Section M: Skin Cancer

PATIENT STORY

A 70-year-old man presented with a small ulcer on the nasal tip that he noticed while washing his face. The lesion bled easily, and on occasion the bleeding was hard to stop (Figure 177-1). He noticed it first about 6 months ago, and at times it seemed to almost heal. A photograph was taken to document the location of the lesion. Histology from a shave biopsy confirmed an infiltrative basal cell carcinoma (BCC), and he was referred for Mohs microsurgery for excellent margin control.

INTRODUCTION

Basal cell carcinoma is the most common cancer in humans. Usually found on the head and neck, it tends to grow slowly and almost never kills or metastasizes when treated in a timely fashion. However, the treatment necessary is often surgical, and this may cause scarring and changes in function.

EPIDEMIOLOGY

• BCC is the most common skin cancer, with more than 2 million cases diagnosed annually.¹

• Incidence increases with age, related to cumulative sun exposure.

• Nodular BCCs—Most common type (70%) (Figures 177-2, 177-3, 177-4).

• Superficial BCCs—Next most common type (Figures 177-5 and 177-6).

• Sclerosing (or morpheaform) BCCs—The least common type (Figures 177-1, 177-7 and 177-8).

Other clinical variants including pigmented, polypoid, giant, keloidal, linear, and fibroepithelioma of Pinkus have been recognized, but are less common to very rare.²

ETIOLOGY AND PATHOPHYSIOLOGY

• BCCs spread locally and very rarely metastasize.

• Basal cell nevus syndrome, also known as Gorlin syndrome, is a rare autosomal dominant condition in which affected individuals have multiple BCCs that may clinically mimic nevi (Figure 177-9).

RISK FACTORS

• Advanced age.

• Cumulative sun exposure.

• Radiation exposure.

• Latitude.

• Immunosuppression.

• Genetic predisposition.

• Family history.

• Skin type.³

DIAGNOSIS

CLINICAL FEATURES

Common clinical features of the three most common morphologic types are listed below.

Nodular BCC

• Raised pearly pink to white papule, often with telangiectasias.

• Smooth translucent surface with loss of the normal pore pattern (Figures 177-2, 177-3, 177-4).

• May be moderately to deeply pigmented (Figures 177-10, 177-11, 177-12).

• May ulcerate (Figures 177-1, 177-3, 177-6, 177-13, 177-14, 177-15, 177-16) and leave a bloody crust.

• Micronodular types grow deeper and are more aggressive.

Superficial BCC

• Red or pink patches to plaques often with mild scale and a thready border (slightly raised and pearly) (see Figure 177-5).

• More commonly on the trunk and upper extremities than the face.

Sclerosing (morpheaform) and infiltrating (infiltrative) BCCs

• Ivory or colorless, flat or atrophic, indurated, may resemble scars (see Figures 177-7 and 177-8).

• Called morpheaform because of their resemblance to localized scleroderma (morphea).

• The border is not well defined and tumor may extend far beyond the clinical border (Figure 177-17).

• Infiltrating BCCs are also aggressive but may not appear morpheaform.

• These BCCs are the most dangerous and have the worst prognosis.

TYPICAL DISTRIBUTION

Most appear on face, ears, and head, with some found on the trunk and upper extremities (especially the superficial type).

Some may occur in relatively sun-protected areas.

Recently lesions on the ears have been associated with a more aggressive behavior (Figure 177-18).⁴

DERMOSCOPY

Common dermoscopic characteristics of BCCs (Figures 177-19 and 177-20) include:

• Arborizing "treelike" telangiectasias.

• Leaf-like areas.

• Brown dots in focus.

• Shiny white structures (see Chapter 181, Advanced Dermoscopy of Skin Cancer).

BIOPSY

• A shave biopsy is adequate to diagnose a nodular BCC or a superficial BCC.

• A deeper scoop shave or punch biopsy is preferred if a sclerosing BCC is suspected.

• In some instances, excision at the time of definitive treatment reveals a different morphologic type in deeper tissue.⁵

DIFFERENTIAL DIAGNOSIS

Nodular BCC

• Intradermal (dermal) nevi may look very similar to nodular BCCs with telangiectasias and smooth pearly borders (Figure 177-21). A history of stable size and lack of ulceration may be helpful in distinguishing them from a nodular BCC. A simple shave biopsy is diagnostic and produces a good cosmetic result. Excisional biopsy is usually unnecessary. It is remarkable how similar Figure 177-21 may appear to a small nodular BCC (see Chapter 168, Benign Nevi).

• Sebaceous hyperplasia is a benign adnexal tumor common on the face in adults and usually presents with multiple lesions (Figure 177-22). These are characterized as small waxy yellow to pink papules with telangiectasias. Dermoscopy may show vessels that radiate out from the center like spokes on a wheel and a central dell (see Chapter 165, Sebaceous Hyperplasia).

• Fibrous papule of the face is a benign condition with small papules that can be firm, vascular, and smooth.

• Trichoepitheliomas/trichoblastomas/trichilemmomas are benign tumors of the midface. They may lack vascular markings. These are best diagnosed with a shave biopsy, but trichoepitheliomas can even mimic a BCC on histology.

• Keratoacanthoma is a type of squamous cell carcinoma that is raised, nodular, and may be pearly with telangiectasias. A central keratin-filled crater or horn may help to distinguish this from a BCC (see Chapter 174, Keratoacanthoma).

Superficial BCC

• Actinic keratoses are precancers that are generally flat, pink, and scaly. They lack the pearly or thready border of the superficial BCC (see Chapter 173, Actinic Keratosis and Bowen Disease).

• Bowen disease is a squamous cell carcinoma in situ that appears like a larger and thicker actinic keratosis. It lacks the pearly and thready border of the superficial BCC (see Chapter 173, Actinic Keratosis and Bowen Disease).

• Nummular eczema can usually be distinguished by its multiple coinlike shapes, transient nature, and rapid response to potent topical steroids. These lesions are pruritic, and most patients will have other signs and symptoms of atopy (see Chapter 151, Atopic Dermatitis).

Sclerosing (morpheaform) and infiltrating (infiltrative) BCC

• Scars may look like a sclerosing BCC. Ask about previous trauma to the area. If the so-called scar is flat, shiny, and enlarging, a biopsy may be needed to rule out a sclerosing BCC.

• Infiltrating BCCs may appear as nonhealing ulcers with bloody crusts. Any nonhealing ulcer on the face or other sun-exposed areas should be biopsied to rule out skin cancer.

MANAGEMENT

• Mohs micrographic surgery (3 studies, n = 2660) is the gold standard but is not needed for all BCCs. Recurrence rate is 0.8% to 1.1% (see Figure 177-17B). Mohs micrographic surgery (pioneered by Dr. Frederick Mohs) involves surgical removal of tumors near the clinical margin with immediate histologic processing in sequential horizontal layers preserving a continuous peripheral margin that is mapped to the clinical lesion. Gradually larger surgical margins are taken until all margins are clear (see Figure 177-17). This is the treatment of choice for large and recurrent BCCs as well as those with poorly defined clinical margins or in areas of significant cosmetic or functional importance such as the face.⁶ SORⒶ

• A clinical photograph locating the lesion at the time of biopsy eliminates wrong-site surgery, which is a risk when the surgeon performing the definitive procedure is different from the physician performing the biopsy. A study of 271 surgical sites referred to a Mohs clinic showed that the physician and patient incorrectly identified the biopsy site 4.4% of the time when a clinical photograph was not available.⁷

• Surgical excision of small (<2 cm) nodular and superficial BCCs results in clearance rates of 85% with 3-mm margins and 95% with 5-mm margins.⁸ However, with morpheaform BCCs, the cure rate drops to 66% with 3-mm margins, 82% with 4- to 5-mm margins, and >95% with 13- to 15-mm margins, emphasizing the importance of a biopsy prior to definitive treatment.⁸ SORⒶ

• Cryosurgery (4 studies, n = 796)—Recurrence rate was 3.0% to 4.3%. Cumulative 5-year recurrence rate (3 studies) ranged from 0% to 16.5%.⁶ SORⒶ Recommended freeze times are 30 to 60 seconds with a 5-mm halo. This can be divided up into two 30-second freezes with a thaw in between. For such long freeze times, most patients will prefer a local anesthetic (Figure 177-23). SORⒸ

