Patient Presentation
An 83-year-old Caucasian man was brought by his daughter for consultation because of a non-healing, slowly progressive lesion on his right earlobe, which lead to piercing of the earlobe. The lesion had been present for at least 2 years. He denied trauma, acupuncture or application of caustic products to this area. His past medical history was significant for substantial sun damage.
What’s Your Diagnosis?
Diagnosis: Basal Cell Carcinoma Causing Ear Piercing
Basal Cell Carcinoma (BCC) is the most common skin cancer diagnosed in the United States, comprising up to 75% of nonmelanoma skin cancers.1 It arises from the basal layer of the epidermis, and although it has low metastatic potential, it may result in local destruction of the skin and surrounding structures. BCC has an annual incidence between 500 and 1000 per 100,000, which increases with age. Risk factors can be attributed to both environmental as well as genetic causes. Solar radiation is the most important environmental cause of BCC.1 Therapeutic radiation, such as PUVA for the treatment of psoriasis, may result in BCC 20 years after exposure.2 Chronic arsenic exposure, which may result from ingestion of contaminated water, seafood or medications, can contribute to development of superficial BCCs. Genetic characteristics, such as fair skin, light-colored eyes and red hair, are also important risk factors. Basal nevus syndrome is an autosomal dominant disorder that causes development of multiple BCCs by the age of 35. Characteristic features of this syndrome include macrocephaly, frontal bossing, hypertelorism, bifid ribs, palmar and plantar pitting and bone cysts in the mandible. These patients have a mutation in the tumor suppressor gene patched (PTCH) on chromosome 9.3
A WORD ON CLINICAL PRESENTATIONS AND LOCAL DESTRUCTION
About 70% of BCCs occur on the face, with the nose being the most common site. Around 15% tend to occur on the trunk, and rarely on other sites, such as the penis, vulva and perianal areas.4 BCC occurring in the axilla has also been reported.5 Sixty percent of all BCCs are of the nodular subtype, presenting as a pearly, pink papule on the nose with telangiectasia. This type of BCC has a tendency to ulcerate. About 30% of all BCCs are superficial in type, which are most likely to occur on the trunk. They present as scaly plaques or papules that may have a rim of fine translucent micropapules. Morpheaform BCC comprises 5% to 10% of all BCCs,6 and presents as a smooth and slightly erythematous patch or plaque with ill-defined borders.1 BCC is a locally invasive neoplasm with potential for local destruction and disfigurement. The risk of BCC recurrence is related to tumor location and size, histologic type and treatment modality and history of UV exposure.7 Cases of BCC invading the mandible or maxilla with consequently radical resection of facial structures, including soft tissue and bone, followed by comprehensive reconstruction, were reported.8
THE FACTS ON BCC OF THE EAR
Approximately 2% of all BCCs of the head and neck region occur on the external ear.9 Most occur on the auricle, but cases involving the earlobe leaving a full-thickness cleft with indurated margins and telangiectasia have been reported.10 Aggressive BCC may extend to the middle ear, to soft tissue anterior to the ear canal, and to the parotid gland.11 Joachims et al, reported a case of BCC of the middle ear of a young man who first presented with earache, followed by deafness and local destruction of the temporal and parietal bones, facial palsy and multiple distant metastases. BCC is extremely rare in the middle ear.12
METASTATIC BASAL CELL CARCINOMA
Metastatic Basal Cell Carcinoma (MBCC) was first reported in 1894 by Beadles, and so far there have been 300 reported cases in the literature.13 About 66% to 85% of all cases of MBCC arise from primary lesions in the head and neck region and occur mostly in men.14 The incidence of MBCC ranges from 0.0028% to 0.5%.15 Risk factors include large tumor size, local invasion, recurrence and previous irradiation. The median age of onset for primary tumors is 45 years and median interval between appearance of the primary tumor and metastasis is 9 years.15 There have been case reports of BCC metastases to lymph nodes, bone, lung, sinuses and parotid gland,16 and all histologic subtypes of BCC have been associated with metastasis.
