University of Medicine and Pharmacy Iuliu Ha ṭieganu [625693]

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University of Medicine and Pharmacy “Iuliu Ha ṭieganu”
Cluj- Napoca
Faculty of Medicine

LICENSE THESIS

The Ultrasonographic Examination and Staging of
the Superficial Tumors of the Face

Coordinator:
Assist. Univ. Dr Manuela Lenghel

Graduate:
Paola Maria Valadà

2019

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Contents
1. General Review ………………………….. ………………………….. …………………….. 3
1.1. Introduction ………………………….. ………………………….. ……………………. 4
1.2. Epidemiology ………………………….. ………………………….. ………………….. 5
1.3. Brief histology of the ski n ………………………….. ………………………….. …. 7
1.4. Lesions ………………………….. ………………………….. ………………………….. 8
1.4.1. Benign lesions ………………………….. ………………………….. …………………….. 8
1.4.2. Malignant lesions ………………………….. ………………………….. ………. 9
1.5. Risk factors ………………………….. ………………………….. ………………….. 15
1.6. Prophylaxis and prevention ………………………….. …………………………. 18
1.7. Diagnosis ………………………….. ………………………….. …………………….. 19
1.8. Staging ………………………….. ………………………….. ………………………… 26
1.9. Skin cancer treatment options ………………………….. ……………………… 30
1.9.1. Surgery ………………………….. ………………………….. …………………. 30
1.9.2. Topical treatments ………………………….. ………………………….. …… 33
1.9.3. Radiation therapy ………………………….. ………………………….. ……. 34
1.9.4. Targeted therapy ………………………….. ………………………….. …….. 35
1.10. Prognosis ………………………….. ………………………….. …………………….. 35
2. Special Review ………………………….. ………………………….. …………………… 39
2.1. Approach considerations ………………………….. ………………………….. … 40
2.2. Materials and Methods ………………………….. ………………………….. …… 40
2.3. Results ………………………….. ………………………….. ………………………… 40
2.4. Discussion ………………………….. ………………………….. ……………………. 40
2.5. Conclusion ………………………….. ………………………….. …………………… 40
2.6. Bibliography ………………………….. ………………………….. …………………. 40

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General Review

4
Introduction

Ultrasonography is an ultrasound -based diagnostic imaging technique with
variable frequency, able to assess in a noninvasiv e way various cutaneous
diseases.
The aim of this study is to understand the applications of high- resolution
ultrasonography using 20 -40 MHz frequencies, Doppler US, Dermoscan in the
examination and staging of superficial tumors of the face.
Compared to other imaging methods, ultrasonography has several
advantages. I t is porta ble, cheap and can be brought to the patient’s bedside
and does not use ionizing radiation.
It is applied in the evaluation of superficial cutaneous lesions that are too small
to be evaluated on computed tomography, magnetic resonance imaging and it
decreases the number of invasive procedures like biopsies and fine needle
aspiration.
Differentiating benign from maligna nt skin lesions is very important for accurate
staging, determination of optimal therapeutic options, and prognosis.

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Epidemiology

Understanding the incidence of specific diseases is necessary for decision
making regarding collocation of resources in clinical care and research. The
gold standard for the study of epidemiolo gy is population -based to obtain an
accurate and generalized incidence.
The epidemiology of skin cancers has always been a cente r of interest.
Nonmelanocytic skin cancers occur worldwide in all races. Approximately 5.5
million lesions occurred in around 3.3 million individuals in the US in 2012. It is
estimated that one in five Americans will develop skin cancer during their
lifetime, with over 95% being NMSC (1).
The exact incidence of BCCs and SCCs may be difficult to determine due to
issues such as diagnostic accuracy an d diagnostic criteria (e.g. differentiation
between actinic keratosis and SCC in situ ). In addition, data is thwarted due to
the fact that many lesions are often treated in private offices and not included
in the state cancer registries (2).
Important is the direct relationship be tween the incidence and latitude, the
closer individuals are to the equator, the greater their exposure to UVR. In
Australia, in 2002, the cumulative risk by age 70 years of having at least one
BCC or SCC was 70% for men and 58% for women. Incidence also i ncreases
with age, with a sharp increase in BCCs in men after the age of 60 years. In
those under 40 years of age, the majority of NMSC is found in women, but, by
age 80, the incidence in men exceeds that in women by a 2 –3: 1 ratio (3).
Actinic keratosis (AKs) are mo st often found in fair -skinned individuals but can
be seen in all races. AKs are very common and their estimation is currently up
to 12% individuals diagnosed in the US (4).
The SCC demographic results are analogous to those of AK s. SCC prevalent
in men (3: 1 M: F) with a significant incidence after age 60 years (3).

