Gary S. Wood,Juliet Gunkel,
Daniel Stewart,
Ellen Gordon,
Mamad M. Bagheri,
Manish Gharia,
Stephen N. Snow
SUMMARY OF KEY POINTS
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Incidence
Etiology and Epidemiology
Pathology and Biology
Clinical Findings
Differential Diagnosis and Staging
Primary Therapy and Salvage Therapy
Complications
Prognosis
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INTRODUCTION
Most nonmelanoma skin cancers (NMSCs) are basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs). However, several rarer forms of NMSC exist, including four malignant neoplasms discussed in this chapter: sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, and dermatofibrosarcoma protuberans (DFSP). Each of these neoplasms is discussed separately after a summary of genetic alterations in BCC, SCC, and selected genodermatoses. Understanding the genetic basis of skin cancer is an important step in improving prognosis among patients with these neoplasms. Analysis of germline mutations in familial cancer syndromes and somatic mutations in sporadic skin cancers is providing new information that will facilitate the diagnosis of cutaneous malignant diseases and revolutionize their management.
GENETICS OF NONMELANOMA SKIN CANCER
Advances in molecular genetics have allowed for key advances in our understanding of NMSC, the most common cancer in the United States. Like visceral malignant neoplasms, cancer of the integument is caused by defects in the normal genetic code. These genomic defects are either germline mutations (those caused by inherited mutations) or somatic mutations (those caused by acquired mutations). Actual tumor formation, however, is a complicated process, usually requiring more than a single mutation and sometimes a combination of germline and somatic mutations. In addition, these cancerous cells are frequently altered in ways that help them escape detection by the host's immune system.
Tumor suppressor genes and oncogenes are two basic classes of genes that undergo mutations leading to skin cancer. Examples of tumor suppressor genes include the patched gene involved in development of BCC, p53 involved in development of SCC, and the xeroderma pigmentosum genes involved in development of BCC, SCC, and melanoma. [1] [2] [3] These genes can be further divided into tumor suppressor genes that directly participate in growth regulation, such as the patched and p53 genes, and those that participate indirectly and are called caretaker genes, such as the xeroderma pigmentosum genes encoding DNA repair enzymes.
Oncogenes are the other class of genes contributing to skin cancer formation. These are generally growth-signaling molecules that once mutated can perpetually lead normal cells to become malignant cells by altering cellular growth. One example is the ras oncogene implicated in several skin cancers, including BCC, SCC, and melanoma. [4] [5]
Sonic Hedgehog Pathway
The sonic hedgehog (Shh) pathway has been implicated in both hereditary and sporadic cases of BCC. These tumors are the most common of all skin cancers, with an estimated 1 million new cases per year.[6] In the Shh pathway, the transmembrane protein receptor for Shh, known as patched1 (Ptch1), binds and inhibits another transmembrane protein called smoothened (Smoh).[7] Smoh is responsible for growth promotion, and binding by Ptch1 keeps this growth in check. However, when the soluble lipoprotein Shh binds Ptch1, this regulation is disrupted. Smoh is thus activated, and unregulated growth is promoted through downstream zinc-finger family transcription factors, such as gli1, gli2, and gli3.
The hedgehog pathway was originally elucidated in the fruit fly (Drosophila melanogaster), in which mutations in the gene cause segmental patterning defects, hence the name patched.[8] Involvement in human disease was found through analysis of nevoid BCC kindreds (Gorlin's syndrome, basal cell nevus syndrome).[9] Persons with this autosomal dominant disease have odontogenic cysts, skeletal defects, palmar pits, various associated visceral tumors (medulloblastoma, meningioma, fibrosarcoma, cardiac fibroma, and ovarian fibroma), and multiple BCCs by a median age of 20 years. Early analyses mapped the defect to a tumor suppressor gene on chromosome 9q22–q31.[10] This site proved to be the location of the Ptch1 gene. It was later elucidated that patients with nevoid BCC syndrome inherit one defective chromosome 9q region with loss of heterozygosity in the Ptch1 locus. Many BCCs from these patients show inactivation of the remaining Ptch1 gene through acquired somatic mutations, consistent with the view that the BCC phenotype develops once both alleles are nonfunctional. Thus, Ptch1 acts as a classic tumor suppressor gene in the skin. Mutations in Ptch1 also are present in many sporadic BCCs, as are mutations in other Shh pathway genes, including Smoh, Ptch2, and Shh.[11]
p53 Mutations
The protein p53 is encoded by the TP53 gene on chromosome 17p and is an important regulator of cell proliferation, DNA repair, and apoptosis.[12] TP53 can act classically as a tumor suppressor gene or act in a dominant-negative role whereby abnormal, mutant p53 protein can bind normal p53 molecules and disrupt their function.
Inactivation of the p53 gene seems to play a principal role in the development of both premalignant actinic keratosis and SCC.[13] SCC is the second most common skin cancer, accounting for approximately 200,000 cases per year and 2000 deaths per year.[6] p53 mutations causing SCC are ultraviolet (UV) induced, and many are pyrimidine alterations with CC to TT changes. [14] [15] It seems that it is both the loss of the tumor suppressor ability of p53 and the ability of UV irradiation to affect induction of apoptosis by p53 that leads to tumor formation.[13]
Mutations of TP53 have been implicated in development of sporadic BCC.[15] It seems that UV-induced alterations similar to those in SCC are involved in BCC induction. Many of the mutations are CC to TT or C to T alterations, consistent with UV damage.
Mutations of Caretaker Genes
Tumor suppressor genes involved in maintaining genomic integrity are called caretaker genes.[16] Examples of diseases associated with cutaneous malignant tumors and known defects in caretaker genes include xeroderma pigmentosum, Bloom syndrome, Rothmund-Thomson syndrome, Werner's syndrome, and Muir-Torre syndrome.
The tumor suppressor genes involved in all of these familial syndromes have the common feature of being involved in an enzymatic DNA reparative process following a mutagenic insult. Defects in these genes inhibit the ability to repair genetic damage from naturally occurring events or environmental carcinogens such as UV radiation.
Xeroderma pigmentosum is a collection of autosomal recessive disorders characterized by severe photosensitivity with onset of cutaneous malignant lesions at a very early age. BCC, actinic keratosis, SCC, and melanoma develop during the first decade of life in persons without adequate photoprotection. Mutations in eight genes have been implicated in different xeroderma pigmentosum phenotypes, which vary in severity of cutaneous neoplasia and frequency of neurologic delay.[17] All xeroderma pigmentosum-associated genes encode proteins that are part of a DNA repair process known as nucleotide excision repair, which responds to UV-induced DNA damage.[3] These proteins recognize the damaged DNA, unwind the coiled DNA structure, and repair the damaged strand. Germline mutations in these genes result in defects in the repair process and their genomic caretaker role; however, actual tumor production is still caused by mutagenic inactivation of tumor suppressor genes such as TP53 and activation of oncogenes such as ras. [18] [19]
Rothmund-Thomson syndrome, Bloom syndrome, and Werner's syndrome all are rare autosomal recessive disorders that have known defects in helicase genes and affect nucleotide excision repair. Like xeroderma pigmentosum, these defects allow development of malignant skin lesions in affected patients. Rothmund-Thomson and Bloom syndromes both are marked by early onset of SCC; however, patients with Werner's syndrome seem to have only increased risk of melanoma. Other syndromes with helicase gene defects, such as Cockayne's syndrome and photosensitive trichothiodystrophy, have no associated increase in cutaneous malignant tumors. It is becoming clear that development of cutaneous malignant tumors is a complex process in which ability to repair DNA is but one part of an intricate pathway. It seems that other mutations in tumor suppressor genes and oncogenes, whether germline or somatic, are necessary to invoke a tumor phenotype, as seen in xeroderma pigmentosum.
Muir-Torre syndrome (MTS) is an autosomal dominant syndrome characterized by various sebaceous gland tumors and internal malignant lesions. The sebaceous gland tumors range from benign sebaceous adenoma to malignant sebaceous gland carcinoma predominantly on the face. Keratoacanthoma is another cutaneous neoplasm of variable malignant potential that has been reported in as many as 20% of MTS patients.[20]
In initial studies of MTS families, investigators identified germline mutations in the human MSH2 gene. [21] [22] Subsequently, mutations in human MLH1 have also been identified in patients with MTS.[23]It seems that, like other caretaker genes, human MSH2 and MLH1 encode a type of DNA-mismatch repair enzyme involved in repairing errors in DNA replication that occur naturally at a low rate.