• Curettage and desiccation (6 studies, n = 4212): Recurrence rate ranged from 4.3% to 18.1%; cumulative 5-year rate ranged from 5.7% to 18.8%. Three cycles of curettage and desiccation can produce higher cure rates than one cycle (Figure 177-24).⁶ SORⒶ

• Imiquimod is approved by the U.S. Food and Drug Administration (FDA) for the treatment of superficial BCCs less than 2 cm in diameter.⁹ SORⒷ Confirm diagnosis with biopsy and use when surgical methods are contraindicated. A recent small study combining cryotherapy with imiquimod improved the recurrence rate.¹⁰

• Vismodegib and sonidegib are an FDA-approved targeted chemotherapies for the treatment of metastatic, locally advanced, or nonresectable BCCs that cannot be treated with radiation. It targets the smoothened pathway, which is mutated in basal cell nevus syndrome and altered in most BCCs.¹¹ SORⒷ These hedgehog inhibitors may also be used to treat basal cell nevus syndrome (see Figure 177-9).

PREVENTION AND SCREENING

• All skin cancer prevention starts with sun protection.

• While it is known that UV causes BCCs and sunscreen blocks UV, high-quality studies showing real-world use of sunscreen preventing BCCs are lacking.¹²

• Most experts recommend SPF 30 or greater sunscreen applied and reapplied every 2 hours. SORⒷ

• Sun protection should include sun avoidance, especially during peak hours of UV transmission, and protective clothing. SORⒷ

• The U.S. Preventive Services Task Force has found insufficient evidence to recommend regular screening for any skin cancer in the general population.¹³

• Most experts believe that persons at high risk for BCC (including previous personal history of BCC, family history, and fair skin types with significant sun exposure) should be screened regularly for skin cancer by a physician trained in screening. SORⒸ

• Evidence for the value of self-screening is lacking, but persons at high risk for skin cancer should also be encouraged to observe their own skin and to come in for evaluation if they see any suspicious changes or growths. SORⒸ

• Nicotinamide 500 mg twice daily for 1 year reduced the incidence of BCCs by 20% compared to placebo in patients with a history of at least 2 nonmelanoma skin cancers in the previous 2 years.¹⁴

PROGNOSIS

The prognosis for basal cell carcinoma is generally excellent, with high cure rates with surgery and destructive modalities. The rate of metastasis has been estimated between 0.0028% and 0.55%. Large lesions on the face or lesions locally invading to deeper tissues have a poorer prognosis.¹⁵

FOLLOW-UP

Patients should be seen at least yearly after the diagnosis and treatment of a BCC. The 3-year risk of BCC recurrence after having a single BCC is 44%.¹⁶

PATIENT EDUCATION

Patients should practice skin cancer prevention by sun-protective behaviors such as avoiding peak sun, covering up, and using sunscreen.

REFERENCES

PATIENT STORY

A 75-year-old man presents with a 2.6-cm enlarging inflamed tumor on the right cheek (Figure 178-1). He has a history of many actinic keratoses and grew up with significant sun exposure. Scoop shave biopsy is consistent with squamous cell carcinoma (SCC), and he undergoes Mohs surgery. Figure 178-2 shows a shave biopsy of a smaller lesion on the scalp. Following excision, he follows up regularly for skin exams in order to detect any skin cancers or recurrence at an early stage.

INTRODUCTION

Cutaneous SCC is the second most common cancer in humans and arises most often as a result of cumulative sun damage. Incidence of cutaneous SCC (cSCC) in U.S. Medicare patients has been shown to have reached an incidence equal to that of basal cell carcinoma.¹ Although the mortality is declining, incidence is increasing in all populations, making this cancer a common and significant burden on patients.

EPIDEMIOLOGY

• Mortality from SCC has been observed as 0.29 per 100,000 population.²

• Metastasis from SCC occurs in 2% to 9.9% of cases.³

• The incidence is increasing in all age groups and populations at a rate of 3% to 10%.³

• In the United States, at least 200,000 to 400,000 new cases of cutaneous SCC are expected per year. Disease-related death occurs in more than 3000 people yearly.^4,5

• SCC is the second most common skin cancer and accounts for at least 25% of nonmelanoma skin cancers.⁴

• SCC is the most common skin cancer in Hispanic, black, and Asian patients.⁶

PATHOPHYSIOLOGY

SCC is a malignant tumor of keratinocytes. Most SCCs arise from precursor lesions called actinic keratoses. SCCs usually spread by local extension but are capable of regional lymph node metastasis and distant metastasis. Human papillomavirus (HPV)-related lesions may be found on the penis, labia, and perianal mucosa, or in the periungual region or elsewhere associated with immunosuppression.⁷

SCCs that metastasize most often start on mucosal surfaces and sites of chronic inflammation.

RISK FACTORS

• Long-term cumulative UV exposure is the greatest risk factor.

• Childhood sunburns.

• Occupational exposure.

• Other UV exposure including psoralen and UVA (PUVA) therapy and tanning beds.

• Smoking.

• HPV exposure.

• Exposure to ionizing radiation.

• Arsenic exposure.

• Fair skin.

• Age older than 60 years.

• Male gender.

• Living at lower latitude and higher altitude.

• Nonhealing ulcers.

• Chronic or severe immunosuppression, including posttransplant⁸ immunosuppression, HIV, and long-term steroid use.

• Genetic syndromes, including Muir Torre, xeroderma pigmentosum, dystrophic epidermolysis bullosa, epidermodysplasia verruciformis, and oculocutaneous albinism.⁴

DIAGNOSIS

• Diagnosis is best made by shave, punch, or incisional biopsy.

CLINICAL FEATURES

SCC frequently presents as a rough keratotic papule, plaque, or tumor on chronically sun-damaged skin. SCC can partially ulcerate or present as a nonhealing ulcer.

Less common types of SCC:

• Marjolin ulcer—SCC of the extremities found in chronic skin ulcers or burn scars. This is a more common risk in darker pigmented individuals (Figure 178-3).

• Erythroplasia of Queyrat—SCC in situ on the penis or vulva related to HPV infection (Figure 178-4). This can progress to invasive SCC of the penis (Figure 178-5).

TYPICAL DISTRIBUTION

SCC is found in all sun-exposed areas and on mucous membranes. The most common sites are:

• Face (Figures 178-6 and 178-7).

• Lower lip (Figures 178-8 and 178-9).

• Ears (Figure 178-10).

• Scalp (Figures 178-1 and 178-11).

• Extremities—arm—(Figures 178-12 and 178-13).

• Hands (Figure 178-14).

• Fingers (Figure 178-15).

• Mucous membranes (Figure 178-16) (see Chapter 43, Aphthous Ulcer).

DERMOSCOPY

There are many dermoscopic features that are helpful to diagnose SCC. See Chapters 111, Dermoscopy, and 181, Advanced Dermoscopy of Skin Cancer, for details on how dermoscopy helps make the diagnosis of SCC.

BIOPSY

• Deep shave biopsy is adequate to make the diagnosis of most SCCs.

• Punch biopsy or incisional biopsy is an alternative and useful for pigmented lesions or lesions with an unclear depth of involvement.

FACTORS AFFECTING METASTATIC POTENTIAL OF CUTANEOUS SQUAMOUS CELL CARCINOMA

Site

Tumor location influences prognosis: sites are listed in order of increasing metastatic potential.^{2 9}

1. SCC arising at sun-exposed sites excluding lip and ear.

2. SCC of the lip (see Figures 178-8 and 178-9).

3. SCC of the ear (see Figure 178-10).

4. Tumors arising in non–sun-exposed sites (e.g., perineum, sacrum, sole of foot) (see Figures 178-4, 178-5, and 178-16).

5. SCC arising in areas of radiation or thermal injury, chronic draining sinuses, chronic ulcers, chronic inflammation, or Bowen disease, such as the SCC arising in a burn site (see Figure 178-3).