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Worldwide the incidence of SCC is increased in all age groups over the last
several decades of 3 -10% year, with 400 000 cases of invasive SCC newly
diagnosed annually.
BCC is the most common skin cancer in humans, and men generally have
higher rates of BCC than women (1.5 –2: 1) with the incidence rates of
diagnosis at 68 years (5).
In the last 30 years, it is estimated that incidence rates have risen between
20% and 80%. In the US, a disproportionate increase has been observed in
young women. Similar increases in incidence rates have been noted
worldwide, with the incidence doubling in Finland and Switzerland and
increasing in Wales by 50% over the past two decades (6).
Studies about skin melanoma provided by The National Cancer institute
reports an annually increasing of new cases by an average of 1.5%. Taking in
consideration statistics made in 2011 -2015, 22.8 new cas es of skin melanoma
per 100,000 US men and women were detected annually, while 2013 -2015
studied noticed that at some point of their lives about 2.3% of US population
will be newly diagnosed. Most of the lesions being located in the head and
neck region. Even though the rate of new cases progresses, the positive news
is that the mortality rate keeps decreasing by an average of 1.2% per year.

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Brief histology of the skin

The skin, with a surface area of two square meters in adult age , is the most
extended organ in the human body. It is divided in to three main layers, from
superficial to deep: epidermis, dermis and subcutis (7)(1).
The epidermis is essential protection against the environmental factors and
their pathogens. It is of ectodermal origin, varies in thickness according to body
areas, the thinnest found on eyelids (0.05 mm) an d thickest on palms an d
soles ( up to 0.6 mm). The Keratinocytes are its main component, proliferating
in the basal layer where they synthesize keratin filaments and desmosomal
proteins for strength and cohesion, they migrate towards the surface where
they shed after completing their differentiation process (8)(9).
The underlying dermis with a thickness varying from 1 to 4 mm takes its o rigin
from the mesoderm and it has a matrix of collagen and elastin fibers in an
extracellular gel -like substance (ground substance) for strength and elasticity.
It contains a range of cells: fibroblasts, mast cells, lymphocytes and dermal
dendritic cells . Blood and lymphatic vessels are part of it as well as nerves,
muscles and appendages ( sweat glands, sebaceous glands and hair follicles).
Hypodermis with a thickness ranging from 5 to 20 mm , is mainly m ade of
adipose cells arranged in lobules and separated by fibrous septa who provide
cushi oning between the underlying bone and the dermo -epidermal layers in
case of trauma. It also contains blood vessels and nerves (1).
Establishing skin structure we can imagine that in normal skin, during
Ultrasonographic examination, the echogenicity of each layer depends on its
main component , which summ ed up in the epidermis is represented by keratin
will result in an hyperechoic line, in dermis b y collagen as a hyperechoic band
less bright than the epidermis and hypodermis by fat lobules as a hypoechoic
layer with hyperechoic fibrous septa in between (7)(1).

