Skin cancers and melanoma
Basal Cell and Squamous Cell Carcinomas
I. Epidemiology and etiology
A. Incidence. In
At least I millioew cases of cutaneous basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) are diagnosed annually in the
B. Risk factors
1. Actinic (sun) damage appears to be a major carcinogenic factor. Ninety percent of these cancers develop in sun-exposed areas of the body. The incidence in white populations rises dramatically near the equator and is greater at higher altitudes than at sea level. Blue-eyed, fair-skinned, blond and red-haired people and those who are easily sunburned are at increased risk. The incidence in blacks is much lower than in whites.
2. Other carcinogens
a. Arsenic. Arsenical exposure predisposes to the development of Bowen’s disease, multiple BCC, and SCC, and is also associated with a higher incidence of intestinal carcinoma. Hard, yellowish hyperkeratotic plaques on the palms and soles provide a clue that the patient was exposed to arsenic.
b. Irradiation given for benign conditions (such as acne or hirsutism) or resulting from occupational exposure is associated with up to a 20% risk for skin cancer. The tumor develops many years after the initial exposure; latent periods may extend up to 50 years. About two thirds of these cancers are BCC, and one third is SCC. Radiation-associated SCC tends to be aggressive and has a 10% mortality rate.
c. Coal tar and quinacrine exposures appear to be risk factors for SCC.
d. Immunosuppression, such as with renal transplantation, predisposes patients to an increased incidence of cutaneous SCC. Cyclosporine is associated with cutaneous SCC and lymphomas.
3. Chronic inflammation and trauma
a. Chronic draining osteomyelitis predisposes to the development of SCC. The local tumor is usually evident but may first be manifested by metastases to a draining lymph node.
b. Fistulas, stasis dermatitis, and areas of irritative leukoplakia can also give rise to skin cancers.
c. Thermal or electrical burns and chronic heat exposure are associated with increased risk for high-grade, aggressive SCC. Certain ethnic groups are burned from hot coals used as bed or clothing warmers.
d. Atrophic skin lesions of discoid lupus or epidermolysis bullosa give rise to SCC.
4. Hereditary factors
a. Xeroderma pigmentosum is an autosomal recessive disease with one or more defects in DNA repair enzymes. Patients sunburn and freckle easily. Young children with xeroderma pigmentosum are at high risk for BCC, SCC, or malignant melanoma before their teenage years. Disturbances in speech, mentation, and convulsive disorders may also be present. A severe form (De Sanctis-Cacchione syndrome) includes microcephaly, mental deficiency, dwarfism, and failure of gonadal development.
b. Basal cell nevus syndrome appears to be inherited as an autosomal dominant trait. Multiple BCC lesions appear over the face, arms, and trunk during the late teenage years. A large variety of associated lesions can occur and include jaw cysts, palmar pits, bifid ribs, kyphoscoliosis, spina bifida, short metacarpals, and hyporesponsiveness to parathyroid hormone. Patients with this syndrome also appear to be at increased risk for medulloblastoma and ovarian fibroma.
5. Infection
a. Epidermodysplasia verruciformis is primarily caused by human papillomaviruses (HPV) types 5 and 8 and results in in situ and invasive SCC synergistically with other carcinogens, such as sunlight.
b. SCCs of the genitals and anal regions are strongly associated with HPV types 16 and 18. Infection, usually through sexual transmission, increases the risk for regional SCC.
c. Periungual SCC is associated with HPV type 16.
6. Oncogene (Ha-ras, Ki-ras, N-ras, c-myc, and others) mutation and amplification, as well as anti-oncogene p53 mutations, have been reported for BCC and SCC.
II. Pathology and natural history
A. SCC nearly always arises in skin that is visibly damaged. Lesions most commonly are ulcerative but may be exophytic.
1 Aggressive squamous cell cancers are unlikely to arise from actinic keratosis or actinic skin damage. The lower extremities are frequently involved and may have to be amputated to effect cure. Aggressive SCC also develops from burn scars, radiation dermatitis, and erythroplasia of Queyrat and Bowen’s disease.