Size: diameter

Tumors larger than 2 cm in diameter double the risk of recurrence and triple the risk of metastasis compared with smaller tumors⁶ (Figure 178-17).

Size: depth

Depth is the most important factor associated with recurrence and metastasis. Tumors greater than 2 mm thick have 10 times the risk of recurrence. Tumors that extend beyond the subcutaneous fat recur and metastasize in 28% and 27% of cases, respectively.¹⁰

Histologic differentiation

Poorly differentiated tumors have a worse prognosis, with more than double the local recurrence rate and triple the metastatic rate of better-differentiated SCC.¹¹ Tumors with significant perineural involvement have very high rates of local recurrence (47%) and metastasis (35%) with standard excision alone. Mohs microsurgery and radiation reduce this risk.¹⁰

Host immunosuppression

Tumors arising in patients who are immunosuppressed have a poorer prognosis. Host cellular immune response may be important in determining both the local invasiveness of SCC and the host's response to metastases. Figures 178-16, 178-17, and 178-18 are SCCs in patients who are HIV-positive.⁹

Previous treatment and treatment modality

The risk of local recurrence depends on the treatment modality. Locally recurrent disease itself is a risk factor for metastatic disease. Local recurrence rates are considerably less with Mohs micrographic surgery than with any other treatment modality.

DIFFERENTIAL DIAGNOSIS

• Actinic keratoses are precancers on sun-exposed areas, which can progress to SCC (see Chapter 173, Actinic Keratosis and Bowen Disease).

• Bowen disease is SCC in situ before it invades the basement membrane (see Chapter 173, Actinic Keratosis and Bowen Disease).

• Keratoacanthoma is a subtype of SCC that may resolve spontaneously but is generally treated as a low-risk SCC. Figure 178-19 shows an invasive SCC resembling a lower-risk keratoacanthoma subtype (see Chapter 174, Keratoacanthoma).

• Basal cell carcinoma (BCC) cannot always be distinguished from SCC by clinical appearance alone. Figure 178-19 could be a BCC by appearance but was proven to be SCC by biopsy (see Chapter 177, Basal Cell Carcinoma).

• Merkel cell carcinoma (neuroendocrine carcinoma of the skin) is a rare aggressive malignancy. It is most commonly seen on the heads of elderly fair-skinned patients. It resembles an SCC, and the diagnosis is made by biopsy (Figure 178-20).

• Nummular eczema can usually be distinguished by the multiple coin-like shapes, transient nature, and pruritus (Chapter 151, Atopic Dermatitis).

MANAGEMENT

Table 178-1 provides a summary of treatment options.

Surgical resection for definitive treatment should include margins as given below:

• 4-mm margin—Adequate for well-defined, low-risk tumors less than 2 cm in diameter; such margins are expected to remove the primary tumor mass completely in 95% of cases.¹² SORⒶ

• 6-mm margin—Recommended for larger tumors, high-risk tumors, tumors extending into the subcutaneous tissue, and those in high-risk locations (ear, lip, scalp, eyelids, nose).¹²

• The tumor should be cut out to the deep subcutaneous fat and submitted for pathologic confirmation of complete excision.

MOHS MICROGRAPHIC SURGERY

Frederic Mohs pioneered the technique of excising skin cancers and immediately assessing the continuous margin via mapped en face sectioning—which involves sectioning the tumor like a bagel rather than standard breadboard sectioning, which cuts the tumor like a loaf of bread. Sequential mapped stages are removed until all margins are clear. Mohs surgery offers superior cure rates compared with standard excision or destructive techniques, spares uninvolved tissue, and allows for reconstruction at the time of excision.

Mohs surgery is specifically indicated for lesions larger than 2 cm, lesions with ill-defined clinical borders, lesions with aggressive histologic subtypes, recurrent lesions, and lesions on or near the eye, nose, ear, mouth, hair-bearing scalp, or chronic ulcers. Patients with chronic immunosuppression or genetic tumor syndromes may also benefit from Mohs surgery compared to standard excision.¹²

CURETTAGE AND ELECTRODESICCATION

Excellent cure rates have been reported in several case series, and small (<1 cm), well-differentiated, primary, slow-growing tumors arising on sun-exposed sites can be removed by experienced physicians with electrodesiccation and curettage (EDC).⁵ EDC should be avoided on terminal hair-bearing areas such as scalp, pubis, axilla, and bearded area in men because of the risk of deep follicular invasion.

The experienced clinician undertaking EDC can detect tumor tissue by its soft consistency, which allows detection of clinically invisible tumor extension and ensures adequate treatment. Electrodesiccation is applied to the curetted wound, and the curettage-cautery cycle is then repeated twice.¹²

CRYOSURGERY

Good short-term cure rates have been reported for small, histologically confirmed SCC treated by cryosurgery in experienced hands. Prior biopsy is necessary to establish the diagnosis histologically. There is great variability in the use of liquid nitrogen for cryotherapy. Start by drawing a 4- to 6-mm margin around the SCC and then apply two 30-second freezes with a thaw in between. It is best to use local anesthesia with lidocaine first, because these long freeze times are quite painful. SORⒸ

Cryosurgery and curettage and electrodesiccation are not appropriate for locally recurrent disease but may be useful in patients presenting with multiple or eruptive low-grade SCCs who may have a number of tumors effectively treated at a single visit.

RADIOTHERAPY

Primary treatment with radiation therapy alone offers short- and long-term cure rates for SCC that are comparable with other treatments, but radiation therapy is usually reserved for special situations where surgical therapies are contraindicated. Certain very advanced tumors, where surgical morbidity would be unacceptably high, may also be best treated by radiotherapy. SORⒸ

PREVENTION AND SCREENING

• All skin cancer prevention starts with sun protection.

• There is good evidence from multiple randomized controlled trials (RCTs) that daily sunscreen use decreases the risk of developing sun-related SCCs.^13,14 SORⒶ In the longest RCT, sunscreen was applied regularly to the head, neck, hands, and forearms for 4.5 years with a decrease in SCC during the study period.¹³ At the end of the trial, the participants were followed for another 8 years and SCC tumor rates decreased by almost 40% during the follow-up period.¹⁴

• Sun protection should include sun avoidance, especially during peak hours of UV transmission; protective clothing; and sunscreen use.

• Indoor tanning is not safe and should be avoided.

• The U.S. Preventive Services Task Force has not found sufficient evidence to recommend regular screening for any skin cancer in the general population.¹⁵

• Most experts believe that persons at high risk for SCC (including previous personal history of any skin cancer, high-risk family history, high-risk skin types with significant sun exposure, or immunosuppression after an organ transplant) should be screened regularly for skin cancer by a physician trained in such screening.

• Evidence for the value of self-screening is lacking, but persons at high risk for skin cancer should also be encouraged to observe their own skin and to come in for evaluation if they see any suspicious changes or growths.

• A recent RCT of nicotinamide, 500 mg BID, showed a 30% reduction in the development of cutaneous SCC and a 23% reduction in nonmelanoma skin cancer over a 12-month period.¹⁶

PROGNOSIS

Prognosis is excellent for small, thin lesions less than 2 mm thick that are removed with clear margins in immunocompetent patients. In these patients, the risk of metastasis is near zero. The risk of metastasis increases markedly with thicker lesions, and lesions with thicknesses greater than 6 mm metastasize to the regional nodes 16% of the time.¹¹

FOLLOW-UP

Patients should be seen at least yearly for skin examinations after the diagnosis and treatment of an SCC. The 3-year risk of recurrence of a new SCC after having a single SCC is 18%.¹⁷

PATIENT EDUCATION

Includes use of a hat and sunscreen on a regular basis with frequent follow-up for early recognition of new skin cancers.

REFERENCES

PATIENT STORIES

A 51-year-old woman noticed a rapidly growing black lesion on the upper arm (Figure 179-1) and presented to her doctor. A narrow-margin biopsy confirmed an 8-mm-thick nodular melanoma. She was referred to surgical oncology for sentinel lymph-node biopsy, and one node was positive. She underwent a course of chemotherapy, and though she remains disease-free 2 years later, she is carefully monitored for metastasis and new primary lesions by a multidisciplinary team including family medicine, dermatology, and medical and surgical oncology.

