SKIN NEOPLASIA AND MELANOMA by hilen

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									                                                                                        11/2002
                        SKIN NEOPLASIA AND MELANOMA
                          DR N J FERIS
COMMENTORS: DRS P. MOODLEY & M. MORAKE
                                                            MODERATOR: DR G. LANDERS

                                      INTRODUCTION
Skin cancer is the most common malignancy occurring in humans. Sun exposure remains
the most important risk factor for all skin neoplasms. The current epidemic probably
reflects changes in dress and lifestyle that allow for greater sun exposure as well as mans
overt disrespect for the mighty sun. Additionally, depletion of the ozone layer, which filters
out carcinogenic ultraviolet rays, certainly contribute to the alarming increase in the
incidence of skin cancer.
Early detection and intervention of skin cancer can improve morbidity and mortality.

A completely revised staging system for cutaneous melanoma has now been approved by
the American Joint committee on cancer (AJCC) as well as the International Union Against
Cancer (IUCC) tumor-node-metastasis (TNM) committees. The new staging system
should now form the basis for all statistical design and analysis of future adjuvant therapy
trials.

SKIN ANATOMY
3 LAYERS
i) Epidermis: Keratinocytes (mechanical barrier)
     Melanocytes (radiation barrier)
     Langerhans cells (immunological barrier)
ii) Dermis: contains an extracellular matrix for support of nerves, vasculature and
adnexal
               structures.
iii) Basement membrane: anchors the epidermis to dermis.
Melanocytes arise from precursor cells in the neural crest; produce melanin form cysteine
and tyrosine. Melanin is contained within the melanosomes and is transferred to the
keratinocytes via the dendritic processes. Melanocyte density is constant between
individuals of different color. It is the difference in the rate of melanin production, transfers
to keratinocytes and melanosomes degradation, which determine skin color.

CLASSIFICATION 1
In the skin the classification of tumors may be broken down as shown in the following
table.
Table 1.
                                 BENIGN              PRE-           MALIGNANT
                                                     MALIGNANT
EPIDERMIS                        Simple squamous Keratosis          Squamous cell
Squamous                          Papilloma          Carcinoma-in   Carcinoma
                                 Keratoacanthoma     situ
Basal                            Basal          cell                Basal           cell
                                 papilloma                          carcinoma
                                 (seborrheic wart)
Pigmented                        Cellular nevus      Dysplastic     Malignant
                                                     nevus          Melanoma
                                                     LentigoMaligna
                                                     Melanoma-in-
                                                     situ
                                                                                           2
DERMIS
Glandular Epithelium (Sweat Adenoma                                          Carcinoma
glands       and   sebaceous                                                 (very rare)
glands)
Hair follicles               Trichoepithelioma                               Basal         cell
                                                                             carcinoma
Connective tissue        Various                                             Various
Nerves, vessels & Smooth Various                                             Various
muscle
                                                                     2,3,4
DELETERIOUS EFFECTS OF ULTRAVIOLET RADIATION (UVR)

All UV light from whatever source damages the skin. Just as x-rays penetrate the body,
UV rays penetrate the skin. The longer the wavelength, the deeper the penetration. The
shorter the wavelength, the higher the energy and therefore the potential for damage.
UVR consists of 3 main components:
i)        UVC:      200-290nm most destructive
ii)       UVB:      290-320nm causes sunburn, delayed tanning
iii)      UVA:      320-400nm immediate tanning, also ageing

UVB MONITORING:
A countrywide network of UV monitors measuring sunburn units was established in South
Africa in 1993. A sunburn unit equals the amount of UV radiation that will cause fair skin to
pinken. In summer, SA UV levels rank amongst the highest in the world (30 su). For a fair
skinned person, sunburn units can be directly related to sun protection factor in numerical
terms.
This implies that a fair skinned person will need a SPF of 30 for high protection during
summer. While the role of sunscreens has been questioned, most evidence suggests that
their correct use can lower the risk of skin cancer.4 Sufficient amounts must be applied at
least 30 minutes before exposure, with reapplication after prolonged exposure or
swimming.
There are 6 skin phototypes varying from Type 1 (always burns easily, never tans –
freckled, redheads, Celtic) to Type 6 (burns very slightly, deeply pigmented – Negroid).
DAMAGE
Acute/sporadic:             caused by sun exposure alone
Chronic and progressive: caused by sun exposure alone in genetically normal skin
Long term and progressive:         due to sun exposure in genetically compromised skin

It is the combination of DNA damage and immunosuppression that make UV exposure so
hazardous.

Primary prevention of skin cancer is based on increasing public awareness of the risks of
sun exposure and providing patients with individualized guidance. Patients who are
educated about risk factors for skin cancer are more likely to self-select for clinical
screening and to bring malignant lesions to the attention of the health care provider.
Thus, patients should be taught basic “safe sun” measures: sun avoidance during peak
UVB hours; proper use of sunscreen and protective clothing; and avoidance of sun
tanning. For Tanning enthusiasts, available topical preparations include physical reflectors
(titanium dioxide & zinc oxide) and the chemical absorbers (para-aminobenzoic acid and
its esters).

              PRECURSORS TO NON-MELANOMA SKIN CANCER4,5,6,7,8
                                                                                        3
                            6,7,8
ACTINIC KERATOSIS (AK)
Actinic Keratosis, sometimes-called solar keratosis, are extremely common lesions on sun
exposed body areas such as the face, ears, arms and hands. The most important risk
factors are a combination of genetic propensity ("fair skin phenotype") and cumulative sun
exposure. They may serve as an indication of a person‟s cumulative UV light exposure
and therefore, that person‟s risk for all types of skin cancer. In order for a person to
manifest an AK, he or she must have attained a critical cumulative dose of solar radiation
for their individual skin type.

AK‟s are often ill defined and irregular, ranging from 1mm to several centimeters in size.
They generally have a scaly appearance but may be macular or papillar. Patients often
have multiple lesions. The lesions are usually pale brown or flesh-colored but may be
yellow, reddish-brown or even dark brown or black following trauma.

Differential diagnosis for AK includes benign inflammatory disorders with secondary
reactive keratinocytic atypia, Bowen‟s disease (squamous cell carcinoma in situ), discoid
lupus erythematosus, lichen planus and superficial basal cell carcinoma.
The conversion rate of malignant transformation of individual AK‟s to SCC is one per 1000
per annum. (0,1%/yr)
Many involute spontaneously if the patient has not received substantial solar exposure for
a reasonable period of time. (25% within a12-month period).
Histological changes:
i)          Dyskeratosis: loss of granular layer
ii)         Parakeratosis: retention of nuclei in the keratin layer
iii)        Hyperkeratosis

TREATMENT
Cryotherapy with Liquid nitrogen is the treatment of choice for most cases of AK.
Curettage may also be used or in conjunction with cryosurgery and electrodessication.
Surgical excision is rarely required but may be useful in excluding SCC as a possible
cause in lesions larger than 0.5 cm in diameter.
Chemical destruction of superficial lesions may be used when there are many lesions,
particularly on the head and face.
5-fluorouracil (5-FU), a pyrimidine antagonist that inhibits DNA synthesis is most
commonly used. In conventional regimens, 5-FU is applied twice daily for two to five
weeks.
Other therapies used occasionally include carbon dioxide laser, topical tretinoin,
chemexfoliation (chemical peeling) and facial dermabrasion. Although tretinoin is capable
of reversing photo damage, the effect is not permanent and requires maintenance
therapy.8

BOWEN’S DISEASE (BD)
Bowen‟s disease is an intraepidermal or in situ SCC.

HISTOPATHOLOGY
Features include hyperkeratosis, parakeratosis, acanthosis and destruction of the normal
progression of epidermal maturation. No invasion into the dermis by atypical keratinocytes

CLINICAL FEATURES
BD presents as an erythematous scaling plaque with an irregular but sharp outline.
Lesions may be up to several centimeters in size and are most commonly found on the
head, neck, and trunk. Although BD rarely transform into invasive SCC, the presence of
induration or thickening should alert the physician to this possibility. At least 5% may
undergo invasion of the dermis in which case the result is SCC. Once invasion has
                                                                                            4
occurred at least one third have metastatic capacity. Forty two (42) % of BD patients will
develop other premalignant or malignant cutaneous and/ or mucosal lesions within 7 years
of follow up.

TREATMENT
See below

KERATOACANTHOMA (KA)
KA is a self-healing neoplasm that presents as a rapidly growing nodule with central
keratin filled plug on sun-exposed areas of middle-aged and elderly persons. The majority
of KAs will involute after 2-6 months, leaving a depressed scar. The clinical and histologic
appearance of KA can be similar to that of a well-differentiated SCC, and the true biologic
nature of KA is a subject of much debate. Many clinicians regard KA as a type of well-
differentiated SCC and treat KA as if it were a malignant neoplasm.


NON-MELANOMA SKIN CANCERS (NMSC)9,10
Basal cell carcinoma (BCC) constitutes the majority of NMSC, but 20% are squamous cell
carcinoma (SCC). The typical patient who develops NMSC has a fair complexion, burns
easily, and tans poorly. Often patients have a history of chronic sun exposure as a result of
either occupational exposure or recreational pursuits. Men are more commonly affected
than women.
Besides UV light, other factors may contribute to the development of NMSC. NMSC may
arise in scars of various causes, including those associated with burns, trauma, and
vaccinations. Chronic stasis ulcers and sinuses associated with osteomyelitis may also
give rise to NMSC. Radiation exposure may lead to NMSC in later years.
Immunosuppression because of lymphoproliferative diseases, acquired immunodeficiency
syndrome (AIDS), and the use of immunosuppressive agents for transplantation has been
associated with an increase incidence of NMSC, especially SCC.

The mode of local spread in NMSC is always along the path of least resistance. Thus,
these tumors are more likely to spread along the perichondrium, periosteum, or fascia
rather than to invade cartilage, bone or muscle. This type of spread can result in an
iceberg phenomenon with extensive subclinical spread and, in part, explains the high
recurrence rates reported for NMSC of the nose, ear, scalp, and periocular area.
Embryonic fusion planes (e.g. nasolabial fold, periauricular area, retroauricular sulcus,
inner canthus, philtrum, and midlower lip and chin) offer little resistance to spread of tumor
and allow for extensive subclinical spread of tumor, again accounting for the high
recurrence rates reported after treatment of tumors in these anatomical locations.
Scar tissue offers resistance to tumor penetration; thus, tumor buried beneath scar is more
likely to spread laterally or penetrate deeply rather than try to reach the surface. Such
behavior may result in delay in diagnosing a recurrence and may follow substantial
subclinical spread.

