Bartosz Chmielowski, Antoni Ribas, and Richard F. Wagner Jr
MALIGNANT MELANOMA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Malignant melanoma is the sixth most common cancer among women and the fifth most common cancer among men in the United States. Malignant melanoma accounts for about 4% of all skin cancers, but it is responsible for 80% of deaths. The incidence of melanoma in the United States is 18.2 cases per 100,000/year, two-thirds in males and one-third in women. The median age at the time of diagnosis is 58 years, and only 0.9% of cases are diagnosed before the age of 20. The estimated number of new cases in the United States in 2010 is 68,130, and 8,700 patients would die of melanoma.
The incidence of melanoma rose rapidly in the 1970s at about 6% per year; this rate decreased in the 1980s to about 3% per year. In the past decade, the death rate from melanoma has decreased. White people have a 17 to 25 times higher risk for the development of melanoma than blacks, but melanoma is diagnosed among all races.
B. Risk factors. The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma. The list of additional risk factors includes immunosuppression, sun sensitivity, and exposure to ultraviolet (UV) radiation.
1. Familial factors. Approximately 10% of melanomas are familial. The higher risk of melanoma in these families may be attributed to both shared susceptibility genes and shared environment.
a. High-penetrance susceptibility genes. Two genes, CDKN2A and CDK4, are associated with high-penetrance susceptibility. Mutated CDKN2A is the most prevalent gene in families with melanoma. It is located on chromosome 9p21 and it encodes cyclin-dependent kinase inhibitor 2A (p16INK4a). CDK4 encodes cyclin-dependent kinase 4, which is one of the binding partners of p16INK4a. Mutations in CDK4 are found much less frequently than in CDKN2A. Also evidence exists for another, as yet unidentified, high-penetrance susceptibility gene at chromosome 1p22.
The higher the number of family members with melanoma, the higher the probability of carrying a high-penetrance gene. Mutated CDKN2A was found in 14% families with 2 cases of melanoma, in 67% families with 6 to 7 cases, and 100% families with 7 to 10 cases. Overall, between 20% (in Australia) and 57% (in Europe) of the cases of familial melanoma are associated with CDKN2A.
b. Low-penetrance susceptibility genes. Epidemiologic studies suggest that low-penetrance susceptibility genes are found frequently among families with melanoma. The MC1R gene, which encodes the melanocyte-stimulating hormone receptor, has been characterized best.
c. Familial atypical multiple mole-melanoma (FAMMM) syndrome, also known as the familial dysplastic nevus syndrome, was described in 1978 in families whose members suffered from melanoma and had multiple (usually >100) large moles of variable size and color (reddish brown to bright red) with pigmentary leakage. The median age of the development of melanoma in persons with this syndrome is 33 years, and 9% of affected people develop it before the age of 20. The syndrome is transmitted in autosomal dominant fashion, but there are sex differences in penetrance. Males develop melanoma less frequently and at an older age than women.
2. Nevi. Typical nevi are frequently precursors of melanoma, but more importantly they are markers of increased risk. One study showed that men who have at least 17 and women who have at least 12 small moles on the back are at 4.6 and 5.1 times higher risk of the development of melanoma, respectively. The lifetime risk for any mole to transform into melanoma by age 80 years is 0.03% for men and 0.009% for women.
Congenital nevi are benign neoplasms that are present at birth and composed of nevomelanocytes. The malignant potential of giant congenital nevi varies between different types. Pigmented giant nevi have especially high risk for malignant transformation. Nevus sebaceous is associated with the development of basal cell carcinoma. Verrucous epidermal nevi and woolly hair nevi do not have malignant potential.
3. Previous melanoma. The rate of a second primary cutaneous melanoma is more than 10 times higher than the first one. The 1-, 5-, and 10-year probability of developing the second primary melanoma are 1% to 2%, 2.1% to 3.4%, and 3.2% to 5.3%, respectively. The greatest risk is within the first 2 years, but it remains elevated for at least 20 years. Males, elderly patients, and individuals with the first melanoma on the face, the neck, and the trunk are at especially high risk. The incidence of a third primary melanoma from the time of second primary melanoma is 16% at 1 year and 31% at 5 years.
4. Immunosuppression. Among organ allograft recipients, melanoma constituted 5% of skin cancers and was significantly higher than in the general population (2.7%). A six- to eightfold increase in melanoma rates has been observed among male kidney transplant recipients.
5. Sun sensitivity. Light-skinned and redheaded people frequently carry a polymorphism in the melanocortin receptor gene (MC1R) that results in a decreased melanin production after exposure to ultraviolet (UV) radiation and in an increased risk of melanoma.
6. Exposure to sun and to UV radiation. It is known that UV radiation causes genetic changes in the skin, impairs cutaneous immune function, increases the local production of growth factors, and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes. Epidemiologic studies revealed that intermittent sun exposure and frequent sunburns, especially during childhood, increase the risk of melanoma. Chronic low-grade sun exposure may be protective, although data also show that higher total exposure to the sun is associated with a higher risk of melanoma among non-Hispanic white individuals. In addition, exposure to UV light from recreational tanning salons is emerging as an important risk factor for melanoma.
7. Occupational exposure. Exposure to coal tar, pitch, creosote, arsenic compounds, or radium increases the risk of melanoma development.
II. PREVENTION. Avoidance of exposure to the sun during the midday hours, wearing skin-protecting clothing, sunglasses, use of sunscreens with a sun protective factor (SPF) of 15 or higher, and avoidance of sunburns and tanning beds are recommended as a primary prevention. Patients with a family or personal history of melanoma should undergo at least one annual skin examination performed by a dermatologist as a secondary prevention. Suspicious lesions must be biopsied.
III. PATHOLOGY AND NATURAL HISTORY
A. Pathology. Melanoma originates from melanocytes, the neural crest-derived cells that migrate into the epidermis during embryogenesis to reside in the basal layer of the epidermis. The overwhelming majority of melanomas originate in the skin, but some melanomas may arise from other primary sites. Potential extracutaneous sites include the choroidal layer of the eye and mucosal surfaces in the upper respiratory tract (most frequently, the nose and nasopharynx), gastrointestinal (GI) tract (most frequently, the anus), and genitourinary tract (most frequently, the vagina).
Several steps occur in the process of their malignant transformation. According to the Clark model, initially normal melanocytes proliferate and form a benign nevus. In the next phase, abnormal growth appears in the form of a dysplastic nevus. Melanoma may originate from a benign nevus, but it can also start from scattered melanocytes present in the normal skin. Next, in the radial growth phase, the cells acquire the ability to grow intraepidermally and have all the features of cancerous cells. Then, the lesion invades the dermis (vertical-growth phase) and finally spreads to other organs and other areas of the skin (metastasis). Not all melanomas pass through each of these individual phases, however.
