Chapter 45 Malignant melanoma
2. How common is malignant melanoma in the United States?
In terms of incidence, melanoma is the most rapidly increasing form of cancer in the United States. Its incidence has increased more than 15-fold over the past 40 years. In 2005, the age-adjusted incidence was 24.6 per 100,000 for men and 15.6 per 100,000 for women. More than 59,000 cases of invasive melanoma and approximately 46,000 new cases of melanoma in situ were diagnosed in the United States in 2005. Malignant melanoma is the fifth and sixth most common form of cancer in men and women, respectively. It is now the most common cancer in young women aged 25 to 29 years. The lifetime risk of developing melanoma has increased from 1 in 1500 for someone born in the early 1900s to 1 in 100 for people born in 1990 to an estimated 1 in 41 to 61 for persons born in the year 2007. Incidence rates differ between genders, ages, ethnic groups, and regions. In this regard, before the age of 40, the incidence of melanoma is higher in young women; subsequently the incidence of melanoma increases rapidly in men, but the rate of increase slows in women.
DevCan: Probability of developing or dying of cancer software, version 6.2.1, Statistical Research and Applications Branch, NCI, 2007. Available at: http://srab.cancer.gov/devcan. Accessed July 28, 2010.
Tucker MA: Melanoma epidemiology, Hematol Oncol Clin North Am 23:383–395, 2009.
3. What causes melanoma?
At present the causes of melanoma are not known with certainty, but epidemiologic studies suggest that brief, intense exposure to ultraviolet A (long-wave UVA radiation) contributes to the development of melanoma. Current evidence suggests that long-wave UV radiation (UVA) is more important than short-wave radiation (UVB). Other potential causes include mutations in, or loss of, tumor suppressor genes.
4. What groups have a genetic predisposition to familial melanoma?
Germline genetic mutations and polymorphisms can predispose to melanoma. The major high-penetrance melanoma susceptibility gene locus associated with familial melanoma is CDKN2A, which encodes p16 and p14ARF; p16 and p14ARF regulate retinoblastoma (Rb) nd p53 pathways, respectively. Germline CDKN2A mutations are observed in 25% of familial melanoma.
Meyle KD, Guldberg P: Genetic risk factors for melanoma, Hum Genet 126:499–510, 2009.
5. List the risk factors for melanoma.
Risk factors for malignant melanoma may be divided into genetic factors, environmental factors, and the interaction between the two.
Genetic factors include past medical history of melanoma, familial medical history of melanoma in a first-degree relative, Fitzpatrick type I or II skin, large congential nevi, the presence of dysplastic (atypical) nevi, >50 benign nevi (>2 mm in size), xeroderma pigmentosum, and familial dysplastic mole syndrome (FDMS). In FDMS, which is defined as occurring in families with atypical nevi and two or more blood relatives with melanoma, the estimated prevalence of melanoma approaches 85% by age 48. It is noteworthy that variations in the melanocortin receptor 1 (MCR1) gene, which is a component of pigment diversity, also confer an increased risk of melanoma. Variants differ in their associations with melanoma and nonmelanoma skin cancer, but both red hair and non–red hair variants confer increased risk.
6. List the high-risk groups for developing melanoma.
7. Do all melanomas develop from atypical nevi?
In the past, the development of melanoma has been modeled as a stepwise process from a cutaneous melanocyte through nevus through atypical nevus stages to melanoma in situ and eventually invasive melanoma. However, around 40% to 75% of melanomas develop in normal skin de novo, and, of those melanomas that develop in association with a preexisting nevus, <50% of the nevi are atypical. At present it is difficult to determine whether an atypical nevus is any more likely to become a melanoma than any other nevus or isolated melanocyte. Moreover, it is now clear that a preexisting nevus is not required for a melanoma to develop. It is thought that the discrepancy between melanomas arising in preexisting nevi and de novo melanomas can best be explained by the cancer stem cell theory. In this regard, the risk of melanoma associated with nevi may be due to the potential for secondary mutations within nevi, as well as due to the inherent properties of the stem cell population in individuals with numerous moles. Therefore, although there is a clear association between nevi and melanoma risk, only a portion of this risk may be related to the acquisition of genetic mutations within the nevi. The majority of the risk may be associated with the inherent properties of melanocyte stem cell populations in individuals with numerous nevi.