In cells that have this defect, the result is varying lengths of repetitive DNA sequences known as microsatellite instability.[23] This microsatellite instability can result in functional gene mutations and has been observed in keratoacanthoma and sebaceous tumors from MTS patients.[24]
ras Oncogene
Mutations in ras have been implicated in development of sporadic BCC, premalignant actinic keratosis, and sporadic SCC. They are among the most common mutations in human malignant disease.[25] ras proteins are small G-proteins responsible for transducing intracellular signaling. Activation of ras occurs only when guanosine triphosphate (GTP) is bound. The signal is attenuated by hydrolysis of GTP to guanosine diphosphate (GDP). Mutations in ras alter the rate of this hydrolysis, resulting in activated protein and promotion of cell growth and hence tumor growth. There is a class of proteins that deactivates ras by increasing GTP hydrolysis to GDP (GTPase-activating proteins).[26] There is evidence that alterations in GTPase-activating proteins are implicated in the development of sporadic BCC.
BASAL CELL CARCINOMA
Epidemiology and Pathogenesis
BCC is the most common malignant tumor in the United States and in other areas with predominantly white populations. Approximately 900,000 cases per year are identified in the United States.[6]Australia has the highest incidence of skin cancer, the incidence of BCC being more than 2% among men and that of SCC being approximately 1% among men.[27] The incidence of BCC has increased over the past decades in a manner similar to the increase in melanoma. It is estimated that the incidence of NMSC is increasing 2% to 3% yearly.[28] One study, conducted in New Hampshire, showed an annual increase in incidence of SCC of approximately 10% and of BCC of approximately 5%.[29] Cumulative UV exposure and, more important, severe sunburn during childhood and adolescence are risk factors for BCC.[30] Other associated risk factors are Fitzpatrick skin types 1 and 2, red hair, freckling in childhood, family history of skin cancer, male sex, and Celtic ancestry.[31] BCC is more common in lighter skinned African Americans than in darker persons.[32] Immunodeficiency secondary to acquired immunodeficiency syndrome or transplantation also is associated with increased risk of BCC. Other uncommon risk factors include exposure to arsenic and ionizing radiation, especially among patients who have received radiation for acne.
Keratin pattern and immunohistochemical results suggest the origin of BCC is the outer root sheath of the hair follicle below the isthmus.[33] The locally invasive characteristic of BCC could be related to the presence of abnormal hemidesmosome-anchoring fibril complex.[34] Genetic abnormalities and mutations are thought to play a major role in development of BCC, especially in inherited syndromes of BCC. Patients with xeroderma pigmentosum cannot repair the UV-induced DNA mutations; therefore, they are at increased risk of cutaneous carcinogenesis. Mutations in the hedgehog signaling pathway genes and TP53 are important in the pathogenesis of sporadic BCC and those arising in patients with the nevoid BCC syndrome and xeroderma pigmentosum. [11] [13] [35] [36] [37]
Clinical Manifestations
The most common location for BCC is the head and neck, especially the nose. BCC occurs on hair-bearing skin; mucosal surfaces are notinvolved. The major types of BCC include nodular, pigmented, superficial, and morpheaform. The typical nodular BCC is a dome-shaped, pearly papule with a telangiectatic surface and translucent rolled borders ( Fig. 74-1 ). The surface might become ulcerated ( Fig. 74-2 ). In darker skinned individuals, especially African Americans, the more darkly pigmented BCCs may be misdiagnosed as seborrheic keratosis or nodular melanoma. Superficial BCC is a well-demarcated erythematous scaly plaque with elevated borders that often occurs on the trunk or extremities. It might be confused with Bowen's disease or nummular eczema. The most difficult BCC to diagnose and manage is the morpheaform or sclerosing variant. This ill-defined, white, indurated plaque can be mistaken for a scar or localized patch of scleroderma and therefore is ignored by patient and physician, with resulting wide subclinical extension.
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Figure 74-1 Typical presentation of basal cell carcinoma on the nose. |
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Figure 74-2 Ulcerated basal cell carcinoma with rolled borders on posterior ear. |
Histopathology
In common nodular BCC, nodular masses of basaloid cells extend from the epidermis or outer root sheath into the dermis with surrounding connective tissue stroma ( Fig. 74-3 ). A palisade arrangement of cells is present in the periphery. Sometimes as a result of tumor necrosis and disintegration, cystic spaces form. The surrounding stroma may retract from the tumor mass forming the typical lacunae, a sign that aids in diagnosis. In the pigmented type of BCC, large amounts of melanin are produced in the melanocytes that colonize the tumor. The many melanophages in the surrounding stroma also contribute to pigmentation. The superficial type of BCC shows multifocal small nests of basaloid tumor cells budding off the epidermis and adnexa. Morpheaform BCC is different in that strands of tumor cells are embedded in a dense fibrous tissue stroma. These strands often extend in the deeper dermis. Micronodular BCCs contain small nodules of tumor cells that invade surrounding stroma. The morpheaform and micronodular types are generally the most locally invasive variants of BCC. It is common for BCCs to show mixed histologic patterns of these various types. Even the less invasive variants may invade deeply when located in regions of embryonic fusion planes, such as around the nose and ears.
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Figure 74-3 Histopathology of basal cell carcinoma. (From Skarin AK [ed]: Atlas of Diagnostic Oncology, 3rd ed. St. Louis, Mosby, 2003, p 374.) |
Treatment
BCC is rarely metastatic but can be locally invasive ( Fig. 74-4 ). Therefore, eradicating the primary tumor is the goal of therapy. Several treatment options are available, both surgical and nonsurgical. Selection depends on the tumor type, patient profile, size and location of tumor, recurrence, physician's experience, and patient preference. Surgical modalities include Mohs’ micrographic surgery, surgical excision, cryosurgery, and electrodessication and curettage (EDC).[32] Nonsurgical options include radiation therapy and photodynamic therapy.[38] Other treatment modalities, such as immunotherapy with intralesional interferon[39] and topical 5% imiquimod (Aldara),[40] chemotherapy with 5-fluorouracil,[41] and retinoids,[42] have been reported with variable success ( Fig. 74-5 ).
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Figure 74-4 Basal cell carcinoma of 10 years’ duration invading the scapula. |
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Figure 74-5 Treatment for basal cell carcinoma. EDC, electrodesiccation and curettage; 5-FU, 5-fluorouracil; PDT, photodynamic therapy; XRT, radiation therapy. |
A systematic review of studies in which investigators reported recurrence rates of BCC after different treatment modalities showed that the mean 5-year recurrence rates after Mohs’ surgery and surgical excision were approximately 1% and 5.3%, respectively.[43] Risk factors for BCC recurrence include greatest dimension larger than 2 cm, location in the midface (H zone) or ear, morpheaform or other aggressive histologic pattern, and long duration.[44] These tumors should be completely resected, preferably by Mohs’ technique or excision with margin control. Mohs’ surgery should be used in areas where preserving maximum tissue is important, such as eyelids, nose, and lips. It is also indicated for recurrent BCC and tumors with ill-defined clinical margins. If simple excision is used, the margin for excision should be at least 4 mm around tumors of 1 cm or less and 5 to 10 mm for tumors larger than 1 cm.[45] If there are contraindications to surgery, or the tumor is small and located on less critical sites such as the trunk, cryotherapy or EDC can be used with good outcome. Because of the less favorable long-term cosmetic results and possibility of secondary radiation-induced skin cancer, radiation therapy is best avoided in the care of relatively young patients. Very large or poorly controlled BCC may necessitate a coordinated approach of standard surgical excision, Mohs’ surgery, radiation therapy, and immunotherapy or chemotherapy.[46]
Prognosis and Follow-up Evaluation
The prognosis of BCC is generally good. Metastasis is rare, and tumor growth is slow. Two thirds of recurrences occur during the fist 3 years after treatment.[47] The risk of development of another BCC is approximately 45% within 5 years.[48] The risk of development of another NMSC is associated with the number of previous NMSCs. In an Australian study of patients with three to nine previous NMSCs, the risk of development of a new cancer was 93%.[49] Patients treated for BCC need to be examined at least once a year for the first few years, preferably for 5 years after the last cancer was diagnosed. For patients with a history of multiple skin cancers, more frequent follow-up examinations are recommended. Photoprotection starting at a young age is advised to reduce the cumulative damage induced by the sun.
SQUAMOUS CELL CARCINOMA AND BOWEN'S DISEASE
Epidemiology and Pathogenesis
SCC is a malignant tumor of keratinocytes of the skin or mucosal surfaces. SCC has greater metastatic potential than BCC and causes the majority of NMSC deaths. SCC can arise de novo or from a precursor like actinic keratosis. Bowen's disease is a SCC in situ arising de novo. If Bowen's disease occurs on the glans penis or rarely vulva it is referred as erythroplasia of Queyrat. Bowen's disease can slowly progress into invasive SCC.
