Ophthalmology reported a 5-year recurrence rate of 0% for primary tumors and of 7.8% for recurring tumors after Mohs microsurgery.

Small margin excision (ie, 2-mm margin instead of traditional 3- to 4-mm margin) with delayed primary closure is another viable option in surgical management. This procedure has been shown to be safe and efficacious with preservation of healthy tissue, allowing for less radical reconstructive surgery and/or labor intensive Mohs microsurgery.

• Goals of surgical management
  • Wide excision to ensure complete removal of tumor cells
  • Preservation of the delicate tissues of the eye
  • Preservation of the lacrimal system
  • Prevention of metastasis into the orbit and deeper structures
  • Cosmetically pleasing
  • Prevention of recurrences by wearing sunscreens, a hat, and covering sunexposed areas
  • Early detection of recurrences and any new tumors
• Simple surgical excision is the traditional treatment modality that often relies on surgical margins ranging from 3-10 mm, depending on the diameter of the tumor. Since only a small fraction of the total tumor margin is examined microscopically, tumor recurrence is not uncommon. The 5-year recurrence rate for primary tumors greater than 1.5 cm in diameter is approximately 12%. The diameter of a primary tumor that measures greater than 3 cm has a 5-year recurrence rate of 23%.
• Although Mohs micrographic surgery has the highest cure rate of all surgical treatments, this surgical technique is complicated and requires special training. This method allows the tumor to be microscopically delineated until it is removed completely. While other treatment modalities for recurrent BCC have a cure rate of approximately 50%, the cure rates have been reported at 96% when treated by Mohs micrographic surgery. Mohs micrographic surgery is indicated for the following tumors:
  • Primary BCCs occurring at sites known to have a high initial treatment failure rate with traditional method
  • Tumors with poorly defined clinical borders
  • Tumors with diameters greater than 2 cm
  • Tumors with morpheaform/sclerotic histopathologic patterns
  • Tumors arising in regions where maximum preservation of uninvolved tissue is desirable and for desirable cosmetic outcome
• Electrodesiccation and curettage is the most widely used method for removing primary BCCs. Although quick to destroy tumor cells, the adequacy of this treatment cannot be assessed immediately, since the surgeon cannot visually detect the depth of microscopic tumor invasion and surgical margin. Tumors ranging from 2-5 mm in diameter have a 15% recurrence rate, while tumors with a diameter of 3 cm or greater have a 50% recurrence rate within 5 years when treated by electrodesiccation and curettage.
• Cryosurgery may be considered for small, clinically well-defined primary tumors. It is especially useful for patients who are debilitated with medical conditions that preclude other types of surgery. Cryosurgery is a viable alternative in treating BCC involving the inner canthus, thereby minimizing damage to the lacrimal system.
  • Absolute contraindications for cryosurgery include patients with cold intolerance, cryoglobulinemia, cryofibrinogenemia, Raynaud disease (only for treatment of lesions on hands and feet), platelet deficiency disorders, and morphea or sclerosing type BCC.
  • Relative contraindications to cryosurgery include tumors of the free eyelid margin.
  • Caution should be used before treating nodular ulcerative type BCC greater than 3 cm or recurrent carcinomas following surgical excision. Edema is common following treatment, especially around the periorbital region. Eschar may form and may persist for about 4 weeks. Following treatment, permanent pigment loss at the treatment site is sometimes unavoidable. Atrophy and hypertrophic scarring, as well as instances of motor and sensory neuropathies, have been reported.
  • Overall, BCC of the eyelid treated with cryosurgery has a high cure rate; 92% of BCCs treated did not recur during a mean follow-up period of 5 years (range, 1.6-8.4 y). Cryosurgery is also cost-effective and well tolerated.
• Carbon dioxide laser is applied most frequently to the superficial type of BCC. It may be considered when a bleeding diathesis is present, since bleeding is unusual when this laser is used. This laser approach provides a bloodless field, minimal postoperative pain, and good postoperative appearance without scar formation. In cases of superficial T1-T2 BCC, laser microsurgery appears to be a safe and effective treatment modality without conjunctival extension.

Consultations

• Oculoplastic surgeon
• Plastic surgeon
• Radiation oncologist
• Oncologist

MEDICATION

Section 7 of 11  

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Although there are no proven topical or systemic medications to combat BCC, tazarotene has been shown to decrease tumor size, and, in 50% of the studied cases, it has been shown to eliminate the tumor.

Drug Category: Receptor-selective acetylenic retinoids

Decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. Modulate keratinocyte differentiation.

FOLLOW-UP

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Further Outpatient Care

• After treatment of BCC, patients should perform the following:
• • A clinical examination 1, 3, 6, and 12 months after the initial surgery
  • Thereafter, an annual comprehensive ophthalmic examination to examine for recurrent or new primary tumors
• Prospective studies have shown that 36% of patients who develop BCC will develop a second primary BCC within the next 5 years. Early detection, diagnosis, and treatment of recurrent or another primary BCC is desirable since the treatment of the disease in its earliest stages results in less patient morbidity.

Deterrence/Prevention

• Avoidance of sun exposure is recommended.

Prognosis

• The prognosis is good with early detection and treatment of BCC. However, a recurring tumor has the propensity to be aggressive and problematic to manage.
• Recurrence is rare with BCC.
• A 5-year cure rate of 95% exists for lesions less than 10 mm.

Patient Education

• Patients are encouraged to complete the following:
• • Apply sunscreen with SPF of 20 and higher.
  • Wear sunglasses, a long sleeve shirt, and a broad-brimmed hat.
  • Avoid sun exposure during midday.
  • Schedule regular follow-up care after treatment.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The diagnosis of BCC often is easily made clinically and confirmed histologically. However, there have been a few cases where a more aggressive tumor (ie, squamous cell carcinoma) may mimic the clinical presentation of BCC. Ultimately, all biopsy samples should be sent for pathological diagnosis.
• Although BCC is often diagnosed in the sixth and seventh decades, BCC diagnosed in young adults should warrant a full workup to rule out other systemic diseases.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Basal cell carcinoma of the right lower lid.
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Media type:  Photo

Media file 2:  Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor.
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Media type:  Photo

Media file 3:  Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will impact its treatment and reconstruction.
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Mar 9, 2007