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Lesions
Benign Lesions

Benign nevus commonly known as moles are benign overgrowth of
melanocytes and are common in fair -skinned people. They can be congenital
or acquired. Acquired benign n evi appear in a life span going from childhood
until early adult life (35 -year-old). Usually , have homogenous pigmentation and
regular borders. They start as non -palpable flat brown macules with the
proliferation of melanocytes at the dermo -epidermal junction, as th ey develop
their extension can reach the dermis, they become raised and palpable
eventually maturing into an intradermal n evus with loss of pigment (7).
Basal cell papilloma or seborrheic keratosis is a common, benign gro wth that
affects the older adults and the result o f clonal expansion of basal
keratinocytes . Flat or raised papule or plaque, their ap pearance ranges from
flesh -colored to very dark brown and have a greasy ‘stuck -on’ morphology at
naked eye. Their diameter ranges from 1 mm to several cm s. The surface is
rough and tiny keratin cysts may be present. It presents solitary or
grouped (10)(11).
Solar lentigo s are small, well -circumscribed pigmented macule on a normal –
appearing skin linked to sun exposure on fair -skinned people . Histological
results analyze hyperplasia of the epidermis with increased pigmentation,
homogeneous or variegated ranging from brown to black, of the basal layer
due to a variable number of melanocytes that do not form nests. Solar lentigo s
can appear over years or suddenly (12).
Studies elucidate a common key for the appearance of these benign lesions,
exposure to ultraviolet ra diations. However , studies do not quantify time of
exposure and intensity but mark the correlation with sunburns derived from UV.

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Actinic Keratosis represents a junctional bridge between benign and malignant
nature of skin lesions. The typical picture of a patient with actinic keratosis is
an elderly, fair -skinned, sun -sensitive person who was exposed to the sun on a
chronic base (13). The logical location , where this type of lesion is found, is
represented by an area forced on a long term to be exposed to the sun like the
face, ears, and, in men, bald scalp. The vermilion of the lower lip, not so often
of the upper lip, is involved with a much higher incidence in men than
women (14)(15).
The lesion’s morphology is given by papules or patched who appear rough,
scaly and erythematous on a chronic sun damaged skin with wrinkles and solar
lentigo . Most lesions have a size of 3 -10 mm but they may enlarge to several
cms and are usually asymptomatic. Due to this, many small lesions my pass
unnoticed and the diagnostic final changes appear as a dry rough adherent
yellow or brown colored scale . The per centage of lesions that undergo
malignant transformation into squamous cell carcinoma is equal to 1 %. AK
has been histologically classified according to the keratinocyte intraepithelial
neoplasia (KIN) divided in the three following histopathological grad es. In
grade I (KIN I) the keratinocyt e atypia is limited to the lower third of the
epidermis, whereas in grade II (KIN II) the lower two -thirds of the epidermis is
involved and in grade III (KIN III) full -thickness atypia is found. KIN III is
currently al so defined as SCC in situ. As clinical classification grade 1
describes slightly palpable AK, grade 2 shows moderately thick AK and grade
3 very thick and hyperkeratotic AK (1)(16)(17)(18).

Malignant Lesions

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The focus of this study is centered on Basal cell carcinoma and squamous cell
carcinoma .
BCCs
The etiology of BCCs is not known, but it is thought to arise from pluripotent
cells in the basal epidermis or follicular structures. In some sporadic BBCs
cases and Hereditary BCC syndrome, detection of mutations in the PTCH1
gene, who is in charge of regulating the Hedgehog intracellular signaling
pathway, have been detected (19)(20).
Basal cell carcinoma is known as “rodent ulcer” is the most common malignant
skin lesion and its incidence is increasing in aging populations , unlike SCC
there is no pre -alerting premalignant stage . It typically manifests as a slowly
enlarging, shiny nodule on head and neck area for approximately 80% of
cases , which i f exposed to minor trauma, bleeds and rarely heals. The contour
of ulcerated l esions is elevated and characterized by a pearly appearance and
overlying abnormal visible dilated blood vessels. Variants of Basal cell
carcinoma do exist, small lesions can be keratotic or present pigment which is
usually unevenly distributed over the le sion, superficial and scar -like
morphology. Here we have a close definition of the clinical variants (1)(21):
Nodular BCC: is the commonest subtype and usually presents on head and
neck. The contour usually becomes irregular as the lesion grows. The degree
of vascularity varies. There may be surface t elangiectasia over a flesh -colored
mass or the tumor may be pink or red. Some or all the component nodules
may have cystic centers that m ay be more deeply pigmented than the
periphery. Th ese features may lead to confusion with melanoma.
Superficial BCC: are less common. These are bounded by a slightly raised
thread -like margin which is irregular in outline. The epidermis covering the
centra l zone is usually atrophic and scaly. The vascularity is increased. These
lesions are often pigmented and can sometimes be difficult to make a