SCC is the second most common skin cancer in the United States, representing about 20% of NMSCs. Interestingly, SCC occurs more than BCC in blacks and Asians.[50] It is more common in men than women.[6] There are many risk factors for SCC, the most important being solar radiation. The incidence of SCC is increasing especially on the head and neck area as a result of exposure to sunlight.[51]SCC is thought to be correlated with recent (in the 10 years preceding diagnosis) chronic sunlight exposure[52] and cumulative sun exposure.[53] Phototherapy with PUVA (psoralen + ultraviolet A) increases the risk of SCC. Other risk factors for SCC include fair skin, red hair, albinism, and Celtic origin. Nonsolar risk factors include exposure to chemicals (insecticides and herbicides),[54] arsenic, organic hydrocarbons, chronic thermal injury and scars, ionizing radiation, and chronic immunosuppresion.[55] SCC is increased 18 to 36 times in organ transplant patients.[56] This increase of risk is correlated with the type of organ transplantation and elapsed time after transplantation. Heart transplant recipients have a higher risk of NMSC than kidney transplant recipients, possibly because of more intense immunosuppression.[57] Tobacco is a risk factor for oral SCC. Viruses, especially human papillomavirus (HPV), have been linked to epithelial malignancies including SCC. This is especially true among patients with epidermodysplasia verruciformis, who have an underlying immunodeficiency and can develop SCCs within HPV-infected warts.[55]
Carcinogens such as ultraviolet radiation (UVR), certain chemicals and viruses play a role in the pathogenesis of SCC by damaging keratinocyte DNA and other cellular contents. It is known that UVR, especially UVB, causes mutations in DNA of keratinocytes.[58] Early repair of these mutations is important for the prevention of SCC. Patients with NMSC are thought to have decreased ability for DNA repair compared with controls, thus making them more susceptible to the effects of UVR.[59] One example is the effect of UVR on DNA alterations in patients with xeroderma pigmentosum who are genetically unable to repair these defects. UVR also causes cutaneous immunosuppression, weakening the host's immune response against tumor cells and promoting tumor growth. [60] [61] Studies of SCCs have shown that mutations in the TP53 tumor suppressor gene are an early event. [2] [62] Most of the mutations occur at dipyrimidine sequences, in the form of UV-induced cyclobutane pyrimidine dimers.[63] The development of SCC does not occur by a simple single step, but rather through a multistage process. Conversion of susceptible keratinocytes to premalignant cells and then progression to carcinoma occurs as a result of successive genetic hits.[64] In the initiation stage of carcinogenesis there is clonal expansion of premalignant cells. The next stage is increased proliferation of premalignant cells and subsequent chromosomal aberrations. The final stage is conversion to SCC. DNA aneuploidy with a single peak was detected by flow cytometry in lesions of Bowen's disease, suggesting a monoclonal proliferation of abnormal keratinocytes and a clonal basis for skin cancer.[65] Aberrant expression of P-cadherin, and changes in expressions of cytokeratins and transforming growth factors all play a role in tumor progression.[66]
Clinical Manifestations
SCC occurs more on the head and neck area in whites, but in blacks there is no predilection for sun-exposed areas of the body.[67] SCC in situ may develop from premalignant lesions such as actinic keratosis or arsenical keratosis. In fact, in whites the majority of SCCs arise from actinic keratoses. These can eventually spread beyond the epidermis and become invasive. Invasive SCC can also arise from normal skin. It starts as a small, firm, dull red nodule, which can undergo central ulceration. Sometimes if SCC arises from solar keratosis an adherent keratotic scale can be seen. If ignored, the lesion grows horizontally and vertically and may become fixed to the underlying tissue. The surface might become ulcerated with bleeding, malodorous exudate or crust. The borders are usually elevated and firm. Occasionally a fungoid lesion without ulceration can be seen. SCC of the lower lip often arises from previously solar-damaged areas (actinic cheilitis). Initially local thickening of the vermilion border occurs that then progresses into a noduloulcerative lesion ( Fig. 74-6 ). Persistent subungual erythema with pain and swelling should alert the physician for SCC of the nail region. This form of SCC may be confused with warts ( Fig. 74-7 ). As mentioned earlier, SCCs can arise from chronic sinuses, scars, and chronic thermal damage.
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Figure 74-6 Squamous cell carcinoma of the lip of 5 years’ duration. |
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Figure 74-7 Squamous cell carcinoma of the nail bed. Patient was being treated for a wart. |
Verrucous carcinoma is a distinct slow-growing low-grade type of SCC. The most common location is the plantar foot (epithelioma cuniculatum) but it can occur on the buttocks, genitals (giant condyloma of Buschke and Löwenstein), face, oral cavity (oral florid papillomatosis), trunk, nails, and extremities. It grows as an exophytic verrucous mass. Clinically, on the foot it can be mistaken for a plantar wart. It is locally aggressive and may penetrate into deep soft tissue or bone.
Bowen's disease often appears as a well-defined single red plaque with dry surface scaling. Lesions are slow growing and asymptomatic, thus ignored by many patients. The physician might initially treat it as psoriasis or nummular eczema with no response. There is a 3% to 5% chance that Bowen's disease can progress into invasive SCC.[68] Clinically erythroplasia of Queyrat resembles Bowen's disease butlacks the dry superficial scale. Instead the surface is moist and smooth.
The risk of metastasis of SCC is variable, depending on the site and tumor characteristics. The deeper and larger the tumor, the higher is the chance of metastasis. Recurrent tumors are at high risk for metastasis. Lesions with perineural involvement have a 35% metastatic rate.[69] Among the different histologic types, desmoplastic SCCs are more likely to metastasize.[70] The risk of metastasis of SCC derived from actinic keratosis is low (0.5% to 3.7%) compared with SCC arising in radiation-induced SCC and chronic osteomyelitis (20% and 31%, respectively). [71] [72] High-risk areas for metastasis include tumors arising from the dorsal hands, lips, ears, and penis. For example, SCC of the lower lip has a 15% risk of metastasis.[73] Bowen's disease and erythroplasia of Queyrat also have a low chance of metastasis, but once they become invasive the risk of metastasis increases significantly.
Histopathology
A deep shave or punch biopsy that includes the base of the tumor is needed to distinguish SCC in situ from invasive SCC. Bowen's disease is carcinoma in situ. The stratum corneum is thickened, and epidermis is hyperplastic with disordered maturation of keratinocytes. Mitotic figures, mutinucleated keratinocytes, and dyskeratotic cells with hyperchromatic nuclei and eosinophilic cytoplasm are seen in the epidermis. The histology of SCC shows masses of epidermal cells proliferating into the dermis. Atypical squamous cells and mitotic figures are seen ( Fig. 74-8 ). The cells have abundant eosinophilic cytoplasm and large nuclei. Horn pearls, which are a result of keratinization of squamous cells, are seen. The dermis may show a marked inflammatory reaction. Spindle cell SCC is a rare variant composed of mainly spindle cells, but some squamous differentiation may be seen. Spindle cells have large vesicular nuclei and scant cytoplasm and intermingle with the collagenous stroma. Spindle cell SCC is poorly differentiated with numerous mitoses and deep invasion and requires immunohistochemistry to differentiate it from other spindle cell tumors. Another uncommon histologic variant of SCC is the acantholytic or adenoid SCC, seen more on the face and neck. There are nests of tumor cells with dyskeratotic cells and central acantholysis forming pseudoglandular structures.
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Figure 74-8 Histopathology of squamous cell carcinoma. (From Skarin AK [ed]: Atlas of Diagnostic Oncology, 3rd ed. St. Louis, Mosby, 2003, p 376.) |
Treatment
The treatment options for SCC are similar to BCC treatment, with some differences ( Fig. 74-9 ). The first step is to estimate the peripheral and vertical extension of tumor cells. Tumors at high risk for local or distant spread are those larger than 2 cm or deeper than 6 mm, recurrent tumors, poorly differentiated tumors, and those with perineural invasion or arising in immunocompromised hosts.[74] Second, the patient should be evaluated for metastasis to the lymph nodes and other organs.
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Figure 74-9 Treatment for squamous cell carcinoma (SCC). EDC, electrodesiccation and curettage; 5-FU, 5-fluorouracil; PDT, photodynamic therapy; XRT, radiation therapy. |
Destructive methods or surgical excision can treat Bowen's disease effectively. Small uncomplicated SCCs (<1 cm) in low-risk locations are frequently treated with EDC. Cryotherapy is an alternative treatment. Simple surgical excision with margin control is commonly used for smaller tumors and those on the trunk and extremities. The recommended margin for low-risk SCC is 4 mm and for high-risk tumor is 6 mm.[75] The excision should include the subcutaneous fat. Mohs’ micrographic surgery is the treatment of choice for high-risk SCCs or for tissue preservation where tissue sparing is cosmetically or functionally vital.[76] Aggressive or deeply invasive SCCs are treated with deep surgical excision with margin control when practical. Mohs’ surgery may be helpful in delineating critical areas in massive tumors or tumors with ill-defined borders. SCC invading surrounding structures such as bone and cartilage must also be excised. Tumors with neural or perineural involvement that are at high risk of recurrence should be completely excised preferably with the Mohs’ technique. High-risk tumors may require adjuvant therapy with radiation therapy[77] or chemotherapy. [78] [79]
Radiation can also be used as a primary choice of treatment. Usually 4000 cGy of radiation is given in 5 to 16 fractions. This form of treatment might be appropriate in the elderly at high risk for surgical complications or other patients with contraindications to anesthesia or surgery. Radiation can be useful to treat tumors on the eyelids, nose, ears, and lips when surgery is not practical. The disadvantages are the cost, blind margin control, and prolonged treatment duration. The cure rate for tumors larger than 2 cm is about 85% to 95%.[80] Radiation therapy is best avoided in treating verrucous carcinomas and younger patients because of poor long-term cosmetic results. SCCs that have arisen from ulcers, scars, and irradiated sites are better removed by margin-controlled surgery than by radiation therapy.