B. Molecular events in the pathogenesis of melanoma. Several molecular alterations have known pathogenic effects in the transformation of melanocytes and the evolution of melanoma. In general, germline or somatic alterations in cell-cycle control, together with somatic activating mutations or amplifications of factors involved in signal transduction pathways, are required for melanoma development.
1. Alterations in signal transduction pathways. Mutually exclusive somatic activating point mutations in NRAS (15% of melanomas) and BRAF (50% to 60% of melanomas), two members of the mitogen-activated protein kinase (MAPK) that provides proliferation signaling from surface receptors to the nucleus, are present in most melanomas of skin primary. Paradoxically, BRAF mutation is also frequent in benign nevi, where its transforming effect may be counteracted by the phenomenon of oncogene-induced senescence.
Somatic alterations in another signaling pathway important in cell growth, the phosphoinositide-3-OH kinase (PI3K) pathway, are also frequently found in melanoma, including loss of PTEN (phosphate and tensin homologue) and overexpression of protein kinase B (PKB, also known as Akt). About 20% to 40% of melanomas originating from mucosal membranes or from chronic sun damage skin and acral melanomas can harbor an activating mutation in c-kitkinase. This mutation is not found in melanoma originating from the trunk.
Finally, about 50% of uveal melanomas have an activating mutation in GNAQ or GNA11, two small GTP-binding proteins that couple cell-surface G-coupled receptors and are involved in their signal transduction.
2. Aberrant cell cycle control. As described above, inherited mutations in the CDKN2A and CDK4 genes are associated with high-penetrance susceptibility to melanoma. Somatic mutations in these and other cell-cycle control genes seem a requisite for the development of melanoma and escape from oncogene-induced senescence.
3. Other genetic events in melanoma pathogenesis. The microphthalmia-associated transcription factor (MITF) is required for melanocyte development. MITF gene amplifications are noted in a small subset of melanomas, and this gene has a complex relationship with melanoma oncogenesis. Several genetic alterations common in melanoma reduce sensitivity to apoptosis, including overexpression of Bcl-2 (B-cell leukemia/lymphoma-2), silencing of APAF-1 (apoptotic peptidase activating factor-1), and activation of NF-κB (nuclear factor kappa B).
C. Major clinical-histopathologic subtypes. Traditionally melanomas have been divided based on the histologic subtypes. Recently, it has become more important to sequence individual somatic mutations in key genes (i.e., NRAS, BRAF, c-kit, GNAQ, or GNA11) and use these findings to distinguish different melanoma subtypes. The progress in understanding the molecular biology of melanoma will soon lead to further subtyping of the disease.
1. Superficial spreading melanoma compromises about 70% of all melanomas. It is most common in middle age and develops most frequently on the upper back of both sexes and on the legs of women, but it can occur in any anatomic location. Only 25% of lesions are associated with a pre-existing nevus. It spreads laterally (radial growth) for a period of time before it becomes invasive. The lesions appear as variably pigmented plaques or macules that have a bizarre shape with irregular borders. As the lesion progresses, the shape becomes more irregular and areas of regression can be noted. Progression correlates with the evolution of multiple shades of color from red (inflammation) through gray (regressed areas) to black (neoplastic melanocytes).
2. Nodular melanoma compromises about 15% to 20% of all melanomas. It is more common among older adults (the fifth and sixth decade of life), and it occurs twice as frequently in male than in female patients. The lesion appears as a darkly pigmented dome-shaped or polypoid nodule that can ulcerate and bleed early. Occasionally, it can be amelanotic. These tumors grow rapidly and vertically from the onset.
3. Lentigo maligna melanoma (4% to 15% of melanomas) is most commonly seen in older individuals (in the sixth and seventh decade of life). It arises in sun-damaged areas of the skin, mainly on the face (90% cases). The lesion appears as a tan-brown macule, very often large in size (3 to 6 cm). The lesion grows slowly and the radial growth phase may last between 5 and 50 years before it starts growing vertically. Partial regression is not uncommon during evolution. The radial growth phase is called lentigo maligna (LM) or Hutchinson freckle.
4. Acral lentiginous melanoma is the least common variant of radial growth phase melanomas. It compromises only 2% to 8% of melanomas in whites, but 30% to 75% cases in blacks, Hispanics, and Asians. It appears on the palms, soles, and terminal phalanges as a dark brown to black, unevenly pigmented patch. Small elevation may suggest vertical growth.
5. Rare types
a. Nevoid melanoma resembles benign nevi. It has verrucoid or dome-shaped appearance and can metastasize.
b. Desmoplastic melanomas resemble a scar or fibroma and appear mainly on sun-exposed areas. Very often they are amelanotic. They tend to recur locally or as isolated metastasis.
D. Mode of spread. Melanoma first spreads through the lymphatic system forming satellite lesions and in-transit metastases and then it involves regional lymph nodes. Satellite lesions are skin or subcutaneous lesions within 2 cm of the primary tumor and represent intralymphatic extension of the tumor. In transit metastases are defined as lesions that are >2 cm from the primary tumor, but not beyond the regional lymph node basin. Melanoma also spreads hematogenously, sometimes after the nodal spread or skipping the draining nodes, forming distant metastases in the skin, subcutaneous soft tissue, lungs, liver, brain, and other organs.
E. Metastatic melanoma from an unknown primary site accounts for approximately 2% to 6% of all melanoma cases. It is assumed that in most these cases the primary cutaneous melanoma regressed spontaneously. Metastases most often develop as cutaneous or subcutaneous nodules or as lymph node metastases. The survival of patients with unknown primary melanoma is similar to that of patients with known primary tumors when corresponding stages are compared.
F. Paraneoplastic syndromes. Most paraneoplastic syndromes occur in patients with widely metastatic melanoma, but some may precede the diagnosis (i.e., dermatomyositis, pemphigus, and melanosis). A variety of paraneoplastic syndromes are associated with melanoma and can affect multiple organ systems, including
1. Skin (vitiligo, pemphigus, dermatomyositis, melanosis, acanthosis nigricans, systemic sclerosis). Generalized melanosis is a syndrome of progressive gray-blue skin discoloration frequently accompanied by melanuria, and sometimes also by melanoptysis or a dark brown blood serum. Melanosis is caused by the melanin (or its precursor) that is produced and secreted in an increased amount by malignant cells, and then deposited within macrophages throughout the body.