Friedman RJ, Farber MJ, Warycha MA, et al: The “dysplastic” nevus. Clin Dermatol 27:103–115, 2009.
Elder, DE: Dysplastic nevi: an update, Histopathology 56:112–120, 2010.
8. What are cancer stem cells?
In recent years, there has been increasing evidence demonstrating that melanoma, as well as other solid tumors, contain a subpopulation of cancer stem cells (CSCs). CSCs are rare cells within tumors with the ability to self-renew, drive tumorigenesis, and give rise to a phenotypically diverse tumor cell population. They are considered the source of the primary tumor mass and are thought to be responsible for drug resistance and cancer recurrence. Experimental evidence supports the existence of CSCs in leukemia and melanoma, as well as in breast, brain, colon, pancreatic, and ovarian cancer. Although controversy exists regarding the location of melanoma stem cells in the skin, it has been hypothesized that most melanomas arise from mutations that accumulate in a common precursor CSC, which subsequently drives the establishment of primary and metastatic lesions. This CSC-like precursor is thought to be responsible for the metastatic process, while the less stable progeny are unable to spread locally or distantly. Although definitive markers are still lacking for melanoma CSC, CD133, ABCB5, and ABCG2 have been identified as potential markers.
La Porta C: Cancer stem cells: lessons from melanoma, Stem Cell Rev 5(1):61–65, 2009.
9. Is melanoma a single disease?
No. Melanoma has historically been divided into major subsets based on the clinical and histologic appearance and varied associations with skin color, sun exposure, and anatomic site. However, recent molecular investigations have demonstrated biologically distinct subsets of the disease that vary in their relationship to anatomic site, sun exposure, nevus phenotype, and mutational analysis.
Key Points: Diagnosis of Malignant Melanoma
1. Melanoma, the most aggressive malignant neoplasm arising in the skin, has one of the most rapidly increasing incidence rates of all human malignancies.
10. What are the molecular pathways in melanoma?
Major molecular pathways that have been implicated in melanoma include p16 (25% to 50%) and p14ARF (25% to 50%), microphthalmia-associated transcription factor (MITF) (50% to 75%), B-Raf (50% to 60%), and PTEN (15% to 25%). Furthermore, the antiapoptotic factor Bcl-2 is often overexpressed in melanoma. It should be stressed, that as noted above, not all melanomas are the same. In this regard, those melanomas that develop in younger patients on intermittently sun-exposed skin demonstrate a greater percentage of B-Raf mutations (>60%) than those melanomas that develop on chronically sun-exposed skin in older patients (<15%). In contrast, those melanomas that develop on chronically sun-exposed skin in older patients demonstrate a greater percentage of N-Ras mutations (20% to 40%). Along the same lines, melanomas that develop on acral and mucosal sites more demonstrate a greater percentage of c-Kit mutations (∼40%) compared to non–sun-exposed (0%) and sun-exposed (30%) melanomas. Further, acral and mucosal melanomas demonstrate a lower percentage of B-Raf mutations (∼20% and ∼10%, respectively).
Bauer J, Bastian B: Genomic analysis of melanocytic neoplasia, Adv Dermatol 21:81–99, 2005.
11. Is there a host immune response to melanoma?
Yes. Observations such as incomplete or complete regression of melanoma, occurrence of vitiligo and halo nevi in patients, as well as increased rates of melanoma in immune suppressed patients indicate that immunologic events appear to play a role in the clinical course of the melanoma and may occasionally cause clinical regressions. Tumor antigen (TA)–specific T cells have been shown to play an active role in eliminating tumors and metastases, as well as in inducing TA-specific T-cell memory responses in a wide range of animal tumor models. Similarly, in vitro studies employing human peripheral blood lymphocytes (PBL) isolated from patients with melanoma have been reported to contain TA-specific CD8+ and CD4+ T-cell precursors, as well as natural killer (NK) cells and macrophages that are capable of killing tumor cell targets after appropriate in vitro activation. CD8+ T cells are believed to play a major role in control of melanoma growth. It is thought that this immunosurveillance of melanoma often fails in patients. This has been the rationale for the development of immunotherapy of melanoma.