2. Bowen’s disease consists of small eczematoid plaques. By histology, the plaques demonstrate intraepithelial carcinoma in situ. Invasion may occur; thus, treatment is necessary. Although historically suspected, Bowen’s disease is not associated with an increased risk for internal cancer.
3. Bowenoid papulosis is characterized by multiple genital papules that are histologically indistinguishable from Bowen’s disease. They are usually caused by HPV type 16 and, when present on the female patient or her sexual partner, may indicate increased risk for cervical carcinoma.
4. Metastases. Tumors that metastasize are usually poorly differentiated. The incidence of metastasis is less than 3% for actinically induced SCC and 35% for nonactinically induced SCC. The draining lymph nodes are the most frequent sites of metastases, although distant organs are eventually involved.
B. BCC is the most common type of skin cancer. It has several recognized subtypes.
1. Nodular-ulcerated BCC, the most common type, usually appears on the face as a waxy papule with pearly or waxy borders. Some lesions are pigmented and clinically indistinguishable from melanoma. They spread both over the surface and deeply into the tissues to invade cartilage and bone. Ulceration is common (“rodent ulcer”). Inadequately treated BCC can result in severely deforming facial ulcerations and death through invasion of the vital structures of the head and neck. Distant metastases from BCC are extremely rare.
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2. Superficial BCC lesions usually arise on the trunk, are often multiple, and appear as red, scaly patches with areas of brown or black pigmentation. They spread over the skin surface and may have areas of nodularity.
3. Sclerosing BCC usually affects the face. The tumors closely resemble scars and may have an ivory-colored and ill-defined border. Histologically, the cancer cells are surrounded by a dense bed of fibrosis (“morphea-like”). Considering all types of BCC, they have the highest recurrence rate after treatment.
4. Cystic BCC is uncommon. The tumor undergoes central degeneration to form a cystic lesion.
5. Linear BCC is a recently recognized morphologic clinical entity characterized by an increased risk for aggressive histopathologic pattern and increased subclinical tumor extension.
6. Micronodular BCC is defined histopathologically by small tumor nests and often exhibits covert subclinical growth.
III. Diagnosis. Skin biopsy is necessary to confirm the clinical suspicion of skin cancer. A shave or curette biopsy is usually adequate to diagnose BCC or SCC. If the first biopsy is negative and the tumor is still suspected, a deeper biopsy is necessary.
IV. Staging system and prognostic factors
TNM system (the 6th edition, 2002) for classification of cutaneous carcinomas uses TX, T0 for unassessed or absent primary tumor, respectively, NX, NO, or Nl for unassessed, absent, or present regional lymph node metastases, respectively, and MX, MO, or Ml for unassessed, absent, or present distant metastases, respectively.
Tis, pTis Carcinoma in situ
Tl, pTl Tumor
T2, pT2 Tumor >2 but ≤
T3, pT3 Tumor more than
T4, pT4 Tumor any size extends into surrounding tissues (cartilages, muscles, bones).
B. BCC does not ordinarily require staging because of the rarity of metastases. However, the clinician should record the diameter and location of the lesion and whether the tumor is primary or recurrent. The prognosis for BCC is worsened if the tumor is morpheaform, linear, micronodular, recurrent, or greater than
C. Cutaneous SCC is clinically staged based on clinical examination of the lesion and regional lymph nodes. No other metastatic workup is indicated. The prognosis for SCC is worsened if the tumor is recurrent, arises in a scar, occurs in immunocompromised patients, is greater than
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V. Prevention. Primary prevention is largely achieved by encouraging patients and other responsible parties to minimize sunlight exposure and other reducible risk factors. Secondary prevention is provided by lesional treatment.
Skin erythema from solar exposure, even from ultraviolet light on cloudy days, represents skin damage that is cumulative over the years. The “healthy tan” represents the body’s reaction to skin damage, and freckling should be recognized as an early sign of skin injury. Sunscreens with a sun protective factor (SPF) of 15 or greater and protective clothing, including hats, are helpful.