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distinction from an early noninvasive form of SCC that most ly occur s on sun –
damaged skin areas.
Morphoeic BCC: accounts for 5%, has ill -defined borders that make the exact
margin of the lesion impossible to define. The surface is smooth and yellowish
and may be minimally raised above or depressed below the normal skin.
Morphoeic BCC is also known as scleroder miform due to the dense fibrosis of
the stroma that gives a thickened plaque rather than a tumor, ulceration is very
uncommon.
Fibroepithelial BCC: rare variant occurring in individuals with multiple
superficial SCCs. U sually , it presents as a skin -colored or pink, sessile plaque
or pedunculated papulonodule with a smooth surface. It favors the trunk,
especially the lower back.
Ulcerated BCC: may start as a small macule or papul e but with the expansion
of margins, its surface ulcerates. The edge is usually raised above the normal
level but in some areas like nasolabial folds, it may be deep with in the surface.
The pavement of the ulcer is depressed, fleshy in appearance and not very
vascular ized. If left untreated the ulcer could spread deeply until the bony
structures and cause great destruction , especially around the eye, nose and
ears.
Advanced and metastatic BCCs: the progression to metastatic lesions is
extremely rare, counting for 0.0028 -0.55% of BCC , but when left neglected for
a long time is encountered at a rate of 1 -2-%. At records, there are cases of
direct bloodstream metastasis, other of spread via lymphatics to regional lymph
nodes. Rarely and unusually, fragments of tumor cells and stroma may be
inhaled and seed the lungs. These specifi c features will divide BCC into high
and low risk which may direct the line of management (22)(23).

SCC

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Although SCC is not often fatal, it can cause significant morbidity, especially
when it involves the facial skin. Most SCCs are located in the head -and-neck
region, and extensive excision required in an advanced stage of the disease
can cause disfigurement (24)(19)(25).
It is a more aggressive tumor than BCC and has a higher metastatic potential.
It can arise in p re-existing solar keratosis or B owen’s disease and it can also
complicate areas of chronic inflammati on. Rarely, multiple tumors occur in
people who have had prolonged periods of immunosuppression, such a renal
transplant, where certain type HPV may be involved in malignan t
transformation (5)(26).
In situ SCCs is comm only called Bowen’s disease. It s most common
presenta tion is a n erythematous scaly patch or slightly elevat ed plaque. It is
usually found in elderly individuals but it can develop in younger individuals
with significant photodamage. Lesions can become crusted. It can arise de
novo or from a pre -existing AK. Head and neck, followed by the extremities
and trunk, are the most common sites.The c linical distinction of SCC in situ
and AK is generally made keeping in mind that AKs are smaller
sized(8)(24)(18).
Invasive SCCs are often keratotic, ill -defined nodules that may ulcerate. They
can grow ver y rapidly in contrast to BCC , of which the rate of growth is slow,
but it is relatively slower compared to KA, which can reach to the same size in
weeks as SCC does in months. SCC is common on sun -exposed skin areas in
adults like the upper par t of the face, in males it is very commo n to appear on
the lower lip and pinna. Ulcerated lesions on lower lip or ear are more
aggressive. Very important the examination of regional lymph nodes (20)(19).
As said, SCC arise s on sun -exposed and damaged areas. The fir st clinical
evidence of malignancy is given by induration. The surface may be plaque -like,
verrucous, ulcerated but generally , the lesion feels firm when pressed between
the finger and thumb. The induration’s borders are not sharp and usually , they

