SEMINARS I N NEUKOLOGY-VOI,UMk:
12, N O . 4 DECEMBER 1992
Malignant Melanoma Jason K. Kiuers, M .D., F.R.C.P.(C), and Szkina F. Rossi, M.D.
EPIDEMIOLOGY There is now strong evidence that links ultraviolet B (UVB) radiation from the sun with the development of MM.2 Intermittent acute exposure prior to age 15 years seems to be criticaL3Sun-sensitive individuals with blonde or red hair, blue eyes, a tendency to burn rather than tan, an increased number of melanocytic nevi (moles), and the presence of dysplastic nevi (DN) are at an increased risk to develop MM.4
GENETIC S USCEPTZBILITY
Some individuals have a genetic susceptibility to MM. Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder in which there is an inability to repair UVB-induced DNA damage.5 Patients with XP have a 2000-fold increased risk of developing MM and other cutaneous neoplasms by age 20 years6 Individuals with the familial DN syndrome also have a genetic predisposition to melanoma (see discussion of "Precursor Lesions").
PRECURSOR LESIONS A number of different cutaneous pigmented lesions may give rise to MM. Congenital melanocytic nevi (CMN) occur in 1% of live births, whereas CMN 10 cm or larger are uncommon (1:20,500 live birth^).^ T h e lifetime risk of developing MM in a large CMN is estimated at 6%.8The majority of these MM develop before age 10 years, and therefore most authorities would recommend the excision of these nevi in childhood.Wowever, surgical excision may not eliminate the risk for MM because it nlay still arise directly from the underlying muscle, fascia, or lept~meninges.~ CMN 1.5 cm or smaller may give rise to MM,'" most of which usually develop after puberty. Because the lifetime risk in the general population of developing MM from these lesions is unknown, the management of' small CMN is controversial. Sonle clinicians advise surgical excision early in life," whereas others advocate observing these lesions over time, excising nevi only if signs of MM develop. l 2 Neurocutaneous melanosis (NCM) is a rare congenital condition characterized by numerous CMN (with or without a large CMN) in association with benign o r malignant melanotic tumors of the CNS.'"'"n a recent review of 39 cases, Kadonga and Frieden15 found that most patients presented with symptoms of increased intracranial pressure before age 2 years. Hydrocephalus was found in 64% of patients. Sixty-two percent had leptomeningeal MM. Abnormal cerebrospinal fluid (CSF) findings included elevated pressure, sterile leukocytosis, xanthochromia, and elevated red blood cell count. CSF cytologic examination occasionally revealed malignant cells or free melanin granules. Magnetic resonance imaging (MKI) with gadolinium contrast is recommended as the imaging pro-
T h e Division of Dermatology, T h e University of British Columbia, Vancouver., British Columbia, Canada Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
This year, over 32,000 Americans will have developed malignant melanoma (MM) and more than 6500 will die from the disease.' However, with early detection and prompt treatment, MM is curable in the majority of patients. Therefore it becomes important for physicians to recognize the clinical features of early, evolving MM in order to minimize the morbidity from this neoplasm. In particular, rleurologists should be well acquainted with it because patients with primary central nervous system (CNS) or metastatic MM may develop neurologic symptoms.
sons with DN.24-26Although the risk in the familial type is high, that in individuals with sporadic DN has not yet been accurately determined. The management of patients with DN includes a complete cutaneous examination, including the scalp, optional photographic documentation, follow-up at 3- to 12-month intervals (more often if lesions are changing), and excision of any lesions suspicious for MM." Acquired melanocytic nevi are extremely common. These lesions are characterized by a smooth texture, uniform color, and regular contour (Fig. 2). The results of several case-control studies have shown that the risk for MM varies directly with the number of moles.'"2R Melanoma has been shown to arise in histologic continuity with an acquired melanocytic nevus in 18 to 85% of cases.29However, the great majority of acquired nevi are stable, benign lesions and therefore prophylactic removal is seldom warranted.