VI. Management
A. Actinic keratoses may become SCC (1% risk). Lesions may be treated by liquid nitrogen or by curettage with electrical cautery of the base. The use of topical applications of fluorouracil or masoprocol can be successful in highly motivated patients.
B. BCC and SCC are treated by several techniques, which have various cure rates.
1. Traditional surgical resection requires a surgical margin of 4 to
· Skin Squamous Cell Cancer of Neck, T4N0M0
· Postoperative wound is temporary covered with pig skin xenografts.
· granulation wound after removing of xenografts
· skin autografting.
· complete recovery 12 months later
2. Mohs micrographic chemosurgery has the highest cure rates, maximally spares uninvolved tissue, and is less costly than radiation therapy (RT) or traditional excision surgery with frozen-section control. With this method, the tumor is microscopically mapped after it is excised. Mohs surgery is indicated for the following lesions:
a. Primary BCC or SCC with the following characteristics:
(1) Located in regions at high risk for tumor recurrence (i.e., the periorbital area, nasolabial fold, nose-cheek angle;, posterior ear sulcus, pinna, ear canal, nose, forehead, and scar tissue)
(2) Located in regions where tissue conservation is mandated
(3) Poorly defined clinical borders
(4) Diameter greater than
(5) Perineural invasion
(6) Morpheaform, sclerotic, infiltrating, micronodular, or basosquamous histopathologic features or linear clinical presentation
b. Recurrent BCC or SCC. Of all therapeutic modalities for recurrent tumors, Mohs surgery has the greatest success rate (95%) and should ordinarily be considered the preferred treatment.
3. Curettage of the tumor with electrodesiccation of the apparently normal base to an additional depth of 3 or
4. Cryosurgery using liquid nitrogen to freeze the tumor to
5. RT has the same indications as cryosurgery. It is relatively contraindicated in patients with xeroderma pigmentosa, epidermodysplasia verruciformis, or the basal cell nevus syndrome because RT may induce more tumors in the treated field. RT may have adjuvant use for unusually aggressive SCC and is used with or without surgery when metastasis involves regional lymph nodes.
6. Laser therapy. A laser beam in a regimen of laser scalpel and laser coagulation is applied for the treatment of cutaneous cancer (high-intensive laser radiation). Recently the method of a photodynamic photoradiotherapy of the skin cancer and its relapses is more widely used. The essence of the method is, that the photosensitinogen is inlet into the organism and selectively collects in a tumour. After 24-48 hours the tumour is irradiated with the therapeutic laser that causes a photodestruction of tumour. The method can be combined with the other known methods of cancer treatment
7. Large, deeply eroding tumors can partially or totally destroy the face. These far-advanced cancers often cannot be cured. Computed tomography (CT) or magnetic resonance imaging (MRI) scans are useful for determining the extent of disease resulting from local invasion. Often, extensive reconstructive surgery is necessary after a surgical intervention. In the most severe cases, the patient may elect to wear prosthesis.
Squamous Cell Carcinoma of left cheek, T4N0M0
Results after half course of gamma-therapy, 45 Gy
7. Chemotherapy. Chemotherapy has no adjuvant use for BCC or SCC. Experience in treating metastatic skin cancers is extremely limited. Fluorouracil, cisplatin, methotrexate, bleomycin, retinoids, and cyclophosphamide given singly and in combination have produced temporary tumor regression. Excellent response rates have been reported for advanced cases of SCC and BCC treated with cisplatin in combination with either a 5-day infusion of 5-fluorouracil or doxorubicin.
1. Single agents. Methotrexate, bleomycin, carboplatin, cisplatin, vinorelbine, epirubicin, and 5-fluorouracil (5-FU) are active single agents, each achieving significant tumor reduction in 15% to 30% of patients.