2. Eyes. Melanoma-associated retinopathy is a paraneoplastic syndrome characterized by frequent sudden onset of symptoms of night blindness, light sensations, visual loss, defect in visual fields, and reduced b-waves in the electroretinogram.
3. Blood (leukemoid reaction, eosinophilia, autoimmune neutropenia)
4. Endocrine system (hypercalcemia, Cushing syndrome, hypertrophic osteoarthropathy)
5. Central and peripheral nervous system (chronic inflammatory demyelinating polyneuropathy, opsoclonus–myoclonus)
IV. DIAGNOSIS
A. Symptoms
1. The ABCDE rule. Warning signs of melanoma are
A: asymmetry
B: irregular borders
C: changes in color; pigmentation is not uniform
D: diameter >6 mm
E: enlarging or evolving lesion
The changes in preexisting moles and appearance of a new mole with these features are highly suspicious for melanoma. More than 50% of the cases arise in apparently normal areas of the skin. Ulceration or bleeding usually represents deeper lesions.
2. In-transit lesions and skin metastases appear as skin or subcutaneous erythematous nodules between the primary tumor site and the regional nodal basin. The nodules do not have to be pigmented. As they grow, they can coalesce and ulcerate.
3. Symptoms of the metastatic disease are related to the involved site.
B. Physical examination. A complete skin examination of the whole body should be performed, including scalp, axillae, genital area, interdigital webs, and mouth. Melanoma in men occurs more frequently on the trunk or head and neck, and in women on the back and legs, but it can arise from any site on the skin surface. Although most primary lesions are usually pigmented, frequently skin metastases are not pigmented, and they may appear as red or subcutaneous nodules.
C. Differential diagnosis. Compound nevi, halo nevi, dermal nevi, basal cell carcinoma, seborrheic keratosis, angiomas, and dermatofibromas may have features that suggest melanoma. Biopsy specimens of these lesions should be obtained. Precision of the diagnosis can be increased by use of a dermatoscope, an instrument that magnifies pigmented lesions about 10 times. The dermatoscope is especially invaluable for examination of flat to slightly raised pigmented lesions.
D. Biopsy. Suspicious lesions should be biopsied and analyzed pathologically. A full-thickness excision with 1- to 3-mm margins should be performed if the tumor is highly suspected to be melanoma. Larger margins may interfere with planned sentinel lymph node biopsy. Incisional biopsies (punch biopsy or tangential), where part of the pigmented lesion is sampled for pathologic diagnosis, may be used for very large lesions or lesions on the face, palmar surfaces of the hand, sole of the foot, ear, distal digits, genitalia, or under nails. Incisional biopsies may fail, however, to diagnose melanoma or result in a more favorable early staging impression owing to sampling error. If melanoma continues to be suspected or is diagnosed, the biopsy should be repeated or the lesion completely excised for pathologic re-evaluation and staging. Incisional biopsies do not increase the chance for melanoma metastases.
V. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The current staging system was developed by the American Joint Committee on Cancer (AJCC) in 2010 (Table 16.1).
B. Prognostic factors
1. Primary lesion. Tumor thickness and ulceration are the most powerful predictors of survival.
a. Tumor thickness as a prognostic factor was first described by Alexander Breslow and it is traditionally reported as Breslow thickness in millimeters. The AJCC staging system uses 1-, 2-, and 4-mm cutoffs, but tumor thickness is really a continuous prognostic variable.
b. Ulceration (the absence of intact epithelium over the tumor determined by pathologic analysis) indicates aggressive biology of melanoma.
c. Mitotic rate. Increased mitotic rate correlates with a decreased survival.
d. Clark levels, which specify the anatomic depth of invasion (see Fig. 16.1), are no longer utilized in the most recent staging system.
2. Status of the regional lymph nodes. The total number of nodal metastases is a significant predictor of outcome in patients with lymph node involvement. Moreover, patients in whom lymph node involvement was detected clinically have worse prognosis than those who required microscopic analysis. Satellite and in-transit lesions are considered an intralymphatic spread.
3. Metastatic disease. Patients who have nonvisceral metastases (skin, subcutaneous tissue, lymph nodes) carry a better prognosis than those who have visceral metastases. Elevated level of lactate dehydrogenase (LDH) is a poor prognostic factor.
4. Survival according to the stage
Table 16.1 TNM Staging System for Cutaneous Melanoma
aPathologic staging includes pathologic information about regional lymph nodes after complete or partial (sentinel) lymphadenectomy; pathologic stages 0 and IA do not require this information.
LDH, serum lactic dehydrogenase.
From the AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
C. Staging workup
1. Breslow thickness, ulceration status, Clark level, mitotic rate, margin status, and the presence of satellite lesions should be reported by the pathologist. Reporting of location, regression, tumor infiltrating lymphocytes, vertical growth phase, angiolymphatic invasion, neurotropism, and histologic subtype is encouraged.
2. Physicians should obtain a complete history and physical examination, including the entire skin and locoregional lymph nodes.
3. Patients with stage 0 or IA melanoma do not require further studies. For deeper primary melanomas (stages II and III), further tests may be performed (LFT, LDH, and baseline whole body imaging).
Figure 16.1. Clark levels of invasion for malignant melanoma.
4. All patients with surgically incurable locally advanced melanoma (stage IIIc) and metastatic melanoma (stage IV) should undergo complete blood work including LDH and whole body imaging. Specific brain imaging is required because approximately 20% of these cases will present with brain metastasis. Adequate brain imaging can be achieved with an MRI (preferable, because it has higher sensitivity for metastasis) or a CT scan of the brain with IV contrast.
Imaging of the rest of the body can be obtained by CT of the chest, abdomen, and pelvis with both oral and IV contrast, or a combined whole body 18fluoro-deoxyglucose (FDG) positron emission tomography (PET) CT. The benefit of the FDG PET scan is that melanoma is associated with one with the highest accumulation rates of this PET tracer. If specific areas are involved that are not adequately imaged with CT scans (spinal, soft tissue, or bone metastasis), dedicated MRI may be required.
VI. MANAGEMENT
A. Surgery
1. Management of the primary tumor
a. Cutaneous melanoma. The definitive surgical treatment for primary cutaneous melanoma is a wide excision. Some specialists recommend a 3-cm margin for lesions >2 mm. The usual recommended margin of the normal tissue depends on the depth of invasion of the primary tumor as follows:
Often, it is difficult to achieve a recommended excision margin in cases of melanoma located on the head or neck without skin grafting. Although some studies suggest that a narrower margin may result in better cosmetic results without influencing the overall survival, it is recommended that the tumor thickness—as opposed to cosmetic factors—guides the extent of the excisional surgery. Mohs’ micrographic surgery may contribute to favorable outcomes, especially on the head and neck where extensive subclinical spread is relatively common.
b. Melanoma of unusual sites
(1) Subungual melanoma is treated with partial digital amputation.