CLINICAL FEATURES OF MALIGNANT MELANOMA The hallmark of MM is irregularity. In general, an early MM is asymmetrical, poorly circumscribed with notched or scalloped borders, and mottled in pigmentation with nuances of black, blue, and even pink (Fig. 3). Melanoma should be considered when a pigmented lesion develops new symptoms or undergoes a disproportionate change in color, size, shape, or surface characteristics com-
Figure 1. A dysplastic nevus. Note the large size, variable pigmentation, and blurred, irregular margin.
Downloaded by: Universite Laval. Copyrighted material.
cedure of choice for the detection of leptomeningeal involvement, and extent and character of the tumor, in these patients.I6 There is minimal response to radiotherapy or chemotherapy, but palliation with ventriculoperitoneal (VP) shunting may be helpful. Seventy percent die before age 10 years, most within 3 years of developing neurologic symptoms.l" Nevus of Ota (oculodermal melanocytosis) is an uncommon disorder in which there is unilateral hyperpigmentation of the skin supplied by the ophthalmic and maxillary divisions of the trigeminal nerve. The color is derived from dermal melanocytes and may be either blue or brown. There is involvement of the sclera and occasional involvement of the hard palate, iris, retina, ocular mus~ " risk of MM in these individcles, and ~ r b i t . The uals is low. Rarely, MM has been reported to develop directly from the skin, eye, or brain. Individuals with the familial DN syndromeix have a 56% chance of developing MM by age 59 years.lWN in both the familial and sporadic setting are markers for and potential precursors of MM. I!',Z) DN are generally 6 mm or more in diameter and characterized by a so-called shoulder, namely, a macular, tan area of pigmentation extending beyond the central, usually raised portion. In addition most DN display multiple colors and have an irregular margin (Fig. 1) Bale et al" have suggested a linkage of the DN gene to chromosome lp36. However, this has not been confirmed by Case-control and prospective follow-up studies have shown an increased risk for MM in per-
SEMINARS I N NEURO1,OGY
VOI.UME 12. NUMBER 4 DECEMBER 1992
pared with other pigmented lesions. Bleeding and ulceration may be late signs of malignancy. There are four clinical-histologic subtypes of MM: superficial spreading MM, nodular MM, lentigo maligna MM, and acral lentiginous MM (Figs. 4-7). T h e last may present as a longitudinal band of pigmentation arising from the proximal nailfold (melanonychia striata) (Fig. 8). Although melanonychia striata is often seen in dark-skinned individuals, a new, widening, or darkening band must be biopsied in order to rule out MM, especially in those who are fair-skinned.""
PROGNOSIS There are a number of prognostic factors that have been shown to influence the survival of patients with MM. The most important of these is stage of disease."' For stage I, (localized disease only), tumor thickness has been shown to correlate best with outcome." Patients with lesions 0.75 mm or smaller have a 90% 10-year survival, whereas those with lesions 4.0 mm or larger have less than a 40% chance of living 10 years.32 When the regional lymph nodes are involved
Figure 3. This lesion illustrates the ABCD's of malignant melanoma: asymmetry, border irregularity, color variegation, diameter greater than 6 mm.
Downloaded by: Universite Laval. Copyrighted material.
Figure 2. An acquired melanocytic nevus with uniform color and regular contour.
Figure 4. Superficial spreading malignant melanoma.