2. Combination chemotherapy regimens. The most useful regimens combine cisplatin and 5-FU (PF regimen) without leucovorin or with it (PFL regimen). Adding other drugs to this combination has not improved results. Representative regimens, which are given every 21 to 28 days, include the following:
a. PF
Cisplatin, 100 mg/m² IV on day 1
5-FU, 1000 mg/m²/day by continuous IV infusion (CIV) for 5 days (total, 5 g/m²)
b. PFL
Cisplatin, 25 mg/m² IV on days 1 through 5 by CIV (total, 125 mg/m²)
5-FU, 800 mg/m²/day on days 2 through 6 by CIV (total, 4 g/m²)
Leucovorin, 500 mg/m² on days 1 through 6 by CIV (total, 3 g/m²).
Education materials prepared by:
Igor Y. Galaychuk, MD, DSc,
Professor, Chief, Department of Oncology and Radiology,
Malignant Melanoma
I. Epidemiology and etiology
A. Incidence. In
Melanoma used to be a rather uncommon tumor. However, the incidence has gradually been rising with a tenfold increase in the period of 1945 to 1990. Now about 40,000 new cases of melanoma are diagnosed in the
1. Sex. The risk for melanoma is the same for men and women. Men are more likely to develop melanoma on the trunk, and women are more likely to develop lesions on the lower extremities.
2. Age. Melanoma is rare in young children. The incidence begins to rise with puberty, increases until 65 to 70 years of age, and then decreases.
3. Race. The incidence of melanoma is low in people of color.
4. Multiplicity. About 5% of patients with a primary cutaneous melanoma have or will develop another primary melanoma or multiple primary melanomas.
B. Risk factors
1. Sun exposure appears to increase the risk for cutaneous and ocular melanoma.
2. Hereditary factors. About 10% of melanomas occur in family clusters.
a. “Melanoma families” appear to have a dominant mode of inheritance with incomplete penetrance. Ocular or cutaneous melanoma occurs in several members of these families. Members of melanoma families who get melanoma do so at a younger age and have a higher incidence of multiple primary tumors than do patients with sporadic melanomas.
b. Atypical mole syndrome (AMS), or dysplastic nevus syndrome (DNS), is a recently described clinical syndrome of acquired atypical-appearing nevi that are associated with melanoma. Inheritance appears to be autosomal dominant with incomplete expression and penetrance.
3. Nevi
a. About 70% of patients with melanoma have had a preexisting nevus at the primary tumor site. Congenital nevi may engender increased risk for melanoma. Giant congenital nevi have an extremely high incidence of malignant transformation. When feasible, removal is advised.
b. White men have 20 to 40 moles by the third decade of life. Nevi continue to form throughout adult life; however, only 1 mole out of 500,000 becomes malignant.
4. Other melanoma risk factors include chemical exposure, physical agents (i.e., nonsolar ultraviolet radiation, ionizing radiation, trauma, and burns), immunosuppression, and profession.
5. Oncogene mutations (N-ras, Ha-ras, Ki-ras) and amplifications (N-ras, Ha-ras), as well as p53 antioncogene mutation.
II. Pathology and natural history
A. Melanocytes are believed to migrate from the embryonic neural crest to the dermal-epidermal junction of the skin. The number of melanocytes per unit of skin surface appears to be the same for all races, even albinos. Pigmentary differences between races are dependent on how the melanin is “packaged” in each cell.
B. Histopathologic types of melanoma
1. Superficial spreading melanoma, or radial spreading melanoma (70% of melanomas), is more common in women and is most frequently located on the back.
The lesion is a pigmented macule or a barely palpable plaque with variegated colors (black, tan, red, brown, or white). Irregularity of the margins, especially the presence of a notch, is a suspicious feature. These tumors mostly manifest radial growth but eventually enter a vertical growth phase.
2. Nodular melanoma (15% of melanomas) occur more frequently in men. Most of these lesions are jet-black or dark-blue with a distinct border. Occasionally, no pigment is present, and electron microscopy or special tissue stains are needed to determine the diagnosis. These tumors grow rapidly and vertically from the onset.