(2) The wide excision of a plantar melanoma frequently requires a variety of flap reconstructive procedures, especially when the lesion is located on a weight-bearing surface.
(3) Mucosal melanoma may arise from the epithelium lining the respiratory, GI, and genitourinary tracts. It often presents late with locally advanced or metastatic disease. If the disease is localized, it may require a major surgery (i.e., craniofacial resection for skull base tumors, radical vulvectomy for vulvar melanomas, or abdominal–perineal resection for anorectal melanomas).
2. Management of regional lymph nodes
a. SLNB. Randomized clinical trials in the 1980s demonstrated that elective lymph node dissection in patients without clinically involved lymph nodes did not increase survival in cases of melanoma. Conversely, data suggest that lymph node mapping and biopsy of the first draining lymph node (the so-called sentinel lymph node) can adequately detect lymph node metastasis with decreased morbidity. The SLN is identified by lymphoscintigraphy.
Patients who do not have clinically involved regional lymph nodes and whose primary tumor is >1 mm frequently undergo SLNB. SLNB should be done before a wide excision of the primary site, which obfuscates mapping of the SLN location.
Only 1% to 2% of patients who have an uninvolved SLN have metastases to non-SLN. For patients with positive SLNB, the recommendation is to have radical lymph node dissection (RLND). It is uncertain if patients with tumors <1 mm thick but presenting with high-risk features (ulceration, Clark level IV and V, histologic regression, or high mitotic rate) benefit from SLNB as well.
b. Enlarged regional lymph nodes should be surgically removed. RLND for patients with palpable lymph nodes is associated with a 10-year survival of 20% to 40%. A thorough dissection of the involved nodal basin is required. It is recommended that at least 10 inguinal, 15 axillary, or 15 neck lymph nodes be dissected. The procedure can be complicated by delayed wound healing, wound infection, and the development of lymphedema or seromas. Complications occur more frequently after inguinal lymphadenectomy than after axillary lymphadenectomy.
3. Management of in-transit metastases
a. If the patient does not have evidence of disseminated disease, in-transit metastases (single or multiple) could be resected with curative intent, but only 18% to 28% patients will remain free of disease at 5 years.
b. Most patients are treated with isolated limb perfusion (ILP), isolated limb infusion (ILI), or systemic therapy. ILP is a procedure in which vasculature is separated surgically and chemotherapy (e.g., melphalan in high concentrations) can be perfused through the affected limb without exposing the rest of the body. Complete responses can be achieved in approximately 50% of cases, and about half of them are durable. ILI is a less-invasive procedure in which the vein and the artery are accessed percutaneously and is similarly efficacious.
c. Other patients can be treated with standard or experimental immuno-therapies, such as interleukin-2 (IL-2), interferon (IFN), anti-CTLA4 antibodies, and novel targeted oncogene inhibitors.
4. Surgical management of metastases. Patients with solitary metastases, oligometastatic melanoma (limited number of metastatic sites), or residual lesions after successful immunotherapy may benefit from metastectomy.
B. Radiation therapy. In the adjuvant setting, RT to the primary site can be considered for patients with positive surgical margins. RT to the regional nodal basin can be considered for patients who had multiple positive lymph nodes (at least four), bulky disease (lymph nodes >3 cm), extranodal soft tissue extension, involvement of cervical lymph nodes, or recurrence. RT decreases the rate of local recurrence by 30% to 50%, but it does not prolong survival. Adjuvant RT may decrease the risk of local recurrence for desmoplastic melanoma, a benefit since this subtype rarely metastasizes. Patients with metastatic melanoma are rarely treated with RT. Radiation to pain-causing tumor or tumor invading vital structures can be used as palliation. Management of brain metastasis includes RT (see Section VII.A).
C. Systemic therapy. Systemic therapy in patients with melanoma can be divided into three distinct groups: (1) chemotherapy, (2) targeted therapy, and (3) immunotherapy. Chemotherapy targets dividing cells or their environment; it can lead to durable remissions, but almost never results in cure. Targeted therapy uses small molecules that target known molecular alterations. Immunotherapy stimulates the patient’s own immune system to reject tumor; the response rate is frequently lower than with the use of targeted therapy, but it can result in cure in a small percentage of patients. The combination of chemotherapy and immunotherapy is called biochemotherapy. Until the introduction of BRAF inhibitors, the results of treatment with systemic therapy were disappointing; all patients with melanoma should be encouraged to participate in clinical trials.
1. Adjuvant systemic therapy. Patients who present with the involvement of regional lymph nodes (high-risk group) and patients with localized thick tumors (i.e., thickness >4 mm, or between 2 and 4 mm with ulceration, or thickness >4 mm with ulceration [intermediate-risk group]) may benefit from adjuvant therapy. Multiple agents have been tested in the adjuvant setting, but only interferon-alpha (IFN-α) has shown potential benefit.
a. ECOG Trial 1648. Patients enrolled in the large, randomized ECOG 1648 trial were treated with high doses of IFN-α2b. The schedule consisted of IV therapy at maximal-tolerated doses of 20 MU/m2 5 days/week for 4 weeks followed by 10 MU/m2 subcutaneously three times a week for additional 48 weeks. After a median follow-up of 7 years, the treatment resulted in a prolonged relapse-free and overall survival of approximately 10%. Another large, randomized trial confirmed these results. Trials using low or intermediates doses of IFN have showed decreased or no benefit.
b. Further analysis of IFN trials. When patients were followed for a longer time, and when the pooled analysis of three high-dose IFN-α2b clinical trials was performed, the difference in overall survival was not statistically significant. Most patients required dose adjustment because of toxicity.
c. Side effects of INF therapy included fatigue, nausea, fever, depression, neutropenia, and reversible elevation of liver enzymes.
d. Autoimmunity as a complication of therapy with IFN-α can result in the development of clinical syndromes (hyperthyroidism, hypothyroidism, hypopituitarism, vitiligo, antiphospholipid syndrome) or of autoantibodies (antithyroid microsomal, antithyroglobulin, antinuclear, anti-DNA, antiplatelet, or anti–islet-cell antibodies). A marked decrease in the rate of relapse (73% vs. 13%) and mortality (54% vs. 4%) was seen in one series of patients treated with IFN-α who developed evidence of autoimmunity. Autoimmunity developed within the first month of treatment (induction phase with intravenous IFN-α) in 45% of patients, but autoimmunity usually was not observed until months after the initiation of treatment. This observation does not help with selecting patients at the beginning of treatment.
e. Recommendations. After discussion of side effects, adjuvant treatment with IFN-α should be offered to patients with completely resected skin melanoma of stages IIB, IIC, and III, and who are devoid of significant comorbid conditions. No evidence indicates that patients with less advanced melanoma benefit from adjuvant therapy.