TREATMENT
There are a variety of treatment options available for BCC, which depend on characteristics of the tumor type and individual patient. These include: cryosurgery, electrodessication and curettage, surgical excision, Mohs micrographic surgery, radiation therapy, topical therapy such as 5 Fluorouracil (5-FU) and imiquimod (Aldara), photodynamic therapy (PDT) and interferons. The cure rate for primary BCCs is higher than that for recurrent tumors. The 5-year survival rate for primary BCCs, including all techniques, is approximately 90%, whereas the survival for recurrent tumors varies.17 Cryosurgery induces cytotoxicity by production of extracellular and intracellular ice crystals. It causes vascular damage, and disrupts the cellular phospholipid membranes. It is rapid and cost-effective, and demonstrates high cure rates. Electrosurgery is another treatment option specifically for low-risk superficial and nodular BCC on the trunk and extremities. The 5-year cure rates of 95.5% (BCC less than 6 mm) and 82.4% (BCC greater than 6mm) have been reported following elecrosurgery.18 This therapy is not indicated for BCCs located in cosmetically significant areas. Surgical excision is an effective method for BCCs located on lower-risk areas of the head and neck, trunk and extremities, which lack aggressive histologic features. Mohs micrographic surgery is the standard of treatment for high-risk BCCs and BCCs located in cosmetically sensitive locations such as the nasolabial fold and periorbital areas. The cure rate is 99% for primary BCCs and 94.4% for recurrent lesions. The advantages of Mohs surgery include precision in removing tumor cells, preservation of normal tissue and better cosmetic results. Disadvantages include its high cost and long procedural duration. A number of techniques have been described for earlobe repair. Tannir has reported the use of a bilayered banner transposition flap in reconstruction of the lower third of the pinna. Relative laxity, as well as redundancy of preauricular skin, facilitates reconstruction of this area. The new earlobe is composed of a bulky bilayer flap and a single flap that resurfaces the lobule anteriorly and posteriorly. The length and width of the flap can be adjusted in order to achieve perfect lobule size. This reconstruction can be done in a single stage and it is a valuable technique for reconstruction of a full-thickness earlobe defect.19 Radiation therapy is also an important option for the treatment of both primary and recurrent BCCs. The 5-year survival rate of primary and recurrent BCCs is around 93% and 86%, respectively. Larger or more deeply invasive tumors that invade cartilage, bone and/or muscle have cure rates of 30% to 40% with radiation.17
Radiation therapy is associated with various side effects, such as erythema, edema, cataracts, chronic radiation dermatitis, permanent alopecia, infection and secondary cutaneous malignancies, such as BCCs and SCCs. Radiation therapy is also associated with a “comedo reaction,” which appears at the periphery of treated areas in sites such as nose or the cheeks, and is characterized by the appearance of large, open comedones. Pseudorecidives (keratosis-like nodules that develop within the irradiated field immediately following treatment), and more rarely gangrene, are other side effects associated with radiation.20 The topical chemotherapeutic agent 5-FU has been accepted by the FDA for the treatment of BCC. The drug interferes with DNA synthesis through inhibition of thymidylate synthetase; rapidly proliferating cells are most sensitive to its cytotoxic effect. One small pilot study suggests that application of 5-FU using a phosphatidyl choline-based cream rather than a petrolatum-based cream may increase transepidermal absorption, leading to improved cure rates.21 Such a formulation is not yet commercially available. Also, 5-FU can be associated with an intense inflammatory reaction that develops in treated sites during therapy. Other unusual side effects include temporary reversible onycholysis and onychodystrophy, persistent telangiectasias, hypertrophic scarring in high-risk areas, bullous pemphigoid, cardiac ischemia, and life-threatening toxicity in patients who are deficient in the metabolizing enzyme dihydropyrimidine dehydrogenase.21 Interferons have also been used to treat superficial and nodular BCCs. Interferon alpha 2b (IFN-a) has been injected intralesionally into BCCs, and has been associated with clinical and histologic response rates in the range of 80% to 100%. One and one half million IU per injection of IFN 3 times per week, for a minimum of 3 weeks are necessary to achieve response rates of 80%. The 1-year local recurrence rate is 19%, and the failure rate for aggressive BCCs has been reported as high as 73%.22