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3. Lentigo maligna melanoma (10% to 15% of melanomas) have no sexual predilection. The lesion appears as a large, flat, tan-to-black macule of up to
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The in situ lentigo maligna lesion (or Hutchinson`s freckle) shows a horizontal growth phase for up to 20 years and eventually a vertical growth phase anywhere in the involved area. The vertical phase resembles superficial spreading melanoma rather thaodular melanoma.
4. Acral lentiginous melanoma is melanoma involving the palms, fingers, soles, and toes.
5. Unclassified and rare desmoplastic variants also exist.
C. Natural history
1. Mode of spread. Most cutaneous melanomas are believed to arise near the basal lamina.
a. Radial growth. The superficial spreading and lentigo maligna melanomas grow horizontally along the lamina (radial growth phase) before penetrating the deep skin structures (vertical growth phase). The radial phase may last as long as 20 years in lentigo maligna and 5 years in superficial spreading melanoma.
b. Vertical growth. Nodular melanomas have a vertical growth phase from the outset. The vertical phase is associated with invasion of dermal blood and lymphatic vessels.
c. Lymphatics. Local lymphatic spread results in satellite nodules of melanoma appearing near the site of the primary tumor (satellitosis). Draining lymph nodes are frequently involved after the vertical growth phase develops. The first lymph node to become involved is termed the sentinel node.
d. Distant metastases. Metastatic melanomas can involve any organ in the body, including the placenta and fetus. About 5% of patients with melanoma present with symptoms of distant metastases without an apparent primary site.
2. Unusual primary sites of melanoma
a. Melanomas can occur on the soles of the feet and under fingernails, especially of the thumbs and large toes. These sites are more likely to be affected in people of color.
b. Ocular melanoma can develop in the choroid, ciliary body, or uvea. Melanomas occurring in the eye itself have been divided into a variety of histologic subtypes, which have different prognoses. These tumors have a peculiar tendency of metastasizing to the liver, sometimes many years after diagnosis of the primary site, giving rise to the “syndrome” of hepatomegaly, unilateral scleral icterus, and a prosthetic glass eye.
c. Melanomas may rarely arise in the palate or gingiva, usually in a site in which increased pigmentation was previously noted.
d. The anus and vulva are also potential sites for development of melanoma; 5% of melanomas in women occur on the vulva and 5% to 10% of vulvar cancers are melanomas, even though the vulva accounts for less than 2% of the body surface area.
e. Internal sites with a melanocyte population, such as the foregut or central nervous system, may rarely be the site of a primary melanoma.
3. Metastatic melanoma from an unknown primary site accounts for 4% to 5% of all cases. To further complicate the problems of diagnosis and management, amelanotic melanoma may be mistaken for undifferentiated carcinoma. Patients usually have lymphatic metastases, but any organ may be involved. The occult primary site may have disappeared spontaneously or may have been excised or cauterized years before the appearance of the metastasis. The prognosis for these patients depends on the stage of disease and appears to be the same as for patients with clinically evident primary sites.
4. Paraneoplastic syndromes associated with melanoma have a wide scope and include vitiligo, dermatomyositis, melanosis, gynecomastia, ectopic Cushing’s syndrome, and neurologic abnormalities.
III. Diagnosis
A. Symptoms
1. Change in a preexisting pigmented lesion is the first sign of melanoma in 70% of patients. The lesion becomes lighter, darker, or variegated in color; increases in size; or may be associated with an itching sensation. Ulceration or bleeding usually represents advanced disease.
2. De novo melanomas, not associated with previously observed skin lesions, occur in about 30% of patients.
3. Symptoms of distant metastases depend on the anatomic site involved.
B. Physical examination. Patients should be viewed completely for skin lesions. Special attention is given to areas not usually inspected, such as axillae, scalp, interdigital webs, mouth, genitals, and anal and oral regions. Palpation may reveal lymph node enlargement or organomegaly.