If lymph node metastasis has occurred, treatment is wide surgical resection of tumor with regional lymph node dissection with or without adjunctive radiation. However, elective lymph node dissection is not commonly performed in the absence of evidence for regional spread. Sentinel lymph node biopsy may be considered.[81]
For patients with Bowen's disease or advanced SCC, chemotherapy with isotretinoin alone or in combination with a interferon has been used with success. [82] [83] Promising chemopreventive agents for lesions in the actinic keratosis–SCC spectrum include retinoids, COX-2 inhibitors, and difluoromethylornithine.
Prognosis and Follow-Up
SCCs in general have a greater potential for recurrence and metastasis than BCCs; therefore, the follow-up must be more aggressive. The patient should be followed at close intervals (every 3–6 months) for the first several years, depending on the location, size, aggressiveness, and node status of the primary tumor. The exception would be small SCCs arising from actinic keratoses on sun-exposed surfaces, where the rate of metastasis is very small (0.5%). In these patients, routine follow-up every 6 to 12 months is all that is required.
KERATOACANTHOMA
Keratoacanthomas are common cutaneous neoplasms that are thought to derive from the infundibular portion of hair follicles. They most often present as solitary rapidly growing, pink or flesh-colored, dome-shaped, or cratiform nodules. They occur most commonly on sun-exposed areas in fair-skinned elderly individuals. Keratoacanthomas are historically characterized by their spontaneous involution over several months with residual atrophic scarring and local tissue destruction. Histologically, a mature keratoacanthoma has a distinctive architecture characterized by a keratin-filled crater lined by a proliferating squamous epithelium with abundant pale eosinophilic “glassy” cytoplasm, epithelial lipping, and multiple keratin horn pearls with central orthokeratosis. Cytology is often indistinguishable from that of a well-differentiated cystic SCC. At the base of the tumor, islands and strands of atypical cells may invade the dermis. Frequently there is a heavy inflammatory infiltrate at the base of the lesion comprising lymphocytes, plasma cells, neutrophils, and eosinophils. Atypical mitoses as well as perineural and perivascular invasion may also be present, particularly in tumors involving the head and neck. Several cases of highly aggressive and metastatic keratoacanthomas have also been reported; however, some have questioned whether these were truly keratoacanthomas or rather keratoacanthoma-like SCCs.[84]
Although most cases of keratoacanthoma are solitary, subsets of individuals with multiple keratoacanthomas have been described. These include the familial Ferguson Smith type comprising multiple keratoacanthomas at an early age, and the generalized eruption of thousands of small keratoacanthomas as described by Grzybowski (see ref. 84). Keratoacanthomas frequently occur in individuals with the Muir-Torre syndrome, xeroderma pigmentosum, and solid-organ transplantation.[85] They also occur in areas of scarring from prior trauma, thermal burns, and surgical treatment, and in association with many benign conditions such as stasis dermatitis, lichen planus, lichen simplex chronicus, psoriasis, and discoid lupus erythematosus.
Debate exists as to whether keratoacanthomas are a distinct clinical entity or a subtype of well-differentiated SCC. Significant efforts have been made to find practical, reliable criteria to distinguish keratoacanthoma from SCC, but none have yielded reliable criteria for routinely distinguishing these entities. Recent studies with the apoptotic marker P2X7 and with comparative genomic hybridization suggest that keratoacanthoma and SCC possess distinct genetic aberrations that result in separate developmental pathways. [86] [87] These findings may provide an avenue in the future for reliable separation of keratoacanthoma and SCC. However, given the potential for local destruction and metastatic disease, it is recommended that keratoacanthomas be treated in the same manner as SCCs. Complete conservative excision is the most common treatment technique for keratoacanthomas. Radiotherapy, EDC, systemic medications, and topical and intralesional modalities have been reported with varying success.
NONMELANOMA SKIN CANCER IN IMMUNOCOMPROMISED HOSTS
The incidence of NMSC is significantly increased in patients who are immunocompromised secondary to human immunodeficiency virus/acquired immunodeficiency syndrome, heritable immunodeficiencies, the effective immunosuppression of chronic lymphocytic leukemia, and immunosuppressive medications. Patients with human immunodeficiency virus infection, congenital immunodeficiency, and lymphoma manifest decreased immunosurveillance due to defects in cell-mediated immunity. An increased susceptibility to infection with oncogenic HPV types may be important in the pathogenesis of Bowen's disease (SCC in situ), SCC, keratoacanthomas, and genital dysplasias in these patients.[88] Epidermodysplasia verruciformis is a rare inherited disorder of unknown etiology that predisposes those affected to widespread infection with HPV types 5 and 8, which is associated with the development of SCC. A history of UV exposure further compounds the risk in these populations.[89]
Iatrogenic immunosuppression, an important treatment modality for autoimmune diseases and for prevention of transplant rejection, is associated with both direct carcinogenic effects and decreased immunosurveillance. Solid-organ transplant recipients (OTRs) require long-term immunosuppression and, therefore, are at increased risk for BCC, melanoma, Kaposi's sarcoma, and especially SCC over their lifetime. The highest incidence is seen in heart transplantation followed by renal and then liver transplantation. The impact on public health is significant, in that more than 25,000 solid-organ transplants are performed in the United States annually, the majority being renal, and survival rates for OTRs are increasing. In OTRs, SCC can be more aggressive and the SCC/BCC ratio is increased.[90]
Factors associated with SCC in OTRs include sun exposure, epidermodysplasia verruciformis-associated HPV types 5 and 8, fair skin, heart transplant, older age at transplant, male sex, and intense immunosuppression. Indeed, intensity and duration of immunosuppression have been associated with development of aggressive SCC.[89] Studies suggest that antirejection therapies using tacrolimus, mycophenolate mofetil, or rapamycin versus cyclosporine, glucocorticoids, or azathioprine may decrease incidence of NMSC in OTRs. [89] [91]
The burden of skin cancer, especially SCC, is markedly elevated in OTRs. The magnitude and severity of disease can be devastating.[90] Many are diagnosed with numerous lesions annually, each lesion with an increased potential for aggressive behavior and metastasis relative to occurrences in the general population.[92] Metastatic disease usually involves noncontiguous spread along lymphatic vessels and nerves, and represents a poor prognosis and therapeutic challenge.[93]
Management of NMSC in OTRs consists of the same treatment modalities described for NMSC in the general population. Increased vigilance including frequent follow-up, a high level of suspicion for new or changing skin lesions, and a low threshold for biopsy is essential to ensure early detection and timely treatment. By stratifying lesions as lower versus higher risk (rapid growth, large size, recurrence, aggressive histology, or location on lip, ear, or scalp), those lesions more likely to recur or metastasize can be prioritized in a treatment regimen in OTRs with an overwhelming burden of disease. [90] [93]Whereas topical agents, curettage, and cryotherapy may be appropriate for treatment of lower risk lesions, higher risk lesions usually require a surgical approach (excision or Mohs’ micrographic surgery) to ensure clear margins. Radiation therapy can be an important adjunct for metastatic and perineural disease. Although the diagnostic and therapeutic role of sentinel lymph node biopsy in such cases is not established, it may be considered in selected high-risk cases. [89] [90]
Data suggest that acitretin may be beneficial as a chemopreventive agent in this population. Moreover, reducing immunosuppressive therapy has been shown to decrease the development of NMSC and metastatic disease, although coordination with the primary transplant physician is essential to avoid allograft rejection. [89] [90]
SEBACEOUS CARCINOMA
Epidemiology and Pathogenesis
Sebaceous carcinoma is a rare, potentially devastating tumor derived from the adnexal epithelium of sebaceous glands. Principally, the tumor occurs in two different clinical scenarios: ocular sebaceous carcinoma (OSC) and extraocular sebaceous carcinoma. [94] [95] OSC accounts for 0.2% to 0.8% of all eyelid tumors and 1% to 1.5% of all malignant tumors of the eyelid. Approximately 400 cases have been described in the English literature.[96] OSC affects women 1.5 times more frequently than men; however, a slight male preponderance occurs in cases of extraocular sebaceous carcinoma. [97] [98] [99] [100] [101] The mean age at diagnosis is 65 years (range, 40–60 years), but OSC has been reported in young children (12 years of age, after radiation therapy for retinoblastoma) and in persons as old as 90 years. [102] [103] Sebaceous carcinoma seems to have a higher incidence in the Asian population. [102] [104] [105] [106] This tumor has been associated with MTS, an autosomal dominant disorder of mismatch repair genes characterized by sebaceous tumors (benign and malignant) as well as other visceral malignant tumors. [20] [107] Sebaceous carcinoma with microsatellite instability has been found in several renal organ transplant recipients.[107]
Clinical Manifestations
OSC typically manifests as a painless, slowly growing, yellowish papule ( Fig. 74-10 ). The upper lid is affected two to three times more frequently than the lower lid. The tumor usually originates from the meibomian gland (sebaceous gland in the tarsus) or from a sebaceous gland of the eyelash (glands of Zeis). [101] [103] Clinically, the signs can be subtle with only moderate lid thickening, eyelash alopecia, pale corneal changes, conjunctival injection, or thickening along the temporal or inferior temporal limbus. [97] [108] [109] [110] There have been case reports of ipsilateral upper and lower eyelid involvement and bilateral upper and lower lid involvement. [96] [109] [111] The diagnosis is often elusive, because OSC is notorious for masquerading as more common ocular disorders, such as chalazion (most common), keratoconjunctivitis, blepharoconjunctivitis, SCC, BCC, granulomatous disorders, and benign neoplasms. [97] [109] [110] [111] [112] Initial recognition is 50% among ophthalmologists and only 18.6% among general practitioners. [113] [114] [115] Often there is a delay in diagnosis of 6 months to a year and in some series up to 2.9 years, contributing to increased morbidity and mortality. [97] [113] With regard to the rarer extraocular sebaceous gland carcinoma, initial diagnosis can be elusive because the clinical appearance often is pleomorphic and nonspecific and varies from a banal-appearing nodule to large ulcerating masses. [116] [117] [118] [119] This variant of sebaceous gland carcinoma most often occurs on the head and neck region, reflecting the abundance of sebaceous glands there.
