Skin Cancer

• The skin is the largest organ of the human body

that is embryologically derived from the
neuroectoderm and the mesoderm to be
organized into three layers namely epidermis,
dermis, and subcutis.
Cancer of the skin arises from the cell types of
structures in all the three layers
• The direct exposure to sun’s ultraviolet
radiation and a wide variety of environmental
carcinogens predisposes skin cells to genetic
damage and increased risk of cancer.
• The skin cancers are best divided into
melanoma and nonmelanoma
 MELANOMA
• Melanoma arises from the
melanocyte, a neural crest–
derived cell that migrates
during embryogenesis
predominantly to the basal
layer of the epidermal skin and
less commonly to the other
tissues in the body such as
– mucosa of the upper
aerodigestive and the
– lower genitourinary tract,
– the meninges, and the
– ocular choroid, where
melanoma is rarely encountered.
• Melanoma ranks as the
fifth and seventh
leading type of cancer
in men and women
• 10 times greater in
whites than in blacks.
• Australia has the
highest incidence of
melanoma in the world,
approximately 40 cases
per 100,000
populations per year.
 Familial Melanoma
• About 5% to 10% of melanomas are familial
and up to 40% have hereditary basis.
• A tumor suppressor gene cyclin-dependent
kinase inhibitor 2A (CDKN2A) is the most
commonly mutated gene located on the short
arm of chromosome 9.
• Other candidate genes in this category include
cyclin-dependent kinase 4 and CDKN2A/p14
alternate reading frame CDKN2A/ARF.
• Precursor lesions of melanoma include
– Dysplastic nevi locus of which resides on short arm
of chromosome 1
– Congenital nevi and acquired melanocytic nevi
 Risk Factors for Melanoma
• Xeroderma pigmentosum
• Familial atypical mole melanoma syndrome
(FAMMS)
• Advanced age and immune-suppressive states
• Sun exposure and sun-sensitive phenotype
• ■■ Melanoma in a first-degree relative and
previous history of melanoma
Xeroderma pigmentosum (XP) is a
genetic disorder (autosomal recessive) in
which there is a decreased ability to repair
DNA damage such as that caused by ultraviolet
(UV) light.[1] Symptoms may include a severe
sunburn after only a few minutes in the sun,
freckling in sun exposed areas, dry skin, and
changes in skin pigmentatio

genetic defect in which nucleotide excision repair (NER)

enzymes are mutated, leading to a reduction in or
elimination of NER.[9] If left unchecked, damage caused by
ultraviolet light can cause mutations in individual cell's
DNA.
 Common Chromosomal Abnormalities in
Melanoma
• Early chromosomal abnormalities:
– Loss of 10q
– •Loss of 9p
• Late chromosomal abnormalities:
– Deletion of 6q
– Loss of terminal part of 1p
– Duplication of chromosome 7
– Deletion of 11q23
Clinical Features of Melanoma (abcde)
Pathologic Diagnosis of Cutaneous
Melanoma
 Clinicohistologic Types of Melanoma:
Microstaging
• Clark Levels
• Clark et al. subdivided melanoma invasion of
the papillary dermis into a
– deep group in which tumor cells accumulate at the
junction of the papillary and reticular dermis and a
– superficial group in which tumor cells did not
invade deeper
• Breslow Thickness
• Breslow used an ocular micrometer to measure the vertical
depth of penetration of tumor from the granular layer of the
epidermis or from the base of the ulcerated melanoma to the
deepest identifiable contiguous melanoma cell (Breslow
thickness)
Clarke levels
Melanoma Staging
Prediction of Patient Outcome Based on
AJCC Melanoma Staging
 Cutaneous Melanoma: Prevention and
Early Diagnosis
• Patient education: increasing awareness of
melanoma as a serious cancer, its risk factors, self-
skin examination (SSE), sun avoidance, light
clothing, and effective use of sunscreens.
• Close surveillance: Total body skin examination
(TBSE) performed by a dermatologist provides
close surveillance to identify suspicious skin
lesions for biopsy and early diagnosis.
• Digital photography
Melanoma Management: General Surgical
Treatment Principles
• Principle: Complete surgical excision of primary melanoma
confirmed by comprehensive histologic examination of the
entire excised specimen forms the basis of surgical
treatment.
• Risk of local recurrence: Relates to completeness of
resection of the primary tumor, but is not significantly
associated with the extent of surgical margin of excision
stage I, II - surgery
stage III - surgery + adjuvant immunotherapy
pembrolizumab
stage IV - consider surgery
systemic treatment
-BRAF is mutated - targeted therapy -
tafinlar/mekinist - vemurafenib
BRAF is not mutated - immunotherapy
pembrolizumab
Assessment of the Regional Lymph Node
Metastasis and Lymph Node Dissection
Historically, complete excision of primary cutaneous melanoma is followed with elective,
therapeutic, or delayed lymph node dissection from the respective basin.
■■ Elective lymph node dissection: Although clinically not palpable, all the lymph nodes are
dissected from the respective basin because of concerns of melanoma metastasis.