A 60-year-old man underwent a skin exam as part of his regular physical exam. His family doctor noticed an irregular brown black patch on the back (Figure 179-2) and performed a narrow-margin scoop shave, which was diagnostic for melanoma in situ. The patient underwent wide local excision in the office with 5-mm margins and follows up regularly for skin exams with a cure rate very near 100%.

INTRODUCTION

Melanoma is the third most common skin cancer and the most deadly. The incidence of melanoma and the mortality from it are rising. Most lesions are found by clinicians on routine examination. When discovered early, surgical treatment is almost always curative. However, as depth increases, so does the risk of metastasis and mortality. New chemotherapy regimens are more promising than ever, but the best prognosis comes with prevention and early detection.

EPIDEMIOLOGY

• In 2018, the American Cancer Society estimates that 91,270 people in the United States will be diagnosed with melanoma, and 9320 will die from it.¹

• Melanoma incidence has increased in every age group and in every thickness over the course of 1992 to 2006 among non-Hispanic whites, with death rates increasing in those older than age 65 years.²

• Incidence continues to increase worldwide at approximately 4% to 8% per year.³

• In the United States, the death rate for melanoma is decreasing among persons younger than age 65 years.²

• Deaths from thin melanomas account for more than 30% of total deaths.

• The lifetime risk of developing melanoma is 2.6%.¹

RISK FACTORS

Risk factors can be broadly thought of as genetic risks, environmental risks, and phenotypic risks arising from a combination of genetic and environmental risks. For example, a fair-skinned child (genetic) who gets a sunburn (environmental) is much more likely to develop freckles (phenotypic) and melanoma.

ENVIRONMENTAL RISKS

• Exposure to sunlight.

  • History of sunburn doubles the risk of melanoma and is worse at a young age.

• Living closer to the equator.

• Indoor tanning.

• History of immunosuppression.

• Higher socioeconomic status (likely associated with more frequent opportunity for sunburns).

GENETIC RISKS

• Fair skin, blue or green eyes, red or blonde hair.

• Male sex.

• Melanoma in a first-degree relative.

• History of xeroderma pigmentosum or familial atypical mole melanoma syndrome.

PHENOTYPIC RISKS

• Many nevi.

• Multiple dysplastic nevi.

• Increased age.

• Personal history of any skin cancer.

DIAGNOSIS

CLINICAL FEATURES

Remember the ABCDE guidelines for diagnosing melanoma (Figure 179-3).⁴

• A = Asymmetry. Most early melanomas are asymmetric: a line through the middle will not create matching halves. Benign nevi are usually round and symmetric.

• B = Border. The borders of early melanomas are often uneven and may have scalloped or notched edges. Benign nevi have smoother, more even borders.

• C = Color variation. Benign nevi are usually a single shade of brown. Melanomas are often in varied shades of brown, tan, or black, but may also exhibit red, white, or blue.

• D = Diameter greater than or equal to 6 mm. Early melanomas tend to grow larger than most nevi. (Note: Congenital nevi are often large.)

• E = Evolving. Any evolving or enlarging nevus should make you suspect melanoma. Evolving could be in size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color.

• A prospective controlled study compared 460 cases of melanoma with 680 cases of benign pigmented tumors and found significant differences for all individual ABCDE criteria (p <0.001) between melanomas and benign nevi.⁴

• Sensitivity of each criterion: A 57%, B 57%, C 65%, D 90%, E 84%; specificity of each criterion: A 72%, B 71%, C 59%, D 63%, E 90%.⁴

• Sensitivity of ABCDE criteria varies depending on the number of criteria needed: using 2 criteria it was 89.3%; with 3 criteria, it was 65.5%. Specificity was 65.3% using 2 criteria and 81% using 3.⁴

• The number of criteria present was different between benign nevi (1.24 ± 1.26) and melanomas (3.53 ± 1.53; p <0.001). Unfortunately, no significant difference was found between melanomas and atypical nevi.⁴

There are 4 major categories of melanomas. With the exception of nodular melanoma, the growth patterns of the 3 other subtypes are characterized by a radial growth phase prior to dermal invasion. At the present time, the thickness of the lesion, ulceration, and lymphovascular invasion histologically are used for tumor staging and prognosis regardless of the morphologic subtype. Here are the major categories of melanomas:

1. Superficial spreading melanoma is the most common type, representing about 69% of all melanoma (Figures 179-3, 179-4, 179-5, 179-6). This melanoma has the radial growth pattern before dermal invasion occurs. The first sign is the appearance of a flat macule or slightly raised discolored plaque that has irregular borders and is somewhat geometric in form. The color varies, with areas of tan, brown, black, red, blue, or white. These lesions can arise in an older nevus. The melanoma can be seen almost anywhere on the body, but is most likely to occur on the trunk in men, the legs in women, and the upper back in both. Superficial spreading melanoma is the most common type identified in young non-Hispanic white adults.⁶

2. Nodular melanoma occurs in 14% of cases (Figures 179-1, 179-7, 179-8, 179-9).⁶ It is usually invasive at the time it is first diagnosed, and the malignancy is recognized when it becomes raised. The color is often black, but occasionally blue, gray, white, brown, tan, red, or nonpigmented. The nodule in Figure 179-9 is multicolored.

3. Lentigo maligna melanoma occurs in about 15% of cutaneous melanoma.⁶ It is similar to the superficial spreading type and appears as a flat or mildly elevated mottled tan, brown, or dark brown discoloration on sun-damaged skin (Figures 179-10 and 179-11). This type of melanoma is found most often in 50- to 80-year-olds and occurs on the head 90% of the time. Although it is most often found on the face and scalp, it can occur in other areas of sun-damaged skin. These grow slowly over 3–15 years, arising from the precursor lesion, lentigo maligna, which is melanoma in situ (Figure 179-10). The in situ precursor lesion may be quite large and has often existed for years or over a decade (see Chapter 175, Lentigo Maligna).

4. Acral lentiginous melanoma is the least common major subtype of melanoma and accounts for about 2% of all melanomas; however, it is one of the most frequent subtypes seen in African Americans (37%) though it actually occurs even more often in Hispanic and non-Hispanic whites.⁶ It may occur under the nail plate or on the soles or palms (Figures 179-12, 179-13, 179-14, 179-15, 179-16). This subtype often carries a worse prognosis because of delays in diagnosis and the accompanying thickness at the time of diagnosis. Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band within the nail plate. When subungual pigment spreads to the proximal or lateral nail fold, it is referred to as the Hutchinson sign and is highly suggestive of acral lentiginous melanoma (Figure 179-14) (see Chapter 199, Pigmented Nail Disorders).

Less common types of melanomas include:

• Amelanotic melanoma (<5% of melanomas) is nonpigmented and appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma or a ruptured hair follicle. Any of the 4 principal subtypes may present as an amelanotic variant, but nodular melanomas are highly represented. These may be intrinsically more aggressive and often present with a thicker Breslow depth than similarly pigmented melanomas (Figures 179-17, 179-18, 179-19).⁷

• Other rare melanoma variants include (a) nevoid melanomas, (b) malignant blue nevus, (c) desmoplastic/spindled/neurotropic melanoma, (d) clear cell sarcoma (in fact a melanoma), (e) animal-type melanoma, (f) ocular melanoma, and (g) mucosal (lentiginous) melanoma.⁸

TYPICAL DISTRIBUTION

Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females, but may occur in any location where melanocytes exist. The most common site in African Americans, Hispanics, and Asians is the plantar foot, followed by the subungual, palmar, and mucosal sites.

