Chapter 44 Common cutaneous malignancies
1. How are skin cancers classified?
Primary cutaneous cancers are classified on the basis of their cell of origin within the skin (Table 44-1). Skin cancers are most commonly derived from keratinocytes (e.g., squamous cell carcinoma) or melanocytes (e.g., malignant melanoma), which are normal components of the epidermis. Less commonly, they arise from other cells within the epidermis, dermis, or subcutis.
2. What are the most common nonmelanoma skin cancers (NMSCs)?
Basal cell carcinoma and squamous cell carcinoma. In the United States, over 1 million cases of NMSCs occur yearly, which makes these the most prevalent of all malignancies. Common nonmelanoma skin premalignancies include actinic keratosis, actinic cheilitis, and squamous cell carcinoma in situ (Bowen’s disease).
| MALIGNANCY | CELL OF ORIGIN |
|---|---|
| Premalignancies (in situ) | |
| Actinic keratosis | Keratinocyte |
| Squamous cell carcinoma in situ (Bowen’s disease) | Keratinocyte |
| Malignant melanoma in situ | Melanocyte |
| Lentigo maligna (Hutchinson’s freckle) | Melanocyte |
| Common Cutaneous Malignancies | |
| Basal cell carcinoma | Follicular keratinocyte origin (probable) |
| Squamous cell carcinoma | Epidermal keratinocyte |
| Keratoacanthoma | Follicular keratinocyte |
| Melanomas | |
| Malignant melanoma | Melanocyte |
| Lentigo maligna melanoma | Melanocyte |
| Uncommon Cutaneous Epithelial Malignancies | |
| Sweat gland carcinoma (numerous variants) | Apocrine or eccrine sweat gland/duct |
| Follicular carcinomas (several variants) | Follicular epithelial cells |
| Extramammary Paget’s disease | Modified keratinocytes (Toker cell) |
| Merkel cell carcinoma | Neuroendocrine cell |
| Cutaneous Mesenchymal Malignancies | |
| Atypical fibroxanthoma | Fibroblast |
| Dermatofibrosarcoma protuberans | CD34+ dermal dendrocyte |
| Fibrosarcoma | Fibroblast |
| Angiosarcoma | Endothelial cell |
| Kaposi’s sarcoma | Endothelial cell |
| Hemangiopericytoma | Pericyte |
| Malignant peripheral nerve sheath tumors | Schwann cells |
| Liposarcoma | Lipocyte |
Diepgen TL, Mahler V: The epidemiology of skin cancer, Br J Dermatol 146:1–6, 2002.
Nguyen TH, Ho DQ: Nonmelanoma skin cancer, Curr Treat Options Oncol 3:193–203, 2002.
3. What is the most important cause of NMSC?
The overwhelming majority of precancerous and cancerous skin lesions are caused by sun exposure. Several observations and epidemiologic studies support the role of ultraviolet light in the production of skin cancers:
1. Most NMSCs develop on skin chronically exposed to the sun, with 85% or more occurring on the head and neck.
2. The incidence of NMSC is lower in more polar latitudes (e.g., Minneapolis) than equatorial latitudes (e.g., Hawaii).
3. Epidemiologic studies clearly demonstrate that NMSCs are much more common in individuals with lighter skin than in individuals with darker skin.
5. What special populations are at increased risk of NMSC?
• Organ transplant patients: NMSC is the most common malignancy in solid organ transplant recipients. Increased rates of NMSC are seen on average 8 to 10 years after transplantation, and the development of skin cancer in these patients appears to be linked to the duration and degree of immunosuppression required to prevent transplant rejection. The ratio of squamous cell carcinomas (SCCs) to basal cell carcinomas (BCCs) is higher in transplant patients, a reversal of the normal ratio seen in the general population.
• Human immunodeficiency virus (HIV) patients: NMSC is the most common nonacquired immune deficiency syndrome (AIDS)–defining cancer seen in HIV-positive patients. HIV-positive patients appear to maintain a normal ratio of BCCs to SCCs, but are two- to sevenfold more likely to develop NMSC than the general population.
Honda K: HIV and skin cancer, Dermatol Clin 24:521–530, 2006.