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Figure 74-10 Ocular sebaceous carcinoma involving the lower eyelid. |
Histopathology
Full-thickness biopsy is required to ensure adequate tissue sampling. Microscopic examination shows that OSC invades surrounding tissue by direct extension into the dermis or the overlying epithelium.[113] [120] [121] The tumor demonstrates epitheliotropic spread in 37% to 80% of cases. Atypical sebaceous cells have a pagetoid distribution within the conjunctival epithelium. [103] [113] As many as 18% of cases of OSC may have multifocal regions of tumor involvement.[96]
There are basically two broad classification schemes with regard to light microscopic findings. Font[122] described three classes of tumor based on degree of differentiation: well differentiated, moderately well differentiated, and poorly differentiated. Others prefer to classify the tumor on the basis of growth pattern: lobular, comedocarcinoma, papillary, and mixed.[100] The intraepithelial neoplasia growth pattern and pagetoid spread are not addressed in this classification scheme. The histologic features are anaplastic cells with varying degrees of differentiation. Squamoid or basaloid features may be present.[97] Lobulated aggregates of basaloid cells usually contain irregular, hyperchromatic nuclei and vacuolated cytoplasm. [96] [109] [123] [124] In cases of intraepithelial neoplasia, the epithelial pagetoid cells lack intercellular bridges and contain large hyperchromatic nuclei, prominent nucleoli, and abundant, pale-staining cytoplasm. Special stains, such as oil red O or Sudan black, often are helpful in delineating the atypical sebocytes; however, poorly differentiated tumors may not stain positively for lipids. [110] [113] In addition, undifferentiated sebocytes often lack the foamy cytoplasm of their more differentiated counterparts and may resemble atypical SCC at standard hematoxylin and eosin staining. [97] [109] [123] Recognition of this particular biphasic nature of OSC is critical to appreciating the biologic behavior of this recalcitrant tumor. Ophthalmologists have known for years about the difficulty of assessing the tumor margins of this epitheliotropic neoplasm. It has been recommended that as many as nine mucosal biopsy specimens be obtained and mapped from the medial and lateral portions of the bulbar and palpebral conjunctiva of the upper and lower lids. [125] [126]
Treatment
Evaluation of patients with known or suspected sebaceous gland carcinoma includes complete history with review of systems, family history and consideration of MTS, complete skin examination, and palpation of nodal basins and structures adjacent to the lesion. A chest radiograph, complete blood cell count, liver function tests, and electrolytes are recommended. If MTS is a consideration, colonoscopy is warranted.
Management of sebaceous gland carcinoma is primarily surgical, although there are a few reports of tumors managed primarily with radiation.[127] Given the paucity of cases, no randomized, controlled studies have been conducted to evaluate therapy. Traditionally, wide local excision with a margin of 4 to 6 mm of clinically normal tissue has been used.[97] Exenteration is recommended for extensive bulbar conjunctival involvement or evidence of orbital invasion.[101] In his personal series of 60 consecutive patients with a mean follow-up of 41 months, Shields and colleagues reported a local recurrence rate of 18%, exenteration of 13%, and metastasis of 8%.[113] Some experts consider Mohs’ micrographic surgical technique the treatment of choice, because it preserves the maximum amount of healthy tissue. This quality is especially crucial in the treatment of ocular tissue. [109] [113] [128] [129] [130] [131] In addition, it allows for microscopic examination of all margins of the obtained tissue to ensure complete tumor eradication. In 2002, we reported our results of nine cases treated by Mohs’ micrographic surgery achieving a 90% success rate with 3-year follow-up.[118] Four of these patients have now gone 5 years without evidence of local recurrence in all patients (unpublished data).
Local recurrence usually is the result of inadequate management of the primary tumor.[97] If the recurrent lesion is small enough, treatment can be repeated with Mohs’ micrographic surgery or local excision.[113] More extensive OSC tumor involvement usually necessitates exenteration. [115] [124] Ophthalmologists have considered cryotherapy a useful modality in the management of epibulbar disease in a small subset of patients, and this therapy may be an alternative to exenteration. [105] [132] [133] Regional lymph node metastasis is managed by surgical resection and adjuvant radiation.
Prognosis and Follow-up Evaluation
Both OSC and extraocular sebaceous gland carcinoma are aggressive tumors that recur locally if inadequately managed and readily metastasize. Metastasis may occur through lymphatic vessels, and in the case of OSC, it is postulated to occur through the lacrimal and excretory systems.[97] Risk factors associated with poor prognosis include duration longer than 6 months; vascular or lymphatic involvement; orbital extension; poorly differentiated tumor morphology; multicentricity; pagetoid spread into the conjunctival epithelium, cornea, or skin; upper and lower lid involvement; and history of radiation exposure. [102] [103] [109] [113] In the past, 14% to 25% of patients reportedly had metastasis, most frequently involving regional nodal basins, followed by spread to the liver, lung, brain, and bones. [97] [99] [100] [101] [102] Because of increased index of suspicion, physician education, and earlier recognition with biopsy, the metastatic rate has decreased to 10% in some series.[113] Among industrialized countries, periocular mortality is reportedly 9% to 15%. Systemic disease is associated with a grave prognosis.
Follow-up care includes examining the individual on a regular basis, probably for the rest of his or her life. Given the complex issues in dealing with this aggressive tumor, individuals are best served by being cared for in a tertiary care setting with a multidisciplinary approach. Physical examination, evaluation of the surgical site, and a low threshold for biopsy of suspicious lesions is a reasonable approach.
MERKEL CELL CARCINOMA
Epidemiology and Pathogenesis
Merkel cell carcinoma (MCC) is a rare aggressive tumor of unknown incidence. Fewer than 700 cases have been reported since the tumor was first described by Toker in 1972. [134] [135] Many names have been ascribed to this neoplasm, including primary small cell carcinoma of the skin, trabecular carcinoma, APUDoma, neuroendocrine carcinoma, endocrine carcinoma, and primary undifferentiated tumor of the skin. [135] [136] [137] [138] New SEER data indicates that the incidence of MCC is rising with about 470 new cases reported annually.[139]
MCC is a tumor that primarily affects elderly persons. Ninety percent of cases reported occur in patients older than 50 years, and the mean age at diagnosis is 69 years. [135] [138] [139] There does not appear to be a sex predilection.[140] White persons are more frequently affected than those of other races; however, MCC has been reported among Asian and black persons. [141] [142] [143] [144] [145] MCC has been reported in association with BCC, SCC, a history of radiation exposure, certain familial cancer syndromes, and immunosuppressed states [121] [142] [146] [147] [148] such as OTRs.[149]
Clinical Manifestations
MCC often manifests as a painless, indurated, erythematous to violaceous nodule on sun-damaged skin, 50% of tumors arising on the head and neck. [134] [135] [136] [137] [138] [139] [142] [150] Ten percent of these tumors are in the periocular areas ( Fig. 74-11 ).[151] The extremities are the second most affected site, followed by the trunk. [136] [141] [152] [153] MCC also has been reported in areas not normally exposed to sunlight, such as the vulva, endocervix, penis, esophagus, bladder, and calvarium. [154] [155] [156] [157] [158] The overlying epidermis usually is unremarkable; however, ulceration may be found.[138] [142] [159] In addition, there may be overlying or surrounding telangiectasis.[135] The clinical differential diagnosis includes BCC, SCC, amelanotic melanoma, lymphoma, and metastatic disease. The ultimate diagnosis is made on the basis of clinical appearance, histologic findings, and supporting immunohistochemical studies of the tissue subjected to biopsy.