2. Chemotherapy for metastatic melanoma. Metastatic melanoma is associated with median survival of 6 to 9 months. As of early 2011, only two agents have been approved by the U.S. Food and Drug Administration (FDA) for the use in metastatic melanoma, the chemotherapy agent DTIC and the immunotherapy agent IL-2.
a. Dacarbazine (DTIC) is a well-tolerated agent when 250 mg/m2 is given IV daily for 5 days, or 850 to 1,000 mg/m2 once every 2 to 4 weeks. The response rates to DTIC are <20% (in newer trials, <12%), and most of these are partial responses with a median duration of response between 4 and 6 months. No randomized trials have been performed to show survival benefit for DTIC over placebo. Despite its low activity, DTIC remains the standard against which most new agents are compared.
b. Temozolomide is an oral analog of dacarbazine that degrades to MTIC, the active metabolite of DTIC. It does penetrate the blood–brain barrier, so it can be used in patients with brain metastasis. When compared with DTIC, treatment with temozolomide resulted in no significant improvement in median survival. The drug is used at the doses of 200 mg/m2/d orally for 5 days every 28 days or 75 mg/m2/d for 6 weeks every 8 weeks. The extended dosing regimen of temozolomide may result in CD4 lymphocytopenia and opportunistic infections.
c. Other single agents. Platinum-containing agents (cisplatin, carboplatin), nitrosoureas (carmustine, lomustine, fotemustine), microtubule toxins (vinblastine, vindesine), and taxanes (paclitaxel, docetaxel, nab-paclitaxel) resulted in modest responses. None of these agents has been proved to be superior to DTIC in a randomized clinical trial.
d. Combination chemotherapy. Multiple attempts have been made to improve treatment of metastatic melanoma by combining several cytotoxic agents. These regimens resulted in increased response rates, significant toxicity, and no prolongation in survival in randomized trials when compared with DTIC.
3. Molecularly targeted therapy for metastatic melanoma
a. BRAF inhibitors. The V600E BRAF mutation is present in about 50% of melanomas, and recently the treatment with two BRAF inhibitors, vemurafenib (previously known as PLX4032, RG7204, or RO5185426) and GSK2118436, showed a spectacular response rate of 50% to 60% and a clinical benefit rate of 70% to 80%. The median duration of the response was 7 months.
b. MEK inhibitors are a new category of agents that block activity of MEK, a downstream kinase from BRAF in the MAPK pathway. They will be most useful in the treatment in combination with BRAF inhibitors or in patients with GNAQ/GNA11-mutated uveal melanoma.
c. Kit inhibitors (imatinib, nilotinib) revolutionized the treatment of patients with GIST. Occasionally, the same kit mutations are present in patients with melanoma. The treatment with imatinib resulted in 33% to 50% response rates in c-kit-mutated melanomas.
4. Immunotherapy for metastatic melanoma
a. IL-2 given in high doses (600,000 to 720,000 U/kg every 8 hours for a maximum of 15 doses/cycle) resulted in a 16% response rates. Responses were higher in patients with stages M1a and M1b melanoma compared with patients with other visceral metastasis. Of responders, 44% were alive at 6-year follow-up. Because of these results, the FDA approved high-dose IL-2 for patients with metastatic melanoma. The treatment is associated with extensive toxicity and can be administered only in experienced centers.
b. Ipilimumab. CTLA-4 is a molecule on the surface of activated T lymphocytes that is responsible for inhibiting immune responses. Blocking this molecule can potentially result in the enhancement of antitumor responses. Treatment with ipilimumab, a human CTLA4-blocking antibody, resulted in improvement in overall survival when compared to a vaccine treatment (10 vs. 6 months). The treatment can be complicated by the development of myriad autoimmune side effects including dermatitis, colitis, hepatitis, and endocrinopathies.
c. Interferon-α produces responses in up to 16% of patients.
d. Adoptive immunotherapy. Adoptive transfer of ex vivo expanded tumor infiltrating lymphocytes followed by treatment with high-dose IL-2 to patients who received a nonmyeloablative lymphocyte-depleting conditioning regimen with fludarabine and cyclophosphamide resulted in 51% responses, including 9% complete responses. Adoptive transfer of lymphocytes that were transduced ex vivo with a retrovirus encoding a T-cell receptor for a melanoma-specific peptide led to response in 2 of 18 patients.
e. Vaccines. A variety of therapeutic vaccination methods have been tested in patients with metastatic melanoma, including autologous dendritic cells pulsed with peptides, proteins, or tumor-derived RNA/DNA. Responses have been marginal.
5. Biochemotherapy. The combination of cisplatin-based chemotherapy with either high-dose IL-2 or IL-2 plus IFN-α has been tested in multiple trials. Phase II trials reported promising response rates. These trials were followed by multiple phase III trials that consistently revealed that the addition of immunotherapy to combination chemotherapy increased toxicity significantly, but did not increase survival (in one study, it decreased survival). The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols.
VII. SPECIAL CLINICAL PROBLEMS ASSOCIATED WITH MALIGNANT MELANOMA
A. Brain metastases are a common development in patients with malignant melanoma. Patients at especially high risk for the development of brain metastases are males with primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, with thick or ulcerated primary lesions, or with acral lentiginous or nodular lesions. These metastases contribute to death in 95% of these patients. The median survival from the time of diagnosis of brain metastasis is 4 months, and only 14% to 19% patients survive 1 year.
Favorable prognostic factors include good performance status, younger age, absence of extracranial metastases, and the presence of a solitary brain metastasis. All patients with a new diagnosis of brain metastasis from melanoma should be evaluated for possible surgical resection or stereotactic irradiation utilizing convergent radiation beams. Control of progression in >90% of lesions can be achieved with these methods.
With multiple simultaneous metastasis (>6), whole brain radiation therapy may be the only feasible treatment approach. It is questionable whether chemotherapy with agents that can penetrate through the blood–brain barrier, such as temozolomide or fotemustine (not available in the United States), can enhance the response to radiation.
B. Cardiac metastases. Metastatic tumors to the heart are uncommon with the exception of melanoma. More than half of the patients with disseminated melanoma have cardiac involvement. Clinical findings are related to the location of the metastases and include heart failure symptoms caused by obstructive masses, syncope or arrhythmia caused by endomyocardial or conduction system involvement, and tamponade caused by pericardial involvement and effusion. Most patients remain asymptomatic.