                    SQUAMOUS CELL CARCINOMA (SCC)5,11,12,13 14

SCC, a malignant proliferation of keratinocytes of the epidermis, is the second most
common skin cancer, comprising 20% of all cases of NMSC. This is the most common
tumor in elderly patients, and it is usually the result of a high lifetime cumulative dose of
solar radiation. As many as 60% of SCCs occur at the site of a previous AK. Thirty percent
of SCC can expect to develop a second SCC and 52% can expect to develop a second
NMSC within 5 years of therapy for the initial SCC. Over 50% of these subsequent NMSCs
were detected during the first year of follow-up.13 Changes in an AK suggesting
                                                                                               5
transformation to SCC include pain, erythema, ulceration, induration, hyperkeratosis and
increasing size.
Up to 50 – 60 % of SCCs occur on the head and neck.

CLINICALLY: SCCs typically appear as exophytic tumors that may grow moderately
rapidly over a period of months and rage from a few millimeters to centimeters in size.
They may appear nodular or papillar, and may be reddish-brown, pink or flesh-colored.
Larger SCCs may appear crusted, erythematous or ulcerated.
In contrast with BCC, a definitive edge is difficult to demonstrate when a SCC lesion is
stretched.
NMSC, especially SCC, may spread along vessels and nerves, especially the latter. The
tumor may travel along a major nerve, enter a foramen, and spread intracranially.
SCC has a much greater propensity to metastasize than does BCC. Even the smallest,
most superficially invasive, well-differentiated SCC may metastasize. For this reason,
palpation of the regional lymph nodes is mandatory.
HISTOLOGICALLY: acanthotic surface epithelium, irregularly penetrating into dermis.
Variable parakeratosis and hyperkeratosis occur. Also varying degree of anaplasia and
mitosis.



PROGNOSIS
Risk factors for metastasis include poor cell differentiation, increasing lesion depth and
location on the lip or ear. Anatomically the vermillion of the lip is the only site that has been
definitively identified in the literature as being at high risk for developing metastasis.
(Reported incidence between 6.8% and 15.8%)14 Depth of tumor invasion to Clarks IV/V
levels increases the risk of recurrence. Once metastases occur, the five-year cure rate for
SCC is 34%. Recurrence and metastasis typically occur within three years of initial
treatment.

                           BASAL CALL CARCINOMA(BCC)15,16

EPIDEMIOLOGY AND ETIOLOGY
Basal cell carcinoma is the most common skin neoplasm, and represents 75–80% of
NMSC The lifetime risk for development of BCC in Caucasians is approximately 33%, and
men are slightly more at risk than women. The incidence of BCC peaks around 70.

PRECURSOR LESIONS AND CLINICAL CHARACTERISTICS
Eighty percent of BCC arise on the sun-exposed areas of the head and neck, and 30% are
found on the nose, making it the most common site for BCC. There is no commonly
recognized precursor to BCC. They typically grow slowly and generally spread only locally.
Metastatic disease is rare.
Basal cell carcinomas may be classified into several different subtypes based on clinical
and histological patterns:
     I. Nodular
    II. Superficial
   III. Micronodular
  IV. Infiltrative
    V. Morpeaform
  VI. Basosquamous
Another classification include the following morphological types: nodular, ulcerative,
pigmented, morphoeic, sclerosing, superficial.
                                                                                            6
Nodular BCC is the most common histologic subtype and represent 75% of all BCCs.
This lesion clinically presents as a well-defined, pearly, translucent nodule. Round or oval
in shape, and a rolled border can be appreciated when the surrounding skin is stretched.
Central ulceration may be present and, in some cases, ulceration can be the predominant
feature. (“rodent ulcer”). Nodular BCCs can be cystic in appearance or can have variable
amounts of pigment, at times resembling melanoma.

HISTOLOGY
BCCs are cutaneous epithelial tumors characterized by nests of sheets of small basal-type
cells having a relatively large basophilic nucleus, cell borders are often poorly defined, the
peripheral layer of tumor cells in each island is usually arranged in a palisading fashion.
Tumours are classified into two groups; differentiated and undifferentiated.

Micronodular, infiltrative, and morphoeform BCCs have been associated with more
aggressive histologic appearances and clinical courses, and together they account for
approxiamately 10% of all BCCs. Microscopically, the tumor cells are arranged in
dispersed micronodules or irregular cords and strands. Clinically, these more aggressive
subtypes typically eppear flat, white or yellow plaques with ill-defined margins.

Basosquamous carcinomas are rare skin neoplasms that show evidence of both basal cell
and squamous cell differentiation. It has increased rates of growth and metastasis as
compared to BCC.


MANAGEMENT16
In managing patients with BCC and SCC, the following goals should be kept in mind:
     I. Identify high risk patients for prevention and surveillance
    II. Total removal or destruction of the tumor
   III. Maximal preservation of normal tissue
   IV. Preservation of function
    V. Optimal cosmesis
   VI. Careful follow up after successful treatment.
Elderly patients should not be denied definitive therapy on the basis of age considerations
alone. With people living longer and enjoying better health, with technological and surgical
advancements, these patient should be offered the same treatment options as younger
individuals.
A biopsy is mandatory if the diagnosis is in question, a major surgical procedure is
planned, or the patient is referred for radiation therapy.

BIOPSY TECHNIQUES
There are three main biopsy techniques.
    i. Punch biopsy provides a full-thickness skin biopsy with minimal skin damage and
       minimal scarring. It is best used for most benign and malignant tumors, except
       malignant melanoma, and for most inflammatory diseases.
   ii. Shave biopsy is useful when full thickness tissue samples are not required. This
       technique is best used with elevated, nodular lesions, including NMSC‟s, such as
       SCC and BCC, but should not be used for inflammatory lesions.
  iii. Excisional biopsy is the gold-standard for biopsy techniques. It provides a full
       thickness specimen with margins, allowing the pathologist to determine whether the
       lesion was totally removed. It is the biopsy technique of choice when one is
       concerned about malignant melanoma, but may also be used for any type of skin
       lesion.
                                                                                            7
The modality of treatment depends on many factors including the type of lesion, the size
and stage of lesion and the location of the tumor. Although age and cosmesis may be
independent factors in deciding on the best management of an NMSC, the two often go
hand in hand. Age alone should not be used as a reason for delivering inappropriate or
non-curative treatment.

Surgical Excision
In terms of size, 2cm appears to be the critical point at which the cure rate for invasive
BCC and SCC declines significantly and for SCC the size at which the incidence if
metastases increases significantly.
Excision is used on all sizes and types of lesions, but those that are over 2 cm are
preferable excised. Excision is, however, a blind procedure, because the margins of
excision depend on the physician‟s clinical judgement. Tumors such as morpheaform BCC
may extend well beyond clinical margins histologically, and may not be excised completely
with conventional methods.
In these cases Mohs‟ microscopic controlled excision may be used. Mohs‟ surgery
consists of careful dissection, staining and anatomical mapping. Any areas showing
residual tumor are marked and additional tissue is removed. The process is repeated until
a tumor-free wound is achieved. Mohs‟ microscopic surgery (MMS) offers the highest
chance of cure while maximally preserving healthy tissue. The cure rates for MMS for SCC
is 98.8% and primary and recurrent BCC is 99.8%. The major disadvantage is that it is not
always readily accessible and requires special equipment (cryostats) and highly trained
personnel (histotechnologists). It is only used in a few centers today.
Cure rates for traditional excision approach 98% for BCC and SCC, given that adequate
clinical margins are provided.(Hochman)For clearly demarcated, non-morphoform BCCs of
less than 2cm, a 4mm margin of normal-appearing skin is recommended. Tumors larger
than 2cm, tumors with poorly delineated borders, or those that are poorly differentiated
on histological examination require 6mm margins, including subcutaneous fat if invasion is
present.


Electrodessication & Curettage (Hochman)
It is best suited for small ( 1cm), well-defined, superficially invasive(upper dermis),
exophytic lesions, that are not located in areas that pose an increased risk for metastasis.
It too is a blind method of removal, but unlike excision, it provides no margins to confirm
that the lesion was totally removed. However, it is an easy and safe technique for skin
cancer treatment and provides 5-year cure rates of greater than 90% in properly selected
patients.
Cryosurgery
Indicated for a variety of skin lesions, including BCC and SCC, and it is particularly
effective in the treatment of Actinic Keratosis. Cryotherapy is one of the best modalities for
treatment of lesions on the face, lips, nose, eyelids, arms, legs and hands.
In general, a double freeze-thaw cycle with a tissue temperature of -50c is required to
ensure the destruction of most tumors.
Cure rates appear improved with freeze-thaw-freeze applications. As with all modalities, a
margin of clinically normal skin (usually 5 mm) is included in the treated area to destroy
subclinical extensions of the tumor.
Cure rates for primary BCC and SCC of 2cm or less in size have been reported as high as
98%in some series. To achieve these high cure rates, careful patient selection and proper
execution of the procedure is mandatory. May also be used for palliation in advanced
tumors. It should not be used melanomas, recurrences, deeply invasive tumors,
morpheaform or sclerosing BCC or patients with cold intolerance.

Radiation therapy
                                                                                          8
The major advantage of radiation therapy is that is spares normal tissue. Thus, it is often
advocated for managing tumors of the nose, ear, and periocular area because it obviates
the need for reconstructive surgery and spares the lacrimal apparatus. It can also be used
for patients too frail to undergo surgery or in patients who refuse surgery. It can also be
used to palliate inoperable tumors. Radiation therapy may also be used postoperatively as
an adjunct if the patient is considered high risk for recurrent disease or occult nodal
metastases are expected. In general radiation therapy should be reserved for the older
individual because of the slight risk of inducing another cancer and because with passage
of time, the risk of radiation necrosis and the cosmetic result deteriorates.
Cure rates for primary BCC and SCC that are less than 2 cm in size, do not exhibit an
aggressive growth pattern, and are not in high-risk locations have been reported to be in
excess of 90%.
Risk of radiation osteitis and chondritis.

Interferon
Interferes with cell growth, affect cell differentiation and modulate a variety of other
immunologic and cellular functions. Intra-lesional interferon has been used to treat BCC
and SCC successfully with rates as high as 96%.
The tumor is usually injected thrice weekly for 3 weeks. Side effects include discomfort at
the site of injection, leucopenia, and flu-like symptoms. This treatment is still considered
experimental. It carries the risk of incompletely destroying the tumor and allowing
subclinical spread before the tumor is detected.

Lasers
Lasers play a limited role in the day-to-day management of BCC and SCC. The safety
hazards and awkwardness of the carbon dioxide laser system usually outweigh any
benefits.

Photodynamic therapy
Photodynamic therapy is an experimental form of treatment in which a photosensitizer (eg.
Haemoatoporphyrin) is administered intravenously, intralesionally, or topically and
subsequently activated by light from Argon pumped tunable dye laser, gold vapor laser, or
another light source. The lesion takes up the drug and upon exposure to the laser the drug
is fully activated, stimulating the production of oxygen radicals which result in tumor
necrosis.
Disadvantages include cost and the need for special expensive equipment. Furthermore,
intravenous administration of hematoporphyrin is associated with a generalized
photosensitivity that may last up to 6 weeks and can be activated by sunlight causing
severe burns.