6. How are NMSCs diagnosed?
A cutaneous malignancy should always be considered in any patient who reports a new lesion on the skin, particularly in sun-exposed skin. Currently, the diagnosis is established by shave, punch, incisional, or excisional biopsy, with the choice of biopsy technique depending on the size and location of the suspected malignancy. Current research is focused on developing non-invasive methods of diagnosing NMSC by using techniques such as specialized types of ultrasonography and microscopy. However, these methods are currently in development and have not replaced skin biopsy with histologic examination as the gold standard for diagnosis.
7. How frequently do NMSCs occur?
The exact incidence of NMSCs is unknown, because they are not routinely entered into tumor registries. It is estimated that 1.3 million new cases of NMSC occur each year in the United States, making them by far the most common cancers in this country. The annual cost to Medicare for the management and treatment of NMSCs is 426 million dollars. The lifetime risk of developing NMSC is 1 in 5. Statistically, if a patient develops one NMSC, the risk of another new lesion in 5 years is 30% to 50%.
8. How can NMSCs be prevented?
The easy answer is to avoid sun exposure, particularly during childhood. It has been estimated that 25% of the total lifetime dose of solar radiation is received before the age of 18. Sun protection techniques for children and adults alike include avoidance of the midday sun, liberal use of sunscreens, and wearing of protective clothing. Tans, whether received from natural sunlight or tanning booths, represent damaged skin that is more likely to develop NMSC. It is important for health care providers to nurture the idea that pale skin is more attractive than tanned skin.
9. What factors should you consider in treating NMSC?
The method of destruction depends upon the type and subtype of malignancy, degree of invasion, location, health of the patient, potential for recurrence or metastasis, and availability of various methods (Table 44-2).
Table 44-2. Management of Cutaneous Premalignancies and Malignancies
| LESION | TREATMENT |
|---|---|
| Actinic keratosis | Cryosurgery Curettage Fluorouracil, topical Chemical peel Dermabrasion Imiquimod Photodynamic therapy |
| Actinic cheilitis | Cryosurgery Electrosurgery Chemical peel Laser ablation Lip shave and advancement Imiquimod |
| Basal cell carcinoma (BCC) | |
| Superficial spreading | Cryosurgery Curettage ± electrosurgery Laser ablation Imiquimod Photodynamic therapy |
| Nodular BCC | Cryosurgery Curettage and electrosurgery Excision Radiation therapy Photodynamic therapy Mohs surgery |
| Morpheaform, aggressive BCC, or recurrent BCC | Excision Mohs surgery |
| Nonresectable BCC | Cryosurgery Radiation therapy Chemotherapy |
| Keratoacanthoma | Deep shave plus curettage Curettage plus electrosurgery Intralesional 5-fluorouracil Cryosurgery Excision Mohs surgery |
| SCC in situ (Bowen’s disease) | Curettage ± electrosurgery Fluorouracil, topical Imiquimod Cryosurgery Laser Excision Photodynamic therapy |
| Squamous cell carcinoma (SCC) | |
| Small, nonaggressive | Curettage plus electrosurgery Cryosurgery Excision |
| Large or aggressive | Excision Mohs surgery Radiation therapy Lymph node dissection |
| Nonresectable SCC | Radiation Chemotherapy |
Neville J, Welch E, Leffell D: Management of nonmelanoma skin cancer in 2007, Nat Clin Pract Oncol 4:462–469, 2007.
10. What are basal cell carcinomas?
Basal cell carcinomas (BCCs) are the most common cutaneous malignancy and outnumber squamous cell carcinomas by a 4:1 ratio. They are low-grade malignancies of the skin and are microscopically composed of basaloid cells with characteristic peripheral palisading of the nuclei. These basaloid tumor islands usually demonstrate connections to the overlying epidermis or follicular epithelium. BCCs are locally invasive tumors that rarely metastasize. The origin of these common tumors has been debated. The theory with the greatest supporting evidence is that BCCs originate from the follicular epithelium, specifically from the stem cells of the outer root sheath.
