B. Basal cell carcinoma C. Merkel cell carcinoma D. Squamous cell carcinoma E. Viral wart
V. TREATMENT MODALITIES
Treatment modalities are defined by the location and size of the tumor.
A. Complete excision; close resemblance in clinical and histological appearance of KA and SCC suggests treatment of KA as invasive SCC.
B. Mohs micrographic surgery.
C. Electrodessication and curettage (ED&C).
D. Radiation therapy.
E. Intralesional pharmacologic therapy.
VI. PROGNOSIS
The risk of metastasis is low in KA, but complete excision of the lesion is recommended when there is no clear distinction between KA and SCC. Although some believe that a KA is a benign tumor, it is commonly treated rather than observed for spontaneous resolution. KA has potential for recurrence, but it is highly curable.
PATIENT EDUCATION
I. OVERVIEW
Cutaneous malignant melanoma (MM) is a potentially life-threatening, dangerous skin cancer.
The development of melanoma and its progression can be determined by genetic predisposition and mutation, mutagenic environmental factors, and the host’s immune response. Melanoma can be successfully cured when detected and adequately treated early. Melanoma may disseminate to any organ, most commonly in skin and subcutaneous tissue, lymph nodes, lungs, liver, brain, bone, and gastrointestinal tract.
A. Definition: melanoma is a malignant neoplasm of melanocytes (pigment-forming cells) and nevus cells, with a manifestation of irregular size, shape, or atypical pigmentation. It may arise from a preexisting nevus or de novo (from a new nevus).
B. Incidence:
1. Melanoma is the most dangerous form of skin cancer.
2. Most common form of malignant disease in young adults between 25 and 29 years old and the second most common form of malignant disease in adolescents.
3. Estimated 9,710 melanoma deaths and 76,100 new cases projected in 2014.
4. Melanoma accounts for approximately 75% of skin cancer–related deaths.
5. The lifetime risk of developing melanoma is 1 in 50 for Whites, 1 in 200 for Hispanics, and 1 in 1,000 for African Americans.
6. Gender difference in melanoma incidence varies by age groups:
a. Men < women (under 40 years old)
b. Men > women (over 40; twofold by age 60)
7. The risk of developing melanoma increases with advanced age.
8. The 5-year survival rate is 98% for early detected melanoma before lymph node involvement; the rate decreases to 62% and 16% for regional and distant metastasis, respectively.
9. Risk factors:
a. History of excessive sun exposure and blistering sunburns b. Dysplastic nevi and familial multiple dysplastic nevi syndrome c. Multiple moles (>50)
d. Freckling
e. Personal and family history of melanoma f. Genetic factors: fair skin, red hair, freckles g. Socioeconomic status
h. Immunosuppression i. Advanced in age
j. Gender (male > female) C. Etiology:
1. Occupational or recreational UV exposure (e.g., outdoor occupations, use of tanning beds, sun bathing)
a. UVA rays cause skin aging, wrinkling, and DNA damage.
b. UVB rays cause sunburn and skin DNA damage.
2. Dysplastic nevi (atypical moles) or multiple dysplastic nevi syndrome
a. Lifetime risk for persons with dysplastic nevi syndrome is greater than 10%.
b. Persons with congenital melanocytic nevi (moles present at birth) have risk of developing melanoma estimated between 0% and 10% depends on the size and location of the moles.
3. Fair skin, light hair and freckling, and burns easily
a. Ten times higher risk of developing melanoma for Whites compared to African Americans
b. More than double the risk of developing melanoma in people who had five or more severe sunburns during childhood and adolescence
4. Personal history of melanoma:
a. 5% chance of recurrence in persons with history of melanoma 5. Family history of melanoma:
a. About 10% of people with melanoma have family history of melanoma among their first-degree relatives.
b. Approximately 10% to 40% of genetic mutation involved in families with high rate of melanoma.
c. Abnormalities on chromosome 9p21 and melanoma-susceptible genes such as p16.
6. Genetic disorders such as XP-defective DNA mechanism to repair chronic UV damage led to development of skin cancers including melanoma in sun-exposed areas
D. Pathogenesis:
1. Different sites of the body, different amount of UV radiation, and different genetic makeups and oncogene mutations in each individual result in different types of melanoma.