Retinoids
They are more effective as chemopreventive agents than as chemotherapeutic agents.
Once they are stopped, their protective effect is lost. SCC are more responsive to these
agents than are BCC. Investigators have used retinoids in combination with interferon and
achieved response rates of 93% in patients with advanced cutaneous SCC.18 Response
rate with retinoids alone is 71%.

Other
Imiquimod 5% cream is a cytokine and interferon inducer and showed clinical efficacy in a
double blind randomized trials in the USA.19

                                    MELANOMA20,21,22
                                                                                          9
                                   22
EPIDEMIOLOGY AND ETIOLOGY
Melanoma is an aggressive cutaneous neoplasm that result from the malignant
transformation of melanocytes, cells of neural crest origin. Although most malignant
melanoma arise in the skin, they may also arise from mucosal surfaces or other sites to
which neural crest cells may migrate. Neural crest cells give rise to the spinal ganglia of
the autonomic nervous system. They form sheaths of nerves and also contribute to the
formation of pigment cells, the suprarenal medulla, and several skeletal and muscular
components in the head. Melanoma can arise from sites in the eye, including the retina
and iris.

Malignant melanoma is an important health problem in countries with populations of
Caucasian origin where the incidence has risen steadily over the last 50 years with the
rates doubling in some countries every 10 to 15 years, the fastest growth rate of any
malignancy, except for lung and breast cancer in woman. Another worrying aspect about
this trend is the relative youth of the adult population involved, the median age for this
condition is 50 years .The steepest increase in the incidence rate is in the 30 to 40 year
age group.

The aetiology of malignant melanoma is related to a mixture of host and environmental
factors with the most prominent being skin colour and reaction to sunlight. Ethnicity has an
important influence on the incidence of MM. Rates in populations of Asian and African
origin are far lower than those of Caucasian populations and have not shown the same
marked increases in recent years. In Japan the incidence rates remain around 1.0 – 1,5
per 100 000 population, compared with rates of 7,8 (males) and 12,3 (females) per 100
000 population in Scotland. (Mackie et al, 1997)

Geographical factors also influence the incidence of melanoma with the rate increasing
with proximity to the equator. The incidence of melanoma in whites increases dramatically
in populations closest to the equator, with the highest worldwide incidence in Queensland,
Australia. Malignant melanoma is responsible for six out of every seven deaths resulting
from skin cancer.

A history of NMSC (BCC or SCC) may increase a person‟s risk of developing melanoma
by threefold to fivefold. Similar to NMSC, there is a strong correlation between sun
exposure and the development of malignant melanoma. In contrast to NMSC (BC and
SCC), whose development correlates with chronic sun exposure, except for lentigo
maligna and lentigo maligna melanoma, the development of malignant melanoma
correlates better with intermittent intense exposure to UV radiation. Consequently, it is
more likely to occur in the office worker who goes to the beach on weekends rather than
the outdoor worker. The exact role of UV radiation in the etiology of melanoma is not fully
understood. A history of 3 or more blistering sunburns before the age of 20 has been
identified as an independent risk factor for melanoma, as has the presence of freckles.
The presence of sunburning and freckles may reflect a pattern of intense intermittent sun
exposure and a degree of sun sensitivity. The use of tanning beds (10 times per year or
more) and PUVA treatments (more than 250/psoriatics) appear to increase the risk for
developing melanoma.
Heredity is a factor in the etiology of melanoma. Eight to 12% of persons with melanoma
have a history of melanoma in a first degree relative.
Immunosuppressed patients – such as those with lymphoma, leukemia or organ
transplants etc. - have an increased risk of melanoma.
The presence of a changing nevus is another significant risk factor for developing
melanoma.
Mortality rates in melanoma have revealed a similar pattern as the increasing incidence
rate. In males, the mortality has increased whereas in females the trend is reversed. The
                                                                                            10
exact explanation for this is not clear but is thought to be due to earlier diagnosis in
women as reflected by the decrease in tumour thickness in females, measured at
diagnosis. In males, the anatomic distribution and possibly a reluctance to seek early
medical advice may explain the increased mortality.

DIAGNOSIS AND STAGING
Early detection of malignant melanoma is crucial to the success of treatment as is
illustrated by the influence on survival of increasing tumour thickness quoted in the AJCC
staging classification. Early diagnosis can mean a cure with relatively simple surgery and
little risk of recurrence. Historically, there has been a wide margin of error associated with
the clinical diagnosis of MM, even by trained specialists. This problem is exacerbated by
the different medical personnel involved in the initial diagnosis e.g. GP, Dermatologist,
Surgeon.

CLINICAL EXAMINATION
MM is an aggressive disease. The majority of melanomas arises in the epidermal layer of
the skin and is usually flat, spreading out sideways (radial growth phase) from their initial
focal point. Although they are difficult to distinguish from other benign lesions, esp. in they
early stages, they do have a number of characteristic features which form the basis of the
„ABCD „ system of recognition. (Rivers 1996) which enables a rapid visual distinction to be
made between benign and malignant lesions. (See table)

Clinical application of the ABCD checklist may improve detections of suspicious lesions.
Although melanomas may lack one or more of these features, their presence, especially in
combination, should raise suspicion of malignancy. The ABCD checklist has been reported
to have a sensitivity of 92% to100% and a specificity of 98% for the detection of
melanoma.

A Asymmetry
B Border
C Colour variegation
D large Diameter / Dermatoscopical structures
E Evolution (clinical changes)
F risk Factors
The accuracy of diagnosis can also be improved by two additional factors viz clinical
changes in the lesion (Evolution) and risk factors (Argenziano 1997) Any change in size or
colour, whether over a period of weeks or months, should give rise to a suspicion of
malignancy. Careful history should help elucidate likely risk factors commonly associated
with MM viz skin phenotype, total number of naevi more than 2mm in diameter, presence
of atypical naevi, solar lentigo, previous h/o sunburn, h/o of high sun exposure during
childhood, h/o pre-existing melanoma or familial melanoma.

Another seven-point checklist incorporates signs for suspected malignant melanoma.
MAJOR SIGNS
Change in size
Change in shape
Change in color
MINOR SIGNS
Inflammation
Crusting or bleeding
Sensory change
Diameter of 7mm or more
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One or more major signs: needs biopsy; additional presence of one or more minor signs
increases the possibility of melanoma.
Three or four minor signs without any major signs: consider biopsy.

DERMATOSCOPY
Closer dermatoscopic assessment of the lesion can provide useful information enabling a
more accurate diagnosis. Skin surface microscopy and epiluminescence microscopy
magnify skin lesions up to 50 fold and can be used to identify over 90% of malignant
lesions. The technique is dependent though on expertise of the operator. Computer
technology is enabling comparison of the magnified skin lesion to those in a stored
database resulting in success rates of > 90%

As yet, non of these techniques can provide sufficient information on precursor lesions to
identify them before they progress to malignancy .The majority of malignant lesions arise
de novo on the skin with the transformation of dysplastic lesions being responsible in less
than 40% of cases.

                                  PRECURSOR LESIONS
Melanoma may arise de novo or from a previous melanocytic nevus, either a common
acquired, dysplastic, or congenital nevus. The actual percentage of melanomas arising
from pre-existing nevi is not known precisely but is estimated to be between 33% and 50%

ACQUIRED MELANOCYTIC NEVI
Common acquired nevi typically appear after 6 to 12 months of age. These nevi enlarge
and increase in number in early childhood and puberty. Most common acquired nevi
remain less than 5 mm in diameter. Nevi continue to increase in number throughout the
third and fourth decades, and then slowly disappear.
Environmental, genetic, and immunologic factors all play a role in determining the number
of melanocytic nevi that will develop in a person. Nevi in children tend to be concentrated
on sun-exposed areas, particularly those sites that are at risk for sunburn.
Although statistics from different studies23,24 vary, the overwhelming majority of evidence
indicates that patients with an increased number of benign melanocytic nevi have an
increased risk for the development of melanoma. The critical number at which point the
relative risk becomes significant likely varies from person to person, depending not only on
the number of nevi, but also on other coexisting risk factors (e.g. family history,
environmental sun exposure)

DYSPLASTIC NEVI (ATYPICAL NEVI/ CLINICALLY ATYPICAL MOLES)
Dysplatic nevi may be observed in persons with or without melanoma and may be
inherited in a familial pattern or occur sporadically. Whilst the frequency of conversion is
generally low, its occurrence in melanoma-prone families is 80%. In these families the risk
appears to be transmitted in an autosomal dominant fashion. The dysplastic nevus trait is
associated with a region on the short arm of chromosome 9. Additionally, persons with
dysplastic nevi and two family members with cutaneous melanoma have a lifetime risk of
melanoma development greater than 50%.
Dysplastic nevi are usually larger than 5 mm in diameter and are either flat or flat with a
raised center (“fried egg”). They are darkly or irregularly pigmented with shades of brown
and pink and usually have irregular or indistinct borders. Dysplastic nevi are fairly
common, with a prevalence rate as documented by biopsy specimens estimated to be
approximately 5%. Clinically, dysplastic nevi differ from common acquired nevi by (1)
beginning to appear near puberty instead of in childhood; (2) remaining dynamic
throughout adulthood, with an increase or decrease in atypicality; and (3) continuing to
develop throughout life, past the fourth decade.
                                                                                             12
HISTOPATHOLOGICAL FEATURES
Architectural disorder with asymmetry
Subepidermal/Papillary dermal fibroplasias (concentric eosinophylic and/ or lamellar)
Lentiginous melanocytic hyperplasia with spindle or epitheloid melanocytes aggregating in
nests of variable size and forming bridges between adjacent rete ridges.
Melanocytic atypia (in basilar location) may be present to a variable degree.
There may be dermal infiltration with lymphocytes.
Intradermal melanocytes extending singly or in nests beyond the main dermal component
(shoulder phenomenon)
Neovascularization

In evaluation of patients with dysplastic nevi, it is important to correlate the histologic
findings with the clinical phenotype. The risk for development of melanoma in patients with
dysplastic nevi is most likely related to several factors, including the total number of nevi
(both dysplastic and benign) and family history. Dysplastic nevi most likely represent both
a marker for those patients at increased risk for development of melanoma and a
precursor lesion to melanoma. Therefore prophylactic removal of dysplastic nevi does not
eliminate the risk of subsequent melanoma formation. No data are available to assess
what effect (if any) such removal has on decreasing the risk for future development of
melanoma.