C. Breast metastases. Melanoma is among the most commonly reported primary tumors to metastasize to the breast. Patients may have bilateral breast involvement. Breast involvement is usually associated with disseminated disease, but rare cases of the primary melanoma of the breast have been reported.
D. Gastrointestinal metastases. Malignant melanoma shows an unusual predilection to metastasize to the small intestine. Metastatic melanoma in the small bowel should be suspected in any patient with a history of malignant melanoma who develops GI symptoms or chronic blood loss. Uncontrolled bleeding, bowel obstruction, and intussusception may require palliative surgical resection of small bowel metastasis.
VIII. FOLLOW-UP. The goal of a follow-up is to identify potentially curable recurrence and to screen for secondary primary tumors. At least one annual skin examination by a dermatologist is recommended. Patients with high-risk factors (including family history of melanoma, skin type, and presence of dysplastic nevi or nonmelanoma skin cancers) may require more frequent examination.
Patients with stage IA melanoma should be seen every 3 to 12 months, and the examination of regional lymph nodes should be emphasized. For patients with stage IB to III melanomas, history and physical should be performed every 3 to 6 months for 3 years, then every 4 to 12 months for 2 years, and annually thereafter. Patients with stage IV disease who are rendered disease free are followed as are patients with stage III disease. The regular follow-up should last between 5 and 10 years.
At clinician discretion, a chest x-ray study, LDH, LFT, and CBC may be obtained. Imaging studies (CT scan, PET scan) are ordered if clinically indicated. Abdominal or chest CT scans should be considered in patients with node-positive disease.
BASAL CELL AND SQUAMOUS CELL CARCINOMAS
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Nonmelanoma skin cancers (NMSC), mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common type of malignancy, but they account for <0.1% of cancer-related deaths. BCC is four to five times more common than SCC. The exact incidence is unknown, because these cancers are not reported to the registry; estimate is that there are 1.3 million cases a year.
B. Risk factors
1. UV light exposure. Excessive UV light exposure is the main risk factor. NMSC are >50 times less common in nonwhite population than in white persons. Of these cancers, 90% develop in sun-exposed areas of the body. Blue-eyed, fair-skinned, blond and red-haired people, and those who are easily sunburned are at increased risk.
2. Exposure to ionizing radiation. Individuals who were exposed to ionizing radiation (uranium miners, individuals treated with radiation, cancer survivors) have a higher risk of NMSC.
3. Chronic immunosuppression and chronic use of glucocorticoids. Organ transplant recipients have 60- to 250-fold higher risk of development of SCC than the general population. BCC occurs in this population only 10 times more commonly.
4. Inorganic arsenic 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.
5. Other environmental risk factors include smoking and phototherapy combined with psoralens.
6. Infection
a. Epidermodysplasia verruciformis, which is primarily caused by human papillomaviruses (HPV) types 5 and 8, results in in situ and invasive SCC synergistically with other carcinogens, such as sunlight.
b. SCC of the genitals and anal regions are strongly associated with HPV serotypes 16 and 18. Infection, usually through sexual transmission, increases the risk for regional SCC. Verrucous carcinoma (Buschke-Lowenstein tumor) is typically a slow-growing, HPV-associated (usually serotypes 6 and 11) neoplasm of the anogenital region that may deeply invade underlying structures.
c. Periungual SCC is associated with HPV type 16.
7. Chronic inflammation. SCC can occasionally originate from the site of chronic ulcers or scars, sites of thermal burns, chronic draining osteomyelitis, and sinus tracts.
8. Hereditary factors
a. Basal cell nevus syndrome (Gorlin syndrome) is a rare autosomal-dominant disorder caused by mutations in the human patched gene (PTCH1). Under normal conditions, the PTCH1 protein is in complex with another protein called smoothened (SMO) and they are in an inactive state. When the hedgehog (HH) protein binds to PTCH1, SMO is released and activates transcription factors that results in cell proliferation. In patients with Gorlin syndrome, PTCH1 is mutated and therefore cannot form complexes with SMO; it results in constant pathway activation. Multiple BCC lesions appear over the face, arms, and trunk during the late teenage years. Individuals also present with macrocephaly, frontal bossing, bifid ribs, bone cysts, palmar and plantar pitting, kyphoscoliosis, spina bifida, short metacarpals, hyporesponsiveness to parathyroid hormone, medulloblastoma, and ovarian fibromata.
b. Xeroderma pigmentosum is a multigenic, autosomal-recessive disorder in which DNA repair ability is impaired. Homozygotes have severe skin and eye sensitivity to sunshine. They develop SCC, BCC, and melanomas in the early childhood. Eye abnormalities include keratitis, iritis, opacification of the cornea, and choroidal melanoma. Frequently, they also suffer from neurologic disorders (seizures, mental and speech disturbances). A severe form (De Sanctis-Cacchione syndrome) includes microcephaly, mental deficiency, dwarfism, and failure of gonadal development.
c. Oculocutaneous albinism is a group of genetic disorders characterized by generalized decrease in pigmentation.
II. PATHOLOGY AND NATURAL HISTORY
A. BCC originates in the basal cell layer of the epidermis. Distant metastases from BCC are extremely rare. It has several recognized subtypes:
1. Nodular BCC is the most common type (approximately 60% of cases). It arises predominantly on the head and neck as a well-circumscribed nodule with pearly or rolled borders and telangiectasias. 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. Larger tumors may develop central necrosis and ulcerate, forming a so-called rodent ulcer.
2. Superficial BCC represents 30% of cases. 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 (morpheaform) BCC represents 5% to 10% of cases. Lesions usually affect the face. The tumors resemble scars and may have an ivory-colored, ill-defined, indurated border. Histologically, the cancer cells are surrounded by a dense bed of fibrosis (“morphealike”). Considering all types of BCC, these 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.
B. SCC usually presents as a hyperkeratotic papule, plaque, or nodule. Hyperkeratosis is an important feature of SCC. In 60% of cases, SCC arises from actinic keratoses.
1. Cutaneous horns usually represent a premalignant process of hyperkeratosis on an erythematous base, but occasionally may be a SCC.
2. Bowen’s disease is a form of intraepithelial SCC in situ, but invasion may occur. It appears as a red-brown eczematoid plaque. It usually occurs on sun-damaged areas in older persons, but it may arise in mucous membranes. Although historically suspected, Bowen’s disease is not associated with an increased risk for internal cancer. Bowenoid papulosis is an intraepithelial neoplasia of the genital area caused by HPV.