(stage 11) 5-year survival drops to 36%." Stage I1 prognosis worsens when two or more lymph nodes are involved or when there is ulceration of the primary 1esi0n.~' Melanoma can metastasize beyond the regional draining lymph nodes (stage 111) by a hematogenous
Figure 5.
route. Skin, subcutaneous tissue, lung, bone, liver, and CNS are often involved. The 5-year survival depends on the site and number of metastatic lesions, with the median survival being 6 months3' Metastases are divided into two groups: visceral (lung, brain, liver, and bone) and nonvisceral (skin, subcutaneous tissue, and distant lymph nodes). Patients with nonvisceral metastases have a l-year survival of 46%, compared with 18% for visceral metastases. Other prognostic variables in disseminated disease include the number of metastases Patients with solitary and duration of remi~sion.~' brain metastases have a median survival of 5 months, compared with 1.4 months for patients with multiple lesion^.^' Melanoma is the third most common metastatic tumor of the CNS after lung and breast carcinoma.""he most common presenting symptoms are headache and mental status change, and focal neurologic deficits are the most common presenting sign .33.34 Cerebral metastases are solitary in 25 to 40% of patients."'.Vhe most common sites of metastases are cerebrum, cerebellum, and brainstem. Leptomeninges and spinal cord can also be affected. Techniques for imaging intracerebral metastases include contrast enhanced computed tomography (C'T) and MRI." MRI scans ark the preferred imaging procedure for the evaluation of spinal tumdrs." 8eningeal involvement occurs in 3 to 13% of patients. Patients present with headache, confusion and signs of meningeal i r r i t a t i ~ n . ~ ~ 'The diagnosis can be made by cytologic examination of the CSF. Abnormal findings include an elevated CSF pressure, leukocytosis, elevated protein, and positive cytology in the majority of pa-
Nodular malignant melanoma.
Downloaded by: Universite Laval. Copyrighted material.
MALIGNANT MELANOMA-RIVERS, Ross1
SEMINAKS I N NEUKOLOGY
VOLUME 12, NUMBER 4 DECEMBER I992
tients. Several CSF samples may be necessary to detect malignant cells.""
INVESTIGATIONS Any cutaneous lesion suspected of being MM should be biopsied. Excisional biopsy is preferred because this preserves the architecture of the lesion and allows accurate determination of lesional thickness. If excisional biopsy is not feasible, then punch or incisional biopsy through the darkest or most raised portion of the lesion is recommended.40 A complete history and physical ex-
amination is important to rule out disseminated disease. Special attention should be focused on regional lymph nodes, liver, spleen, and the central nervous system (CNS). Baseline chest radiograph, complete blood count, and liver function tests are generally performed. Further investigations are not indicated in the absence of focal symptoms or
sign^.^',^^ TREATMENT Surgical excision is the treatment of choice for localized cutaneous MM. Melanoma in situ does
Figure 7. Acral lentiginous malignant melanoma causing destruction of the nail plate.
Downloaded by: Universite Laval. Copyrighted material.
Figure 6. Lentigo maligna melanoma.
Figure 8. Melanonychia striata. An enlarging, widening, or darkening band should prompt a biopsy of the nail matrix.
not metastasize, since malignant cells are confined Surgical treatment is effective for skin, subcutato the epidermis. However, there is a risk of local neous, and lymph node di~ease.~"esection of recurrence and the biopsy site should be reexcised brain lesions may prolong survival. The 6-month with a 1 cm margin of normal skin4% recent pro- survival in patients with solitary brain metastasis is spective study has confirmed that invasive lesions 58%. Twenty-five percent of these patients survive 1.0 mm or less thick can be safely excised with a over 2 years.50Dexamethasone is useful in the pal1.0 cm margin.44Thicker lesions, 1.0 mm or more, liation of brain metastases that cannot be e x c i ~ e d . ~ ' are removed (when feasible) with a 2 to 3 cm marPatients with multiple metastases are candigin in order to reduce the incidence of local recur- dates for chemotherapy. Dacarbazine, an alkylatrence. All patients should be followed on a regular ing agent, is the single agent most commonly used. basis to detect