12. Describe the clinical appearance of melanoma.
Cutaneous melanoma can have a number of different appearances. Malignant melanomas can begin in a preexisting melanocytic nevus; however, as noted above, the exact percentage of malignant melanomas arising in preexisting nevi versus those arising de novo is controversial. When malignant melanoma arises in a preexisting nevus, the nevus usually demonstrates a change in appearance, such as an increase in size or change in shape, or it may bleed easily when traumatized. A changing nevus is the most important risk factor for melanoma. The development of a new pigmented nevus in any patient over 35 years of age should be evaluated. Classically, early melanoma lesions are characterized by containing different colors, such as different hues of brown, black, red, and blue. Melanoma may also appear as a brown or black discoloration of the nail or as a skin ulcer that does not heal.
13. What are the ABCDEs of melanoma?
The development of a new or changing pigmented lesion is the classic initial presentation of melanoma. A lesion that demonstrates a noticeable increase in size over a period of weeks to months or development of pigment irregularity (black, hues of brown, red, blue, or white) should be evaluated by a physician and biopsied. The ABCDEs of melanoma (Fig. 45-1) are a helpful guideline for determining which moles could be suspicious for melanoma:
• Border and bleeding. The border of any melanocytic nevus should be relatively smooth, with a clear demarcation between the nevus and surrounding normal skin. Nevi that develop irregular or ill-defined borders should be evaluated. B is also for bleeding, and any mole that bleeds needs careful evaluation.
• Color. Most moles have a homogeneous tan or brown color. Moles that develop pigment variegation within an otherwise homogeneous background should be evaluated.
• Diameter. Most melanomas are 0.6 mm in diameter, but an otherwise suspicious lesion that is small might also be malignant.
14. What is dermoscopy?
Dermoscopy, also known as skin surface microscopy, or epiluminescence microscopy, is a noninvasive tool to assist in the diagnosis of melanocytic and nonmelanocytic tumors. A number of dermoscopy algorithms have been developed to aid in the diagnosis of melanocytic tumors. However, these algorithms cannot be applied to lesions located on the face, acral and mucosal surfaces, and the nails. The sensitivity of dermoscopy in the diagnosis of melanoma ranges from 70% to 95%, compared to clinical investigation with the unaided eye, which ranges from 60% to 90%. It is noteworthy that the success of dermoscopy depends critically on appropriate training.
Campos-do-Carmo G, Ramos-e-Silva M: Dermoscopy: basic concepts, Int J Dermatol 47:712–719, 2008.
16. Are there different types of melanoma?
There are several different types of melanoma, and each may appear somewhat differently:
• Superficial spreading malignant melanoma (SSMM) is the most common form of melanoma in Caucasians (∼70% of cases). It is most commonly diagnosed in the fourth or fifth decade. It usually presents as a slowly enlarging, brown (usually) or black spot that may have both a macular and papular component. The lesion may show color variegation and irregular borders (Fig. 45-2A). About 30% arise in a preexisting nevus, and 75% of these lesions demonstrate regression on clinical exam.
• Nodular melanoma is the second most common type of melanoma and represents about 15% to 20% of all cases. It is most commonly diagnosed in men between the fifth and sixth decade. Nodular melanoma usually presents as a pigmented (usually brown or black) papule that slowly enlarges and frequently ulcerates. These lesions most commonly present on the head, neck or trunk. Nodular melanomas may ulcerate, presenting as a nonhealing skin ulcer (Fig. 45-2B).
• Lentigo maligna melanoma, also known as the Hutchinson freckle, represents ∼15% of all cases of melanoma. It usually presents as an irregularly shaped, flat, pigmented lesion on actinically damaged skin. It is seen most frequently on the face or other sun-exposed sites. Most patients are in their seventh decade. More advanced lesions can develop papules or nodules, indicating the lesions have developed a vertical or downward growth component.
• Acral lentiginous melanoma represents 5% to 10% of all cases of melanoma. It is the most common form of melanoma in African-Americans, Asians, and Hispanics (Fig. 45-2C). The latter does not reflect an increase incidence of acral lentiginous melanoma in these races. It usually appears as brown or black macules arising on the glabrous (non–hair-bearing) skin of an extremity (palms, soles, or nail beds). It can also occur on mucosal surfaces. The latter have an extremely poor prognosis.