■■ Therapeutic lymph node dissection: Is performed if the regional lymph nodes are
enlarged and clinically palpable (suspected lymph node metastasis).

■■ Delayed lymph node dissection: Is performed when initially nonpalpable regional lymph
nodes become palpable over a follow-up period (delayed metastasis).

Lymph node dissection is recommended only if regional lymph node metastasis is present and is
avoided if lack of lymph node metastasis could be predicted by a reliable test.
Sentinel Node Biopsy
■■ Sentinel lymph node biopsy as a tool to detect regional lymph node metastasis.
■■ Characteristics of a sentinel lymph node:
• First lymph node in the basin at greatest risk of metastasis.
• Easily accessible and identified by lymphoscintigraphy.
• Pathologic evaluation helps to detect occult melanoma lymph node metastasis.

■■ Surgical approach to obtain a sentinel lymph node: lymphoscintigraphy

• Preoperative lymphoscintigraphy uses vital blue dye injected around cutaneous
melanoma that provides a road map of the lymph node basin.
• Intraoperative lymphoscintigraphy uses radio colloid injection around the primary
tumor, and a handheld device detects the radioactivity from the involved lymph
node.
• The combination of vital blue dye and technetium-labeled sulfur colloid helps the
surgeon navigate the identity of sentinel lymph node in the respective nodal basin
for metastasis in 94% of cases
■■ Implications of sentinel lymph node biopsy:
Complete lymph node dissection is recommended only if sentinel lymph node is
positive.

• A negative sentinel lymph node saves the patient morbidity of this procedure.
• Sentinel lymph node biopsy–guided information about the extent of lymph node
metastasis helps in prognostication of primary melanoma and reduces the risk of
local recurrence.
• In one study, immediate lymph node dissection after positive microscopic
metastasis in the sentinel lymph node conferred survival advantage in a subset
analysis.
Adjuvant Treatment of Melanoma in Patients at Risk of Recurrence
after Surgery

Interferon alpha (IFN-α) Treatment Principle:

•There is a high rate of relapse of cutaneous melanoma (35% to 75%) among patients
with melanoma stages IIB, IIC, and III after primary surgical treatment.
Based on antiproliferative and immunomodulatory effects, prolonged use of IFN-α
(high dose, low dose, intermediate dose for variable periods of time) has been
extensively studied.
■■ IFN-α treatment conferred consistent relapse and disease-free survival benefit.
■■ Impact upon overall survival has been variable and less consistent.
■■ High-dose IFN-α is superior when compared to low-dose.
• One month of high-dose intravenous IFN-α induction-only therapy is not sufficient
and must be followed by the maintenance phase to confer any benefit.
• Pegylated form of IFN-α (slow release) given subcutaneously once weekly for up
to 5 years
Conferred elapse-free survival advantage without overall survival benefit.
The predominant toxicity of high-dose IFN-α severe
• flu-like symptoms,
• liver toxicity, and
• depression
■■ Ongoing clinical trials are evaluating the role of
ipilimumab, an anti-CTLA antibody, and vemurafenib, an
agent that targets BRAF mutation as adjuvant treatment of
melanoma after primary surgery.
• Both of these agents have recently been approved for use
in patients with metastatic melanoma.
Role of Radiation Therapy
■■ Pain relief of melanoma metastasis to the musculoskeletal region
■■ As an adjuvant treatment after the regional lymph node dissection:
• In melanoma of the head and neck region
• When lymph node metastases are bulky and/or involve four or more lymph nodes or exhibit
extracapsular spread
• Local recurrence of melanoma in a previously dissected lymph node basin
■■ After surgical resection of desmoplastic melanoma with neurotropism
■■ Brain metastasis of melanoma
Radiation therapy of brain metastasis of melanoma includes
■■ Whole-brain radiation if multiple and large size brain metastases are present
■■ Stereotactic brain radiation is preferred if small-sized or isolated or fewer (two to three)
brain metastases are present
Isolated Limb Perfusion or Infusion as a Treatment of Melanoma
Principle: To deliver maximally tolerated chemotherapy doses in patients with locally
advanced and metastatic melanoma to a regionally confined tumor area such as a limb while
limiting systemic toxicity.
Isolated limb perfusion (ILP): Involves hyperthermia and oxygenation of the circulation that
potentiate the tumoricidal effects of the chemotherapeutic agents that include melphalan (L-
PAM), thiotepa, mechlorethamine with or without tumor necrosis factor (TNF-α), and IFNγ.
This procedure provides palliative benefit to patients with in-transit metastasis of melanoma
otherwise difficult to resect surgically or at high risk of recurrence after surgery (Table 22.6).
Management of Patients with Metastatic Melanoma