metastatic disease o r a second pri- Clinical response is seen in 20 to 25% of patient^,^' mary MM. Follow-up schedules vary from center but it is usually short-lived and most evident for to center, but in general, a complete cutaneous ex- skin, soft tissue, lymph node, and lung metastases. amination with palpation of liver, spleen, and re- Brain, liver, and bone metastases respond poorly. gional lymph nodes should be performed at each Fotemustine is a new nitrosourea with activity in visit.40 MM patients with cerebral metastases. In a recent The role of elective regional lymph node dis- series of 42 patients the response rate was 28%.53 section (ERLND) is c o n t r o ~ e r s i a l . There ~ ~ . ~ ~is~ ~ There are many combination chemotherapy some evidence to suggest that survival is increased regimens for MM. For example, the Dartmouth by 8 to 15% in a subgroup of patients with lesions regimen54 combines cisplatin, carmustine, dacarbetween 1.5 and 4.0 mm Patients with le- bazine, and tamoxifen. The response rates for a sions 1.5 mm or less infrequently develop meta- number of combination chemotherapy protocols static disease, whereas those with lesions 4.0 mm or range between 40 and 50%.52Unfortunately, the more have a high probability of developing hema- responses are generally temporary. Melanoma has been considered a radioresistogenous dissemination and therefore would not tant tumor. However, with high-dose fractionabenefit from ERLND.47 In stage 11, regional lymph node dissection is tions, local control of skin and regional lymph recommended unless distant metastases are pre- node disease can be achieved.55As a palliative tool, sent.40Fine needle aspiration biopsy may be used radiotherapy is effective in controlling bone and to determine whether lymph nodes contain tumor CNS metastases, including epidural compression.56.57 cells.48 In patients with metastatic disease, the use of Advances in radiotherapy include the use of surgery, chemotherapy, and radiation therapy de- boron conjugated to compounds that have a high pends on the site and the number of metastases. affinity for melanin. T h e boron absorbs thermal 343
Downloaded by: Universite Laval. Copyrighted material.
MALIGNANT MELANOMA-RIVERS, Ross1
neutrons and emits short-range ionizing radiation that selectively kills M M cells. Recently, Mishima et alS8reported the use of this treatment modality to cause regression of a metastatic occipital tumor. Research continues in the area of immunotherapy for MM. Injections with bacille CalmetteGuerin and Corynebacteriuni parvum have been used in the past as nonspecific immunoniodulators. More recently, interest has focused on biologic response modulators such as interferon and interleukin-2.""Iumor vaccines are being developed6' and recombinant gene therapy may exist in the near f ~ t u r e . ~ ' ACKNOWLEDGMENT We thank Dermtek Pharmaceuticals Ltd. for their generous support in providing the color plate.
REFERENCES I. Boring CC, Squires TS, Tsong T. Cancer statistics 1991. 1991;41:19-36 2. Kopf AW, Kripke ML, Stern RS. Sun and malignant mclanoma. J Am Acad Dermatol 1984; 1 1:674-84 3. Elwood JM, Gallagher RP, Hill GB, Pearson JCG. Cutaneous melanoma in relation to intermittent and constant sun exposure-the western Canada melanoma study. l n t J Cancer 1985;35:427-33 4. Evans RD, Kopf AW, Lew RA, Rigel DS, Bart RS, Friedman KJ, Rivers JK. Kisk factors for the development of malignant melanoma-I: review of case-control studies. J Uermatol Surg Oncol 1988; 14:393%408 5. Robbins J . Xeroderma pigmentosum. Defective DNA repair causes skin cancer a n d neurodegeneration. JAMA 1988;260:384-8 6. Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous a n d internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis 1984;5: 511-4 '7. Castilla EE, Ua Graca Dutra M , Orioli-Parrciras IM. Epidemiology of congenital pigrriented naevi. 1. Iricidence rates and relative frequencies. Br J Uermatol 1981;104:307-15 8. Rhodes AK, Wood WC, Sober A.1, Mihm MC. Nonepiderrrial origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 198 1;67:782-90 9. Kaplan J N . T h e risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974;53:421-4 10. Illig L, Weidner F, Hundeiker M, et al. Congenital nevi
12, N O . 4 DECEMBER 1992
Malignant Melanoma Jason K. Kiuers, M .D., F.R.C.P.(C), and Szkina F. Rossi, M.D.