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extend beyond the visible margin. The skin around the tumor shows signs of
inflammation and the edge is opaque yellowish red color. The better –
differe ntiated tumors are usually papillomatou s and covered by a keratotic
crust in the early stage. This crust will be shed later revealing an ulcer or
eroded lesion with indurated margin and bleeds easily. On the mobile body’s
structure like lips and ears , the visible sign can be represented by a fissure or
small erosion that is not able to heal and bleeds recurrently.
Risk factors for metastasis of invasive SCCs are elevated when the diameter is
>2cm and tumor thickness is >2 mm, high when >6 mm. Arising within a scar
due to burns or radiation, developing within Bowen’s disease and being located
on ears, lips , and mucos ae increase the metastatic potential.
Immunosuppression plays an important role as well. Histopathologically
studies underline that poor differentiated or undifferentiated SCCs with or
without acantholytic features bring the same risk (27)(25).
Keratoacanthomas are considered by some authors to be a variant of SCC and
by others a pseudomalignancy. The classification is still uncertain, although
there are some data that support its differ entiation from conventional SCC.
Typically, a rapidly enlarging papule evolves into a well circumscrib ed, centrally
depressed nodule with a keratotic core over a period of few weeks and then it
may resolve slowly over months to leave an atrophic scar. Most lesions are
painless and present in the same areas as SCCs. There are several clinical
presentations of KA, from solitary to multiple, grouped, giant, subungual,
intraoral, multiple spontaneous regressing and non -regressing, KA centrifugum
marginatum . By far the most common one is the solitary KA.
Melanomas
Melanomas develop from melanocytes malignant transformation. Melanocytes
are neural crest -derived cells located in the basal layer of the epidermis, who
produce melanin pigment responsible for ski n color. From the histological point

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of view Melanoma is classified into 4 types: superficial spreading, nodular,
lentigo maligna and acral lentiginous melanomas.
Superficial spreading melanomas appear as flat lesions. These lesions can
assume irregular an d elevated contour morphology in advanced stages. The
average size in diameter is 2 cm, presenting variegated colors, peripheral
notches, indentations or both. It represents the most common form of
melanoma cases, 70%. Many of them arise from pigmented dys plastic nevus,
always identified as a stable lesion. The usual changes noted include
enlargement, ulceration and color changes. Superficial spreading melanomas
are usually found on head and neck region of males while in females the lower
extremities are mo re affected.
Nodular melanoma lesions are the second most frequent with a rate of 15 -30%
of total cases and are found especially on the trunk of males. This type of
melanoma is the most symmetrical and uniform in morphology compared to the
other types. The color usually is dark brown or black but in 5% of cases they
present as amelanotic. This type of lesion advances rapidly in vertical path
thus it is considered a high -risk lesion.
Lentigo maligna melanomas account for 10% of melanoma cases. Usually they
are found on hand, neck being the two most sun exposed areas. LMMs are
often large and have hypopigmentation spots.
Acral lentiginous melanoma accounts for 2 -8% of melanomas in white
population and 35 -60% in dark skinned people. Malignant lesions appear on
palms, soles and subungual as non elevated, brown stains with irregular
margins. As NM, ALM has fast progression from radial to vertical phase and it
is particularly aggressive (28).

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Risk factors

A risk factor is anything that could present the chance for a person to develop
cancer . Miscellaneous cancers have not equal risk factors. Some risk factors,
like smoking, can be modified . Others, like a perso n's age or family histor y
remain unmodifiable (6).
But risk factors don't mean us everything. Having a risk factor, or even many
risk factors does not mean that a specific person will get the disease. And
many people who get the disease could have not presented any risk factor . In
a diagnosis of basal or s quamous cell skin cancer, it is often very hard to know
which risk factor may have played in getting cancer (3)(29)(30).

Ultraviolet (UV) light

Sunlight is the main source of ultraviolet (UV) radiation, which can damage the
genes in our skin cells. The UV light is the chief risk factor for most skin
cancers . Tanning lamps and booths are another source s of UV radiation.
People with frequent exposure to UV light are at greater risk for skin cancer.
The amount of UV exposure plays on the strength of the light, how long was
the exposure , and whether the skin was protected with clothing and sunscreen.
Many studies show that being exposed to a lot of sun since childhood is an
added risk factor (29)(31).
Living in places with year -round, bright sunlight have a higher risk. For
example, the risk of skin cancer is doube in Arizona compared to Minnesot a.
The highest rate of skin cancer in the world is in Australia. Spending a lot of
time outdoors without proper protections increases the risk (29).