CONGENITAL NEVI
Congenital nevi have arbitrarily been divided into groups according to their size in infancy:
   i. Small (1.5 cm in diameter)
  ii. Medium (1.5 – 20 cm in diameter)
 iii. Large (20 cm in diameter)

Large congenital nevi usually do have the classic microscopic findings of congenital nevi,
whereas small congenital nevi often do not show these features. Medium-sized congenital
nevi may or may not show these classic microscopic features.

 MICROSCOPIC FEATURES
 Include nevus cells in the following locations:
  i.  The lower two thirds of the dermis, occasionally extending into the subcutis
 ii.  Between collagen bundles distributed as single cells or cells in single file or both
iii.  In the lower two thirds of the reticular dermis or subcutis associated with appendages,
      nerves, and vessels

The lifetime risk of malignant transformation in patients with large congenital nevi has been
estimated to be between 5% and 20%. Almost all melanomas arising from small congenital
nevi are of the epidermal variety and the incidence of malignant transformation is
extremely low. From a therapeutic point of view prophylactic removal of these small nevi
is not essential.
Because of the high risk of malignant transformation in giant congenital nevi, prophylactic
excision is often recommended. Unfortunately, this is not always feasible because of their
size and multiple satellite lesions. In contrast to small congenital nevi, the greatest risk for
malignant degeneration in giant congenital nevi, exist before the age of 10 years.
Therefore, to confer a benefit from prophylactic removal, these procedures should be
performed early in life. (The greatest risk appears to be before 5 years of age and next
before 10 years, although melanoma transformation can occur in later life.)

It appears that the malignant potential of congenital nevi may be more dependent on the
histologic pattern of the lesion than the clinical size of the nevus. Small congenital nevi
frequently lack melanocytes in the deeper dermis, classically associated with the histologic
                                                                                            13
diagnosis of congenital nevi. The increased risk of melanoma formation in large
congenital nevi may be a result of transformation of pleuripotential neuromesenchymal
cells residing deep in the dermis. The “wait and watch” approach in these lesions is
inappropriate because melanomas from deep in the dermis are fatal before surface
changes are noted.

Perhaps the best approach to intermediate-sized congenital nevi would be a preoperative
punch or small incisional biopsy to determine the histologic growth pattern of the nevus. If
the histologic pattern is that of an acquired nevus (superficial variant of congenital nevi),
then it could be assumed that the malignant potential is extremely small, and any
malignant transformation would most likely be of the epidermal variety. If however, the
histologic pattern is that of the deeper dermal tumor, then a significant risk may be
present; prophylactic excision at the earliest stage possible would be indicated.

Controversy about management still exists. Complete risk cannot be eliminated by surgical
removal, because the nevus cells may penetrate into underlying muscle and into the
linings of the central nervous system.

LENTIGO MALIGNA (LM)
Known precursor lesion of the lentigo maligna melanoma (LMM).
Presents as a slowly enlarging macule with variegated pigmentation and irregular borders.
LM will progress to LMM in approximately 5% of cases, often after having been present for
many years and attaining a size of several centimeters.
Histological changes include:
     i. Large and bizarre shaped basalar layer melanocytes
    ii. Extension down rete ridges and appendageal structures
   iii. Solar elastotic changes are noted in the dermis, but invasive tumor cells are absent.
Treatment:
Surgical excision is the treatment of choice.
Follow up:
6-12 monthly review. If palpable areas develop or darkening occurs, to return immediately.
After lesion removal, 6 – 12 monthly review for recurrences or the development of new
lesions.

                                   HISTOLOGY
Melanomas are classified into four main clinical and histologic subtypes: Superficial
spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous
melanoma.

Superficial Spreading Melanoma (SSM)
The superficial spreading type is the most common among whites and accounts for 70% of
all melanomas. It usually occurs in adults and may develop anywhere on the body but
appears with increased frequency on the upper back of both men and women and the
lower legs in women. Clinically the typical SSM presents as a darkly pigmented lesion with
color variegation and irregular, asymmetric borders. The lesion may be flat or slightly
elevated with a diameter usually greater than 6 to 8 mm. A history of a gradually changing
lesion over the course of 1 to 5 years often is elicited. It can exhibit a prolonged horizontal
growth pattern over months to years before becoming invasive.
Histologically the cells are characteristically epithelioid or so-called pagetoid. (resembling
Paget‟s disease)

Nodular Melanoma (NM)
NM is the second most common subtype and accounts for 15% to 30% of all melanomas.
                                                                                         14
Clinically, NM presents as a dome-shaped, pedunculated or nodular lesion(1-2cm
diameter) with variable colours (black, brown, blue or red) but it may occasionally be
amelanotic. Surface ulceration, bleeding, and crusting may also be seen. NMs tend to
rapidly invade the dermis from the onset with no apparent horizontal growth phase. These
tumors are frequently misdiagnosed, because they may resemble blood blisters,
hemangiomas, dermal nevi or polyps.
The most common sites of occurrence of NM, as with SSM, are the trunk and legs. NM is
characterized by a more rapid growth rate than SSM.

Lentigo Maligna Melanoma (LMM)
LMM accounts for 4% to 10% of all melanomas. LMM typically arises on the sun-exposed
areas of the head, neck, and arms, corresponding more to regions of high cumulative
rather than intermittent sun exposure. LMM typically occurs in an older age group with the
mean age of diagnosis between 65 and 70 years.
Untreated lentigo maligna tends to exhibit horizontal or radial growth with epidermal
involvement for many years (often decades) before it enters the vertical growth phase and
invades the dermis to become LMM. This change is often indicated clinically by the
development of focal popular or nodular areas.

Acral Lentiginous Melanoma(ALM)
ALM (2% - 8% of all melanomas) occurs on the palmar and plantar surfaces, the digits and
beneath the nail plate (subungual).
The sole is the most common site of occurrence. Clinically, the lesion is darkly pigmented
with irregular borders, and papules and nodules often are present within the lesion.
Subungual melanoma can present as a brown or black discoloration of the proximal nail
bed(Hutchinson‟s sign). ALM has a similar incidence in all ethnic groups, although it
accounts for 35% - 90% of melanoma in Africans and Asians.
Biopsy
Confirmation of diagnosis is by biopsy. Any procedure, which destroys the lesion, should
be discouraged. Not only is the biopsy intended to confirm the diagnosis but also enables
assessment of the tumour thickness which enables planning of the definitive surgical
resection as well as the need for sentinel node biopsy. In general, a full-thickness skin
biopsy including the epidermis, dermis, and a portion of subcutaneous tissue should
provide the pathologist with sufficient material to examine. Small lesions may be entirely
excised during the biopsy process. Excision biopsy is recommended for lesions smaller
than 1.5cm in diameter.
Factors influencing outcome
     Tumour thickness
     Presence of lymph node involvement
     Extent of lymph node involvement
     Ulceration of primary lesion
     Mitotic index
     Evidence of regression
     Lymphocyte infiltration
     Pattern of growth

                                        STAGING
Staging systems enable management strategies to be tailored more effectively according
to the patient‟s condition. Dr Wallace Clark and later Dr Alexander Breslow (1970)
published the observations that the level of invasion into the dermis or subcutaneous fat of
the primary cutaneous melanoma has a direct correlation with disease outcome. Breslow
depth has subsequently been found to have a stronger prognostic value than Clark level.
In 1988, the AJCC revised the staging system for melanoma to incorporate the Clark level
                                                                                           15
and Breslow thickness on a “TNM” (i.e., T, tumor thickness, N, nodal metastasis; M,
distant metastasis) basis.

Tumor thickness (table2) is the most important prognostic indicator and is defined as the
distance in millimeters from the granular cell layer of the epidermis to the greatest depth of
the tumor cell invasion. Furthermore, the presence of ulceration and of high mitotic rate
among the tumor cells is associated with a worse prognosis.
Table 2 Breslow’s Microstages and Clark’s Levels for Melanoma

Breslow’s Microstages                      Five-year    survival
                                           (%)
Stage 1:  0.76 mm
Stage 2: 0.76 to 1.49 mm                    98
Stage 3: 1.50 to 3.99 mm                   87 to 94
Stage 4:  4.0 mm                          66 to 83
                                             50
Clark’s levels                             Five-year    survival
                                           (%)
Level I:   Intraepidermal
Level II: Extend into papillary dermis  99
Level III: Fills the papillary dermis    95
Level IV:         Extends into reticular 82
dermis                                   71
Level V:     Invades the subcutaneous    49
tissue


STAGING OF MELANOMA25
The original staging classification was very simple, but also very imprecise:
Stage I:             Local disease
Stage II:            Regional spread (nodal metastases or in-transit metastases)
Stage III:           Distant metastases
Because each stage encompassed patients with a wide range of prognoses, this staging
system was only of marginal benefit.

A completely revised staging system for cutaneous melanoma has now been approved.
The stage groupings have also been modified to better partition patient subgroups with
approximately the same level of metastatic risk and melanoma specific survival.

To validate the staging system, the complete clinical, pathologic and follow up data of
17600 melanoma patients across 13 cancer centers were analyzed. The analysis
demonstrated that:
   1. In the tumor (T) category, tumor thickness and ulceration were the most powerful
      predictors of survival, whereas level of invasion had a significant impact only within
      the subgroup of thin (  1mm) melanomas ( T1 melanomas).
   2. In the N category, three independent factors were identified:
          a. the number of metastatic nodes rather than their gross dimensions
          b. whether nodal metastases were clinically occult (microscopic) or clinically
             apparent (macroscopic), and
          c. the presence or absence of primary tumor ulceration
   3. In the M category, the SITE of distant metastases and the presence of lactate
      dehydrogenase (LDH) were the most powerful predictors of survival.
                                                                                           16
A marked diversity in the natural history of pathologic stage III melanoma was
demonstrated by five-fold differences in 5-year survival rates for defined subgroups that
ranged from 69 % for patients with non-ulcerated melanoma and a single microscopic
nodal metastasis to 13 % for patients with an ulcerated melanoma and 4 or more clinically
apparent nodal metastases.
CHANGES TO OLD STAGING SYSTEM
1. Clark‟s level of invasion was eliminated from the system, since it adds little to prognosis
   and tends to be less accurate and less reproducible than Breslow depth.
2. Tumor thickness stratification cutoffs were changed to 1, 2, and 4 mm since these
   numbers provided a better prediction of prognosis and were easier to use than the
   previously used cutoffs of 0.75, 1.5, and 4 mm.
3. Since microscopic ulceration was found to be the most statistically significant
   independent adverse prognostic pathologic feature outside of tumor thickness, it is
   incorporated into the classification system by adding an “a” to the T number to indicate
   no ulceration or a “b” to indicate the presence of ulceration. There is an upstaging of all
   patients with stage I, II, and III disease when a primary melanoma is ulcerated. An
   ulcerated melanoma behaves as a more biologically aggressive tumor, similar to those
   categorized as “poorly differentiated” or “locally advanced” tumors.
4. The presence of microsatellites (histologic) has the same prognostic significance as
   macrosatellites (those clinically evident) and local recurrence. All are now classified as
   stage III disease. A new convention accepted for defining clinical and pathologic
   staging, is to take into account the new staging information gained from intraoperative
   lymphatic mapping and sentinel lymph node biopsy. The ability to stage patients more
   accurately with sentinel node biopsy will have a profound impact on the staging of the
   disease, treatment planning, and the conduct of clinical trials in melanoma patients.
5. In-transit or satellite lesions on the head and neck or truncal regions portend a worse
   prognosis than when present on the extremity, and these cases are upgraded to be
   stage IIIb
6. The number of regional lymph nodes involved is a much more powerful predictor of
   survival than the extent of individual lymph node involvement by physical or pathologic
   examination.