DERMOSCOPY

Dermoscopy can be used to determine if a pigmented lesion has features suspicious for a melanoma, and it can also help determine when a biopsy is needed.⁹ In a prospective study of 401 lesions evaluated for melanoma by experts in dermoscopy, the sensitivity of 66.6% with ABCDE criteria improved to 80%, and specificity rose from 79.3% to 89.1% (Figure 179-20).⁹

In a study of dermoscopy done by 60 physicians (35 general practitioners, 10 dermatologists, and 16 dermatology trainees) on unaided photos of 40 lesions using the ABCD rule, the Menzies method, a 7-point checklist, and pattern analysis, the sensitivity rose over the unaided eye.¹⁰ Physicians were instructed in each of the dermoscopy methods using a CD-ROM. The unaided eye using a standard photo of the lesion was 61% sensitive and 85% specific with a 73% diagnostic accuracy. The dermoscopic photo increased sensitivity (68% for pattern analysis, 77% for the ABCD rule, 81% for the 7-point checklist, and 85% for the Menzies method). The specificity did not improve. Sensitivity is more important than specificity to avoid missing melanoma. Although the number of biopsies could increase with some drop in specificity, the biopsy itself is the most specific test to differentiate melanoma from benign pigmented lesions.¹⁰

Accepted dermoscopic features of melanoma include:

• Atypical network (includes branched streaks).

• Streaks: pseudopods and radial streaming.

• Atypical dots and globules.

• Negative pigment network.

• Blotch (off center).

• Blue-white veil/peppering over macular areas (regression).

• Blue-white veil over raised areas.

• Atypical vascular structures.

• Peripheral tan/brown structureless areas.

Figure 179-20 demonstrates a number of these features. (See Chapters 111, Dermoscopy, and 181, Advanced Dermoscopy of Skin Cancer.)

BIOPSY

A full-thickness skin biopsy remains the gold standard for diagnosing melanoma. Narrow-margin (1–3 mm) biopsy by shave saucerization, punch, or elliptical excision is ideal for histologic diagnosis and tumor staging (Box 179-1). Wider margins are avoided to preserve accurate subsequent lymphatic mapping. Although there is evidence that a partial biopsy of a portion of a melanoma does not worsen the prognosis, this should only be performed when a lesion is too large to excise in the office. If the clinical impression differs markedly from the pathology report, discuss with the pathologist and share clinical photos if you haven't done so already. You may need to have the pathologist prepare "deeper sections" or "step sections"—meaning more slices from the same loaf of bread. Additionally, if the diagnosis of melanoma was expected and the result of an incisional biopsy does not meet the expectation, go forward with a complete excision or refer to a colleague who can.

Saucerization (scoop or deep shave biopsy) leads to an accurate diagnosis and staging 97% of the time (Figure 179-21).¹¹ This is because it provides breadth of sampling in addition to depth when performed correctly. The goal of the saucerization is to get under the lesion, especially in the region with the greatest depth. In most cases this is about the depth of a dime, and the visible pigment depth can be the guide (see Chapter 113, Biopsy Principles and Techniques). If pigment is seen at the base of the biopsy, a second saucerization can be added to the first pass to provide the pathologist with more tissue. Too shallow of a biopsy may miss important staging information. For very large lesions, such as a suspected lentigo maligna, a saucerization should provide better tissue to the pathologist than a single or several punch biopsies (see Figure 179-10).¹²

The impact of partial biopsy on histopathologic diagnosis of cutaneous melanoma has been studied extensively by Ng and colleagues in Australia. They found that increased odds of histopathologic misdiagnosis were associated with punch biopsy of part of the melanoma (odds ratio [OR] 16.6) and shallow shave biopsy (OR 2.6) compared with excisional biopsy (including saucerization). Punch biopsy of part of the melanoma was also associated with increased odds of misdiagnosis with an adverse outcome (OR 20).¹³

DIFFERENTIAL DIAGNOSIS

Nevi of all types can mimic melanoma. Congenital nevi can be especially large and asymmetric. Therefore, it is important to ask the patient if the pigmented area has been there from birth. Because some melanomas arise in congenital nevi, a changing congenital nevus needs to be biopsied to rule out melanoma.

• Dysplastic nevi, also called atypical nevi, can mimic melanoma. When an atypical nevus is suspicious for melanoma, perform a narrow-margin biopsy. Only the less-suspicious and flat dysplastic nevi should be monitored with photography or serial exams (see Chapter 171, Dysplastic Nevus and Spitz Nevus).

• Spitz nevi can mimic melanoma or actually be a spitzoid melanoma. If a lesion appears to be a Spitz nevus, it should be biopsied. The only exceptions are typical Spitz nevi in children under age 12. However, if the lesion is atypical, a biopsy is always needed (see Chapter 171, Dysplastic Nevus and Spitz Nevus).

• Seborrheic keratoses (SKs) usually look like they are stuck on, with surface cracks and a verrucous (wartlike) appearance. These are benign and not precancerous. SKs can be darkly pigmented or asymmetric with irregular borders and can have varied colors. Perform a biopsy if the diagnosis is uncertain. Be careful to not mistake a melanoma for an SK (Figure 179-4) (see Chapter 164, Seborrheic Keratosis). Do not perform cryosurgery on an SK with any atypical features. These should be biopsied. A number of malpractice lawsuits have been filed against physicians who froze a melanoma thought to be an SK.

• Solar lentigines appear as light brown macules on the face and the dorsum of the hands. Many patients call them liver spots, but they are unrelated to the liver. A large isolated solar lentigo on the face can mimic lentigo maligna melanoma. In this case, perform a broad scoop shave of the most suspicious area or the whole lesion. Dermoscopy is helpful to guide selecting the area to biopsy (see Chapters 111 and 181 on dermoscopy).

• Dermatofibromas are fibrotic nodules that occur most frequently on the legs and arms. They can be any color from skin color to black and often have a brown halo surrounding them. A pinch test will produce a dimpling of the skin in most cases (see Chapter 166, Dermatofibroma).

• Pyogenic granulomas can resemble an amelanotic melanoma, and sending for pathologic exam will ensure that the clinical diagnosis is correct (Figure 179-22) (see Chapter 167, Pyogenic Granuloma).

• Pigmented basal cell carcinomas (BCCs) may resemble a melanoma. However, the pigment in the BCC is often scattered throughout the lesion, and it has other features of a BCC, such as a pearly appearance with a rolled border (Figure 179-23) (see Chapter 177, Basal Cell Carcinoma). Dermoscopy can be very helpful, as a pigmented BCC has a number of specific dermoscopic structures to look for (see Chapters 111 and 181 on dermoscopy).

• Merkel cell carcinoma (see Figure 178-20) is a rare cutaneous neuroendocrine malignancy that is most common on the head and neck of elderly individuals as an enlarging pink to dark purple nodule that may mimic amelanotic or nodular melanoma.

MANAGEMENT

• Cutaneous melanoma is surgically treated with complete full-skin-depth excision using margins determined by the Breslow depth. This depth is a measure of tumor thickness from the granular layer of the epidermis to the point of deepest invasion using an ocular micrometer.

• Current recommendations for excision margins range from 5 mm for in situ lesions to 1 to 2 cm for invasive lesions. Table 179-1 shows a comparison of world recommendations.¹⁴ SORⒶ

• Mohs micrographic surgery, performed by specially trained physicians, may prove useful in completely removing subclinical tumor extension in certain subtypes of melanoma in situ, such as lentigo maligna, desmoplastic melanoma, and acral lentiginous melanoma in situ.¹⁵

• Sentinel lymph node biopsy (SLNB) is not recommended when the risk of a positive node is less than 5%. This includes tumors less than 0.8 mm without ulceration. SLNB should be discussed and considered when there is a 5%–10% chance of a positive node. This includes tumors >0.8 mm thick with ulceration, mitotic index of ≥2 mitoses per square millimeter, or the presence of lymphovascular invasion. Rare cases with microsatellitosis within the original specimen upstage the tumor to stage III in transit, and SLNB is recommended regardless of the tumor thickness.

• Patients with advanced melanoma (Figure 179-24) should be referred to medical oncology and may receive combination therapy with multiple chemotherapeutic agents and immunotherapy. Many trials are ongoing, and new chemotherapy regimens are emerging rapidly. Consideration should be given to consulting palliative care early to improve quality of life (see Chapter 5, End of Life).

• Systemic therapy options for metastatic or unresectable disease are complex and evolving rapidly based on trial data and include immunotherapy with pembrolizumab, nivolumab, combination nivolumab/ipilimumab, and targeted BRAF therapy with dabrafenib/trametinib or vemurafenib/cobimetinib as well as conventional chemotherapy options.