11. What is the molecular basis for the development of sporadic basal cell carcinoma?
The best evidence suggests that the majority of sporadic BCCs are the result of ultraviolet (UV)-induced alterations in the hedgehog signaling pathway. The most common mutation in sporadic BCCs (90%) occurs in the tumor suppressor gene PTCH, found at locus 9q22, that encodes the Ptch1 protein. This protein is a receptor for a secreted protein ligand called sonic hedgehog (Shh), which is important in signaling processes that control cell growth and fate. Another 10% of sporadic BCCs have activating mutations in the smoothened protein (SMO), another participant in the hedgehog signaling pathway. Investigation into this pathway has led to the development of a small molecule inhibitor of the hedgehog pathway called GDC-0449 that shows promise in the treatment of locally advanced and metastatic BCC.
Epstein EH: Basal cell carcinomas: attack of the hedgehog, Nat Rev Cancer 8(10):743–754, 2008.
12. Describe the clinical and histologic appearance of basal cell carcinomas.
BCCs may have more than one clinical or histologic appearance. The most common presentation is as nodular BCCs, which are typically slow-growing lesions with a smooth or pebbly surface. They characteristically appear translucent or pearly and often demonstrate dilated vessels (Fig. 44-1A). They can gradually break down, bleed, and form ulcers (noduloulcerative BCC, Fig. 44-1B). Superficial spreading BCC are thin lesions that demonstrate a horizontal growth pattern. They present as erythematous, minimally indurated, slow-growing plaques with variable scale that are most commonly located on the trunk (Fig. 44-1C). They can be confused with tinea corporis, nummular dermatitis, or other NMSCs such as Bowen’s disease.
Basal cell carcinomas can also be completely or focally pigmented and mistaken for malignant melanoma. A rare variant of BCC looks like a large skin tag or fibroma. This variant is usually found on the trunk of older men and is called a Pinkus tumor or fibroepithelioma of Pinkus.
13. What is nevoid basal cell carcinoma syndrome?
Nevoid basal cell carcinoma syndrome, also called Gorlin’s syndrome, is an autosomal dominant inherited disorder characterized by a number of different germline mutations of PTCH, the same gene that is found to be mutated in most sporadic basal cell carcinomas. It is characterized by the early onset and continued development of numerous basal cell carcinomas (Fig. 44-2), in addition to other tumors and developmental abnormalities including keratocysts of the jaw, palmar and plantar pits, skeletal abnormalities, medulloblastoma, and calcification of the falx cerebri.
High A, Zedan W: Basal cell nevus syndrome, Curr Opin Oncol 17:160–166, 2005.
14. What do typical squamous cell carcinomas look like clinically?
Squamous cell carcinomas (SCCs) may resemble basal cell carcinomas, actinic keratoses, or warts, but often the initial appearance is that of an ill-defined, red lesion with a rough surface (Fig. 44-3A). SCCs are more likely to demonstrate overlying scale than are BCCs. At times, the scale may project above the skin surface, producing a cutaneous horn. Larger lesions may break down and ulcerate. Verrucous carcinomas are a variant of SCC that look like warts and are often misdiagnosed (Fig. 44-3B). Like warts, they often occur on hands and feet but can also appear on the anogenital epithelium and oral mucosa. These tumors are slow growing and rarely metastasize, but they can be extremely locally aggressive.
15. What is the biologic behavior of cutaneous squamous cell carcinoma?
SCCs are more aggressive than BCCs and are more likely to metastasize. SCCs are currently estimated to metastasize at an overall rate of 2% to 6%. Certain sites have higher rates of metastasis—SCC arising from the lower lip metastasize in 10% to 14% of cases, and those arising from the ear metastasize in 11% of cases. Tumors arising in burn scars, draining sinuses, and modified epithelium (e.g., glans penis, vulva) and in immunocompromised patients are also more likely to metastasize. Other factors associated with a higher metastatic rate are increased depth of invasion, perineural invasion and recurrence, with recurrent tumors estimated to metastasize in about 33% of cases. Multiple genetic mutations are associated with the development of cutaneous SCCs, in particular 90% of these tumors have UV-induced mutations in the p53 tumor suppressor gene.