Disadvantages of intralesional IFN-a are its high cost compared to other treatment modalities, as well as side effects such as local edema and erythema, and systemic flu-like symptoms. It has also been associated with potential electrolyte, cardiovascular, and neurologic side effects, especially in the elderly.23 Imiquimod has been approved for the treatment of external anogenital warts. It induces cytokine production, particularly interferons alpha (IFN-a) and gamma (IFN-g), and interleukin-12, thereby promoting the immune system. It has been used for the treatment of different types of BCCs using many different dosing regimens and treatment lengths.24-26 PDT using various intravenous and topical photosensitizers (ie, intravenous verteporfin, topical 5-aminolevulinic acid (ALA), topical methyl aminolevulinate (mALA)) and different sources of visible light have been used in the treatment of BCC.27-31 PDT causes tumor destruction by activation of the reactive oxygen species within the tumor cells through oxygen, light and porphyrin. Porphyrin is a photosensitizing agent applied on affected skin lesions. The photosensitizer induces reactive oxygen radicals, which cause lipid peroxidation, protein cross-linking, increased membrane permeability, and ultimately cell death. It may also cause damage to blood vessels, leading to consequent tumor destruction. The photosensitizer has higher concentration and longer half-life in tumor cells, and therefore causes selective destruction of cancer cells.27
PDT is mostly used for superficial BCCs and has response rates ranging from 50% to 100% for systemic PDT, and from 82% to 100% for topical application.28 Much lower response rates have been reported in pigmented BCCs, and for larger, thicker, or sclerotic lesions, such as nodular and morpheaform BCCs. ALA-PDT therapy for BCCs may be associated with shorter healing time, less scarring and better cosmetic outcome than cryosurgery.30 PDT may be as effective as surgery in terms of complete response rates in the treatment for nodular BCC, and may also have cosmetic advantage over surgery.32 PDT is associated with several side effects such as prolonged photosensitivity (up to 6 weeks with systemic treatment), erythema, burning and pain at the injection site, edema, ulceration and temporary pigmentary change at the treated site. Healing occurs within 2 weeks and scarring is unusual.31 Recently Marmur et al, reviewed laser and photodynamic therapy treatment for nonmelanoma skin cancer with PDT, and concluded that from the available data it appears that PDT may be capable of achieving clearance rates comparable to radiation therapy for BCC. However, with current technology, PDT treatment of BCC remains inferior to surgical excision and Mohs surgery, for which recurrence rates have been reported to be less than 10%. The reported clearance rates currently limit the usefulness of PDT and laser therapy. However, multiple treatments and the use of penetration enhancers may significantly increase the efficacy of ALA-PDT.33
Call For Cases Do you have a case you’d like to see published in this column? If so, please send a write-up (about 1200 to 1500 words) and an image of the patient’s condition. Please send materials to: Dr. Amor Khachemoune, Georgetown University Medical Center, Division of Dermatology, 3800 Reservoir Road, NW 5 PHC, Washington, DC 20007. Or, e-mail them to amorkh@pol.net.
Patient Presentation
An 83-year-old Caucasian man was brought by his daughter for consultation because of a non-healing, slowly progressive lesion on his right earlobe, which lead to piercing of the earlobe. The lesion had been present for at least 2 years. He denied trauma, acupuncture or application of caustic products to this area. His past medical history was significant for substantial sun damage.
What’s Your Diagnosis?