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Fair skin
The risk of skin cancer is much higher for whites than for dark -skinned African
America ns or Hispanics. M elanin helps protect against UV radiation and dark
skinned people have more melanin. People with light-colored skin with freckles
or sunburned are at extra high risk . The individuals with the highest risk are
identified in Fitzpatrick skin phototype 1 -2-3(32)(33).

Older age
The risk of basal and squamous cell skin cancers goes up as people get older.
Older people have been exposed to the sun for a longer time and probably
precancerous lesions as actinic keratosis or actinic kelitis were nev er
examined by a physician. Nowadays these lesions are seen in younger people
too, due sun exposure without protecting their skin (34).
Men
Men are 2 times as likely as women to have basal cell cancers and about 3
times as likely to have squamous cell cancers of the skin. Men in their fifties
are more likely to develop melanoma and die of it compare to women. This
could be because they spend more time in the sun, smoke or drink more and
had the opportunity to come into contact with toxic compounds due to work (2).
Chemicals
Exposure to toxic compounds like arsenic increases the risk of skin cancer.
Arsenic is a heavy metal used to make some insecticides. It is also found in
well water in some areas. Workers exposed to industrial tar, coal, paraffin, and
certain types of oil may have an increased risk, too (35).
Radiation

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History of radiation treatment gives a higher predisposition to skin cancer in the
area that was treated. This can be a problem for young individuals who have
had cancer treatment.
History of skin cancer
Anyone who has had one keratinocyte cancer has a much higher chance of
having another one.
Long-term or severe skin problems
Scars from burns, areas of skin over bad bo ne infections, and sk in affected by
certain skin diseases are more likely to develop skin cancer, but this risk is
equally small .
Psoriasis treatment
Patient s with psoriasis (a chronic inflammatory skin disease) are treated with
psoralen and ultraviolet light treatments (PUVA). This can increase their risk of
getting squamous cell skin cancer, and maybe other skin cancers, too.
Family diseases
Xeroderma pigmentosum: This very rare disea se turns the skin less prone to
recover from sun damage. This disea se tends to be incidental in families.
People with this disease get many skin cancers, sometimes starting in
childhood (30).
Basal cell nevus syndrome: This rare condition is congenital and carries the
chance of many basal cell cancers (30).
Weakened immune system
People with weak immune systems are more likely to develop non -melanoma
skin cancer. For instance, patients after organ transplant ation are often

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prescribed with medicine s to weake n the immune system to avoid organ
rejection . These people are more likely to develop non -melanoma skin cancer
faster and more likely to be fatal (5).
HPV infection
Few skin cancers seem to be linked to infection with human papillomavirus
(HPV). HPV cause warts. The warts are different from the common type of
warts that people get on their hands and feet. The HPV -related warts are often
in the genital area and around the anus, condyloma acuminata. They are
linked to skin cancers in these areas (36)(26)(37).
Smoking
Smoking is a risk factor for squamous cell ski n can cer, but it is not an identified
risk for basal cell cancer.
Genetics
CDKN2A represents the best understood gene associated with melanoma in
correlation with mutations in another gene,MC1R, in individuals with light skin
and red hair . In these people, certain parts of the normal cells are more
sensitive to being damaged by sunlight (19).

Prophylaxis a nd prevention

Studies report the use of retinoids as prophylaxis against skin cancer
development in solid organ transplant recipients, patients with multiple KAs
and those with multiple NMSCs. The use of acitretin is preferred over
isotretinoin due to the better side -effects p rofile. Lipids and liver have to be
monitored during the course. Acitretin is used in low dose therapy, several
studies confirming its association to lower rates of SCCs.