C. Differential diagnosis
1. Pigmented skin lesions. There are many pigmented skin lesions to consider in the differential diagnosis of melanoma. Common dark skin lesions include atypical mole, pigmented BCCs, seborrheic keratoses and sclerosing hemangiomas. It is often difficult to distinguish early melanoma from a benign lesion clinically. Epilumincscence microscopy has not gained widespread acceptance in the
2. Signs that suggest melanoma are variegated color and irregular borders. The presence of hair in the lesion does not assist in the differentiation of a benign lesion from melanoma. Specific findings that may indicate melanoma include the following:
a. Changes in size, color, sensation, or surface characteristics of a preexisting nevus
b. Lesions with variegated color (shades of brown, black, red, white, or blue)
c. Lesions that contain bluish coloration even if not variegated
d. Lesions with angular indentations or notches
e. Other signs of possible malignancy include the following:
(1) Lesions that do not contain skin creases
(2) Lesions that ulcerate or bleed
ABCD rules for diagnosis of melanoma.
D. Laboratory studies
1. Biopsy of the lesion is the first diagnostic procedure to be undertaken. Suspected melanoma should not be observed for further signs. An excision may be desirable based on the size and location. Excisional margins should only be a few millimeters in order not to interfere with future possible sentinel node mapping. An incisional biopsy may be performed when excision is not desired. There is no reliable evidence that incisional biopsies for melanoma result in increased morbidity or mortality.
2. Patients with many small atypical nevi (AMS, DNS). Several nevi should be excised and examined microscopically. Baseline total-body photographs are recommended. Significantly changed lesions should prompt excision. Monthly skin self-examination is recommended for the purpose of monitoring the atypical moles for malignant changes, with interim physician examination as indicated. Lifetime physician follow-up is recommended for early melanoma diagnosis.
3. Immunohistochemistry. S100 protein (more sensitive) and HMB-45 (more specific) may help distinguish poorly differentiated amelanotic malignant melanoma from tumors of obscure histologic origin.
IV. Staging system and prognostic factors
A. Now TNM classification of cutaneous melanoma (the 6th edition, 2002) takes into account the Clark`s levels by depth of invasion into the skin only in T1:
T1: tumor ≤1.00mm thick
T1a tumor without ulceration and level invasion II/III by
T1b tumor with ulceration or level invasion IV/V by
T2: tumor 1.01 – 2.0mm thick
T2a tumor without ulceration
T2b tumor with ulceration
T3: tumor 2.01 – 4.0mm thick
T3a tumor without ulceration
T3b tumor with ulceration
T4: tumor>4mm thick
T4a tumor without ulceration
T4b tumor with ulceration
N1 Metastases into one lymph node
N1a micrometastases
N1b macrometastases
N2 Metastases into 2 – 3 lymph nodes
N2a micrometastases
N2b macrometastases
N2c transit metastases/satellite without metastases into lymph nodes
N3 Metastases into 4 and more lymph nodes, or conglomerate nodes, or transit metastases/satellite with metastatic nodes.
M1 Distant metastases
M1a distant metastases into skin, subcutaneous fat, or lymph nodes.
M1b distant metastases into lungs.
M1c distant metastases into any other organs.
Nodular Melanoma Т4bNхM0
B. Prognostic factors. Depth of invasion, presence of positive lymph nodes, and presence of distant metastases greatly affect prognosis. Women have a better prognosis than do men when matched by age and stage of disease.
1.
Level Tumor extent
I Tumor is confined to epidermis (in situ)
II Tumor extends beyond basal lamina into papillary dermis
III Tumor extends into papillary dermis and abuts onto, but, does not invade, the reticular dermis
IV Tumor extends into reticular dermis
V Tumor extends into subcutaneous fat
Five-year survival (%): I -100%; II -85%; III -65%; IV -50%; V -15%.