Diagnosis: Basal Cell Carcinoma Causing Ear Piercing
Basal Cell Carcinoma (BCC) is the most common skin cancer diagnosed in the United States, comprising up to 75% of nonmelanoma skin cancers.1 It arises from the basal layer of the epidermis, and although it has low metastatic potential, it may result in local destruction of the skin and surrounding structures. BCC has an annual incidence between 500 and 1000 per 100,000, which increases with age. Risk factors can be attributed to both environmental as well as genetic causes. Solar radiation is the most important environmental cause of BCC.1 Therapeutic radiation, such as PUVA for the treatment of psoriasis, may result in BCC 20 years after exposure.2 Chronic arsenic exposure, which may result from ingestion of contaminated water, seafood or medications, can contribute to development of superficial BCCs. Genetic characteristics, such as fair skin, light-colored eyes and red hair, are also important risk factors. Basal nevus syndrome is an autosomal dominant disorder that causes development of multiple BCCs by the age of 35. Characteristic features of this syndrome include macrocephaly, frontal bossing, hypertelorism, bifid ribs, palmar and plantar pitting and bone cysts in the mandible. These patients have a mutation in the tumor suppressor gene patched (PTCH) on chromosome 9.3
A WORD ON CLINICAL PRESENTATIONS AND LOCAL DESTRUCTION
About 70% of BCCs occur on the face, with the nose being the most common site. Around 15% tend to occur on the trunk, and rarely on other sites, such as the penis, vulva and perianal areas.4 BCC occurring in the axilla has also been reported.5 Sixty percent of all BCCs are of the nodular subtype, presenting as a pearly, pink papule on the nose with telangiectasia. This type of BCC has a tendency to ulcerate. About 30% of all BCCs are superficial in type, which are most likely to occur on the trunk. They present as scaly plaques or papules that may have a rim of fine translucent micropapules. Morpheaform BCC comprises 5% to 10% of all BCCs,6 and presents as a smooth and slightly erythematous patch or plaque with ill-defined borders.1 BCC is a locally invasive neoplasm with potential for local destruction and disfigurement. The risk of BCC recurrence is related to tumor location and size, histologic type and treatment modality and history of UV exposure.7 Cases of BCC invading the mandible or maxilla with consequently radical resection of facial structures, including soft tissue and bone, followed by comprehensive reconstruction, were reported.8
THE FACTS ON BCC OF THE EAR
Approximately 2% of all BCCs of the head and neck region occur on the external ear.9 Most occur on the auricle, but cases involving the earlobe leaving a full-thickness cleft with indurated margins and telangiectasia have been reported.10 Aggressive BCC may extend to the middle ear, to soft tissue anterior to the ear canal, and to the parotid gland.11 Joachims et al, reported a case of BCC of the middle ear of a young man who first presented with earache, followed by deafness and local destruction of the temporal and parietal bones, facial palsy and multiple distant metastases. BCC is extremely rare in the middle ear.12
METASTATIC BASAL CELL CARCINOMA
Metastatic Basal Cell Carcinoma (MBCC) was first reported in 1894 by Beadles, and so far there have been 300 reported cases in the literature.13 About 66% to 85% of all cases of MBCC arise from primary lesions in the head and neck region and occur mostly in men.14 The incidence of MBCC ranges from 0.0028% to 0.5%.15 Risk factors include large tumor size, local invasion, recurrence and previous irradiation. The median age of onset for primary tumors is 45 years and median interval between appearance of the primary tumor and metastasis is 9 years.15 There have been case reports of BCC metastases to lymph nodes, bone, lung, sinuses and parotid gland,16 and all histologic subtypes of BCC have been associated with metastasis.
TREATMENT
There are a variety of treatment options available for BCC, which depend on characteristics of the tumor type and individual patient. These include: cryosurgery, electrodessication and curettage, surgical excision, Mohs micrographic surgery, radiation therapy, topical therapy such as 5 Fluorouracil (5-FU) and imiquimod (Aldara), photodynamic therapy (PDT) and interferons. The cure rate for primary BCCs is higher than that for recurrent tumors. The 5-year survival rate for primary BCCs, including all techniques, is approximately 90%, whereas the survival for recurrent tumors varies.17 Cryosurgery induces cytotoxicity by production of extracellular and intracellular ice crystals. It causes vascular damage, and disrupts the cellular phospholipid membranes. It is rapid and cost-effective, and demonstrates high cure rates. Electrosurgery is another treatment option specifically for low-risk superficial and nodular BCC on the trunk and extremities. The 5-year cure rates of 95.5% (BCC less than 6 mm) and 82.4% (BCC greater than 6mm) have been reported following elecrosurgery.18 This therapy is not indicated for BCCs located in cosmetically significant areas. Surgical excision is an effective method for BCCs located on lower-risk areas of the head and neck, trunk and extremities, which lack aggressive histologic features. Mohs micrographic surgery is the standard of treatment for high-risk BCCs and BCCs located in cosmetically sensitive locations such as the nasolabial fold and periorbital areas. The cure rate is 99% for primary BCCs