Rudolph R, Zelac DE: Squamous cell carcinoma of the skin, Plast Reconstr Surg 114:82e–94e, 2004.
16. What are keratoacanthomas?
Keratoacanthomas are relatively common epidermal tumors that almost invariably appear on sun-exposed skin. There is controversy as to whether these lesions should be considered as benign or malignant. Microscopically, the tumor is composed of well-differentiated but cytologically atypical keratinocytes that are difficult for pathologists to separate from squamous cell carcinoma. Clinically, however, keratoacanthomas can behave in a benign fashion and spontaneously regress over a period of weeks or months if left untreated. Clouding the issue is the fact that approximately 10% of lesions that clinically resemble keratoacanthomas develop into invasive SCC. There are also reports of keratoacanthomas that have metastasized. It is not clear whether such lesions are SCC from their inception, keratoacanthomas that have developed into SCC, or more aggressive keratoacanthomas. Currently, the standard of care is to treat keratoacanthomas as well-differentiated squamous cell carcinomas, and many pathologists will describe their distinctive histology as “squamous cell carcinoma, keratoacanthoma type.” Solitary keratoacanthomas are the most common variant, but the tumor is also associated with specific genetic syndromes. The site of origin of keratoacanthomas is uncertain, but experimental and epidemiologic studies implicate follicular epithelium.
Karaa A: Keratoacanthoma: a tumor in search of a classification, Int J Dermatol 46:671–678, 2007.
17. How do keratoacanthomas present clinically?
Keratoacanthomas are usually easy to recognize. They appear suddenly, typically on sun-exposed skin, as skin-colored domes that develop a central keratin-filled plug (Fig. 44-4). They grow quickly, often over the course of weeks, and usually reach a size of 1 to 2 cm before regressing. Rarely, they may attain a size of 5 cm or more (giant keratoacanthomas).
18. What is Bowen’s disease?
Bowen’s disease is an older term for squamous cell carcinoma in situ (Fig. 44-5A). Clinically, SCC in situ presents as persistent, erythematous, slightly indurated plaques with variable scale. It may resemble superficial spreading BCC, Paget’s disease, or various inflammatory skin conditions. SCC in situ occurring on the male genitalia has also been described under the name erythroplasia of Queyrat and may be associated with human papillomavirus infection (Fig. 44-5B). Microscopically, squamous cell carcinoma in situ demonstrates full-thickness cytologic atypia of the keratinocytes without invasion through the basement membrane.
19. What is an actinic keratosis?
Actinic keratoses (solar keratoses) are sun-induced precancerous lesions of the skin. They are very common in patients with light skin color and significant sun exposure. Microscopically, actinic keratoses are characterized by a proliferation of cytologically atypical keratinocytes that bud off or replace the bottom of the epidermis. The atypical cells do not involve the full thickness of the epidermis. A definitive prospective study has never been done, but epidemiologic and retrospective studies suggest that 6% to 20% of actinic keratoses progress into squamous cell carcinomas if left untreated.
Figure 44-4. Keratoacanthoma demonstrating a crateriform nodule with central keratin plug.
(Courtesy of James E. Fitzpatrick, MD.)
20. What do actinic keratoses look like?
Actinic keratoses initially appear as tiny, palpable bumps on normal sun-exposed skin that gradually enlarge and become red and scaly (Fig. 44-6). The overlying scale may be extensive to the point that markedly exophytic cutaneous horns are produced. Less common variants include atrophic and pigmented actinic keratoses. Actinic cheilitis is a term used for actinic keratoses that present on the sun-exposed vermilion lip. Many patients who complain of chronic dry lower lips actually have extensive actinic cheilitis.
21. How should premalignant lesions, such as actinic keratoses and actinic cheilitis, be treated?
We should probably first ask, “Why should premalignant lesions be treated?” While a small percentage of actinic keratoses regress spontaneously, up to 20% develop into squamous cell carcinoma. Treating actinic keratosis can therefore prevent the development of SCC. Additionally, small SCCs are difficult to separate from actinic keratoses on clinical exam. The smallest SCCs are often picked up when a suspected actinic lesion does not respond to treatment or a lesion appears in a treated area.