2. Breslow’s system by depth of tumor invasion from the basal lamina (measured with an ocular micrometer). Tumors with less than
Depth of tumor invasion Five-year survival (%)
<
>
3. Survival according to regional lymph node involvement.
Node involvement Five-year survival (%)
Negative nodes 75
1-3 positive nodes 50
4 or more positive nodes 25
4. Survival according to metastatic spread
Stage Extent Five-year survival (%)
II Local recurrences within
III Satellitosis <20
IV Distant metastases <10
C. Recommended staging evaluation
1. Breslow’s or Clark’s level should be determined in all instances when a primary tumor is identified.
2. Regional lymph nodes should be palpated and any suspicious finding should undergo biopsy. Lymph nodes containing melanoma require treatment.
3. Sentinel node dissection after lymphoscintigraphy is offered at some centers to patients who have primary melanomas that are 1 to
4. For melanomas thicker than
V. Prevention. Primary prevention of melanoma involves the avoidance of sun and other reducible risk factors. Secondary prevention depends on careful physical examination and biopsy of all suspicious skin lesions.
VI. Management
A. Surgery
1. Management of the primary tumor
a. Cutaneous melanoma. Local excision of early melanoma is the only proven method of curative therapy. The extent of tumor-free margins that is necessary remains controversial. Current required surgical margins are
Mohs micrographic chemosurgery should be considered for facial melanoma and other areas where tissue conservation is desired because of its equivalent cure rate. Tumor margin is often influenced by site. Large defects may require skin grafting or skin flaps.
b. Choroidal melanomas of the eye were treated historically by enucleation. Small tumors have been successfully treated with high-dose irradiation and local surgical measures; this treatment avoids removal of the eye.
2. Management of lymph nodes. Prophylactic resection of clinically uninvolved draining lymph nodes for intermediate-thickness stage I disease is controversial because it may not affect survival. Palpable nodes should be excised.
· Complex treatment of primary melanoma Т3bN1аМ0
(X-ray + Chemotherapy ® Surgery + Chemo. + INF)
3. Management of metastases. Highly selected patients may benefit from resection of metastases, particularly if they are solitary and completely excised.
· Melanoma metastases into spleen (surgical specimen) and lymph node.
· Spleen metastasis of melanoma (2001);
· CT scan in 3 years after splenectomy (2004).
a. Solitary brain metastases. The brain is the third most frequent site of metastases. Operable solitary metastases may be excised, but prolonged survival is rare.
b. Gastrointestinal problems. Melanoma has a tendency to metastasize to the gastrointestinal tract, where it may cause bleeding, intussusception, or obstruction. Endoscopy should be an early study done on patients who have upper gastrointestinal tract bleeding. The characteristic “bull’s eye” appearance on contrast studies of small bowel lesions is highly suggestive of melanoma. Patients with obstruction or uncontrolled bleeding from an apparently isolated intestinal lesion may temporarily benefit from resection of the tumor.
c. Pulmonary metastases from melanoma are rarely beneficially resected, even if they appear to be solitary.
B. RT is occasionally useful as a primary or adjuvant modality for treating melanoma patients who are debilitated or who refuse surgery.
C. Systemic therapy. Caution must be used when interpreting responses of metastatic melanoma to systemic therapies of any kind because melanoma is a capricious neoplasm that is associated with spontaneous regressions. Responses may be temporally but not causally related to treatment.
1. Adjuvant therapy. The use of traditional chemotherapy as an adjuvant to surgery failed to improve survival. Interferon-α (IFN-α), however, has clearly demonstrated effectiveness in melanoma, particularly for patients with lymph node involvement. Treatment should be started shortly after surgery. IFN-α2a and IFN-α2b differ in only one amino acid.