17. What are Clark’s levels?
A system used to describe the depth of invasion of a melanoma that was originally described by Dr. Wallace H. Clark, Jr. The system provides a helpful means to determine the probability of developing progressive disease. Primary tumors are classified according to the degree of invasion into the various anatomic levels of the skin. This classification scheme has been shown to correlate well with 5-year survival rates; however, the new 2009 AJCC Melanoma Staging and Classification System, for the first time, has removed the Clark’s level as a recommended parameter.
18. What is Breslow’s depth?
This is a more precise way of measuring the level of invasion of primary malignant melanoma. An ocular micrometer is used to directly measure the distance that tumor cells have invaded. The distance of invasion is measured from the top of the granular layer of the epidermis, or in ulcerated lesions, the base of the ulcer to the point of deepest invasion by the tumor cells. This measurement appears to be more easily reproducible among institutions and more objective than Clark’s levels. The Breslow tumor thickness is the strongest predictor of survival.
19. What other findings should be reported in the histopathologic diagnosis of melanoma?
The World Health Organization, as well as the American Joint Committee on Cancer (AJCC), recommends reporting the following when reporting on the histologic diagnosis of melanoma: thickness (Breslow depth), mitoses/mm2, level of invasion (Clark’s level), regression, tumor-infiltrating lymphocytes, ulceration, vascular invasion, microscopic satellites, associated nevus, and margins. Because the most recent AJCC staging system for melanoma has deleted the Clark’s level, many pathologists and dermatopathologists no longer include this finding in their reports.
20. What are the common immunohistochemical (IHC) markers utilized in the diagnosis of melanoma?
Most melanomas can be diagnosed on routine histology, but IHC staining can be useful in the difficult cases. A wide range of melanoma- and melanocyte-associated antigens have been identified for use in IHC staining. The most commonly utilized ones are as follows:
• S100: A calcium-binding protein that is expressed in melanocytes, Schwann cells, glial cells, chondrocytes, adipocytes, myoepithelial cells, macrophage, Langerhans cells, and dendritic cells. Despite its low specificity, S100 has a high sensitivity for melanocytes and melanoma.
• gp100: A glycoprotein considered to part of the premelanosome complex. HMB45 is the most commonly utilized antibody to detect gp100. HMB45 has a higher specificity for melanocytes and nevus cells, but its use is limited by its sensitivity, with false negative rates up to 35%.
• MART1: A melanocyte differentiation antigen known as melanoma antigen recognized by T cells–1. It represents a protein associated with melanosomes. MART1 is more specific than S100 and HMB45, as well as more sensitive than HMB45.
Piris A, Mihm MC Jr: Progress in melanoma histopathology and diagnosis, Hematol Oncol Clin North Am 23:467–480, 2009.
21. Are there other factors with prognostic impact in patients with melanoma?
The strongest predictors of prognosis are Breslow’s depth, presence of ulceration in the primary tumor, and presence of nodal disease. Secondary predictors of prognosis include the number of positive lymph nodes, extension of the tumor into extranodal soft tissue, age at time of diagnosis, sex (women > men), and anatomic site of primary tumor. In this regard, extremities, excluding the hands and feet, have the most favorable prognosis, while lesions on the scalp, hands, feet, and mucosal surfaces have the worst.
22. How are patients with melanoma evaluated after the initial diagnosis?
Baseline evaluations then should be performed to determine if there are any detectable secondary primary tumors, local extension of the first primary, or if metastatic disease is present. These evaluations should include a complete physical examination—a complete skin evaluation and lymph node exam; a chest x-ray; and may include baseline laboratory tests such as a complete blood count, blood chemistry studies, liver function tests, and possibly serum lactate dehydrogenase. It should be stressed that there is significant evidence to suggest that routine imaging studies and blood work have limited, if any, value in the initial evaluation of asymptomatic patients with a primary cutaneous melanoma 4 mm or less in thickness. The American Academy of Dermatology recommends that these tests should be optional and directed based on a thorough medical history and physical examination. Exceptions for asymptomatic patients include those with a primary tumor > 4 mm and in the setting of clinical trials. Any abnormality detected with these exams should be more fully investigated with the proper diagnostic procedure (e.g., a fine-needle aspirate to assess an enlarged lymph node or computerized tomography of the abdomen for abnormal liver chemistry).