2. Most common genetic mutations in melanoma involve disorders of the cell cycle pathways and transcriptional control mechanisms.
3. The mutation of CDKN2A gene located on chromosome 9p21 (codes for p16 and p14ARF proteins) is highly associated with the predisposition to develop melanoma.
4. The genetic mutation involving CDKN2A interferes with p53 in cell cycle progression and keeps on producing mutagenic DNA via cell division cycles and allows uncontrolled proliferation of mutated melanocytes.
5. CDKN2A involved in germline mutation, which explains the genetic factors in familial melanoma disease.
6. BRAF gene mutation is also found in about 40% to 60% of melanomas in intermittently sun-exposed individuals who developed melanoma, more commonly seen in young people.
7. NRAS-mutated oncogene is found in 15% to 20% of melanomas, more often in people with later age-at-onset melanomas.
8. C-KIT–mutated oncogene is most common in site-specific melanomas such as in mucosal (40%), acral (35%), and sun-damaged skin (25% to 30%) areas.
9. Melanoma is an immunogenic malignant tumor; therefore, complete or partial regression may occur.
II. CLINICAL VARIANTS
A. Superficial spreading melanoma (SSM) (Figure 16-18)
1. Most common subtype appears on any anatomic surface, but most common on the back for men and the legs for women.
2. Accounts for 70% of all diagnosed melanoma and is a leading cause of melanoma death for young adults.
3. It may occur at any age for both men and women, but slightly higher incidence in women.
4. Commonly appear as well-demarcated, asymmetrical, dark-pigmented macule or a patch or even slightly raised.
5. May arise within preexisting melanocytic nevus or de novo, with variegated colors including brown, black, pink, blue, gray, or white areas (possible regression) and with irregular borders.
6. Regression in SSM is a less pigmented area of a dark-pigmented SSM lesion, as a result of host’s immune responses trying to destroy it.
B. Nodular melanoma (NM) (Figure 16-19)
1. The second most common type of melanoma and accounts for 10% to 15% of all melanoma diagnosis.
2. May develop anywhere on the body and more commonly seen among persons aged 60 years and older.
3. Sudden appearance of nodular growth, in black, dark brown, or blue colors with well- defined border.
4. Rapid vertical growth of the tumor warrants deeper invasion and high potential of metastasis with poor prognosis.
5. Commonly arises de novo in uninvolved skin and often delays detection and treatment.
6. NM is typically a dark-pigmented lesion, but it may appear as a nonpigmented, flesh- colored nodule (amelanotic melanoma; Figure 16-20) or mimicking a scar or a benign cyst (desmoplastic neurotropic melanoma).
C. Acral lentiginous melanoma (ALM) (Figure 16-21)
1. Typically occurs on the palms, soles, subungual areas, and mucous membranes (mouth, nose, genitalia, anus, and urinary tract) in persons with more pigmented skin, such as Blacks, Asians, and non-White Hispanics. Accounts for 5% of total melanoma occurrence.
a. 2% to 8% occurrence in Whites b. 29% to 72% in dark-skinned persons
2. It presents as a flat, tan, brown to darkly pigmented macule or patch.
3. Subungual melanoma is a variant type and appears as dark-pigmented spot or fixed streaks from the proximal nail bed that does not move even with the nail growth.
4. Appearance of pigmented nail fold skin and destruction of the nail plate may indicate advanced ALM.
5. Based on the history of no recent trauma and bleeding under the nail plate (subungual hematoma), nail separating from the nail bed should be evaluated.
6. Mucous membrane involvement is often found in the mouth or inside of the nose, with
symptoms including frequent nosebleed, nasal congestion, and pigmented growth or a mass inside the nose and mouth.
D. Lentigo maligna melanoma (LMM) (Figure 16-22)
1. Occurs on exposed surface of the body, often on the face and scalp of elderly persons.
2. Often misdiagnosed as a benign age spot, sun spot, or a lentigo simplex.
3. Typically, gradual growth and evolvement over 10 to 15 years results in irregular pigmentation, shape, and border, but it’s not uncommon to see faster-growing LMM in matter of weeks to months.