Stage Groupings
Revision of the staging system more accurately stratify patients into prognostic categories.
Patients with primary melanomas with no evidence of regional or distant metastases
(either clinical or pathologically) are grouped into two stages: stage I for early-stage
patients with “low risk” for metastases, and stage II for those with “intermediate risk” for
metastases and melanoma-specific mortality.
Stage I constitutes 2 subgroups:
Stage 1A:      T1 melanomas without ulceration or level II/III depth of invasion
Stage 1B:      T1 melanomas with ulceration or level IV/V depth of invasion or
               T2 melanomas without ulceration.
Stage II constitutes 3 subgroups:
Stage IIA:     T2 melanomas with ulceration or T3 without ulceration
Stage IIB:     T3 melanomas with ulceration or T4 without ulceration
Stage IIC:     T4 melanomas with ulceration (In previous version T4N0M0 were stage III)
Stage III: stage grouping uses four criteria to assign patients with regional
metastases into one of three designated groups.
Stage IIIA  3 microscopic (clinically occult) nodal metastases arising from a
NONULCERATED melanoma after sentinel or elective lymphadenectomy.
Stage III B comprise of 3 subgroups
    1.  3 microscopic (clinically occult) nodes and an ULCERATED primary melanoma
    2.  3 macroscopic metastatic nodes and a NONULCERATED primary tumor
    3. satellite or in-transit metastases but no evidence of nodal or distant metastases.
                                                                                        17
Stage IIIC comprise of 3 subgroups
   1.  4 microscopic metastatic nodes and an ULCERATED primary melanoma
   2.  2 macroscopic nodes and a NONULCERATED primary tumor
   3. Any patient with nodal metastases (regardless of number or tumor burden) and the
      presence of satellites or in-transit metastases.

Stage IV: the SITE(S) of metastases and elevated serum levels of LDH are used to assign
patients to one of three categories.
There are no subgroups of stage IV melanoma because the survival differences between
the subgroups are too small.
The analysis of the prognostic influence of different distant metastatic sites demonstrated
that survival differences were significantly greater with skin, subcutaneous, or distant
lymph node metastases compared with lung metastases.

Shortcomings include the lack of incorporation of individual characteristics such as
anatomic location and gender, both of which have been shown to have independent
prognostic significance.

MELANOMA TNM CLASSIFICATION

T                 Thickness                                 Ulceration Status
Classification
T1                 1.0 mm                                  A: Without ulceration and level
                                                            II/III
T2                1.01-2 mm                                 B: With ulceration or level IV/V
                                                            A: Without ulceration
T3                2.01-4 mm                                 B: With ulceration
                                                            A: Without ulceration
T4                 4mm                                     B: With ulceration
                                                            A: Without ulceration
                                                            B: With ulceration
N                 No. of Metastatic Nodes                   Nodal Metastatic Mass
Classification
N1                1 node                                    A: Micrometastasis
                                                            B: Macromatastasis
N2                2-3 nodes                                 A: Micrometastasis
                                                            B: Macromatastasis
                                                            C: In-transit metastasis(es)/
                                                               Satellite(s) without metastatic
N3                4 or more metastatic nodes, or matted nodes
                  nodes,
                  or in-transit metastasis(es)/satellite(s)
                  with metastatic node(s)
M                 Site                                      Serum LDH
Classification
M1a               Distant skin, subcutaneous, or nodal      Normal
                  metastasis
M1b               Lung metastases                           Normal
M1c               All other visceral metastases             Normal
                  Any distant metastasis                    Elevated

COMPARISON OF THE OLD AND NEW MELANOMA STAGING SYSTEMS
                                                                                 18
CRITERION                         PREVIOUS               (1997 NEW (2002 VERSION)
                                  VERSION)

Level of invasion                 Primary criterion for T       Only for defining T1 lesions
Tumor thickness                   staging                       Primary criterion for T
Tumor ulceration                  Secondary criterion for T     staging
Dimensions of nodal metastases    Staging                       Secondary criterion for T
No. of nodal metastases           Not included                  Staging
Metastatic tumor burden           Primary criterion for N       Not used
Lung metastases                   staging                       Primary criterion for N
Elevated       serum    lactate   Not included                  staging
dehydrogenase                     Not included                  Secondary criterion for N
                                  Merged with all visceral      Staging
                                  sites                         Separate category as M1b
                                  Not included                  Secondary criterion of m
                                                                staging
CLINICAL VERSUS PATHOLOGIC STAGING
With the use of sentinel node lymphadenectomy, the range of survival rates among
various subgroups of pathologic stage III patients is enormous because of “upstaging”
based on a direct examination of the sentinel lymph node by histopathologic examination.
Significant differences were identified when survival rates for melanoma patients who were
clinically staged were compared with those whose nodal disease was staged
pathologically.
Tumor         Risk of Metastasis          10 Year Survival (%)
Stage         (%)                    Node-Negative Node-Positive p-value
T3a           20                         73              53            .0001
T3b           22                     61                32              .0001
T4a           24                     62                41               .0116
T4b           26                     41                  37             .2403

The table shows that survival differences between clinically and pathologically staged
patients were statistically significant among all T substages except for T4b.
The differences were most striking in patients with clinical T2bN0M0, T3aN0M0,
T3bN0M0, and T4aN0M0 disease. The importance of having pathologic information is
demonstrated by the 20% to 29% difference in 10-year survival for patients with the same
TNM criteria who had clinical versus pathological staging of their lymph nodes.
This analysis clearly demonstrates that stage III melanoma patients are a very
heterogeneous group with respect to their risk for distant metastases and melanoma-
specific mortality.
These results highlight the compelling prognostic value of knowing the nodal status as
identified by lymphatic mapping and sentinel lymphadenectomy in those situations where
accurate staging is important.

Other Prognostic Factors
AGE
Older patients tend to have thicker lesions and a shorter period of survival than younger
patients.
SEX
Women have an overall better prognosis. This is thought to be due to the higher incidence
of extremity melanomas, which have a better prognosis, in women. In addition,
melanomas in women seldom ulcerate.
SITE OF PRIMARY
                                                                                            19
Patients with upper extremity melanomas have longer survival than patients whose
lesions are in other sites. The other sites in decreasing order of survival are lower
extremity, head and neck and trunk. Scalp tumors do have a worse prognosis but tumors
in the other so-called BANS (upper back, upper outer arm, neck, and scalp) areas have
not been shown to have poor prognoses as proposed in older studies.
TUMOR THICKNESS
This is the most important determinant of survival for patients with clinical stage I
melanoma. And is also the single most important prognostic indicator in patients with
superficial spreading melanoma and nodular melanoma regardless of clinical stage.
ULCERATION
This has an adverse effect on survival e.g. 10 year survival of stage I disease drops from
78% to 50% when there is ulceration. Also ulceration  6mm has a poorer 5-year survival
of 5% compared to 44% if ulceration is less than 6 mm.
PIGMENTATION
Amelanotic melanomas are usually thicker and are associated with a worse 10-year
survival rate (54%) than pigmented melanomas (73%).
GROWTH PATTERNS
Lentigo maligna melanoma has the best prognosis because it tends to be thin as
compared to nodular melanomas, which has the worse prognosis and tends to be thicker.


LYMPHOCYTIC INFILTRATION
The degree of lymphocytic infiltration under a melanoma is inversely proportional to
survival. This is not due to tumor thickness but rather to early spread because these are
actually the thinner tumors.
REGRESSION
The data regarding the prognostic value of regression in melanomas are contradictory and
its significance is yet to be established.

CLINICAL TRIALS
The prognostic factors used to validate the melanoma staging system should be the
primary stratification criteria and end results reporting criteria of melanoma clinical trials,
as listed in the table below.
The difference in survival rates in clinical vs pathologic stages were so great that the AJCC
has strongly recommended that all patients with clinical T2N0M0, T3N0M0, and T4N0M0
melanomas have pathologic nodal staging with sentinel lymphadenectomy before entry
onto melanoma clinical trials.
It should be taken into account that some stage II patients actually have a good prognosis.
It is sometimes assumed that all stage III patients are at particularly high risk for distant
metastases and therefore may be entered onto clinical trials involving very intensive forms
of systemic therapy (e.g., biochemotherapy) with attendant morbidity and cost.

CRITERIA FOR STRATIFICATION IN DESIGN OF ADJUVANT MELANOMA TRIALS
AND REPORTING SURVIVAL RESULTS

Stage I and II               Stage III                     Stage IV
Tumor thickness              No. of metastatic nodes       Metastatic site

Tumor ulceration             Metastatic tumor burden       Elevated LDH

Patient age                  Tumor ulceration              No. of metastases

                                        THERAPY26
                                                                                               20

Primary therapy remains surgical, but sentinel lymph node examination is now becoming a
frequent adjuvant to surgical excision. Whether this examination is simply prognostic or
has real therapeutic benefit is yet to be seen. Immunotherapy and chemotherapy are
continuing to evolve, and radiation therapy is becoming recognized as beneficial in a
variety of settings.

SURGICAL THERAPY
The definitive treatment of primary melanoma depends on its histological features and in
particular the tumour thickness. Tumour thickness and depth of invasion are not exactly
the same thing and are not interchangeable. Thickness is the actual measurement used to
assess prognosis. Melanomas that have not spread beyond the site at which they have
developed are highly curable. Complete surgical excision confirmed by comprehensive
examination of the entire excision specimen is the basis of surgical treatment for primary
melanoma. At the present time a case, supported by the NIH Consensus Panel (JAMA
268:1314) and two randomized clinical trials (Veronisi et al & Balch CM) can be made for a
minimum margin of excision of 1cm clearance of all invasive melanomas. Maximum
margins are based on non-randomized clinical studies. Complete excision results in an 8
year survival rate of more than 95% for thin ( 1mm), invasive melanomas and essentially
cures melanoma in situ. The historical standard of wide local excision (4-5 cm) has been
determined to be unnecessary. While there are varied opinions a summary of adequate
surgical margins based 3 prospective controlled studies is presented in the following table:

Surgical margins for excision of primary cutaneous melanomas based on clinical
and histologic criteria

       Histological depth                          Margin
PTis ( Melanoma –in- situ )                     5mm
pT1, pT2                                        1 cm
pT3                                             Min 1 cm Max 2 cm
pT4                                             Min 2cm Max 3 cm

It should be noted that there is no evidence that a margin greater than 1 cm offers
additional benefit for patients in terms of survival but it may improve local control.(O
„Rourke, Balch CM). The depth of excision should equal the minimum excision margin
where possible, but in no instance is it necessary to excise beyond the deep fascia.
Lesions excised for biopsy with a margin less those recommended should be re-excised to
achieve these margins as soon as possible after the preliminary biopsy excision.