23. What is the most current system for staging melanoma?
The current and preferred staging system for melanoma is that of the American Joint Commission on Cancer (AJCC) from 2009. It is based on the TNM (tumor, lymph node, metastasis) system, which allows the assessment of patients based on the thickness of the primary tumor and whether lymph node or other metastases are present. Staging and survival rates for cutaneous melanoma are summarized in Table 45-1.
24. How is melanoma treated?
The standard of care for treating melanoma is to:
4. Conduct follow-up evaluations for the rest of the patient’s life.
Pathology remains the gold standard for the diagnosis of melanoma. To establish a histologic diagnosis, the suspect lesion should be completely excised with a 1- to 3-mm margin of skin to the depth of the subcuticular fat. If this is not possible, due to anatomic location or size of the lesion, an incisional or punch biopsy to the depth of the subcuticular fat should be performed on the thickest or most atypical portion of the lesion. It is noteworthy that biopsy of lentigo maligna can be problematic, because there are often skip areas, as well as areas of regression, in these lesions that may lead to misdiagnosis. The best biopsy technique to establish the diagnosis of lentigo maligna is usually multiple punch biopsies from different sites or broad shave biopsy from multiple areas.
25. How wide should surgical margins be?
There is ongoing controversy regarding the width of normal-appearing skin that should be excised. At one time, 5.0-cm margins were recommended. With the exception of only four prospective multicenter trials, surgical margins were originally based, at least in part, on consensus decision and tradition. A National Institutes of Health Consensus Conference on Melanoma has recommended surgical margins based on the depth of invasion of the primary tumor. Malignant melanoma in situ should be excised with a 0.5-cm border of normal skin. Lesions that have a Breslow’s depth of 1.0 mm should have wide local reexcision with 1.0-cm margins. Lesions that are 1 to 2 mm thick should be excised with 1- to 2-cm margins (2 cm, if primary closure can be achieved, or no significant difference exists in reconstruction between a 1- and 2-cm margin of excision). Lesions that are intermediate, 2 to 4 mm thick, are excised with 2-cm margins. Lesions 4.0 mm thick should be excised with 2- to 3-cm margins; there are no randomized trials that have determined the optimal margins for excision of melanoma > 4 mm in thickness. These recommendations are meant only as general guidelines, and individual patient considerations must be taken into account. It should be stressed that there are several studies demonstrating that 0.5-cm margins are inadequate for most malignant melanoma in situ on the head, neck, hands, and feet. Moreover, there is evidence to suggest that tumor thickness should not influence surgical margins.
Zitelli JA: Surgical margins for lentigo maligna, Arch Dermatol 2004 140:607–608, 2004.
26. What is the most important risk factor for local recurrence of primary melanoma?
28. Describe the recommended follow-up for a patient with melanoma.
Routine follow-up evaluations vary, depending on the depth of the primary tumor (Table 45-2). It is important to stress that unlike many malignancies, melanoma has a tendency to recur many years after the primary tumor is removed. Therefore, patients at high risk for recurrence need to be followed very closely for long periods of time.
29. Which tests or examinations are conducted during the routine follow-up of patients who have had melanoma?
There is no general consensus regarding the routine follow-up of patients with malignant melanoma. Close follow-up is recommended because the risk of developing a second primary melanoma is around 3% to 4.5%. Follow-up recommendations vary from 1 to 4 times per year during the first 2 years after diagnosis. During the follow-up evaluations, patients should receive a physical exam directed toward the detection of a local recurrence of the primary tumor, the development of metastatic disease in the surrounding skin or the draining lymphatic system, or development of a second primary melanoma. As in the initial staging evaluation, any abnormality detected by physical exam, review of systems, or laboratory tests is more fully investigated. If no abnormalities are detected by routine physical exam and review of systems, repeat laboratory tests, and chest x-ray are often dictated by stage of the patient’s disease.
30. Does local tumor recurrence influence overall survival?
No. Local recurrence is defined as any recurrence of a primary tumor within 2 cm of the excisional scar of a primary melanoma. Most (∼95%) recurrences occur within the first 5 years after excision, and the overall risk for local recurrence is usually depends on ulceration and anatomical sites. In this regard, the risk of local recurrence is increased in ulcerated primary tumors, as well as tumors on the head, neck, hands, and feet. Local recurrence is associated with the development of in-transit, regional, and distant metastatic disease but is not an independent prognostic indicator of survival.