EPIDEMIOLOGY There is now strong evidence that links ultraviolet B (UVB) radiation from the sun with the development of MM.2 Intermittent acute exposure prior to age 15 years seems to be criticaL3Sun-sensitive individuals with blonde or red hair, blue eyes, a tendency to burn rather than tan, an increased number of melanocytic nevi (moles), and the presence of dysplastic nevi (DN) are at an increased risk to develop MM.4
GENETIC S USCEPTZBILITY
Some individuals have a genetic susceptibility to MM. Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder in which there is an inability to repair UVB-induced DNA damage.5 Patients with XP have a 2000-fold increased risk of developing MM and other cutaneous neoplasms by age 20 years6 Individuals with the familial DN syndrome also have a genetic predisposition to melanoma (see discussion of "Precursor Lesions").
PRECURSOR LESIONS A number of different cutaneous pigmented lesions may give rise to MM. Congenital melanocytic nevi (CMN) occur in 1% of live births, whereas CMN 10 cm or larger are uncommon (1:20,500 live birth^).^ T h e lifetime risk of developing MM in a large CMN is estimated at 6%.8The majority of these MM develop before age 10 years, and therefore most authorities would recommend the excision of these nevi in childhood.Wowever, surgical excision may not eliminate the risk for MM because it nlay still arise directly from the underlying muscle, fascia, or lept~meninges.~ CMN 1.5 cm or smaller may give rise to MM,'" most of which usually develop after puberty. Because the lifetime risk in the general population of developing MM from these lesions is unknown, the management of' small CMN is controversial. Sonle clinicians advise surgical excision early in life," whereas others advocate observing these lesions over time, excising nevi only if signs of MM develop. l 2 Neurocutaneous melanosis (NCM) is a rare congenital condition characterized by numerous CMN (with or without a large CMN) in association with benign o r malignant melanotic tumors of the CNS.'"'"n a recent review of 39 cases, Kadonga and Frieden15 found that most patients presented with symptoms of increased intracranial pressure before age 2 years. Hydrocephalus was found in 64% of patients. Sixty-two percent had leptomeningeal MM. Abnormal cerebrospinal fluid (CSF) findings included elevated pressure, sterile leukocytosis, xanthochromia, and elevated red blood cell count. CSF cytologic examination occasionally revealed malignant cells or free melanin granules. Magnetic resonance imaging (MKI) with gadolinium contrast is recommended as the imaging pro-
T h e Division of Dermatology, T h e University of British Columbia, Vancouver., British Columbia, Canada Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: Universite Laval. Copyrighted material.
This year, over 32,000 Americans will have developed malignant melanoma (MM) and more than 6500 will die from the disease.' However, with early detection and prompt treatment, MM is curable in the majority of patients. Therefore it becomes important for physicians to recognize the clinical features of early, evolving MM in order to minimize the morbidity from this neoplasm. In particular, rleurologists should be well acquainted with it because patients with primary central nervous system (CNS) or metastatic MM may develop neurologic symptoms.
sons with DN.24-26Although the risk in the familial type is high, that in individuals with sporadic DN has not yet been accurately determined. The management of patients with DN includes a complete cutaneous examination, including the scalp, optional photographic documentation, follow-up at 3- to 12-month intervals (more often if lesions are changing), and excision of any lesions suspicious for MM." Acquired melanocytic nevi are extremely common. These lesions are characterized by a smooth texture, uniform color, and regular contour (Fig. 2). The results of several case-control studies have shown that the risk for MM varies directly with the number of moles.'"2R Melanoma has been shown to arise in histologic continuity with an acquired melanocytic nevus in 18 to 85% of cases.29However, the great majority of acquired nevi are stable, benign lesions and therefore prophylactic removal is seldom warranted.