PREVENTION AND SCREENING

• Melanoma prevention starts with sun protection.

• Sunscreen use has been shown in a randomized controlled trial to reduce the number of melanomas by roughly half.¹⁶

• Sun protection should include sun avoidance, protective clothing, and sunscreen.

• Indoor tanning is not safe and should be avoided.

• The U.S. Preventive Services Task Force has not found sufficient evidence to recommend regular screening for melanoma or skin cancer in the general population.¹⁷

• Most experts believe that persons at high risk for melanoma (including previous personal history of melanoma, high-risk family history, and high-risk skin types with significant sun exposure) should be screened regularly for melanoma by a physician trained in such screening.

• Evidence for the value of self-screening is lacking, but persons at high risk for melanoma should also be encouraged to observe their own skin and to come in for evaluation if they see any suspicious changes or growths.

PROGNOSIS

Prognosis depends on tumor depth, mitotic rate, the presence of ulceration, positive lymph nodes, and metastases. In stage 0 disease, surgical excision is almost always curative. Five-year survival in patients by tumor thickness is almost 100% for in situ lesions, 92% for lesions less than 0.8 mm thick, 81% for lesions between 1 and 2 mm thick, 70% for lesions 2 to 4 mm thick, and 53% for lesions thicker than 4 mm. When accounting for nodal and distant metastasis, stage III disease carries a 40% to 78% 5-year survival, depending on the number of nodal metastases, and stage IV disease carries a 15% to 20% 5-year survival.¹⁸

FOLLOW-UP

The need for follow-up is largely determined by the stage of the disease (Figure 179-25). The prognosis is worsened by increasing depth, mitotic rate, presence of ulceration, positive lymph nodes, and metastases.

Follow-up for stages 0 and I cutaneous melanoma includes regular skin examinations by a physician trained in skin cancer screening. Total body photography may be of benefit in monitoring patients with multiple nevi (Figure 179-26). The rate of subsequent cutaneous melanomas among persons with a history of melanoma was found to be more than 10 times the rate of a first cutaneous melanoma, and the highest incidence of recurrence was in the first 3 to 5 years after initial diagnosis.^19,20

PATIENT EDUCATION

Advise patients who have had melanoma to avoid future sun exposure and monitor their skin for new and changing moles. Recommend a complete skin examination yearly by a physician trained to detect early melanoma.

REFERENCES

PATIENT STORY

A 52-year-old black woman presented with a 7-month history of a hypopigmented rash in a symmetric distribution on her upper thighs and arms (Figures 180-1 and 180-2). She had been evacuated from New Orleans following Hurricane Katrina. She had waded through polluted waters for hours before being rescued by boat. Four days passed before she had access to a shower, at which time she noticed a single erythematous spot the size of a silver dollar on her left thigh. Over the next several weeks, it faded to hypopigmented macules and plaques and eventually spread to both thighs and arms. The physical examination revealed no lymphadenopathy. A hematoxylin and eosin (H&E) stain of a full-thickness punch biopsy revealed "cerebriform" lymphocytes at the dermal–epidermal junction characteristic of mycosis fungoides (MF), a type of cutaneous T-cell lymphoma (CTCL). Her blood tests were essentially normal, and she was HIV-negative. The patient reported no improvement with topical high-potency generic steroid to affected areas and was started on narrow-band UVB treatment twice weekly.

INTRODUCTION

CTCL clinically and biologically represent a heterogeneous group of non-Hodgkin lymphomas.¹

EPIDEMIOLOGY

• The annual incidence of CTCL in the United States increased from 2.8 per 1 million (1973–1977) to 10.2 per 1 million (2005–2009).² The incidence appears to have stabilized over the past 20 years, with an annual percentage change of only 0.1%.²

• CTCL is a rare disease, with about 3000 new cases per year in the United States.

• The most common types of CTCL are MF (50% to 72%), which is generally indolent in behavior (Figures 180-1, 180-2, 180-3, 180-4, 180-5); primary cutaneous CD30+ lymphoproliferative disorders (LPD; about 30%); and Sézary syndrome (SS; 1% to 3%), an aggressive leukemic form of the disease.³ LPDs include lymphomatoid papulosis (12%) and cutaneous anaplastic large-cell lymphoma (C-ALCL, 9%) (Figure 180-6).^3,4

• CTCL is more common in African Americans than in whites, with an incidence rate ratio of 1.3:1 (2005–2009).²

  • African-American and Hispanic individuals have an earlier onset of disease; in one study database, the mean age at diagnosis was 60.0 ± 14.8 years for Caucasian, 49.3 ± 16.9 years for African-American, and 47.4 ± 17.8 years for Hispanic patients.⁵ In addition, more CTCLs among African Americans were diagnosed at a more advanced clinical stage compared to Caucasians or Hispanics (36.1% vs. 23% and 21.2%, respectively; odds ratio 2.83; 95% confidence interval 1.81, 4.42).⁵

• CTCL is more common in males, with a male-to-female ratio of 2:1; although the most recent data (2005–2009) show a ratio of 1.6:1.²

• Median age at presentation is between 50 and 70 years, although pediatric and young adult cases do occur.¹

ETIOLOGY AND PATHOPHYSIOLOGY

• MF is a malignant lymphoma of helper T cells that usually remain confined to skin and lymph nodes (LNs)³ and are named for the mushroom-like skin tumors seen in severe cases (Figure 180-7).⁶

• Lesions of primary cutaneous CD30+ LPD are defined by the variable number of atypical CD30+ lymphocytes that express the CD30 antigen in most of the tumor cells.³

• The exact etiology of CTCL is unknown, but environmental, infectious, and genetic causes have been suggested.

  • In one study in Texas, there was a clustering of cases in 3 communities with incidence rates 5- to 22-fold higher than the overall Texas population, suggesting an external etiologic factor.⁵ Environmental exposure to Agent Orange may be responsible for some cases.⁶

  • Human T-lymphocytic virus (HTLV) types 1 and 2, HIV-1, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Borrelia burgdorferi have been suggested, but unproven, infectious causes of MF.⁷ There is one case report of possible conjugal transmission of MF between a heterosexual couple who developed advanced MF within 14 months of one another.⁷

  • MF and SS are associated with specific human leukocyte antigen (HLA) types, and prognosis appears to correspond to certain HLA alleles.⁸ Genetic predisposition is also suggested by detection of HLA class II alleles DRB1*11 and DQB1*03 in association with sporadic and familial malignancy and familial clustering among Israeli Jews.⁹ PLCG1 mutations have also been reported in CTCLs.¹⁰

• Abnormal cytokine expression in interleukin-13 and its receptors, among others, may be responsible for the enhanced proliferation of malignant cells and/or depression of the antitumor immune response seen in CTCLs.¹¹ Defective apoptosis is also believed to play a central role in pathogenesis.⁴

• Metastasis to the liver, spleen, lungs, GI tract, bone marrow, and the central nervous system (CNS) may occur via T-cell spread through the lymphatic system.⁷

• The reduction of T-cell receptor complexity contributes to immunosuppression in advanced MF and SS and may manifest clinically as herpes simplex or zoster.¹² Death is usually due to systemic infection, especially from Staphylococcus aureus and Pseudomonas aeruginosa.

• Host antitumor immunity also deteriorates, and patients have an increased risk for secondary malignancies including Hodgkin lymphoma, lymphomatoid papulosis, and non-hematologic malignancies.⁴

DIAGNOSIS

CLINICAL FEATURES

• The most common initial presentation of MF involves patches or scaly plaques with a persistent rash that is often pruritic and usually erythematous (see Figures 180-1, 180-2, 180-3, 180-4).^4,7 Patches may evolve to generalized, infiltrated plaques or to ulcerated, exophytic tumors (see Figures 180-5, 180-6, 180-7).³

• Hypo- or hyperpigmented lesions, petechiae, poikiloderma (skin atrophy with telangiectasia), and alopecia with or without mucinosis are other findings. The folliculotropic variant of MF presents with spotty alopecia (Figure 180-8).