and 94.4% for recurrent lesions. The advantages of Mohs surgery include precision in removing tumor cells, preservation of normal tissue and better cosmetic results. Disadvantages include its high cost and long procedural duration. A number of techniques have been described for earlobe repair. Tannir has reported the use of a bilayered banner transposition flap in reconstruction of the lower third of the pinna. Relative laxity, as well as redundancy of preauricular skin, facilitates reconstruction of this area. The new earlobe is composed of a bulky bilayer flap and a single flap that resurfaces the lobule anteriorly and posteriorly. The length and width of the flap can be adjusted in order to achieve perfect lobule size. This reconstruction can be done in a single stage and it is a valuable technique for reconstruction of a full-thickness earlobe defect.19 Radiation therapy is also an important option for the treatment of both primary and recurrent BCCs. The 5-year survival rate of primary and recurrent BCCs is around 93% and 86%, respectively. Larger or more deeply invasive tumors that invade cartilage, bone and/or muscle have cure rates of 30% to 40% with radiation.17
Radiation therapy is associated with various side effects, such as erythema, edema, cataracts, chronic radiation dermatitis, permanent alopecia, infection and secondary cutaneous malignancies, such as BCCs and SCCs. Radiation therapy is also associated with a “comedo reaction,” which appears at the periphery of treated areas in sites such as nose or the cheeks, and is characterized by the appearance of large, open comedones. Pseudorecidives (keratosis-like nodules that develop within the irradiated field immediately following treatment), and more rarely gangrene, are other side effects associated with radiation.20 The topical chemotherapeutic agent 5-FU has been accepted by the FDA for the treatment of BCC. The drug interferes with DNA synthesis through inhibition of thymidylate synthetase; rapidly proliferating cells are most sensitive to its cytotoxic effect. One small pilot study suggests that application of 5-FU using a phosphatidyl choline-based cream rather than a petrolatum-based cream may increase transepidermal absorption, leading to improved cure rates.21 Such a formulation is not yet commercially available. Also, 5-FU can be associated with an intense inflammatory reaction that develops in treated sites during therapy. Other unusual side effects include temporary reversible onycholysis and onychodystrophy, persistent telangiectasias, hypertrophic scarring in high-risk areas, bullous pemphigoid, cardiac ischemia, and life-threatening toxicity in patients who are deficient in the metabolizing enzyme dihydropyrimidine dehydrogenase.21 Interferons have also been used to treat superficial and nodular BCCs. Interferon alpha 2b (IFN-a) has been injected intralesionally into BCCs, and has been associated with clinical and histologic response rates in the range of 80% to 100%. One and one half million IU per injection of IFN 3 times per week, for a minimum of 3 weeks are necessary to achieve response rates of 80%. The 1-year local recurrence rate is 19%, and the failure rate for aggressive BCCs has been reported as high as 73%.22
Disadvantages of intralesional IFN-a are its high cost compared to other treatment modalities, as well as side effects such as local edema and erythema, and systemic flu-like symptoms. It has also been associated with potential electrolyte, cardiovascular, and neurologic side effects, especially in the elderly.23 Imiquimod has been approved for the treatment of external anogenital warts. It induces cytokine production, particularly interferons alpha (IFN-a) and gamma (IFN-g), and interleukin-12, thereby promoting the immune system. It has been used for the treatment of different types of BCCs using many different dosing regimens and treatment lengths.24-26 PDT using various intravenous and topical photosensitizers (ie, intravenous verteporfin, topical 5-aminolevulinic acid (ALA), topical methyl aminolevulinate (mALA)) and different sources of visible light have been used in the treatment of BCC.27-31 PDT causes tumor destruction by activation of the reactive oxygen species within the tumor cells through oxygen, light and porphyrin. Porphyrin is a photosensitizing agent applied on affected skin lesions. The photosensitizer induces reactive oxygen radicals, which cause lipid peroxidation, protein cross-linking, increased membrane permeability, and ultimately cell death. It may also cause damage to blood vessels, leading to consequent tumor destruction. The photosensitizer has higher concentration and longer half-life in tumor cells, and therefore causes selective destruction of cancer cells.27
PDT is mostly used for superficial BCCs and has response rates ranging from 50% to 100% for systemic PDT, and from 82% to 100% for topical application.28 Much lower response rates have been reported in pigmented BCCs, and for larger, thicker, or sclerotic lesions, such as nodular and morpheaform BCCs. ALA-PDT therapy for BCCs may be associated with shorter healing time, less scarring and better cosmetic outcome than cryosurgery.30 PDT may be as effective as surgery in terms of complete response rates in the treatment for nodular BCC, and may also have cosmetic advantage over surgery.32 PDT is associated with several side effects such as prolonged photosensitivity (up to 6 weeks with systemic treatment), erythema, burning and pain at the injection site, edema, ulceration and temporary pigmentary change at the treated site. Healing occurs within 2 weeks and scarring is unusual.31 Recently Marmur et al, reviewed laser and photodynamic therapy treatment for nonmelanoma skin cancer with PDT, and concluded that from the available data it appears that PDT may be capable of achieving clearance rates comparable to radiation therapy for BCC. However, with current technology, PDT treatment of BCC remains inferior to surgical excision and Mohs surgery, for which recurrence rates have been reported to be less than 10%. The reported clearance rates currently limit the usefulness of PDT and laser therapy. However, multiple treatments and the use of penetration enhancers may significantly increase the efficacy of ALA-PDT.33