CLINICAL FEATURES OF MALIGNANT MELANOMA The hallmark of MM is irregularity. In general, an early MM is asymmetrical, poorly circumscribed with notched or scalloped borders, and mottled in pigmentation with nuances of black, blue, and even pink (Fig. 3). Melanoma should be considered when a pigmented lesion develops new symptoms or undergoes a disproportionate change in color, size, shape, or surface characteristics com-
Figure 1. A dysplastic nevus. Note the large size, variable pigmentation, and blurred, irregular margin.
Downloaded by: Universite Laval. Copyrighted material.
cedure of choice for the detection of leptomeningeal involvement, and extent and character of the tumor, in these patients.I6 There is minimal response to radiotherapy or chemotherapy, but palliation with ventriculoperitoneal (VP) shunting may be helpful. Seventy percent die before age 10 years, most within 3 years of developing neurologic symptoms.l" Nevus of Ota (oculodermal melanocytosis) is an uncommon disorder in which there is unilateral hyperpigmentation of the skin supplied by the ophthalmic and maxillary divisions of the trigeminal nerve. The color is derived from dermal melanocytes and may be either blue or brown. There is involvement of the sclera and occasional involvement of the hard palate, iris, retina, ocular mus~ " risk of MM in these individcles, and ~ r b i t . The uals is low. Rarely, MM has been reported to develop directly from the skin, eye, or brain. Individuals with the familial DN syndromeix have a 56% chance of developing MM by age 59 years.lWN in both the familial and sporadic setting are markers for and potential precursors of MM. I!',Z) DN are generally 6 mm or more in diameter and characterized by a so-called shoulder, namely, a macular, tan area of pigmentation extending beyond the central, usually raised portion. In addition most DN display multiple colors and have an irregular margin (Fig. 1) Bale et al" have suggested a linkage of the DN gene to chromosome lp36. However, this has not been confirmed by Case-control and prospective follow-up studies have shown an increased risk for MM in per-
SEMINARS I N NEURO1,OGY
VOI.UME 12. NUMBER 4 DECEMBER 1992
pared with other pigmented lesions. Bleeding and ulceration may be late signs of malignancy. There are four clinical-histologic subtypes of MM: superficial spreading MM, nodular MM, lentigo maligna MM, and acral lentiginous MM (Figs. 4-7). T h e last may present as a longitudinal band of pigmentation arising from the proximal nailfold (melanonychia striata) (Fig. 8). Although melanonychia striata is often seen in dark-skinned individuals, a new, widening, or darkening band must be biopsied in order to rule out MM, especially in those who are fair-skinned.""
PROGNOSIS There are a number of prognostic factors that have been shown to influence the survival of patients with MM. The most important of these is stage of disease."' For stage I, (localized disease only), tumor thickness has been shown to correlate best with outcome." Patients with lesions 0.75 mm or smaller have a 90% 10-year survival, whereas those with lesions 4.0 mm or larger have less than a 40% chance of living 10 years.32 When the regional lymph nodes are involved
Figure 3. This lesion illustrates the ABCD's of malignant melanoma: asymmetry, border irregularity, color variegation, diameter greater than 6 mm.
Downloaded by: Universite Laval. Copyrighted material.
Figure 2. An acquired melanocytic nevus with uniform color and regular contour.
Figure 4. Superficial spreading malignant melanoma.