31. What is elective lymph node dissection (ELND)? When is it indicated?
ELND is the dissection of the draining lymph node basin in patients with deep primary melanomas who are felt to be at high risk for development of metastasis to the lymph nodes. ELND is based on the notion that melanoma cells migrate in an orderly fashion toward the draining lymph node. Therefore, surgical excision of all involved nodes in patients with stage III disease was postulated to prevent the spread of tumor to other organs. However, five multicenter randomized prospective trials in patients with primary melanoma have not shown a survival benefit for patients treated with ELND plus wide excision as compared to wide excision alone. Most large melanoma centers do not routinely perform ELND.
32. What is sentinel lymph node biopsy? When is it indicated?
In 1990, Morton introduced intraoperative lymphatic mapping and selective lymph node dissection or sentinel lymph node biopsy (SLNB) as an alternative to ELND for melanoma patients. He showed that the histology of the SLN reflects the histology of the entire lymph node basin, because when it is negative, the other lymph nodes within that basin are almost always also negative. The initial data from large series show substantial differences in the survival curves of patients, depending on their SLN status, and, in multivariate analysis, the status of the SLN has been confirmed as the most important prognostic factor for patients with primary melanoma.
To date there is little evidence that early dissection in SLN positive patients improves their survival compared to patients who receive nodal dissection when clinically detectable nodes develop. SLN remains a very controversial topic, and several points need to be emphasized. First, there is little evidence to suggest that melanoma cells migrate in an orderly fashion toward the draining lymph node, and the presence of melanoma cells within a lymph node may merely be an indicator of systemic metastatic disease. Second, surgical alteration of a patient’s regional lymphatic structure may impair the body’s immune response to melanoma. Third, at present we are unable to determine what constitutes relevant nodal disease. In this regard, 60% of patients with primary melanoma <1.0 mm in depth demonstrate positive SLN through polymerase chain reaction (PCR) analysis. These patients have a very favorable survival rate and rarely go on to develop nodal disease. Therefore, the presence of microscopic metastases does not correlate with the clinical course. Fourth, SLN biopsies require close collaboration between the nuclear radiologist, surgeon, and pathologist. Patient selection is also paramount. This procedure is less reliable if a wide excision has been performed; therefore, patients considered candidates should be referred for this procedure prior to the wide excision, which can be carried out simultaneously with the SLNB. Fifth, lymphatic flow is markedly varied in different persons, and it is difficult to predict with any degree of certainty which nodal basin serves a particular area of skin. Lastly, proponents of SLNB argue that SLN may identify patients who may be candidates for adjuvant therapy (see below). Nevertheless, to date no effective adjuvant therapy exists for metastatic melanoma.
Zitelli JA: Sentinel lymph node biopsy: an alternate view, Dermatol Surg 34:544–549, 2008.
33. What is linear melanonychia?
A linear, pigmented streak of the nail (Fig. 45-3). Among the many potential causes, subungual melanoma is the most serious. A biopsy of the nail matrix is required if melanonychia develops rapidly, if it involves only a single digit, or if other causes of the abnormal pigmentation cannot be determined. This is a more common presentation of melanoma in blacks than in whites.
34. What is Hutchinson’s sign?
The development of pigmentation at the base of linear melanonychia involving the proximal nail fold and periungual skin (Fig. 45-4). This sign is felt to be a very specific indication that the linear melanonychia is due to melanoma.
Baran R, Kechijian P: Hutchinson’s sign: a reappraisal, J Am Acad Dermatol 44:87–90, 2001.
36. Are there any new ways to assess prognosis in patients with melanoma?
Some recently reported experimental tests may prove helpful in the early detection of metastatic disease. One such test is a reverse transcriptase polymerase chain reaction test used to detect circulating melanoma cells in the peripheral blood. Two groups have found that this test correlates positively with stage of disease and may be helpful in identifying patients who will eventually develop metastasis. Another test being developed is a positron emission tomography using a glucose analog coupled to a positron emitter. This test also is capable of identifying clinically undetectable lymph node and visceral metastases. Both of these tests may allow earlier detection and thereby more successful treatment of metastatic disease.