Call For Cases Do you have a case you’d like to see published in this column? If so, please send a write-up (about 1200 to 1500 words) and an image of the patient’s condition. Please send materials to: Dr. Amor Khachemoune, Georgetown University Medical Center, Division of Dermatology, 3800 Reservoir Road, NW 5 PHC, Washington, DC 20007. Or, e-mail them to amorkh@pol.net.
Patient Presentation
An 83-year-old Caucasian man was brought by his daughter for consultation because of a non-healing, slowly progressive lesion on his right earlobe, which lead to piercing of the earlobe. The lesion had been present for at least 2 years. He denied trauma, acupuncture or application of caustic products to this area. His past medical history was significant for substantial sun damage.
What’s Your Diagnosis?
Diagnosis: Basal Cell Carcinoma Causing Ear Piercing
Basal Cell Carcinoma (BCC) is the most common skin cancer diagnosed in the United States, comprising up to 75% of nonmelanoma skin cancers.1 It arises from the basal layer of the epidermis, and although it has low metastatic potential, it may result in local destruction of the skin and surrounding structures. BCC has an annual incidence between 500 and 1000 per 100,000, which increases with age. Risk factors can be attributed to both environmental as well as genetic causes. Solar radiation is the most important environmental cause of BCC.1 Therapeutic radiation, such as PUVA for the treatment of psoriasis, may result in BCC 20 years after exposure.2 Chronic arsenic exposure, which may result from ingestion of contaminated water, seafood or medications, can contribute to development of superficial BCCs. Genetic characteristics, such as fair skin, light-colored eyes and red hair, are also important risk factors. Basal nevus syndrome is an autosomal dominant disorder that causes development of multiple BCCs by the age of 35. Characteristic features of this syndrome include macrocephaly, frontal bossing, hypertelorism, bifid ribs, palmar and plantar pitting and bone cysts in the mandible. These patients have a mutation in the tumor suppressor gene patched (PTCH) on chromosome 9.3
A WORD ON CLINICAL PRESENTATIONS AND LOCAL DESTRUCTION
About 70% of BCCs occur on the face, with the nose being the most common site. Around 15% tend to occur on the trunk, and rarely on other sites, such as the penis, vulva and perianal areas.4 BCC occurring in the axilla has also been reported.5 Sixty percent of all BCCs are of the nodular subtype, presenting as a pearly, pink papule on the nose with telangiectasia. This type of BCC has a tendency to ulcerate. About 30% of all BCCs are superficial in type, which are most likely to occur on the trunk. They present as scaly plaques or papules that may have a rim of fine translucent micropapules. Morpheaform BCC comprises 5% to 10% of all BCCs,6 and presents as a smooth and slightly erythematous patch or plaque with ill-defined borders.1 BCC is a locally invasive neoplasm with potential for local destruction and disfigurement. The risk of BCC recurrence is related to tumor location and size, histologic type and treatment modality and history of UV exposure.7 Cases of BCC invading the mandible or maxilla with consequently radical resection of facial structures, including soft tissue and bone, followed by comprehensive reconstruction, were reported.8
THE FACTS ON BCC OF THE EAR
Approximately 2% of all BCCs of the head and neck region occur on the external ear.9 Most occur on the auricle, but cases involving the earlobe leaving a full-thickness cleft with indurated margins and telangiectasia have been reported.10 Aggressive BCC may extend to the middle ear, to soft tissue anterior to the ear canal, and to the parotid gland.11 Joachims et al, reported a case of BCC of the middle ear of a young man who first presented with earache, followed by deafness and local destruction of the temporal and parietal bones, facial palsy and multiple distant metastases. BCC is extremely rare in the middle ear.12
METASTATIC BASAL CELL CARCINOMA
Metastatic Basal Cell Carcinoma (MBCC) was first reported in 1894 by Beadles, and so far there have been 300 reported cases in the literature.13 About 66% to 85% of all cases of MBCC arise from primary lesions in the head and neck region and occur mostly in men.14 The incidence of MBCC ranges from 0.0028% to 0.5%.15 Risk factors include large tumor size, local invasion, recurrence and previous irradiation. The median age of onset for primary tumors is 45 years and median interval between appearance of the primary tumor and metastasis is 9 years.15 There have been case reports of BCC metastases to lymph nodes, bone, lung, sinuses and parotid gland,16 and all histologic subtypes of BCC have been associated with metastasis.