Where tissue flexibility is limited (face, foot, ankle) a skin graft or a flap repair is sometimes
necessary for an adequate margin of removal.

TREATMENT OF THE LYMPH NODES

All patients with invasive melanoma are at risk of developing lymph node metastases. The
impact of tumour spread to the lymph nodes has a major impact on survival. As important
as nodal involvement, is the extent of nodal involvement viz. micro vs. macrometastases
and the number of nodes involved (as outlined in the AJCC staging system) and early
identification of lymph node is crucial in patient management.

Elective Lymph Node Dissection(ELND)
It is the complete dissection of the lymphatic basin draining the site of the primary
melanoma in patients with clinically negative nodes. The rationale for this procedure was
based on the following:
                                                                                             21
   That most of metastases in melanoma progress through the lymph channels to the
    regional lymph nodes on to distant sites.
   That some patients with clinically negative nodes will have occult micrometastases to
    regional nodes
   That these regional metastases will result in distant metastases if not treated
   That the treatment of patients with regional micrometastases will result in improved
    survival rates as compared with survival rates of patients with clinically positive nodal
    disease.

Between 1967 and 1983, four major prospective randomized surgical trails in patients with
tumours thicker than 1 mm were undertaken to test the validity of this hypotheses. (WHO
–1; Mayo clinic trial; Veronesi; Cascinelli; WHO trial–14) None of these studies indicated
significantly improved survival rates with ELND as compared with clinical observation of
the lymph nodes. Only a sub group analysis in the large US intergroup suggested a
survival benefit for ELND in patients with primary lesions between 1 to 2 mm thick. The
overall conclusion from these studies is that ELND represents over treatment in the large
majority of the patients. It is unclear even for patients with microscopic LN involvement
whether early LN dissection cures a significant proportion of these patients. This is
probably because in the large majority of patients, the presence of micro-metastases in the
regional LNs indicates microscopic metastatic disease in the body and this can only be
treated using systemic therapy.

Therapeutic Lymph Node Dissection
Radical lymph node dissections in MM are relatively rare operations and should be
undertaken by appropriately trained surgeons. There is a substantial risk of recurrence in
the dissected field in patients with clinically positive LNs, particularly if extra-nodal spread
is detected. Limited dissections do not guarantee adequate excision of MM positive LNs
and it is not acceptable to undertake „node picking‟ operations for such LNs. Thorough
formal dissection will substantially lower the risk of recurrence in a dissected node field.
Such recurrence is usually fatal (Singletary). Adequate node dissection is associated with
a reasonably good prognosis with a 10-year survival of up to 50% where only one node is
involved. Even when 2 or 3 nodes are involved the 10-year survival rates are up to 30%.
(Balch CM et al) Extra-nodal spread is associated with a high fatality rate and
radiotherapy should be considered if the nodes are extensively involved or there is tumour
spillage during surgery.


Lymphatic Mapping, and Sentinel Lymph Node (SLN) Biopsy
The sentinel lymph node is the initial lymph node in the lymphatic basin at greatest risk for
metastatic deposits.
The rationale for lymphatic mapping and SLN biopsy is to identify preoperatively the
regional basins at greatest risk and the first or sentinel lymph node(s) within those basins.
This information would provide maximum benefit to those patients at greatest risk for
metastases while sparing other patients the morbidity of complete node dissections.
This rationale assumes that for every site, the lymphatic drainage is not only to a specific
basin, but also first to a specific node within that basin and then to other nodes
sequentially. Thus, if the sentinel (or first) lymph node is negative, the remaining distal
nodes will be negative as well, and a complete node dissection is not indicated.
The following facts have been established to date regarding sentinel lymph nodes:
 nodal metastases from melanoma follow an orderly progression
 the incidence of skip metastases in melanoma is reported to be 0-2%
 the histology of the SLN accurately reflects the histology of the remainder of the lymph
   node chain or basin
                                                                                         22
   the SLN is not necessarily the lymph node closest to the primary tumor
   the location of the SLN varies among patients with the same site melanomas
   SLN can be mapped for primary melanomas occurring anywhere on the skin surface
   Success in location the SLN depends in large part on the experience of the surgeon

The following techniques are currently recommended for the identification and biopsy of
SLNs:
 Preoperative lymphoscintigraphy with Tc-99m antimony sulphur colloid to identify the
   lymph node basin at risk for regional metastases and the location of the SLN within the
   perspective lymph node basin.
 Intraoperative vital (biologic) blue dye lymphatic mapping for visual identification. This
   is the simplest method.
 Intraoperative lymphoscintigraphy with a hand-held gamma-detecting probe. Not
   available here.
 Histologic examination of the entire SLN by serial sections of the excised specimen
 Routine and immunoperoxidase S-100 antibody histologic evaluation of the biopsied
   sentinel lymph node.

New techniques for identifying occult metastases are being developed, including
monoclonal antibody staining of cell cultures and an assay using reverse transcription
polymerase chain relation (RT-PCR) to identify the presence of tyrosinase messenger
RNA.
It is now suggested that patients with a positive SLN would undergo complete lymph node
dissection, so-called selective lymphadenectomy. This ensures that only those patients
proven to have metastatic disease will be subjected to the morbidity, in-hospital and
convalescence time, and expense of a regional lymph node dissection. This then
eliminates the whole controversy regarding ELND. However, this remains a complex
procedure requiring close cooperation between the radiologist (lymphoscintigraphy),
surgeons (SLN biopsy) and pathologist (serial sectioning and S-100 immunostaining).

The therapeutic implications of SLND are unproven and await further follow-up data from
multi-institutional series. At present, the most appealing use for SLND is as a staging
procedure to determine which patients might benefit from further adjuvant therapy. The
new staging system refine the prognostic assessment of primary and regional respectable
disease on the basis of the new sentinel node mapping technique.

MEDICAL THERAPY
Initial management options for patients with melanoma are determined by the extent of the
disease on diagnosis, and thus the risk of recurrence as outlined in the AJCC staging
system. While surgical excision of the primary lesion is sufficient to cure 90% of patients
with AJCC stage I MM, for patients with distant metastases, Stage IV, a cure is unlikely.

Adjuvant therapy for melanoma has been tried with virtually every cytotoxic and
immunobiologic modality that has become available to clinical investigators throughout the
years.

Metastatic Disease
 The contribution of cytotoxic drugs to MM management remains limited to metastatic
disease where they are used either as monotherapy or in combination. The most
commonly used single agents come from the nitrosourea group of agents and provide
response rates of less than 20%. Dacarbazine, an alkylator, is probably the most
thoroughly tested and is currently the most frequently used single agent for systemic
melanoma. It is currently the only drug approved by the FDA for the treatment of
                                                                                           23
metastatic melanoma. The response rate to Dacarbazine as a single agent ranges from
10% - 20%, and the median duration of response is 3 to 6 months.

Temozolomide is a promising agent currently under clinical investigation. It is an analog of
DTIC that, unlike, DTIC, is given orally and does not require metabolic activation in the
liver. There is evidence that temozolomide also crosses the blood-brain-barrier and may
be useful in treating patients with CNS disease.

Fotemustine, a nitrosurea, is a new agent that has been studied in France. It also has the
benefit of crossing into the CNS.

Spindle agents (vincristine and vinblastine) and platinum analogs (cisplatin and
carboplatin) have also been tried as single-agent therapy. None of these agents has
consistently shown better response rates than DTIC.
Multiple combination chemotherapeutic regimens have been studied. Most studies have
included DTIC in the combination and have compared results with treatment with DTIC
alone. Although significantly improved response rates have been reported in several
isolated single-institutional studies, multi-institutional, prospective, randomized studies
have not consistently confirmed these findings.
Some investigators have added tamoxifen to combination chemotherapy (chemohormonal
therapy) but no significant improvement in response rate or overall survival rate was
shown. Tamoxifen as a single agent has little activity on melanoma.

The use of combination chemotherapy and cytokines viz interferon and interleukins have
also been used in the treatment of metastatic MM have shown to increase toxicity with no
significant survival benefit. (Jungnelius et al, 1998, Bajetta et al 1994, Falkson et al 1998,
Keiholz et al 1997). Interferon alpha has also been studied in these patients but with no
appreciable benefit over DTIC therapy. The response rates for interferon alpha compares
with that of DTIC.




                                 BIOCHEMOTHERAPY27,28

ADJUVANT THERAPY
Surgery alone is insufficient to achieve a cure in all but the earliest stage of MM (Stage I).
Survival chances for patients at later stages of the disease decrease dramatically at each
successive stage as the risk of relapse and recurrence increases. Adjuvant therapy
following surgery is thus needed for later stage patients to eradicate or prevent outgrowth
of micrometastasic disease.

Although other agents have been tried, it is clear that at the present only IFN alpha has
shown the highest potential for activity in the adjuvant setting. The exact mechanism of
action of IFN in MM is thought to be a mixture of
 Immune modulation
    Enhanced macrophage, cytotoxic T cell and natural killer cell activity
 Direct anti-proliferative effects
     Inhibition of oncogene expression
     Inhibition of DNA synthesis
 Anti-angiogenic effects
 Direct anti tumour activity
                                                                                           24
   Enhanced tumour antigen expression

Nonspecific microbial immunostimulants, such as Bacillus Calmette-Guerin (BCG),
Corynebacterium parvum, and Picibanil, and chemical immunomodulators of T and B cells,
such as levamisole and 7-allyl-8-oxoguanosine, have been shown to be ineffective.

INTERLEUKIN-2 (IL-2), GRANULOCYTE/MACROPHAGE COLONY-STIMULATING
FACTOR (GM-CSF), AND INTERFERON GAMMA
Have been incompletely studied in the adjuvant setting to date; no trials have been
completed to support their use in adjuvant therapy of high-risk melanoma. Current
intergroup trials are investigating the potential functions of GM-CSF and IL-2. The ECOG
(trial E4697) is evaluating GM-CSF (alone or administered with vaccination against a multi-
epitope peptide vaccine) among patients with respectable M1 disease, advanced regional
nodal disease with extracapsular extension, or failure after adjuvant interferon therapy.
The second trial led by Southwest Cooperative Oncology Group(SCOG), trial S0008, is
evaluating the adjuvant role of IL-2, in comparison with high-dose IFN2b(HDI).
IFN has shown no clinical evidence of anti-tumor efficacy in either advanced disease or
the adjuvant setting in trials led by ECOG and SCOG.