4. A pigmented LMM patch may evolve into a nodular tumor, but it may also regress and appear as a blue-gray or white lesion.
5. An LMM can give rise to a desmoplastic melanoma, a fibrous tumor that has tendency to grow down and affect nerves of the skin.
FIGURE 16-18. Superficial spreading melanoma. (From Werner, R. (2012). Massage therapist’s guide to pathology. Philadelphia, PA: Wolters Kluwer.)
FIGURE 16-19. Nodular melanoma. This melanoma lesion was a 1.2-cm diameter nodule on a man’s midback. Its maximum tumor thickness was at least 3.14 mm, with mitotic rate 15/mm2, anatomic level IV, and staged as T3aN0M0. (Courtesy of Grace Chung.)
FIGURE 16-20. Amelanotic melanoma. A 2.5-cm diameter, 6.5-mm maximum tumor thickness, hypopigmented nodular amelanotic melanoma on a man’s back. This patient’s lymph node biopsy showed metastatic melanoma in 2 of 26 nodes. (Courtesy of Grace Chung.)
FIGURE 16-21. Acral lentiginous melanoma. (Courtesy of Art Huntley, MD, University of California at Davis.)
FIGURE 16-22. Lentigo maligna melanoma. (From Penne, R. B. (2011). Wills Eye Institute—
Oculoplastics. Philadelphia, PA: Wolters Kluwer.)
III. CLINICAL ASSESSMENT FOR MELANOMA
Early detection and diagnosis are the most critical factors in overall survival rates.
A. Suspected lesions most commonly include asymmetry, border irregularity, color variation, diameter greater than 6 mm, and elevated lesion (ABCDE rule).
B. The most suspicious sign for melanoma is persistently changing (size, color, elevation, itching) pigmented lesion.
C. Other findings that are suspicious include new pigmented lesions after the age of 30 to 40 and multiple halo nevi in mid-to-late adult life.
D. Ulceration correlates with tumor thickness and is a significant feature.
E. Atypical melanoma lesions may appear as nonpigmented, flesh-colored nodules (amelanotic melanoma) or mimicking scars or benign cysts (desmoplastic neurotropic melanoma).
F. Physical examination of the patient with melanoma should include:
1. History of the patient and family, including history of the lesion
2. Computerized digital imaging to allow retrieval and comparison of previously stored images of new and existing lesions (if available)
3. Meticulous skin examination of entire skin surface including the scalp and genitalia 4. Careful palpation of all lymph nodes with special attention to primary draining nodes 5. Body systems evaluation especially of the brain, lungs, bone, gastrointestinal, and
constitutional symptoms
IV. LABORATORY AND DIAGNOSTIC TESTS
A. Thorough history taking from patients including onset, duration, changes in color, shape, size, spontaneous bleeding and ulcerating, and evolution of the lesion. Visual inspection and comparison to the criteria of ABCDE rule:
1. Asymmetry (A): mismatching half
2. Border (B): poorly defined, atypical, or irregular border
3. Color (C): variegated shades (e.g., black, blue, reddish brown, tan, white) 4. Diameter (D): frequently greater than 6 mm (may be smaller)
5. Elevation/evolution (E): evolving in color, shape, and size
B. Dermoscopy/epiluminescence microscopy: clinical inspection using handheld magnifying/illuminating device for surface analysis
1. Skin biopsy is strongly recommended for definitive diagnosis and guidance for further follow-up.
2. Determination of the type of skin biopsy is based on the clinical presentation of the suspicious lesion: narrow excision biopsy with safety margin of 2-mm normal skin provides entire lesion or avoid transection of the lesion, adequate specimen for analysis, and staging of the lesion.
3. Incisional biopsy (partial sampling) is acceptable for a lesion with low clinical suspicion and large lesions. Repeat biopsy is suggested if the interpretation (e.g., diagnosis or microstaging) is inconclusive due to the inadequate size of specimen.
4. Chest x-ray and CBC/LDH screening for biopsy are proven invasive melanoma diagnosis.
5. Immunohistochemistry including S100 protein and HMB-45 can be used with panel of antibodies against other tumor markers to help diagnose otherwise nonobvious melanoma (performed by dermatopathologists).