37. What forms of chemotherapy are used in the treatment of metastatic melanoma?
Chemotherapy in metastatic melanomas yielded disappointing results with 5-year survival rates for treated patients ranging from 3% to 14%. There are currently no curative forms of therapy for patients with metastatic disease. Dacarbazine has shown some efficacy as single-agent therapy. Response rates average around 10% to 20%, with durations averaging 6 months, and a complete response rate of about 5%. Newer agents such as temozolomide (TMZ) are similar to dacarbazine but offer the advantages of oral administration, as well as penetration through the blood–brain barrier. Nevertheless, response rates average ∼15%. Temozolomide has also been tried in combination with IFN-α and thalidomide; however, no increase in survival rates has been observed. Cisplatin has been shown to be somewhat effective as single-agent therapy, but it has significant toxicities. Other studies have shown that the nitrosoureas (carmustine, lomustine, and semustine) have an overall response rate ranging from 13% to 18%. Similarly, tubular toxins such as vinblastine, vincristine, and Taxol (paclitaxel) have led to response rates of between 12% and 15%. The combination of carboplatin and paclitaxel is currently under investigation.
Wolchok JD, Saenger YM: Current topics in melanoma, Curr Opin Oncol 19:116–120, 2007.
38. Is radiation therapy effective for melanoma?
No. High-dose radiation is utilized for palliative care of cerebral metastases and for local control of unresectable disease.
39. How effective is immunotherapy in malignant melanoma?
The lack of effective treatment for advanced-stage melanoma by conventional therapies, such as radiation and chemotherapy, has highlighted the need to develop alternative therapeutic strategies. Among them, immunotherapy has attracted much attention because immunologic events appear to play a role in the clinical course of the disease and may occasionally cause clinical regressions.
A number of new mAbs are directed against various targets, including vascular endothelial growth factor (VEGF), tumor necrosis family costimulatory receptors (e.g., DR4, DR5, glucocorticoid-induced tumor necrosis factor receptor [GITR], CD134 [OX40], CD137 [4-1BB], and CD40), and integrins also are currently being investigated in clinical trials.
40. Does gene therapy offer any better results?
Several different strategies are being explored that are generically termed “gene therapy.” One strategy involves the genetic modification of tumor-infiltrating lymphocytes to make them more effective at killing tumor cells. Another strategy involves the genetic modification of the tumor cells so that they produce immunostimulatory cytokines, which attract and stimulate cells involved in the immune response. Yet another approach involves the in situ genetic modification of tumor nodules so that they produce nonself human leukocyte antigens; the immune system recognizes and rejects these modified tumor nodules in a manner similar to that in which transplanted organs are rejected. All three approaches have generated promising results in laboratory and/or clinical trials, but all are still in the early investigational phases.
41. How about local perfusion?
The treatment of localized cutaneous and lymphatic metastases by isolated hyperthermic limb perfusion using a combination of chemotherapeutic and immunotherapeutic agents has generated renewed interest following a successful European trial. In this treatment, the circulation of the affected limb is isolated, the blood slowly heated, and then it is returned to the limb along with high doses of melphalan with or without tumor necrosis factor or gamma-interferon. Because the circulation of the limb is isolated from the remaining systemic circulation, much higher doses of the therapeutic agents can be administered than what could be tolerated systemically.
42. What are some newer targeted therapies for melanoma?
The available information regarding the molecular mechanisms underlying melanoma has increased greatly over the past several years. As noted above, the major molecular pathways that have been implicated in melanoma include p16 and p14ARF, B-Raf, N-Ras, microphthalmia-associated transcription factor (MITF), PTEN, and Bcl2. Of particular clinical relevance is the RAS-RAF-MEK-ERK (MAP kinase) signaling pathway. Sorafenib and imatinib are oral multikinase inhibitors that inhibit MAP kinase pathway signaling. Trials of sorafenib or imatinib in combination with dacarbazine and carboplatin/paclitaxel are currently underway. Trials are also underway investigating the Bcl-2 antisense molecule, oblimersen, in combination with dacarbazine. Newer small molecular inhibitors are currently under investigation.
Tawbi H, Nimmagadda N: Targeted therapy in melanoma, Biologics 3:475–484, 2009.