(stage 11) 5-year survival drops to 36%." Stage I1 prognosis worsens when two or more lymph nodes are involved or when there is ulceration of the primary 1esi0n.~' Melanoma can metastasize beyond the regional draining lymph nodes (stage 111) by a hematogenous
Figure 5.
route. Skin, subcutaneous tissue, lung, bone, liver, and CNS are often involved. The 5-year survival depends on the site and number of metastatic lesions, with the median survival being 6 months3' Metastases are divided into two groups: visceral (lung, brain, liver, and bone) and nonvisceral (skin, subcutaneous tissue, and distant lymph nodes). Patients with nonvisceral metastases have a l-year survival of 46%, compared with 18% for visceral metastases. Other prognostic variables in disseminated disease include the number of metastases Patients with solitary and duration of remi~sion.~' brain metastases have a median survival of 5 months, compared with 1.4 months for patients with multiple lesion^.^' Melanoma is the third most common metastatic tumor of the CNS after lung and breast carcinoma.""he most common presenting symptoms are headache and mental status change, and focal neurologic deficits are the most common presenting sign .33.34 Cerebral metastases are solitary in 25 to 40% of patients."'.Vhe most common sites of metastases are cerebrum, cerebellum, and brainstem. Leptomeninges and spinal cord can also be affected. Techniques for imaging intracerebral metastases include contrast enhanced computed tomography (C'T) and MRI." MRI scans ark the preferred imaging procedure for the evaluation of spinal tumdrs." 8eningeal involvement occurs in 3 to 13% of patients. Patients present with headache, confusion and signs of meningeal i r r i t a t i ~ n . ~ ~ 'The diagnosis can be made by cytologic examination of the CSF. Abnormal findings include an elevated CSF pressure, leukocytosis, elevated protein, and positive cytology in the majority of pa-
Nodular malignant melanoma.
Downloaded by: Universite Laval. Copyrighted material.
MALIGNANT MELANOMA-RIVERS, Ross1
SEMINAKS I N NEUKOLOGY
VOLUME 12, NUMBER 4 DECEMBER I992
tients. Several CSF samples may be necessary to detect malignant cells.""
INVESTIGATIONS Any cutaneous lesion suspected of being MM should be biopsied. Excisional biopsy is preferred because this preserves the architecture of the lesion and allows accurate determination of lesional thickness. If excisional biopsy is not feasible, then punch or incisional biopsy through the darkest or most raised portion of the lesion is recommended.40 A complete history and physical ex-
amination is important to rule out disseminated disease. Special attention should be focused on regional lymph nodes, liver, spleen, and the central nervous system (CNS). Baseline chest radiograph, complete blood count, and liver function tests are generally performed. Further investigations are not indicated in the absence of focal symptoms or
sign^.^',^^ TREATMENT Surgical excision is the treatment of choice for localized cutaneous MM. Melanoma in situ does
Figure 7. Acral lentiginous malignant melanoma causing destruction of the nail plate.
Downloaded by: Universite Laval. Copyrighted material.
Figure 6. Lentigo maligna melanoma.
Figure 8. Melanonychia striata. An enlarging, widening, or darkening band should prompt a biopsy of the nail matrix.
not metastasize, since malignant cells are confined Surgical treatment is effective for skin, subcutato the epidermis. However, there is a risk of local neous, and lymph node di~ease.~"esection of recurrence and the biopsy site should be reexcised brain lesions may prolong survival. The 6-month with a 1 cm margin of normal skin4% recent pro- survival in patients with solitary brain metastasis is spective study has confirmed that invasive lesions 58%. Twenty-five percent of these patients survive 1.0 mm or less thick can be safely excised with a over 2 years.50Dexamethasone is useful in the pal1.0 cm margin.44Thicker lesions, 1.0 mm or more, liation of brain metastases that cannot be e x c i ~ e d . ~ ' are removed (when feasible) with a 2 to 3 cm marPatients with multiple metastases are candigin in order to reduce the incidence of local recur- dates for chemotherapy. Dacarbazine, an alkylatrence. All patients should be followed on a regular ing agent, is