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Figure 74-11 Merkel cell carcinoma involving the upper eyelid. |
Histopathology
MCC has a histologic appearance similar to that of other small cell neoplasms and must be differentiated from cutaneous metastatic lesions from carcinoid or small cell undifferentiated carcinoma of the lung. [135] [137] [142] [159] The tumor cells are characteristically uniform in size, monomorphic, basophilic, and ovoid, and measure up to 15 mm in diameter. The nuclei have finely dispersed chromatin with minimal surrounding cytoplasm. [137] [152] [159] [160] [161] Pathognomonic features include numerous mitotic figures, vesicular nuclei with essentially inconspicuous nucleoli, and apoptosis, especially when appreciated with certain architectural features. [135] [137] [162] The tumor involves the dermis, may extend into the subcutaneous fat or deeper, and usually spares the epidermis.[142] There may be a pagetoid pattern of epidermal spreading, which can mimic Bowen's disease, Paget's disease, extramammary Paget's disease, melanoma, and mycosis fungoides. [150] [162] MCC also may have both squamous and adnexal differentiation. [138] [161]
The architectural patterns of MCC have been classified into three separate groups: trabecular, intermediate cell, and small cell.[137] The trabecular pattern is the least common. [134] [163] [164] The cells are arranged in cords admixed among a fibrovascular background. [134] [136] [160] This pattern may be associated with pseudoglandular structures. [164] [165] The tumor often involves tissue surrounding adnexal structures, such as hair follicles. More often, in the intermediate cell type, MCC displays large sheets or clusters of uniform cells with foci of necrosis.[136] The tumor also can arise near adnexal structures and connect with the epidermis. [164] [165] The cells in this pattern are less compact than those in the trabecular type. There often is a surrounding lymphocytic infiltrate. [135] [162] [163] [164] [165] [166]
Finally, the small cell type of MCC arises in the dermis and appears as sheets of cells interrupted by strands of connective tissue.[164] Glandular or pseudoglandular structures are absent. The cells are round and small and may demonstrate “crush” artifact. It has been proposed that the intermediate cell type and the small cell type behave in a clinically more aggressive manner than the trabecular type. [164] [165]Lymphatic invasion is frequently encountered and has negative prognostic implications. [137] [142] [163] [164] [166] [167]
Immunohistochemical studies aid in the diagnosis of MCC and help to differentiate it from other tumors. A characteristic paranuclear dotlike pattern against cytokeratin 20 is probably the most useful immunohistochemical stain. [135] [164] [168] [169] In addition, MCC stains positively for neuron-specific enolase. [136] [160] [164] [168] However, neuron-specific enolase is not specific for MCC and cannot be relied on for differentiation of MCC from small cell carcinoma of the lung. [135] [169] Chromogranin A and synaptophysin are specific for MCC but less sensitive than neuron-specific enolase. MCC also stains positively for epithelial membrane antigen and Ber-EP4. [135] [160] [169]
Treatment
When MCC is diagnosed, a detailed history should be obtained and a physical examination performed with emphasis on the skin and lymph nodes. Complete blood cell count and hepatic and renal function tests are reasonable. Evaluation of the chest, abdomen, and pelvis with computed tomography may be useful in differentiating MCC from metastatic small cell carcinoma and for initial staging.[150]Individuals with MCC of the head and neck region need imaging for evaluation of draining nodal basins, especially if there is clinically evident lymphadenopathy. [135] [150] Tumor staging is performed at clinical presentation.[170] Stage I disease is a primary tumor with no evidence of nodal involvement. Stage II disease equates to regional lymph node involvement. Stage III disease is defined by the presence of systemic metastasis.
Local disease is best managed by surgical excision to lower the tumor burden, and excision is followed by radiation. [139] [141] [150] [166] [170] Wide local excision of 2.5- to 3.0-cm margins is especially suitable for MCC of the trunk or extremity, being the historical standard. [135] [139] [141] [150] [166] [170] The use of Mohs’ micrographic surgery for areas in which this goal would not be achievable, such as the face or neck, has been a logical extension of surgical therapy. [150] [171] In addition to tissue conservation, the technique allows microscopic examination of all margins. [150] [171]
Prophylactic or elective lymph node dissection in all patients has been advocated by some surgeons. [135] [136] [170] [172] Others suggest that sentinel lymph node biopsy for evaluation of draining lymph node basins would be a reasonable approach and avoid the morbidity of elective lymph node dissection. [137] [138] [139] Sentinel lymph node biopsy is best performed when the primary surgical site has been subjected to the least amount of manipulation. Thus far no studies have been conducted to compare the two methods. Elective lymph node dissection currently is recommended for large primary tumors, head and neck lesions, small cell subtype, and evidence of vascular or lymphatic invasion. [136] [139] [141] [153]
MCC is considered a radiosensitive tumor. Thus, radiation therapy has been used as adjuvant primary treatment when surgery is not an option and for palliation. [139] [140] [141] [142] [150] [170] [172] Use of adjuvant external beam radiation therapy has been advocated by many authorities. [139] [141] Current recommendations call for surgical management of the primary MCC followed by radiation to the primary site as well as the regional lymph node draining system. [141] [142] [150] [172] [173] [174] [175] [176] [177] Adjuvant chemotherapy has not been studied in a controlled manner. Many cytotoxic regimens have been used, including cyclophosphamide, methotrexate, 5-fluorouracil, cisplatin, etoposide, doxorubicin, procarbazine, dacarbazine, streptozocin, and nitrogen mustard. [138] [139] [178] [179] [180] Review of the literature on adjuvant chemotherapy has not demonstrated clear clinical benefit regarding relapse or survival. [143] [146] [170] [176] [177] Chemotherapy has been used for salvage therapy in patients with systemic disease. [147] [170] [178] [179] [180] Most regimens involve two or three drugs, and results are modest at best. No large, randomized studies have been conducted because of the rarity of MCC.
Prognosis and Follow-up Evaluation
MCC has been compared to malignant melanoma because of its similar aggressive behavior. [138] [139] [174] The local recurrence rate is 26% to 44% after primary treatment. As many as 30% of patients have regional lymph node involvement at the time of diagnosis with a 55% rate of regional lymph node relapse after treatment and a 34% to 49% rate of distant metastasis. [139] [142] [150] [176] [177] [180] Survival rates reportedly are 68% for women and 36% for men at 3 years. [152] [179] Given the relative rarity of the tumor, no large multicenter randomized trials have been conducted to assess stage, treatment modality, recurrence rate, and overall survival. There have been reports of individuals with spontaneous resolution of MCC. [181] [182] [183]
Patients should be monitored closely for recurrence of locoregional or distant disease. Lymph node or distant metastatic disease has a uniformly grave prognosis; however, there may be a role for chemotherapy in prolonging survival. Almost all individuals with metastatic disease eventually die of the disease.