The management options for a patient with metastatic melanoma have expanded
following the recent FDA approvals of two novel agents:
■■ Ipilimumab is a monoclonal antibody to CTLA-4 antigen on T lymphocytes that
regulate T lymphocyte activation after an encounter with melanoma antigen.
■■ Vemurafenib is a targeted therapy that selectively blocks mutated BRAF in
melanoma patients harboring BRAF mutation.
■■ High-dose interleukin-2 (IL-2)
■■ Surgical resection of an accessible isolated metastatic lesion has a curative
potential in about 25% of patients, while those who are not candidates for
complete surgical resection of a metastatic lesion will require systemic treatment.
■■ Chemotherapy as a single agent, in combination, or with biologic agents
(biochemotherapy) in patients with metastatic melanoma.
Chemotherapy of Metastatic Melanoma: Single-Agent Chemotherapy

■■ Dacarbazine is the only FDA-approved chemotherapeutic agent for melanoma

treatment that has a response rate of about 10% to 20% without overall survival
benefit.
■■ Temozolomide is a synthetic analog of dacarbazine that is orally bioavailable,
crosses the blood–brain barrier, has comparable efficacy, and has a reduced toxicity
profile.
■■ In a recent phase 3 trial, nab-paclitaxel (abraxane) showed a statistically
significant improvement in progression-free survival and a trend toward improved
overall survival as compared to dacarbazine
Combination Chemotherapy Regimens of Metastatic Melanoma
Biologic Agents in the Treatment of Metastatic Melanoma: IFN-𝛂

IFN-α is the first recombinant cytokine investigated in phase 1 and 2 clinical trials of
patients with metastatic melanoma based on its antiproliferative and
immunomodulatory effects.
■■ Initial studies showed response rates of about 15% in patients with metastatic
melanoma.
■■ One-third of these responses were complete and durable.
■■ Responses could be observed up to 6 months after the therapy was initiated.
■■ Small volume disease and uninterrupted use resulted in pronounced responses.

•Falkson et al. reported the outcome of patients with metastatic melanoma treated
with either dacarbazine alone or a combination of dacarbazine and IFN-α-2b.
•The results indicated a response rate and median survival of 20% and 9.6 months,
respectively, with dacarbazine alone compared to a response rate and median survival
of 53% and 17.6 months, respectively, in patients receiving both these agents.

•These results could not be reproduced in subsequent randomized phase 3 studies.

•Essentially, IFN-α is rarely used as primary therapy for metastatic melanoma
IL-2 Based Therapy
■■ IL-2 is a T-cell growth factor produced primarily by T-helper cells upon antigen binding.
■■ Interacts with IL-2 receptors expressed on activated cytotoxic T lymphocytes (CTLs) and
causes:
• Increased production of other interleukins, IFN-γ, and TNF-α
• Proliferation and differentiation of both B and T lymphocytes and cytotoxic cells
■■ Antitumor effects are mediated by its ability to stimulate proliferation of natural killer
cells (NK cells), lymphokine-activated killer cells (LAKs), and CTLs
The overall response rate is about 16%, which includes a complete
response rate of 6%.
■■ Responses are observed in all disease sites.
■■ Durable responses are achieved in those who achieved complete
responses.
■■ Good baseline performance and chemo-naive status are
predictive of response.
■■ A toxicity profile results from capillary leak syndrome that is
dependent on dose, route, and duration
of administration. Common toxicities are as follows:
• High fever and fluid retention
• Gastrointestinal system side effects (i.e., nausea, vomiting, and
diarrhea)
• Cardiovascular system side effects (i.e., hypotension or arrhythmias)
• Pulmonary side effects (i.e., hypoxemia and pleural effusions)
• Renal side effects (i.e., azotemia and renal failure)
• Central nervous system side effects (i.e., confusion and delirium)
Patients with active comorbidities involving heart, lung, kidney, and
liver disease or those with untreated brain metastasis with vasogenic
edema are at high risk of life-threatening complications and mortality
related to capillary leak caused by high-dose IL-2 treatment
emphasizing rigorous patient selection for treatment with this agent.

■■ High-dose IL-2 should only be administered by health care teams

experienced in its use.
■■ Lower doses of IL-2 administered either subcutaneously or as a
continuous intravenous infusion at 9 to 18 million international
units/m2/day for 4 to 5 days have been studied in patients not eligible
for high-dose IL-2 treatment. Although total response rates as high as
20% have been reported, complete responses appear to be lower
than those with high-dose IL-2.