STAGE III MELANOMAS

High Dose Interferon) Experience
The Eastern Cooperative Oncology Group (ECOG) 1684 trial, published in 1996, was the
first randomized control study to significantly demonstrate prolongation of relapse-free and
overall survival rates for high risk resected melanomas in 287stage IIB/III patients
receiving HDI alpha 2b.
With a median follow-up period of 7 years, the median time to relapse increased from 0.98
years in the observation group to 1.7 years in the IFN2b-treated group. The median
survival time increased from 2.8 years to 3.8 years. The 5 year continuous relapse-free
survival rate was improved 40% (from 26% in the observation group to 37% in the
treatment group. The overall 5-year survival rate improved by 25% with treatment (from
36% to 47%)

The E1694 trial (the largest trial ever conducted with HDI-880 patients) has demonstrated
a survival benefit of HDI against a promising ganglioside(GM2) vaccine. The trial was
closed because of the appearance of highly significant differences between GM2 and HDI
in terms of relapse free survival and overall survival rates.

The North Central Cancer Treatment Group (NCCTG) evaluated the efficacy of INF2a in
a mixed group of stageIIA/IIB/III (102 stage II and 160 stage III) patients but demonstrated
no significant differences in relapse-free survival or overall survival times.

The ECOG 1690 study compared HDI vs LDI over a 2 year treatment period with no
significant effect on disease free survival (DFS) and overall survival (OS). It is argued that
it may be due to a short median follow-up period.

LDI (low dose interferon) experience
LDI was evaluated in patients with stage III disease in the WHO-16 trial, randomizing
patients into either the observation arm or the LDI treatment arm. Although a temporary
effect on DFS rates was observed in the treatment arm, in the final analysis no DFS or OS
was observed.
                                                                                            25
The European Organization for Research and Treatment of Cancer (EORTC) 18871/
(DKG)-80 trial with 490 stage III patients did not demonstrate any benefit in either DFS or
OS - not even a trend.

CONCLUSIONS FOR STAGE III MELANOMA
Observations have been inconsistent regarding the efficacy of IFN in the adjuvant setting
for stage III melanomas. The dose intensity and duration of treatment have not been
clearly defined.
High toxicity encountered with HDI - remains a major problem.

STAGE II MELANOMA
LDI experience
Three LDI trials, similar in design, all using IFN2a, have been performed in Europe.
The Scottish trial (6 month treatment) demonstrated a temporary DFS rate benefit at 6
months that was lost at 24 months, but no significant effect on OS rates.
The French study (18 month treatment) demonstrated a significantly prolonged DFS
period. The effect on OS rates failed to reach significance but demonstrated a favorable
trend.
The Austrian study (12 month treatment) has not reached maturity.
In the EORTC 18871/DKG 80 trial, using very low dose interferon, no effect on DFS or OS
rates for 340 stage II patients was observed.
HDI experience
The NCCTG, ECOG 1684 and ECOG 1690 trials have shown no effect on DFS and OS
rates.

CONCLUSIONS FOR STAGE II MELANOMA
To date, IFN effects on DFS rates in stage II melanoma have been observed in only two
trials. In no trial has a significant benefit on OS rates been reported.

In 1996, trial 18952 was initiated with the goal of identifying effective postoperative
adjuvant treatments with tolerable doses of IFN 2b for stage IIB/III patients. In view of the
high toxicity encountered with HDI, intermediate doses of IFN were evaluated in this trial,
in the hope of identifying a threshold with respect to either dose or treatment duration. The
primary endpoint was the distant metastasis-free interval (DMFI), and the secondary end
points were the OS rate, toxicity, quality of life, and cost.
With a median follow-up period of 1.6 years, the 2-year treatment arm had a longer DMFI
than the control, but the 1-year arm had no effect. The effects seemed greater in Stage IIB
than in stage III N1 or III N2. The treatment effect on OS rate was not significant.
Treatment regimes were relatively well tolerated. It is presently unclear whether the
significant effect of the 2-year treatment regime on the DMFI will translate into a significant
survival benefit. Longer follow-up monitoring of the EORTC 18952 trial is necessary to
clarify this issue.


              IMMUNO-THERAPEUTIC APPROACHES TO MELANOMA29

The goals of immunotherapy in melanoma are to overcome the immune escape
mechanisms of melanoma cells, render melanoma cell antigens available to cytotoxic T
lymphocytes (CTLs)/ Antigen presenting cells (APCs), and restore the function of
professional APCs and T cells.

Immunotherapeutic approaches can be classified as:
                                                                                              26
   Specific (induction and elicitation of an immune response against one or more
    specific tumor antigens)
   Non-specific (e.g., IFN, IL-2)
   Active immunotherapy (stimulation of the host immunity with vaccines)
   Passive immunotherapy (transfer of antibodies)
   Adoptive immunotherapy (transfer of cytokines or lymphocytes)
   Restorative immunotherapy (inhibition of suppressors or repletion of T-cell populations)
   Cytomodulatory (upregulation tumor antigens on host tumor cells).

VACCINE THERAPY

The ultimate goal of tumor vaccination is to generate a specific immunity with long-lasting
memory and a potent tumor-destructive effector mechanism. The clinopathologic evidence
for the relevance of cell-mediated immunity in malignant melanoma include:
 An elevated incidence of melanoma patients with suppressed cell-mediated immunity
 The common finding of regression in primary lesions
 The characteristic T-cell infiltrate in precursor and early primary lesions that is
    attenuated in thicker lesions and metastases
 The presence of circulating melanoma-specific cytotoxic T lymphocytes (CTLs)
 The small but reproducible incidence of regression of disseminated disease, either
    spontaneous or after treatment with cytokines such as interleukin 2 (IL-2)
 The relation between response to tumor therapy and vitiligo in patients with malignant
    melanoma.

Both types of T lymphocytes, CD8 and CD4, appear to play a major role in anti-tumor
response; the tumor antigen-specific CTL (CD8) is the important effector cell involved in
recognition of tumor rejection antigens.
Precursors of mature CD4+ lymphocytes can differentiate into two types of cytokine-
secreting cells: one produces cytokines important for generating CD8+ cellular responses
(CD4 TH 1 phenotype); the other produces cytokines that help prime B cells for antibody
production (CD4 TH 2 phenotype)

CTL clones identify 3 categories of melanoma antigens:
 Differentiation antigens of the melanocytic lineage (tyrosinase, Melan-A/MART-1, gp 75
  and gp100), also known as MAAs (melanoma associated antigen)
 Antigens predominantly expressed on neoplastic cells but not confined to melanoma
  (GD, GM, MAGE, BAGE, and GAGE), also known as tumor associated antigens (TAA).
  Found not only in melanoma, but also in kidney, lung, breast, and other solid
  neoplasms.
 Unique antigens derived from substitution of a single amino acid (mutated CDK4 &
  MUM-1)

In addition to cell-mediated immunity, other components of the immune system may play a
role in melanoma immunology. Humoral anti-melanoma IgG and IgM immune responses
have been observed after vaccination against GM2 ganglioside plus KLH-QS-21
immunoadjuvant.

There is some evidence to support the role of natural killer (NK) cells mediating melanoma
cell lysis. While resting NK cells will kill only a limited range of tumor cells, IL-2 activation
of NK cells increases their cytotoxic activity and proliferative capacity. The phenomenon is
called lymphokine-activated killer activity.

Defined Melanoma Antigens
                                                                                          27
The realization that antigen-specific cytotoxic T cells are present on melanoma deposits
has led to the discovery of specific melanoma antigens. Melanoma antigens that are
known to be immunogenic are in two categories: carbohydrates and peptides. The
rationale behind antigen-specific vaccines is to induce specific immune response against
relevant tumor antigens.
Carbohydrate antigens include the melanoma cell-surface gangliosides GM2, GD2, and
GD3. Studies by Jones et al and Livingstone et al showing that patients with naturally
occurring antibodies against GM2 ganglioside have prolonged survival, suggest the
potential effectiveness of ganglioside vaccines
In the Livingstone et al trial, patients with stage III melanoma were randomly assigned to
receive either a vaccine of GM2 adherent to BCG or treatment with BCG alone. Excluding
patients with natural GM2 antibody, patients receiving the vaccine had a 23% increase in
DFI and a 14% increase in the OS rate. This vaccine has been further modified by
conjugating GM2 to keyhole limpet hemocyanin (GM2-KLH) and administering it with
saponin fraction QS-21 as an immunologic adjuvant. This combination not only induced
IgM antibody in a higher percentage of patients (95%), but also resulted in an eight-fold
higher titer and a more prolonged response.
Trials comparing GM2-KLH plus QS-21 vaccine (GMK) with IFN-alpha in the treatment of
stage II and stage III melanoma patients are in progress.
Although carbohydrate antigen vaccines generally induce humoral immunity, vaccines
against peptide antigens enhance cellular (T-cell) immunity. Cell-surface peptides are
HLA-restricted. That is, they are presented to CD8+ T cells in association with specific
subtypes of HLA class I molecules. Also, certain antigens are presented to CD4+ T cells
through HLA class II molecules.
The 3 most extensively studied immunogenic peptides have been tyrosinase, gp 100, and
MART-1
The goals of immunotherapy in melanoma are to overcome the immune

Treatment of In–Transit Metastases

MM recurs locally in the extremities mostly in the form of in transit metastases (5-8%) of
melanoma patients and can result in an appalling problem for the patient. One or a few in–
transit metastases can be surgically excised .CO2 laser can also be used to treat small
nodules < 1,5 cm.