6. Lymphatic mapping with sentinel lymph node biopsy (SLNB) for patients at risk for occult regional lymph node metastases. (Determined and performed by oncologists.)
V. DIFFERENTIAL DIAGNOSES
A. Basal cell carcinoma/pigmented basal cell carcinoma B. Benign melanocytic nevus
C. Blue nevus
D. Epidermal inclusion cyst E. Hypertrophic scar
F. Kaposi sarcoma
G. Merkel cell carcinoma H. Neurofibroma
I. Pigmented seborrheic keratosis J. Pyogenic granuloma
K. Solar lentigo L. Spitz nevus M. Verruca vulgaris
VI. STAGING CLASSIFICATION
A. Summary of 2010 American Joint Commission on Cancer (AJCC) Melanoma Staging System
1. The tumor–node–metastasis (TNM) system by the AJCC is the primary guideline for cancer staging and widely used (Table 16-1 and Box 16-1).
2. 2010 AJCC melanoma staging system update: primary tumor mitotic rate (T1 mitoses/mm2) replaced Clark level of invasion as the primary criterion for staging and prognosis and predictor for survival. The presence of tumor ulceration remains as the criterion for adverse predictor for survival.
3. Tumor ulceration, a condition that has missing parts of the epidermis of the primary tumor, indicates deeper tissue involvement and greater chance of metastasis compared to
nonulcerated tumors. This is determined by pathologists through microscopic examination of the tissue.
4. T is for classifying the tumor based on its three features: thickness (Breslow depth in millimeters [mm]), mitoses, and ulceration.
N is for indicating involvement of the echelon (nearby) lymph nodes.
M is for indicating the metastatic status and involvement of distant sites.
5. Mitotic rate indicating the cell division of the tumor and the tumor thickness (Breslow depth) are the primary predictors of the survival.
6. The metastatic lymph nodes are determined by sentinel lymph node dissection (SLND) or elective lymph node dissection (ELND) of the echelon lymph nodes to examine the presence of the melanoma.
a. Macrometastases can be palpated by physical examination of the lymph nodes.
b. Micrometastases are detected only by microscopic evaluation after SLN biopsy.
7. Metastasis to distant sites of skin and other vital organs is also screened by the level of serum lactate dehydrogenase (LDH). LDH elevation may indicate the metastatic disease status. Staging 0 to IV on the basis of the new TNM staging system:
a. Stage 0 (TisN0M0): melanoma in situ. Tumor is confined to the epidermis.
b. Stage I melanoma: determined by the presence or absence of mitoses and ulceration.
There are no other indications of regional lymph node involvement or distant metastasis.
1. Stage IA, T1aN0M0: tumor 1 mm or smaller without mitosis or ulceration 2. Stage IB, T1bN0M0: tumor 1 mm or smaller with mitosis or ulceration
c. Stage II melanoma: determined by the status of tumor thickness and ulceration. There are no other indications of regional lymph node involvement or distant metastasis.
1. Stage IIA: T2bN0M0 or T3aN0M0 2. Stage IIB: T3bN0M0 or T4aN0M0 3. Stage IIC: T4bN0M0
d. Stage III melanoma: determined by the level of lymph node metastasis. There are no other indications of distant metastasis.
1. Stage IIIA: T1-T4aN1aM0 or T1-T4aN2aM0
2. Stage IIIB: T1-T4bN1aM0, T1-T4bN2aM0, T1-T4aN1bM0, T1-T4aN2bM0, or T1- T4a/bN2cM0
3. Stage IIIC: T1-4bN1bM0, T1-4bN2bM0, or T1-4a/bN3M0
e. Stage IV melanoma: staging is determined by the location of sites of the metastases (e.g., skin, soft tissue, distant lymph nodes, and vital organs including liver, lungs, bones, and brain) and level of serum LDH.
1. M1a: tumor metastasis to distant skin, the subcutaneous layers, or lymph nodes; serum LDH is normal.
2. M1b: tumor metastasis to lungs; serum LDH is normal.
3. M1c: tumor has metastasis to vital organs other than lungs; serum LDH is normal or elevated.
TABLE 16-1 American Joint Committee on Cancer Melanoma Staging
System, 2010 a
aClinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010), published by Springer Science+Business Media. Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer, on behalf of the AJCC.