• A "premycotic" phase may precede definitive diagnosis for months to decades, which involves nonspecific, slightly scaling skin lesions that intermittently appear and may eventually resolve with topical steroids.

• Of the LPDs, lymphomatoid papulosis appears as recurring papules and nodules over the trunk and extremities that disappear in 3–12 weeks, sometimes leaving scars.³ C-ALCL presents with solitary or localized nodular lesions of 1.5 cm or larger that may ulcerate (see Figure 180-6). In 20% of patients with C-ALCL, multifocal lesions are present, which may partially or completely regress; 10% develop extracutaneous dissemination, primarily to regional lymph nodes.³

• SS usually arises de novo and is characterized by generalized exfoliative erythroderma, lymphadenopathy, severe pruritus, and atypical Sézary cells in the peripheral blood.⁴ Diffuse infiltration of atypical T cells in SS may exaggerate facial lines, creating a leonine facies.

TYPICAL DISTRIBUTION

• Lesions of MF may affect any skin surface, but typically initially develop on non–sun-exposed "bathing suit" areas, such as the trunk below the waistline, breasts, buttocks, and the groin areas (Figure 180-9).⁴ Lesions of C-ALCL can be found on the face, trunk, extremities, and buttocks.³

• If there is follicular involvement, lesions may be found on the face or scalp (Figures 180-10 and 180-11).

• MF occasionally presents as a refractory dermatosis of the palms or soles.

BIOPSY AND LABORATORY STUDIES

• A full-thickness punch biopsy of the lesion is the most important diagnostic tool. If the initial biopsy is negative but the rash persists, the biopsy should be repeated.⁷ Topical treatments and systemic immunosuppressants should be discontinued 2 to 4 weeks before the biopsy.¹³

• If the LNs are palpable or lymphadenopathy is suspected, also known as "dermatopathic lymphadenitis," biopsies should be performed (Figure 180-12).

• A bone marrow biopsy should be performed if there is proven nodal or blood involvement.

• Histology—Classic MF is characterized by a proliferation of mature CD4+CD45RO+ memory T lymphocytes. The skin biopsy may reveal Pautrier microabscesses or an inflammatory cell bandlike infiltrate lining the basal layer or in the upper dermis ("mononuclear epidermotropism"). Malignant lymphocytes have hyperchromatic and convoluted or "cerebriform" nuclei.⁴

• Radiography—A chest radiograph and CT scan of the abdomen and pelvis are recommended for advanced stages IIB to IIIB, or if visceral disease is suspected.¹⁴ Positron emission tomography (PET) scans offer more sensitive detection of LN involvement and can be considered in individual cases.¹⁴

• Serology and blood tests—A complete blood cell count with differential, a buffy coat smear to screen for Sézary cells, lactic dehydrogenase and uric acid as markers for bulky or aggressive disease, and liver function tests to detect hepatic involvement should be measured.¹⁴ Peripheral eosinophilia is an independent marker for poor prognosis and disease progression.^15,16

• Flow cytometry—This test may be used to detect malignant clones and to quantify CD8+ lymphocytes to assess immunocompetence.

• Immunophenotyping may be used to support histology results.

• Polymerase chain reaction (PCR) and Southern blot testing are recommended to detect T-cell rearrangements, if histology and immunophenotyping results are equivocal and to detect abnormal cells in LNs.¹⁴

• The International Society for Cutaneous Lymphoma proposed criteria for diagnosing MF and Sézary syndrome by incorporating clinical, histopathologic, molecular biologic, and immunopathologic features, including the percentage of skin coverage with lesions or erythema, presence of clinically abnormal peripheral lymph nodes, visceral organ involvement, and blood involvement (high tumor blood burden defined as absolute Sézary cell count of greater than 1000/mm³).¹⁷

DIFFERENTIAL DIAGNOSIS

• "Premycotic" period preceding diagnosis of MF may resemble parapsoriasis en plaque or nonspecific dermatitis.¹³

• MF with erythroderma must be distinguished from generalized atopic dermatitis, contact dermatitis, photodermatitis, drug eruptions, erythrodermic psoriasis, and idiopathic hyper-eosinophilic syndrome (see Chapter 162, Erythroderma).⁸

• Unilesional MF may resemble nummular eczema, lichen simplex chronicus, erythema chronicum migrans, tinea corporis, or digitate dermatosis (a variant of small plaque parapsoriasis).¹³

• Vitiligo typically involves discrete, hypopigmented macules on the hands and face that coalesce into larger areas.⁶ However, some MF may mimic vitiligo, as seen in Figures 180-1 and 180-2. The distribution of the hypopigmented macules in this case is atypical for vitiligo and this prompted a biopsy that led to the diagnosis of MF (see Chapter 206, Vitiligo and Hypopigmentation).

• Idiopathic guttate hypomelanosis is a benign condition involving smaller hypopigmented macules than those seen in MF.⁶

• In patients with HIV, histopathology resembling MF may represent a reactive inflammatory condition instead. Nonepidermotrophic large T-cell cutaneous lymphoma and B-cell diffuse cutaneous lymphoma are more frequent complications than MF in these patients.¹⁸

MANAGEMENT

• In addition to symptomatic treatments such emollients and antipruritics (Doxepin cream 5%), treatments for CTCL can be divided into skin-directed therapy and systemic therapy. Of the skin-directed therapies, topical corticosteroids are widely used in all stages of CTCL in the hopes that they will help control the disease and palliate any cutaneous symptoms of itch.¹⁵ SORⒷ

• For stage I disease localized to the skin, topical high-potency steroids (clobetasol cream) on an outpatient basis are recommended.¹⁴ SORⒸ Topical retinoids and topical chemotherapy (nitrogen mustard, bischloroethylnitrosourea, or carmustine) are treatment alternatives for localized disease and effective adjuvants in generalized disease.^6,14,19 SORⒷ

  • Bexarotene 1% topical gel or alemtuzumab may be tried if disease persists despite treatment or if other medication is not tolerated.¹⁴ When used in combination with psoralen-enhanced UV light (PUVA), bexarotene decreases the total UVA dosage needed and, if used as maintenance therapy, increases the duration of remission.²⁰ SORⒸ

  • Alternatively, PUVA may also be used concurrently with interferon (IFN), 3 times weekly, or retinoids until skin lesions clear, then continued as maintenance therapy at a reduced frequency.^14,20 SORⒸ

  • Tazarotene, low-dose oral etoposide, and imiquimod may be considered in the treatment of early CTCL.¹⁴

  • For a plaque recalcitrant to PUVA and retinoid combination therapy, 1 case study showed that imiquimod 5% topical cream effectively cleared the lesion.¹² SORⒸ Topical mechlorethamine can also be considered for refractory, stage IA to IIA MF¹⁴; in one trial, both the gel and ointment formulation were safe and effective with a response at 1 year seen in 58.5% and 47.7%, respectively, using the Composite Assessment of Index Lesion Severity.²¹

  • Phototherapy is a safe, effective, and well-tolerated first-line therapy in patients with early-stage CTCL, with prolonged disease-free remissions being achieved. Narrow-band UVB is at least as effective as PUVA for treatment of early stage MF.^22,23 SORⒸ

  • Narrow-band UVB light has proven effective in early MF and prolongs remission, although an optimal maintenance protocol still needs to be established.^14,24 SORⒸ

  • The therapeutic effects of PUVA and UVB in immune-mediated skin diseases have been attributed to the direct apoptosis of lymphocytes, modification of cell surface receptors, and alteration in production of certain mediators.²²

  • Photodynamic therapy with 5-aminolevulinic acid (PDT-ALA) was found to effectively eradicate localized infiltrates better than topical steroids, but more studies are needed before it becomes standardized treatment.¹⁹ SORⒸ In general, photodynamic therapy works via direct cytotoxicity, vascular damage, and immune host response.²⁵

• Stage II disease involves the regional LNs and may be treated the same as for stage I. For stage IIB, the most recommended therapy is total-skin electron-beam therapy (EBT) followed by nitrogen mustard treatment for 6 or more months.²⁰ SORⒸ For disease relapse after EBT, PUVA may be used in combination with IFN or a systemic retinoid.²⁰ SORⒸ Other systemic therapies include fusion toxins, monoclonal antibody treatment, oral retinoids, and single-agent chemotherapy.¹⁴ For recalcitrant tumors, there is no evidence that combination systemic chemotherapy regimens offer survival outcome superior to that for single agents.¹⁴ SORⒸ

• Stage III, or erythrodermic disease without extracutaneous disease or with limited LN involvement, should be treated with chemotherapy or photophoresis for 4 weeks.²⁰ SORⒸ Extracorporeal photochemotherapy involves irradiation of white blood cells with PUVA after leukapheresis before reinfusing the blood cells intravenously. If the response is delayed, photophoresis may be combined with IFN or systemic retinoids.