DERMATOFIBROSARCOMA PROTUBERANS
Epidemiology and Pathogenesis
DFSP is an uncommon tumor of intermediate malignancy that arises in the dermis. It is a locally aggressive neoplasm with notoriously high recurrence rates even after wide local excision. In 1924, Darier and Ferrand[184] first described DFSP as a distinct clinicopathologic entity; however, it was Hoffman in 1925 who introduced the term dermatofibrosarcoma protuberans.[185]
DFSP constitutes less than 1% of all malignant tumors. The estimated incidence is 0.8 to 5 cases per 1 million persons per year. [186] [187] [188] [189] [190] The tumor commonly occurs between 20 and 50 years of age, rare cases occurring in young children.[191] In addition, there have been a few reported cases of congenital DFSP. [191] [192] [193] [194] The sexes are affected equally; however, in some series there is a slight male preponderance. [186] [187] [188] [191] [195] Most reported cases of DFSP occur in white persons, but historically race rarely is mentioned. [186] [187] [188] [196] DFSP also occurs in African Americans and Asians. [191] [196] [197]
DFSP is not known to have a genetic or familial predisposition. [198] [199] The cause of DFSP is unknown. Chromosomal abnormalities consistent with a monoclonal origin have been found in several studies. [200] [201] Most frequently, these abnormalities include ring 22 chromosomes, ring chromosomes containing chromosome 17 sequences, abnormal clones, and t(2;7) translocations. [201] [202] [203] [204]Approximately 10% to 20% of patients report a history of antece-dent trauma. [186] [191] [199] [205] [206] There have been reports of DFSP arising in multiple immunization sites, burn scars, and surgical scars.[196] [207] [208] DFSP has been associated with pregnancy as well as long-term arsenic exposure, acanthosis nigricans, and acrodermatitis enteropathica. [186] [209] [210] [211]
Clinical Manifestations
DFSP usually manifests as a flesh-colored, firm, asymptomatic nodule or plaque ( Fig. 74-12 ). The tumor is firm to palpation, and a subcutaneous component often is appreciated. There may be fixation to overlying skin but rarely to deeper structures. Lesions associated with pigment are known as Bednar's tumors.[212] In addition to pigment, there may be red to violaceous erythema. Characteristically, DFSP initially manifests as a solitary nodule; however, there may be multiple primary lesions. The size typically ranges from 1 to 5 cm, but neglected lesions can be as large as 20 cm in diameter. [186] [188] [196]The lesion slowly enlarges in a relentless manner. Accelerated growth phases can result in nodularity or multiple outcroppings or protuberances. Ulceration occurs when the tumor erupts through the epidermis. Atypical clinical manifestations include sclerotic plaques with a morpheaform appearance.[213]
|
Figure 74-12 Dermatofibrosarcoma protuberans involving the back. Central linear scar from previous partial excision is encircled by ink to highlight clinical margins of the lesion. |
Approximately 50% to 60% of DFSP lesions occur on the trunk, 25% of those occurring on the chest and shoulders. [187] [188] [191] [196] Twenty percent to 30% arise on the proximal aspects of the extremities. [188] [189] [190] [191] Ten percent to 15% occur on the head and neck, the scalp being affected less than 5% of the time. [187] [188] [191] [196] In rare instances acral sites have been reported, mostly in young children and adolescents. [187] [191] [192] [214] Often there is a delay in diagnosis given the indolent and nonspecific features of the tumor. DFSP often is mistaken for lipoma, deep-seated epidermal cyst, scar, hypertrophic scar, keloid, dermatofibroma, nodular fasciitis, and insect bite. The diagnosis is confirmed with biopsy and microscopic examination of the tissue.
Histopathology
The histological features of DFSP often are easily recognized on low-power view. There is densely packed proliferation of monomorphic, bluish, spindle-shaped cells seated in and expanding the dermis. The overlying epidermis usually is normal appearing unless there has been invasion by the tumor. The central or nodular areas of the tumor demonstrate numerous spindle cells arranged in a characteristic “whirling, storiform or herringbone” configuration.[160] The lateral tumor margins have sharply pointed tumor cells and irregular strands dissecting between the native collagen bundles. Inferiorly, the DFSPcells invade downward within the fibrous septa that separate the adipose cells of the panniculus. The peripheral margins may have a deceptively bland appearance resembling normal collagen and making interpretation of tumor margins difficult.[188] Fascia, muscle, and underlying bone may be involved in long-standing lesions. [188] [191] [196] [200] Histological variants include DFSP with entirely myxomatous features (myxoid DFSP) and pigmented DFSP, also known as Bednar's tumor. [212] [214] [215] [216] This variant tends to occur more often in dark-skinned persons and accounts for approximately 1% to 5% of all cases of DFSP.[212] Bednar's tumor has the characteristic storiform pattern of spindle cells admixed with a variable amount of melanin-laden dendritic cells. Immunohistochemical studies that may be helpful include positive staining for CD34, a human hematopoietic progenitor cell antigen. Unlike dermatofibroma, DFSP stains negatively for factor XIIIa.[160]
Treatment
After the diagnosis of DFSP has been confirmed, a complete history, review of systems, and physical examination with focus on the skin and structures contiguous with the tumor and palpation of lymph node basins are performed. Unless the physician suspects metastatic disease, extensive laboratory studies and radiological investigation are not indicated.
The traditional mainstay of therapy for DFSP has been surgical resection, specifically wide local excision with a margin of 2 to 4 cm of normal-appearing skin. [196] [217] [218] Unfortunately, the biological and histological features of the tumor coupled with the inability to clinically determine tumor margins account for exceptionally high recurrence rates with standard surgical therapy. Reported local recurrence rates are as high as 60% after standard surgical excision and 23% after wide local excision with margins greater than 4 cm.[217] Approximately 80% of local recurrences occur within 3 years.[186] [196] [201] Local recurrence after 10 years is rare but has been reported. [188] [191] Mohs’ micrographic surgery has been receiving greater recognition as a useful method of management of DFSP. [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] The capability of microscopic examination of the entire specimen margins allows the surgeon to localize and excise the tumor in a precise manner. This method also allows for maximum conservation of tissue, a crucial factor in certain anatomic areas, such as the face, scalp, distal extremities, and genitalia. Results of several studies have suggested that Mohs’ micrographic surgery may be beneficial in the management of DFSP; however, few series have provided complete 5-year follow-up data. [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] At the University of Wisconsin, Madison, 36 patients with DSFP were treated with Mohs’ micrographic surgery. Of these, 29 participated in follow-up study for 5 or more years (range, 5–20 years). As of this writing, there have been no local recurrences or cases of regional metastasis.[227] Recently, imatinib mesylate (Gleevec), an inhibitor of platelet-derived growth factor receptors, has shown promise for unresectable DFSP.[228]
Prognosis and Follow-up Evaluation
Although it is locally aggressive, DFSP rarely metastasizes. The overall rate of distant metastasis is approximately 5% and of regional metastasis is 1%.[195] In the past the causes of the higher rate of metastasis were probably inclusion of malignant fibrohistiocytoma (MFH) in the database and degeneration of DFSP to a more sarcomatous subtype with its subsequent increased risk of metastasis. [227] [228] [229] MFH is now understood to be a totally different entity from DFSP. Its cellular morphological characteristics and architecture have been clarified, and pathologists and dermatopathologists have reached consensus on the diagnostic criteria for MFH. The regional rate of metastasis of MFH is estimated to be greater than 50%. [160] [226] [227] [228]
Recommendations for patient follow-up care include physical examination every 3 to 6 months postoperatively for 3 years and then annually for life. Particular attention to evaluation of surgical site,regional lymph node palpation, and a complete review of systems is appropriate.
CUTANEOUS ANGIOSARCOMA
Epidemiology and Pathogenesis
Cutaneous angiosarcoma (CAS) is a rare, highly malignant, potentially lethal tumor originating from the dermal vasculature endothelium. Elderly persons are most commonly affected, and there is a 2 : 1 male predominance. [230] [231] [232] [233] White persons are affected most often, but CAS has been reported among other persons as well. [234] [235] With the exception of CAS associated with lymphedema, the cause of CAS is uncertain. Cases have been associated with history of trauma, radiation, herpes zoster, fistula of chronic osteomyelitis, vinyl chloride and arsenic oxide exposure, and arteriovenous fistula sites in renal transplant recipients. [230] [231] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] UV light exposure does not seem to be an inciting factor. Only a minority of patients with CAS have temporally associated skin cancer. [232] [233] [246]
Clinical Manifestations
Principal clinical patterns include (1) CAS of the scalp and face, (2) CAS associated with chronic lymphedema most commonly following mastectomy (Stewart-Treves syndrome), and (3) radiation-associated angiosarcoma, which is the least common variant. [230] [236] CAS of the scalp and face usually manifests as a painless, rapidly proliferating growth of the subcutaneous tissue plane ( Fig. 74-13 ). CAS of this pattern occurs 50% of the time on the scalp and 30% of the time on the face or neck. [230] [231] [232] [233] [237] [240] [246] The tumor may be firm or spongy to palpation, the overlying skin surface smoothened because of tumor distention of the underlying structures.[247] An ill-defined area of dusky to violaceous erythema resembling a bruise or healing contusion often is present. The tumor infiltrates the surrounding tissues in a centrifugal and multifocal manner. As a result tumor involvement extends much farther than the clinical appearance of the margins. Multiple lesions may be separated by an isthmus of normal-appearing skin found at initial presentation if the primary tumor is more than 6 cm in diameter. Long-standing CAS may develop superimposed tumors and nodules. Ulceration and bleeding are not characteristic unless the CAS is larger than 10 cm in diameter. Misdiagnosis is common given the subtlety and nonspecific nature of the clinical findings. Initial differential diagnoses include cellulitis, nonspecific inflammatory changes, fungal infection, trauma, andhemangioma. [230] [231] [247] Reported atypical clinical scenarios include rosacea-like signs and symptoms, chronic edema of the eyelids, xanthelasma-like lesions, and even recurrent angioedema. [235] [247] [248]