Regional Isolated Perfusion

This is the treatment of choice for multiple in-transit mets as it provides excellent local
control but has no survival benefit. ILP has no place in the adjuvant setting in the surgical
management of stage Ii MM of the extremities as was shown in the EORTC–WHO ILP trial
(Schraffordt - Koops et al 1998 )
In isolated perfusion, very high doses of chemotherapeutic agents are administered to
isolated anatomic regions without the unnecessary systemic exposure, thus eliminating
most adverse systemic effects. Theoretically, isolated perfusion can be applied to almost
any anatomic region supplied by a major artery and vein. It is most effective in treating
melanoma of the limbs.
In isolated limb perfusion (ILP), the iliac and femoral vessels are used for proximal and
distal lower extremity lesions, respectively. The axillary vessels are used for upper
extremity lesions. The cannulas are connected through an oxygenated extracorporeal
circuit. A heater/cooler unit is used to warm the perfusate, and a warming blanket
maintains adequate tissue temperature. A tourniquet is applied proximally for further
isolation. Subsequently the extremity is perfused with a high dose cytotoxic agent.
Although multiple agents have been tested, melphalan (1-phenylalanine mustard), remains
the optimal single-agent of choice.
                                                                                        28
At the end of the perfusion, the circuit is washed out with low-molecular-weight dextran
followed with whole blood.
Although objective data regarding the benefits of ILP are still limited, it has to be
considered in patients with an aggressive nonresectable primary or in recurrent disease.
ILP yield reponse rates of 80 % with a 40 CRR (Complete Remission Rate) Although
recurrences after ILP remain high (40%), the possibility of salvaging a limb makes the use
of ILP in this setting a significant alternative.
The most recent and most promising advance in limb perfusion has been the synergistic
combination of melphalan, with the cytokine, tumor necrosis factor alpha (TNF-alpha) and
interferon-gamma (IFN-gamma). Results in the literature show that complete remission
rates with this triple regimen are significantly better than for ILP using melphalan alone.

Isolated Distant metastases
Isolated distant metastases may be treated with surgery providing excellent palliation and
may improve long term survival (Worman et al 1986, Karakousis et al 1995) Excision of
multiple mets from multiple sites does not improve survival.

                                RADIATION THERAPY17,30
Controversy continues surround the use of radiation therapy to treat melanoma. A large
prospective study sponsored by the Radiation Therapy Oncology Group (RTOG)
concluded that the results of both the conventional therapy (200 cGy over 5 days a week)
and the high-dose-per-fraction (HDPF) are comparable, making both options acceptable
for therapy.
The important outcome of all these studies is the demonstration that melanoma is a tumor
that may well respond to radiation therapy and that radiation needs to be considered as a
useful treatment option for metastatic disease.

Summary of indications:

Treatment of Primary lesion
Primary melanoma is seldom treated with radiation. The one exception is the treatment of
lentigo maligna. One method is the conventional fractionated radiation therapy. The other
is the Miesher technique where a contact machine is employed, using large doses of
radiation that penetrate only very superficially. (Excellent success in Europe)

Adjuvant therapy
Several studies have suggested that adjuvant radiation therapy to nodal basin of high-risk
tumors may prolong survival or reduce subsequent metastasis. It has also been used to
treat nodal basins where surgery has shown multiple positive nodes, extracapsular tumor,
or a single node fully replaced by tumor. There appears to be decreased regional
recurrence with radiation therapy in these settings but no increase in long-term survival.

Metastatic Disease
Soft-tissue metastases are amenable to radiation therapy. Both HDPF and conventional
fractionation have been effective. There is an increased complete response in smaller
tumors, so early treatment is recommended.

Brain Metastases

There is a 60% to 70% response rate with whole-brain radiation therapy, with a 1 to 2
month increase in survival time. Long-term control is not expected, however, and most
patients will not survive. When surgical resection can be combined with whole-brain
irradiation, the survival rate improves.
                                                                                           29

Radiation can relieve pain in patients with bone metastases, but full regression of tumor is
rare. Pathologic fractures require both surgical fixation and radiation therapy

Stereo tactic radiotherapy is the treatment of choice for isolated brain metastases.

Specific Sites Types of MM

Mucousal melanoma
This is a rare form of MM (< 1%). Occurs in the mouth, esophagus, gall bladder, urethra,
anus, vagina, vulva, and is usually asymptomatic. They are therefore generally detected
late and have a poor prognosis. Pigmented lesions of the mouth are rare and apart from
amalgam tattoo in the mouth and benign melanosis of the vulva melanoma should always
be considered a possible diagnosis.

Acral Letiginous melanoma

Means melanoma of the acral skin i.e. the thickened skin of the soles and palms. It is the
commonest for all of subungual melanoma. It is rarely associated with a visible pre-
existing benign naevus. It is the predominant MM of dark skinned individuals. Its prognosis
is marginally worse than other MM but this is yet to be conclusively proven. Treatment is
the same as other sites although it may be difficult to close defects on the sole of the foot
and grafts tend to hypertrophy making flap closure preferable.


Subungual MM
Can be difficult to diagnose early but must be considered for any pigmentation of the nail.
The prognosis is generally poor because of it being deeply invasive at the time of
diagnosis. Differential includes haematoma and fungal infection. Subungual melanoma of
the finger justifies amputation through the distal IP joint. A ray amputation of the great toe
may produce better cosmesis.

Desmoplastic MM
This is a rare form of the disease characterized by a spindle cell pattern with sclerosis of
the dermis (Desmoplasia) and may invade nerves (neurotropism). These tumours have a
high risk of local recurrence due to their poorly defined clinical borders, frequent
amelanosis and infiltration along nerve roots. It is therefore reasonable to add a cm to the
excision margins recommended for the other types of MM. Despite the high risk of local
recurrence they do not have a poorer prognosis than other MM of equivalent thickness.
Postop XRT is advocated in some centers for this rare tumour.

These tumours are difficult to diagnose as they are commonly non-pigmented or may
present as subcutaneous nodules and are common in the head and neck region.

MM in childhood
MM is rare in children < 12 years of age. The clinical features are as per those of adult‟s
.The DD include Spitz Naevus, which is usually benign .The treatment, is as per adult
treatment.


                                  CONCLUSION
Therapy for melanoma continues to evolve, and with the expanding work in the basic
pathophysiology, continued development of biologic modifiers is expected. With new
                                                                                          30
treatment regimens, the rate of remissions is improving for patients with metastatic
disease. Much work has yet to be done, however, and there will be continued development
in all areas.


                                         REFERENCES
1.    Rippey FF, General Pathology, 1999, Chapter 28. p 248
2.    Young DM, Mathes SJ, Skin and Subcutaneous Tissue. Schwartz, Principles of
      Surgery, 6thEd.NewYork: McGraw-Hill 1994: 515-530.
3.    Naylor MF, Farmer KC. The case for sunscreens. A review of their use in preventing
      actinic damage and neoplasia. Arch Dermatol 1997;133:1146-54.
4.    Sober AJ, Burnstein JM, Precursors to skin cancer 75(2): 645-650, 1995
5.    Garmyn M, DeGreef H, Gilchrest BA: The effect of acute and chronic photo damage
      on gene expression in human keratinocytes, Dermatology 190:305, 1995
6.    Gloster HM, Brodland DG. The epidemiology of skin cancer. Dermatol surg 1996; 22:
      217-26
7.    Marks R. The epidemiology of non-melanoma skin cancer: who, why and what can
      we do about it. J Dermatol 1995; 22:853-7
8.    Ellison, Weiss JS, Hamilton TA, et al: Sustained improvement with prolonged topical
      tretinoin for photo aged skin. J Am Acad Dermatol 23:629-637, 1990
9.    Padgett JK, Hendrix Jr JD: Management of facial cutaneous defects; Cutaneous
      malignancies and their management. Otol. Clin.of North America, Vol. 34, No. 3,
      2001
10.   Garner KL, Wm Macmillian R: Basal and Squamous cell carcinoma. Primary Care;
      Clinics in Office Practice, Vol. 27, No. 2. 06/2000.
11.   Anderson RG: Skin tumors II: Melanoma. Selected readings in Plastic Surgery 8(7):
      1-38,1995.
12.   Salache SJ, Actinic Keratosis: Scientific evaluation and public health implications; J.
      Am. Ac. Derm. 42(1), 2000
13.   Frankel DH, Hanusa BH, Zitelli JA: New primary nonmelanoma skin cancer in
      patients with a history of squalors cell carcinoma of the skin. J Am Acsd Dermatol
      26:720-726,1992.
14.   Dinehart SM, Pollack SV: Metastases from SCC of the skin and lip: An analysis of
      twenty seven cases. J Am Acad Dermatol 2:241-248, 1989
15.   Goldberg DP: Assessment and surgical treatment of basal cell skin cancer. Clinics in
      plastic surgery 24: 673-686,1997
16.   Hochman M, Land P: Skin cancer of the head and neck. Med Clin North Am 83:261-
      282,1999.
17.   Ang KK, Byers RM, et al: Radiotherapy in melanoma. In Balch CM, Hough ton AN,
      Sober AJ and Soong S(eds): Cutaneous Melanoma. Philadelphia, JB Lippincott,
      1998.
18.   Peck GL: Longterm retinoid therapy is needed for maintenance of cancer
      chemopreventive effect. Dermatologia 175(suppl): 138-144, 1987
19.   Beutner KR: Therapeutic response of BCC to Imiquimod 5% cream. Arch. Derm; 11:
      1002.
20.   Seminar 2000, Kalyan R.
21.   Kanzler MH, Mraz-Gernhard S. Primary cutaneous malignant melanoma and its
      precursor lesions: Diagnostic and therapeutic overview. J Am. Ac. Derm. 45(2),
      08/2001.
22.   Berwick M, Halpern A. Melanoma epidemiology. Curr Opinion Oncol 1997;9:178-82.
23.   Swerdlow AJ, English J, MacKie RM. Benign melanocytic nevi as a risk factor for
      malignant melanoma. BMJ 1986;292:1555-9
                                                                                      31
24. BatailleV, Bishop JA, Sasieni P, Swerdlow AJ, Pinney E, Griffith SK, et al. Risks of
    cutaneous melanoma in relation to the numbers, types, and sites of naevi: a case
    control study. Br J Cancer 1996;73:1605-11
25. BACLCH CM. THE REVISED MELANOMA STAGING SYSTEM: Its use in the
    design and interpretation of melanoma clinical trials, Am. Soc. Of clinical oncology,
    2001:82-7.
26. Pitts JM, Maloney ME. Therapeutic advances in melanoma, Dermatol. Clinics, 18(1),
    2000.
27. Kirkwood JM, Adjuvant Therapy of High-risk resected melanoma: Relapse-Free and
    Overall Survival Effects of High-Dose Interferon Alpha-2b in Randomized Controlled
    Multicenter Trials E1684 and E2696 and Intergroup Trials E1690 and E1694. Am.
    Soc. of Clinical Oncology, 94-101,2001.
28. Eggermont AMM, Kleeberg UR, Ruiter DJ, Suciu S. European Organization for
    Research and Treatment of Cancer Melanoma Group Trial Experience with more
    than 2000 patients, evaluating adjuvant treatment with low or intermediate doses of
    interferon alpha-2b. Am. Soc. of Clinical Oncology, 88-93, 2001.
29. Curiel-Lewandrowski C, Demierre M. Advances in specific immunotherapy of
    malignant melanoma. J. Am. Ac. Dermatol. 43(2), 2000
30. Sober AJ and Soong S(eds): Cutaneous Melanoma. Philadelphia, JB Lippincott, 1998
32

								
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