• Stage IV extracutaneous disease should be treated with systemic chemotherapy. Although response rates are improved with combination chemotherapy, the response duration is less than 1 year. Regimens include cyclophosphamide, vincristine, and prednisone (CVP), CVP plus doxorubicin, CVP plus methotrexate, or cyclophosphamide, vincristine, doxorubicin, and etoposide. Adjuvants treatments may include IFN, systemic retinoids, and photophoresis. Single-agent chemotherapy includes methotrexate, liposomal doxorubicin, gemcitabine, etoposide, cyclophosphamide, and purine analogs.²⁰ SORⒸ The patient should be referred to a dermatologist, and to medical and radiation oncologists.¹⁴

• In patients with Sézary syndrome, risk of death from infection is high and consideration should be given to treatment with combination systemic and skin-directed immunomodulatory therapy before chemotherapy, unless disease burden or therapeutic failure dictates otherwise.¹⁴

PROGNOSIS AND FOLLOW-UP

• Overall 5-year survival for patients with CTCL is as follows: MF 88%, (follicular MF 80%, others 100%), CD30+ LPD 95%–100%, and SS 24%.⁴

• Patient age and stage are the most important clinical prognostic factors.²⁶

• Patients have a normal life expectancy, if diagnosed early during stage IA, in which the patch or plaque is limited to less than 10% of the skin surface area.^6,14

• MF and SS are otherwise difficult to cure and have a prognosis of 3.2 years for stage IIB cutaneous tumors (10-year survival 42%), 4 to 6 years for stage III generalized erythroderma (10-year survival 83%), and less than 1.5 years for stage IVA and stage IVB with LN and visceral involvement, respectively.¹⁴

• The patient should be monitored for development of secondary malignancies.

POTENTIAL COMPLICATIONS

• Infection, particularly from indwelling intravenous catheters or from lymph node biopsy sites.

• High-output cardiac failure.

• Anemia of chronic disorders.

• Edema.

• Secondary malignancies (e.g., skin cancer, melanoma).

PATIENT EDUCATION

• Avoid sun exposure, stay in a cool environment, and keep skin lubricated.

• See your physician if any new skin symptoms and signs appear or the medication is not working.

• Avoid smoking and secondhand smoke.

REFERENCES

ADVANCED DERMOSCOPY OF SKIN CANCER

This chapter is an advanced dermoscopy guide to the 3 most common skin cancers: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The basic dermoscopic patterns of these skin cancers have been covered in Chapter 111 on dermoscopy (an overall introduction) and in the other chapters devoted to each skin cancer. This chapter provides further information and examples of dermoscopy for the various subtypes of these skin cancers.

BASAL CELL CARCINOMA (SUBTYPES)

BCCs have many recognizable dermoscopic features described in Table 111-2. They can be subdivided into pigmented and nonpigmented BCCs depending on the presence or absence of pigment clinically, dermoscopically, and histologically. See Chapter 177 (Basal Cell Carcinoma) for examples.

BCC is also subdivided into the following histologic categories, and each of these histologic types may present with different dermoscopic features:

1. Superficial BCC (Figures 181-1, 181-2, 181-3)

2. Nodular BCC (Figure 181-4)

3. Morpheaform BCC (Figure 181-5)

4. Sclerosing BCC (Figure 181-6)

5. Infiltrative BCC (Figure 181-7)

The features most predictive of superficial BCC are:

1. Leaflike structures

2. Spoke wheel-like structures

3. Concentric structures

4. Short, fine telangiectasias

5. Multiple small erosions

6. Shiny white blotches and strands (see Figures 181-1, 181-2, 181-3).

The evidence supports these features with odds ratio ranging between 2.7 and 7.7.^1-4

Features that support BCCs that are not superficial BCCs are:

1. Arborizing vessels (negative OR 2.1) (see Figures 181-5 and 181-7)

2. Blue-gray ovoid nests (negative OR 3.2) (see Figure 181-4)

3. Ulceration (negative OR 2.1)² (see Figure 181-4)

SQUAMOUS CELL CARCINOMA (SUBTYPES)

The most common features of SCC are described and depicted in Table 111-3. Bowen disease (SCC in situ) can present as pigmented or nonpigmented (see Chapter 173, Actinic Keratosis and Bowen Disease). Nonpigmented Bowen disease typically presents with a glomerular vascular pattern and scale (Figure 181-8). Pigmented Bowen disease presents typically on individuals of dark skin type, and the hallmark of diagnosis is brown circles and brown dots in a linear pattern on the periphery of the lesion (Figure 181-9).⁵

Keratoacanthoma is a well-differentiated variant of SCC which presents with a central keratin core within a raised tumor (see Chapter 174, Keratoacanthoma). On dermoscopy, it has a central structureless yellow keratin mass surrounded by hairpin (looped), linear irregular, and glomerular vessels (Figure 181-10).⁵

Finally, invasive SCC (see Chapter 178, Squamous Cell Carcinoma) presents with yellow keratin, ulcerations, scale, and hairpin and linear irregular vessels (Figure 181-11).⁵

MELANOMA OF SPECIAL LOCATIONS

MELANOMA ON THE FACE AND SCALP

The most common features of melanoma in general are described and depicted in Table 111-7.

Lentigo maligna melanoma (LMM) is a subtype of melanoma that arises on the face, scalp, and other areas of sun-damaged skin (see Chapter 179, Melanoma). Lentigo maligna is the in-situ version of LMM (see Chapter 175, Lentigo Maligna). Angulated lines (polygonal lines) is a melanoma-specific structure that can be found in LMM arising on the face, scalp, or other area of sun-damaged skin.⁶

LMMs present as flat pigmented patches to plaques, light brown to black with color variation and asymmetric shape. They enlarge slowly in size and can cover a wide area of the face or scalp. Dermoscopically LMM is diagnosed by using the classic dermoscopic criteria introduced by Schiffner (Table 181-1).⁷ Pralong and colleagues added red rhomboidal structures, darkening at dermoscopic examination, and increased density of vascularity as additional structures suggestive of LMM⁸ (see Table 181-1). Two examples of LMM on the face are seen in Figures 181-12 and 181-13.

ACROLENTIGINOUS MELANOMA (ALM) (MELANOMA OF HANDS AND FEET)

The dermatoglyphic pattern of the skin at the palms and soles is due to the unique anatomy, specific for these regions, caused by the alteration between ridges and furrows. This anatomy can help us differentiate between nevi and melanoma, since the location of pigmentation differs among the two entities. In nevi, the pigmentation tends to favor the furrows of the lesions, while in melanoma it tends to favor the ridges (Figure 181-14).⁹

In order to distinguish benign acral nevi from ALM, one must know the most common dermoscopy patterns seen in acral nevi¹⁰ (Figure 181-15) and acrolentiginous melanomas¹¹ (Figure 181-16).

Benign acral nevi have these patterns:

1. Parallel furrow pattern—Pigmentation located mainly on and around the furrows (Figure 181-17).

2. Lattice-like pattern—A parallel furrow pattern with the addition of parallel lines crossing over the ridges like a lattice (Figure 181-18).

3. Fibrillar pattern—Composed of multiple, transversely oriented, thin parallel lines that cross both furrows and ridges on areas of weight bearing on the feet (Figure 181-19). When a fibrillar pattern has darker multicolored lines or occurs on the palms or non–weight-bearing areas of the feet, it is considered atypical, and a biopsy is warranted.