TREATMENT
There are a variety of treatment options available for BCC, which depend on characteristics of the tumor type and individual patient. These include: cryosurgery, electrodessication and curettage, surgical excision, Mohs micrographic surgery, radiation therapy, topical therapy such as 5 Fluorouracil (5-FU) and imiquimod (Aldara), photodynamic therapy (PDT) and interferons. The cure rate for primary BCCs is higher than that for recurrent tumors. The 5-year survival rate for primary BCCs, including all techniques, is approximately 90%, whereas the survival for recurrent tumors varies.17 Cryosurgery induces cytotoxicity by production of extracellular and intracellular ice crystals. It causes vascular damage, and disrupts the cellular phospholipid membranes. It is rapid and cost-effective, and demonstrates high cure rates. Electrosurgery is another treatment option specifically for low-risk superficial and nodular BCC on the trunk and extremities. The 5-year cure rates of 95.5% (BCC less than 6 mm) and 82.4% (BCC greater than 6mm) have been reported following elecrosurgery.18 This therapy is not indicated for BCCs located in cosmetically significant areas. Surgical excision is an effective method for BCCs located on lower-risk areas of the head and neck, trunk and extremities, which lack aggressive histologic features. Mohs micrographic surgery is the standard of treatment for high-risk BCCs and BCCs located in cosmetically sensitive locations such as the nasolabial fold and periorbital areas. The cure rate is 99% for primary BCCs and 94.4% for recurrent lesions. The advantages of Mohs surgery include precision in removing tumor cells, preservation of normal tissue and better cosmetic results. Disadvantages include its high cost and long procedural duration. A number of techniques have been described for earlobe repair. Tannir has reported the use of a bilayered banner transposition flap in reconstruction of the lower third of the pinna. Relative laxity, as well as redundancy of preauricular skin, facilitates reconstruction of this area. The new earlobe is composed of a bulky bilayer flap and a single flap that resurfaces the lobule anteriorly and posteriorly. The length and width of the flap can be adjusted in order to achieve perfect lobule size. This reconstruction can be done in a single stage and it is a valuable technique for reconstruction of a full-thickness earlobe defect.19 Radiation therapy is also an important option for the treatment of both primary and recurrent BCCs. The 5-year survival rate of primary and recurrent BCCs is around 93% and 86%, respectively. Larger or more deeply invasive tumors that invade cartilage, bone and/or muscle have cure rates of 30% to 40% with radiation.17
Radiation therapy is associated with various side effects, such as erythema, edema, cataracts, chronic radiation dermatitis, permanent alopecia, infection and secondary cutaneous malignancies, such as BCCs and SCCs. Radiation therapy is also associated with a “comedo reaction,” which appears at the periphery of treated areas in sites such as nose or the cheeks, and is characterized by the appearance of large, open comedones. Pseudorecidives (keratosis-like nodules that develop within the irradiated field immediately following treatment), and more rarely gangrene, are other side effects associated with radiation.20 The topical chemotherapeutic agent 5-FU has been accepted by the FDA for the treatment of BCC. The drug interferes with DNA synthesis through inhibition of thymidylate synthetase; rapidly proliferating cells are most sensitive to its cytotoxic effect. One small pilot study suggests that application of 5-FU using a phosphatidyl choline-based cream rather than a petrolatum-based cream may increase transepidermal absorption, leading to improved cure rates.21 Such a formulation is not yet commercially available. Also, 5-FU can be associated with an intense inflammatory reaction that develops in treated sites during therapy. Other unusual side effects include temporary reversible onycholysis and onychodystrophy, persistent telangiectasias, hypertrophic