3. Keratoacanthoma is a hyperkeratotic nodule with a central keratin plug. It grows rapidly, distinguishing it from other forms of SCC. It may regress spontaneously, but it should be treated because it may further invade the dermis and involve deeper soft tissue.
4. Basosquamous carcinoma has features of both BCC and SCC, but it is usually grouped with SCC because of its more aggressive behavior and metastatic capacity.
5. Metastases. Tumors that metastasize are usually poorly differentiated. The incidence of metastasis is <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.
III. DIAGNOSIS AND WORKUP. Patients with suspicious lesions are offered a complete skin examination. If the lesion suggests SCC, examination of the regional lymph nodes should be performed. All suspicious lesions must be biopsied.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. TNM system of staging was modified by the AJCC for NMSC in its seventh (2010) edition. More than 95% of BCC and SCC involve only local disease, and the staging system is rarely used. The nodal (N) stage is now congruent with the AJCC head and neck staging system (see Table 7.1). MX, M0, or M1 represent unassessed, absent, or present distant metastasis, respectively. Primary tumor (T) stages are as follows:
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ≤2 cm in greatest dimension with <2 high-risk features*
T2 Tumor >2 cm in greatest dimension or tumor of any size with ≥2 high-risk features
T3 Tumor with invasion of maxilla, mandible, orbit, or temporal bone
T4 Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base
B. Prognostic factors. Several prognostic factors are associated with inadequate treatment of primary tumors.
1. NMSC occurring on the head and neck and tumors >2 cm in diameter are more likely to recur.
2. SCC in the genital area, on mucosal surfaces, or on the ear has a higher propensity to metastasize.
3. Tumors that recur more frequently are those that are characterized by illdefined clinical borders or perineural involvement and those that present as recurrent disease or develop in chronically immunosuppressed individuals (especially, organ transplant recipients).
4. BCC with micronodular, infiltrative, sclerosing, or morpheaform features and SCC with desmoplastic histologic features are also more likely to recur.
5. Basosquamous carcinoma has a higher capacity to metastasize than BCC or SCC.
6. Several risk factors also are applicable only to SCC. These factors include tumor at the site of chronic inflammation, rapidly growing tumors, symptomatic nerve involvement, depth of invasion, and moderately or poorly differentiated histology. Patients with any one high-risk feature belong to the high-risk group.
V. PREVENTION. Primary prevention is largely achieved by encouraging patients and other responsible parties to minimize sunlight exposure and other reducible risk factors. Early vaccination with HPV quadrivalent recombinant vaccine (Gardasil) for females holds great potential to reduce the incidence of anogenital SCC. Skin erythema from solar exposure, even from UV 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 an SPF of ≥15 and protective clothing, including hats, are helpful. Those who fastidiously avoid sunlight exposure to decrease their risk for skin cancer should meet their vitamin D requirement through diet or dietary supplements.
Successful secondary prevention is dependent on a regular follow-up. About 40% of patients with NMSC will develop another NMSC within 5 years. These individuals are also at higher risk for development of melanoma.
VI. MANAGEMENT
A. Actinic keratoses (precancerous lesions for SCC) are treated with cryosurgery or topical treatment with 5-fluorouracil or imiquimod. Solaraze gel (diclofenac sodium, 3%) twice daily for 3 months is often effective topically if multiple lesions are present. Cryotherapy is associated with the risk of scarring, infection, and pigmentary changes; topical therapies are associated with application-site irritation. Topical methyl aminolevulinate photodynamic therapy is a new promising method.
B. BCC and SCC can be treated with surgical techniques, radiation therapy, and topical therapies. It is important to customize therapeutic approaches to the particular factors and the individual needs of patients.
1. Mohs’ micrographic surgery is the surgical method with the highest primary tumor cure rate (99% for BCC and 96% for SCC) and excellent cosmetic effects. Other techniques may require less training, be less costly, less invasive, or less time-consuming. Therefore, Mohs surgery is recommended mainly for high-risk lesions and for recurrent tumors wherein the success rates are 95% for BCC and 93% for SCC.
2. Excision with postoperative margin evaluation. The rate of cure is about 90% for primary tumors <2 cm in diameter when a 4- to 6-mm margin is applied. Larger or recurrent tumors require 10-mm margins that may result in significant cosmetic or functional deficits; cure rates range from 50% to 85%.
3. Curettage and electrodessication is effective for low-risk tumors. It should not be used for tumors in the hair-bearing areas, and it should be followed by surgical excision if the subcutaneous layer is reached.
4. Cryosurgery using liquid nitrogen may be considered for patients with small, clinically well-defined primary tumors. It is especially useful for debilitated patients with medical conditions that preclude other types of surgery.
5. Radiation therapy is indicated in patients requiring extensive surgery or whose tumors are in surgically difficult locations. It should be avoided in young individuals because of the risk of secondary malignancies. RT is also 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. Adjuvant RT should be considered after surgery for SCC demonstrating perineural invasion in large-caliber nerves with diameters ≥0.10 mm, tumor thickness >4 mm, or invasion into muscle or periosteum owing to increased risk for local recurrence and nodal metastases.
6. Superficial therapies with topical 5-fluorouracil, imiquimod, or photodynamic therapy are used in patients with low-risk shallow cancers and in those who have contraindications for surgery and radiation therapy.
7. Chemotherapy. Experience in treating metastatic skin cancers is extremely limited. 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 (dosages similar to those used for head and neck cancers) or doxorubicin. Vismodegib (Erivedge), an oral agent involved in Hedgehog signal transduction, has been recently approved for the treatment of advanced BCC.
8. Molecularly targeted agents. GDC-0449 is a small molecule that is a potent SMO inhibitor. It has been used in patients with metastatic and locally advanced basal cell carcinoma with a 55% response rate and a median duration of the response 10 months.
C. Management of enlarged lymph nodes. Occasionally, SCC can spread to the regional lymph nodes. Enlarged regional lymph nodes should undergo fine needle aspiration (FNA) or be biopsied. If lymph nodes are involved by tumor, an RLND followed by radiation therapy is recommended.
MERKEL CELL CARCINOMA
I. EPIDEMIOLOGY. Merkel cell carcinoma (MCC) is a rare type of skin cancer with the estimated incidence in the United States of 0.44 per 100,000 and 33% mortality, which is the highest mortality rate among cutaneous malignancies. The median age at presentation is 68 to 74 years.