a. AJCC stage III: intravenous IFN- α2b improved the 5-year relapse-free survival rate (67% reduction in relapses) and the overall 5-year survival rate for stage III melanoma (pathologically positive nodes) in a large Eastern Cooperative Oncology Group study. IFN-α2b is given as an TV bolus at a dose of 20 MIU/m² for 5 days per week for 4 weeks, followed by SC injections three times weekly of 10 MIU/m²- for 48 weeks. Toxicity of this therapy is substantial, constitutional, hematologic, hepatic, neurologic, and financial. The dose of IFN is withheld until toxicity improves and then reduced by 33% to 50% if the neutrophil count falls to below 500/µL. if the transaminase levels are 5 to 10 times normal, or if the bilirubin is 2 to 5 times normal. IFN therapy is discontinued if the neutrophil count falls to below 250/µL, if the ALT or AST is more than 10 times normal, or if the bilirubin is more than 5 times normal.
b. AJCC stage IIB: IFN-α2b is also being offered to patients with stage IIB melanoma (more than
c. AJCC stage IIA: IFN-α2a, 3 MIU (not per m²) given SC three times weekly for 18 months, has significantly improved relapse-free interval but has not yet been shown to improve overall survival in these patients. The toxicity and cost of this regimen is substantially less than that of the intravenous regimen.
2. Limb perfusion. Patients with melanoma of the extremity and “in-transit” or “satellite” cutaneous metastases may be treated by limb perfusion with cytotoxic agents. Although excision can be considered for a few small satellites, perfusion is considered when the satellites are multiple, recurrent, or unresectable. The arterial and venous blood supplies of the involved extremity are isolated, and heated solutions of melphalan or other drugs are injected. Limb perfusion permits the administration of high doses of drugs while minimizing drug toxicity. Local tumor response rates are reported to be high, but whether the survival rate is affected is unclear.
· “in-transit” cutaneous metastases
3. Cytotoxic agents can be used in patients with distant metastases. Dacarbazine (DTIC) is the most effective drug. “Response rates are 20% for skin and lymph node metastases but less than 5% for visceral or skeletal metastases. The combination of dacarbazine with a vinca alkaloid and an alkylating agent (cisplatin or lomustine) appears to improve the response rate to 30% to 40%. The addition of IFN increases the toxicity but not the response or survival rates. The traditional BOLD regimen is given to suitable patients every 28 days, as follows:
Bleomycin, 15 units IV on days 1 and 4
Vincristine (Oncovin), 1 mg/m² IV on days 1 and 5
Lomustine (CCNU), 80 mg/m²
DTIC, 200 mg/m² IV on days 1 through 5
4. Tamoxifen was shown in small studies to have effectiveness and improved response rate in melanoma for women only. Subsequent studies have not validated those observations.
5. Immunotherapy. The use of bacillus Calmette-Guerin (BCG) does not affect survival of patients with malignant melanoma. The use of IFN in melanoma was discussed previously.
a. Satellite lesions injected with BCG may regress in 40% of treated patients. This treatment can leave chronic, draining BCG infections or scabs on the skin, result in disseminated BCG infection (e.g., granulomatous hepatitis) that requires therapy with isoniazid, and produce a shocklike syndrome.
b. Interleukin-2 (IL-2), with or without lymphokine-activated killer cells, is associated with response rates of about 25% at the expense of high cost and considerable toxicity. Only a small proportion of patients achieve a durable remission.
c. Sequential chemobiotherapy using standard cytotoxic drugs with IFN, IL-2, or both is investigational.
d. Tumor cell vaccines and gene therapies are investigational.
VII. Special clinical problems associated with malignant melanoma
A. Cardiac metastases frequently occur with melanoma and can occasionally result in arrhythmia or cardiac rupture. Antemortem diagnosis is difficult in the absence of malignant pericardial effusion. Patients should be treated with appropriate antiarrhythmic agents. RT to the heart is probably of little benefit.
B. Breast metastases. Poorly differentiated or undifferentiated melanoma metastatic to breast can be confused with primary breast cancer.
C. Slate-gray skin discoloration (melanosis syndrome) results from widespread melanoma, which causes high blood and urinary melanogens. Affected patients often have urine that is dark or darkens on exposure to air.
D. Black sputum, similar to that seen in coal miners, may occur in patients who have pulmonary melanoma lesions that have eroded into the airways.
Metastatic melanoma