scarring in high-risk areas, bullous pemphigoid, cardiac ischemia, and life-threatening toxicity in patients who are deficient in the metabolizing enzyme dihydropyrimidine dehydrogenase.21 Interferons have also been used to treat superficial and nodular BCCs. Interferon alpha 2b (IFN-a) has been injected intralesionally into BCCs, and has been associated with clinical and histologic response rates in the range of 80% to 100%. One and one half million IU per injection of IFN 3 times per week, for a minimum of 3 weeks are necessary to achieve response rates of 80%. The 1-year local recurrence rate is 19%, and the failure rate for aggressive BCCs has been reported as high as 73%.22
Disadvantages of intralesional IFN-a are its high cost compared to other treatment modalities, as well as side effects such as local edema and erythema, and systemic flu-like symptoms. It has also been associated with potential electrolyte, cardiovascular, and neurologic side effects, especially in the elderly.23 Imiquimod has been approved for the treatment of external anogenital warts. It induces cytokine production, particularly interferons alpha (IFN-a) and gamma (IFN-g), and interleukin-12, thereby promoting the immune system. It has been used for the treatment of different types of BCCs using many different dosing regimens and treatment lengths.24-26 PDT using various intravenous and topical photosensitizers (ie, intravenous verteporfin, topical 5-aminolevulinic acid (ALA), topical methyl aminolevulinate (mALA)) and different sources of visible light have been used in the treatment of BCC.27-31 PDT causes tumor destruction by activation of the reactive oxygen species within the tumor cells through oxygen, light and porphyrin. Porphyrin is a photosensitizing agent applied on affected skin lesions. The photosensitizer induces reactive oxygen radicals, which cause lipid peroxidation, protein cross-linking, increased membrane permeability, and ultimately cell death. It may also cause damage to blood vessels, leading to consequent tumor destruction. The photosensitizer has higher concentration and longer half-life in tumor cells, and therefore causes selective destruction of cancer cells.27
PDT is mostly used for superficial BCCs and has response rates ranging from 50% to 100% for systemic PDT, and from 82% to 100% for topical application.28 Much lower response rates have been reported in pigmented BCCs, and for larger, thicker, or sclerotic lesions, such as nodular and morpheaform BCCs. ALA-PDT therapy for BCCs may be associated with shorter healing time, less scarring and better cosmetic outcome than cryosurgery.30 PDT may be as effective as surgery in terms of complete response rates in the treatment for nodular BCC, and may also have cosmetic advantage over surgery.32 PDT is associated with several side effects such as prolonged photosensitivity (up to 6 weeks with systemic treatment), erythema, burning and pain at the injection site, edema, ulceration and temporary pigmentary change at the treated site. Healing occurs within 2 weeks and scarring is unusual.31 Recently Marmur et al, reviewed laser and photodynamic therapy treatment for nonmelanoma skin cancer with PDT, and concluded that from the available data it appears that PDT may be capable of achieving clearance rates comparable to radiation therapy for BCC. However, with current technology, PDT treatment of BCC remains inferior to surgical excision and Mohs surgery, for which recurrence rates have been reported to be less than 10%. The reported clearance rates currently limit the usefulness of PDT and laser therapy. However, multiple treatments and the use of penetration enhancers may significantly increase the efficacy of ALA-PDT.33
Call For Cases Do you have a case you’d like to see published in this column? If so, please send a write-up (about 1200 to 1500 words) and an image of the patient’s condition. Please send materials to: Dr. Amor Khachemoune, Georgetown University Medical Center, Division of Dermatology, 3800 Reservoir Road, NW 5 PHC, Washington, DC 20007. Or, e-mail them to amorkh@pol.net.