the single agent most commonly used. basis to detect metastatic disease o r a second pri- Clinical response is seen in 20 to 25% of patient^,^' mary MM. Follow-up schedules vary from center but it is usually short-lived and most evident for to center, but in general, a complete cutaneous ex- skin, soft tissue, lymph node, and lung metastases. amination with palpation of liver, spleen, and re- Brain, liver, and bone metastases respond poorly. gional lymph nodes should be performed at each Fotemustine is a new nitrosourea with activity in visit.40 MM patients with cerebral metastases. In a recent The role of elective regional lymph node dis- series of 42 patients the response rate was 28%.53 section (ERLND) is c o n t r o ~ e r s i a l . There ~ ~ . ~ ~is~ ~ There are many combination chemotherapy some evidence to suggest that survival is increased regimens for MM. For example, the Dartmouth by 8 to 15% in a subgroup of patients with lesions regimen54 combines cisplatin, carmustine, dacarbetween 1.5 and 4.0 mm Patients with le- bazine, and tamoxifen. The response rates for a sions 1.5 mm or less infrequently develop meta- number of combination chemotherapy protocols static disease, whereas those with lesions 4.0 mm or range between 40 and 50%.52Unfortunately, the more have a high probability of developing hema- responses are generally temporary. Melanoma has been considered a radioresistogenous dissemination and therefore would not tant tumor. However, with high-dose fractionabenefit from ERLND.47 In stage 11, regional lymph node dissection is tions, local control of skin and regional lymph recommended unless distant metastases are pre- node disease can be achieved.55As a palliative tool, sent.40Fine needle aspiration biopsy may be used radiotherapy is effective in controlling bone and to determine whether lymph nodes contain tumor CNS metastases, including epidural compression.56.57 cells.48 In patients with metastatic disease, the use of Advances in radiotherapy include the use of surgery, chemotherapy, and radiation therapy de- boron conjugated to compounds that have a high pends on the site and the number of metastases. affinity for melanin. T h e boron absorbs thermal 343
Downloaded by: Universite Laval. Copyrighted material.
MALIGNANT MELANOMA-RIVERS, Ross1
neutrons and emits short-range ionizing radiation that selectively kills M M cells. Recently, Mishima et alS8reported the use of this treatment modality to cause regression of a metastatic occipital tumor. Research continues in the area of immunotherapy for MM. Injections with bacille CalmetteGuerin and Corynebacteriuni parvum have been used in the past as nonspecific immunoniodulators. More recently, interest has focused on biologic response modulators such as interferon and interleukin-2.""Iumor vaccines are being developed6' and recombinant gene therapy may exist in the near f ~ t u r e . ~ ' ACKNOWLEDGMENT We thank Dermtek Pharmaceuticals Ltd. for their generous support in providing the color plate.
REFERENCES I. Boring CC, Squires TS, Tsong T. Cancer statistics 1991. 1991;41:19-36 2. Kopf AW, Kripke ML, Stern RS. Sun and malignant mclanoma. J Am Acad Dermatol 1984; 1 1:674-84 3. Elwood JM, Gallagher RP, Hill GB, Pearson JCG. Cutaneous melanoma in relation to intermittent and constant sun exposure-the western Canada melanoma study. l n t J Cancer 1985;35:427-33 4. Evans RD, Kopf AW, Lew RA, Rigel DS, Bart RS, Friedman KJ, Rivers JK. Kisk factors for the development of malignant melanoma-I: review of case-control studies. J Uermatol Surg Oncol 1988; 14:393%408 5. Robbins J . Xeroderma pigmentosum. Defective DNA repair causes skin cancer a n d neurodegeneration. JAMA 1988;260:384-8 6. Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous a n d internal neoplasia: evidence from xeroderma pigmentosum. Carcinogenesis 1984;5: 511-4 '7. Castilla EE, Ua Graca Dutra M , Orioli-Parrciras IM. Epidemiology of congenital pigrriented naevi. 1. Iricidence rates and relative frequencies. Br J Uermatol 1981;104:307-15 8. Rhodes AK, Wood WC, Sober A.1, Mihm MC. Nonepiderrrial origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 198 1;67:782-90 9. Kaplan J N . T h e risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974;53:421-4 10. Illig L, Weidner F, Hundeiker M, et al. Congenital nevi