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Figure 74-13 Cutaneous angiosarcoma involving the scalp. Ink highlights clinical margins of the lesion. |
Because the prognosis of advanced CAS is poor, every effort should be made for early diagnosis and treatment. Favorable outcomes are more likely when the tumor (1) has been present for less than 6 months, (2) is less than 5 cm in size, and (3) is amenable to combined surgery and radiation therapy (e.g., CAS of the nose).[246]
In 1948, Stewart and Treves described six patients with postmastectomy chronic lymphedema in whom CAS developed in the affected extremity.[249] The estimated risk among postmastectomy patients who survive more than 5 years is approximately 0.5%.[250] The time interval between mastectomy and recognition of angiosarcoma ranges from 1 to 30 years with a mean duration of 10 years.[251]Clinically, the ipsilateral, upper inner aspect of the arm is a frequent site of early involvement. Less frequent are lesions distal to the elbow or on the chest wall that most often resemble a bruise or blotchy erythema. These color changes initially are attributed to trauma; however, rapid growth and induration often lead to ulceration and hemorrhage. Other causes of chronic lymphedema have been associated with development of angiosarcoma, including congenital lymphedema and postsurgical, post-traumatic, and infectious etiological factors. [251] [252] [253] [254] [255] [256] [257]
Histopathology
Histologically, CAS has essentially three different cell growth patterns: (1) angiomatous or well differentiated with obvious vasoformative activity, (2) spindle cell with a range of differentiation, and (3) undifferentiated or highly anaplastic. [246] [258] A single tumor may have all three growth patterns. [237] [246] [247] [258] The well-differentiated variant (angiomatous) is characterized by recapitulation of atypical endothelial cells lining irregular vascular channels. These atypical vessels are located throughout the dermis, dissect through the collagen, and surround but do not invade the adnexal structures. With time there is infiltration into the subcutaneous fat, muscle, and fascia. This particular variant is often poorly recognized initially with frozen sections. The vessels do not contain red blood cells, because hemolysis of the red blood cells during processing makes microscopic examination difficult. The spindle cell tumor variant forms dense cellular bundles that penetrate the dermis and underlying tissue.[246]Vascular channels are not easily recognized. The more anaplastic or undifferentiated CAS characteristically contains large, basophilic, pleomorphic polyhedral cells arranged in solid sheets or cords. [246] [258] The dermis and subcutaneous structures often are occupied by tumor. Immunohistochemical stains for endothelium-related markers such as CD34 antigen, factor VIII–related antigen, or Ulex europaeus agglutinin I lectin binding may be helpful. Negative cytokeratin staining is helpful for differentiating CAS from carcinoma. Negative staining results for S-100 help to differentiate the tumor from melanoma. [247] [258]
Treatment
Computed tomography and magnetic resonance imaging have not been extremely helpful unless there has been marked bony invasion. [259] [260] Soft-tissue invasion of the tumor may be partially visualized, but the exact extent of the margins is poorly delineated because of the diffuse infiltrating nature of the tumor. Radiographic imaging is even more unreliable if the tumor is poorly appreciated microscopically. The peripheral margin of CAS may be partially assessed with random biopsies performed in a gridlike pattern circumferentially around the tumor.[246] Ideally, the biopsies should be full thickness of the skin and include the muscle and fascia if possible for complete assessment of the depth of the margin.
Traditional management of CAS has been wide local excision with a margin of 3 to 6 cm of normal-appearing skin. More recently, Mohs’ micrographic surgery with adjuvant radiation has been shown to produce favorable outcome. [246] [261] [262] [263] The Mohs’ technique combines the benefits of both fresh-tissue and fixed-tissue technique. Well-localized lesions are good candidates for the fresh-tissue technique, because a microscope can be used for identification of the tumor and excision of the entire lesion. After excision, zinc chloride fixative paste may be applied circumferentially around the surgical skin edges to stimulate an immune response around the operative site.[262] The final defect is repaired with a flap or skin graft.
For scalp lesions, orthovoltage or electron beam radiation with a curvilinear delivery system is administered over the entire scalp in a swimming cap distribution.[264] The region from the eyebrows to the occipital nuchal line is included, and both auricular-temporal sulci are encompassed. The curvilinear delivery system distributes the radiation equally to all parts of the scalp simultaneously. Thus are avoided overlapping and undertreatment of radiation sites that would otherwise accompany conventional flat-plate radiation when applied to curved surfaces, such as the scalp and forehead. Attention to these details of radiation treatment is essential, because CAS is resistant to most forms of surgical therapy, and chemotherapy has not been reported effective.
Recurrence of CAS of the scalp usually is the result of inadequate treatment of the primary tumor. [232] [246] Localized recurrence can be managed with radiation with a good response. [246] [261]Management of regional lymph node metastasis is surgical resection and adjuvant radiation. [232] [246] Systemic disease has a grave prognosis. Given the rarity of angiosarcoma, no single institution has enough experience to establish definitive treatment guidelines. Practical strategies include use of Mohs’ micrographic surgery combined with radiation, in the manner described earlier, for tumors less than 5 cm in diameter. For tumors larger than 5 cm, peripheral margin assessment (because of the multicentricity of the tumor spread), followed by orthovoltage or electron beam radiation should be considered.[246]
Prognosis and Follow-up Evaluation
The prognosis among patients with any form of angiosarcoma is uniformly poor. CAS of the scalp has an expected 5-year survival rate of less than 12%.[232] Histologic degree of differentiation, mitotic index, age, sex, location of primary lesion, and clinical appearance have no statistical bearing on survival. Tumor size has been found the only statistically significant indicator of prognosis. Lesions smaller than 5 cm correlate with improved survival at 5 years.[230] Another favorable indicator has been the presence of prominent lymphocytic infiltrate associated with the tumor. Local recurrence is common, and metastasis occurs hematogenously and through lymphatic vessels to the cervical lymph nodes, lungs, liver, and soft tissues. [232] [234] There have been rare reports of spontaneous regression of CAS of the scalp and face. [265] [266] Complete regression in one unreported case at the University of Wisconsin, Madison, was associated with frequent application of hot compresses.
Follow-up recommendations include frequent physical examinations with particular attention to the surgical site, contiguous structures, and palpation of lymph nodes. A complete review of systems, laboratory data, and radiologic studies should be performed as indicated. These individuals are best treated in a tertiary care center with a multidisciplinary approach.
BEST PRACTICES FOR PATIENT SCREENING AND TUMOR PREVENTION
A full-body skin examination is advised as part of an annual physical, especially for older adults or those with a family history of skin cancer. For those with a personal history of skin cancer, examination every 4 to 6 months is advised. For NMSC, special attention is paid to sites of previous skin cancer, changing or new skin lesions, and sun-exposed areas in general. Peripheral lymph nodes are palpated if there is a history of skin cancer with above average metastatic potential, such as SCC of the lip.
Prevention of NMSC mainly involves protection from the sun. Suntans should be avoided because they are a sign of, and response to, UV damage. The skin should be protected with a combination of clothing and SPF 30 sunblock effective against both UV-A and UV-B wavelengths. Hats should have a 360-degree brim to protect the neck and ears as well as the face. Sunglasses that block UV light should be worn to protect the eyes, eyelids, and periorbital skin. Outdoor daylight activities are best restricted to the early morning, late afternoon, and early evening. The peak sunlight hours of 10 am to 3 pm are best avoided by planning indoor activities during this period. The UV index is a daily rating of local UV intensity on a scale of 1 through 10. Although the scale can be useful in assessment of relative sun exposure risk, the best practice is always to follow the sun protection measures just outlined. Protect children, because sun-induced genetic damage begins in childhood, and most persons receive most of their lifelong sun exposure before adulthood. Retinoids, antioxidants, and COX-2 inhibitors may be beneficial for chemoprevention of NMSC.
WHEN AND HOW TO PERFORM BIOPSY
Unless logistical reasons preclude it, biopsy should be performed on all lesions suspected of being NMSC to establish the correct diagnosis, plan definitive therapy, and obtain prognostic information. The most important subjective symptoms can be summarized under the heading “change”. The changes may be appearance of a new growth or a change in the size, shape, color, sensation (itch or pain), crusting, or bleeding of a pre-existing lesion.
For most cases of NMSC, standard shave biopsy performed with a scalpel or razor blade is adequate. Well-differentiated SCC and keratoacanthoma can be difficult to diagnose unless the deepest portions are included in the biopsy specimen, because these often are the areas most likely to yield enough information for a diagnosis. Deep shave, punch, incisional, or excisional biopsy often is preferable to standard shave biopsy in these cases. For large or ill-defined tumors it is frequently helpful to perform multiple mapping biopsies to identify the most biologically aggressive features, define margins, and plan treatment.
Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
Abeloff: Abeloff's Clinical Oncology, 4th ed.
Copyright © 2008 Churchill Livingstone, An Imprint of Elsevier
REFERENCES
Genetics of Skin Cancer
Basal Cell Carcinoma and Squamous Cell Carcinoma
Keratoacanthoma
Nonmelanoma Skin Cancer in Immunocompromised Hosts
Sebaceous Gland Carcinoma
Merkel Cell Carcinoma
Dermatofibrosarcoma Protuberans
Angiosarcoma