A. Risk factors. Sun exposure, advanced age, and chronic immunosuppression are important risk factors. The tumor occurs mainly on sun-exposed areas and it is more common in patients treated with PUVA (psoralen [a light-sensitizing agent] is combined with controlled exposure to ultraviolet light A [UVA]). It also occurs more frequently in patients who are human immunodeficiency virus (HIV) positive, have had organ transplantation, or have been on chronic immunosuppression for rheumatoid arthritis. Transplant recipients develop MCC at a median age of 46 years.
B. Prognostic factors. The 3-year recurrence rate is 60% in patients with positive SLNB and 20% when SLNB is negative. Contrary to melanoma, the depth of invasion is not a prognostic factor. Studies on other parameters for prognosis, such as tumor size, growth pattern, mitotic activity, necrosis, and inflammation, have revealed conflicting results.
II. PATHOLOGY AND NATURAL HISTORY. These cells, first discovered by Merkel in the snout skin of voles in 1875, are thought to originate from the neural crest and to act as mechanoreceptors. Tumors are assumed to be derived from the large, oval neuroendocrine Merkel cells that are located in the basal layer of the epidermis and are associated with terminal axons.
A new polyoma virus associated with MCC has been recently identified and may play a role in the pathogenesis of MCC. It is present in 80% of MCC samples and not present in patients without MCC or with other cancers, possibly with the exception of SCC of the skin in the immunocompromised patients.
Initially, tumor cells spread from the primary site through the lymphatic system to local lymph nodes and then they can disseminate throughout the whole body. The most common sites of distant metastases are liver, brain, lungs, bones, and skin.
III. DIAGNOSIS
A. Signs. MCC manifests as a rapidly growing, painless, indurated, and erythematous to violaceous nodule. The lesions appear mainly in the sun-exposed areas. Head and neck (30% to 45%) and the extremities (35%) are the most common sites for the primary tumor, but the tumor can occur on the trunk, the buttocks, or genitalia. Most patients (75%) present with the disease localized to the primary skin site. Involvement of regional lymph nodes occurs in 25% of cases and distant metastases develop in 2% to 4%. Some patients (approximately 2%) are diagnosed with the metastatic disease in the setting of the carcinoma of unknown primary site.
B. Diagnosis. Biopsy of the growing lesion is required for diagnosis. The three histologic types are trabecular, intermediate cell, and small cell, but histologic subtypes do not carry prognostic value. It is often difficult to differentiate MCC from other “small blue cell tumors” (see immunohistochemical phenotypes in Appendix C4.II).
C. Staging. Three-stage staging system has been most widely used.
Physical examination, concentrating especially on regional lymph nodes and computerized tomography scan of the chest, abdomen and pelvis, should be used as a part of staging investigations.
IV. MANAGEMENT. Merkel cell carcinoma is a rare disease, and no randomized trials have been performed to establish standard care.
A. Surgery. Patients who have no evidence of metastatic disease should be considered for primary RT or wide excision of the primary tumor with 2- to 3-cm margins. In some centers, primary RT is the treatment of choice because the malignancy is extremely radiosensitive. Some evidence from nonrandomized trials indicates that Mohs’ micrographic surgery improves local tumor control when compared with standard surgical resection.
B. Assessment of the regional lymph nodes. Individuals who had negative lymph nodes on surgical assessment of their status by SNLB, elective lymph node dissection, or therapeutic nodal staging had a 97% 5-year disease-free survival (DFS) compared with a 75% 5-year DFS for individuals whose lymph nodes were assessed only clinically. Most of the centers recommend SNLB as the most appropriate method of lymph node status assessment. Patients who have a positive SNLB or have clinically or radiographically demonstrable nodal involvement are treated with total lymphadenectomy.
C. Radiation therapy. Adjuvant RT to the primary site improves local tumor control. Patients treated with surgery alone are 3.7 times more likely to develop a local recurrence and 2.7 times more likely to develop a regional recurrence than patients who received combination surgery and RT. The rate of distant metastasis is similar between the groups. Adjuvant RT to nodes is recommended when SNLB has not been performed or when clinically or pathologically evident nodal disease is present. Delays before commencement of RT should be minimized because they may result in disease progression.
D. Chemotherapy. The role of adjuvant chemotherapy is controversial and most studies suggest that, although it may improve the locoregional control, it does not prolong survival. In a study performed by Trans-Tasman Radiation Oncology Group, patients with high-risk features (size of the primary tumor >1 cm, lymph node involvement, recurrence after primary therapy, or gross residual disease after resection) received synchronous RT and chemotherapy with carboplatin and etoposide; this approach resulted in an excellent overall survival at 3 years of 76%. In a subsequent follow-up study, a greater number of patients were compared with historical controls, and this comparison revealed no benefit in overall survival for individuals receiving chemotherapy.
Currently, chemotherapy is not recommended for patients with node-negative disease, but can be considered for high-risk patients. Individuals with metastatic disease should be treated with chemotherapy.
No standard chemotherapy regimen has been established, but regimens commonly used for the treatment of small cell lung cancer, such as CAV (cyclophosphamide, doxorubicin, vincristine), CEV (cyclophosphamide, etoposide, vincristine) with or without prednisone, and EP (etoposide, cisplatin), have been prescribed most frequently. Use of CAV or CEV resulted in 75% response rate, including 35% complete responses; EP resulted in 60% response rate and 35% complete responses. Median overall survival for patients treated with any type of chemotherapy is 22 months (ranging from 1 to 118 months), and at 2 years, 36% individuals remain alive.
E. Treatment of recurrent disease. Locally and regionally recurrent disease is treated with surgery and RT or chemoradiation therapy. Systemic recurrence is treated with chemotherapy.
Suggested Reading
Malignant Melanoma
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27(36):6199.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363(9):809.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711. Erratum in: N Engl J Med 2010 363(13):1290.
Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14(1):7.
Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355(1):51.
Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006;355(13):1307.
Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004;351(10):998.
Basal Cell and Squamous Cell Carcinomas
Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344(13):975.
Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol 2005;23(4):759.
Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med 2005;353(21):2262.
Von Hoff DD, LoRusso PM, Rudin CM. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009;361(12):1164.
Merkel Cell Carcinoma
Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319(5866):1096.
Gupta SG et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma. The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 2006;142:685.
Krasagakis K, Tosca AD. Overview of Merkel cell carcinoma and recent advances in research. Int J Dermatol 2003;42(9):749.
Mojica P, Smith D, Ellenhorn JDI. Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol 2007;25:1043.
Swann M, Yoon J. Merkel cell carcinoma. Semin Oncol 2007;34(1):51.
*High-risk features are >2 mm thickness, Clark level ≥ IV, perineural invasion, primary site ear, primary site non-hair-bearing lip, and poorly differentiated or undifferentiated histology.