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New studies have been started, monitoring a new approach for
chemoprevention of SCC in transplant patients using low dose oral
capecitabine, a prodrug of 5 -fluorouracil (38).
Reduction or cessation of immunosuppressive drug therapy has been
associated with decreased numbers of future skin cancers and amelioration of
the outcome in patients with p re-existing skin cancers, several lesions or in
cases of metastatic disease.
Primary prevention programs focused on lowering UV exposure and consistent
use of sunscreens appear to have a positive effect in reducing the incidence of
skin cancer as preventio n, while at the same time open a debate. The side
effect that using sunscreen implies is the decrease in pre -vitamin D3 synthesis.
Since vitamin D has been found to reduce non -skin cancer risk, the delicate
balance between beneficial sun exposure that prod uces vitamin D and the sun
exposure that induces skin damage has become an open and controversial
debate (39)(22)(19)(40).

Diagnosis

ULTRASONOGRAPHY AND DERMOSCOPY
In recent years , great progress has been made in diagnostic methods.
Physicians have gained the possibility to examine the skin with novel advanced
high-resolution imaging techniques. Many advantages are characteristic for
skin sonography like real -time imaging, measureme nts of morphological and
physiological aspects of the skin, the use of non -ionizing media and the lack of
contra indications while performing it .
The first steps were made by Alexander and Miller, who in 1979 introduced the
use of 15 MHz in measuring the s kin thickness. In the following years , new

20
applications have emerged, providing to physicians with great valuable
tools (41).
Back to the basic principles of ultrasound , primary knowledge of the principle is
essential for the correct interpretation of the image. The main component of the
ultraso und device is the transducer. Transducers have a material , usually
piezoelectric crystals, that generates acoustic waves when subjected to an
electric voltage. This wave propagates in the fluid and or surrounding tissue
and the echoes, back waves, reflected by these structures return to the
transducer which transforms them into electrical energy. Th us, the transducer
is the element that transforms electrical energy into a mechanical acoustic
wave and makes the reverse process when receiving the echoes, being the
transmitter and the receiving component. This energy after being processed by
the compute r causes the formation of the image at the monitor. This is
represented on the screen by luminous points that vary in intensity according
to the degree of reflection of different structures that the sound beam crosses.
This variation is what makes the US an excellent method for assessing edges
and interface between different regions. In two -dimensional -us (B mode), the
brightness of each pixel corresponds to the amplitude of the echo. The
intensity of each echo in the image is called echogenicity. Images wi th high –
intensity echoes are called echogenic or hyperechoic; those with low intensity
are called hypoechoic; and those without echoes, anechoic or echolucent.
What influences the echogenicity of each tissue is the speed at which the
sound wave can pass th rough it and the quantity and intensity of echoes
returned to the device (42). In normal skin, the echogenicity of each layer
depends on its main component, for the epidermis is the keratin; in the dermis,
the collagen and in the subcutaneous tissue is fat lobules. The interval
between the emitted and reflected waves allows calculating the distance
between the reflected structures. The ima ges are obtained in vertical sections
and both the resolution and penetration vary according to the frequency. The
higher the frequency, the shorter the wavelength that reaches the tissues:

21
better resolution and less penetration. In this study , the high -resolution devices
with high -frequency transducers are used (20 and 40 MHz). As standard,
devices with these resolutions enable the study of the dermis and epidermis
and are those with the best resolution for the observation of the surface
structures (41).
The skin us examination starts with the inspection of the site to be examined. A
thick layer of gel is applied between the skin and the transducer to obtain the
best focal point, the residual vegetative lesions can be better defined. It is
important the us e of the sensitive transducer, which fits the skin contour of
different body segments such as the face. The contact of the transducer with
the skin should be as smooth as possible to avoid compression of the
anatomical structures that depending on the tiss ue examined can be sup erficial
and thin. In case of a hairy area, the trichotomy should be made with a blade
and not with scissors, allowing better contact between the transducer and the
skin. To study the lesions that have severe crusting or keratinizatio n it is
recommended to remove them, through the help of keratolytic agents, since
they cause attenuation of the sound beam, reducing the accuracy of the
test(43).
An appropriate evaluation using HFUS includes discriminating the exact
topography to be studied, differentiating the skin layers, the thickness and
vascularization and the possible associated pathological f indings. Lesions
should be evaluated regarding three -dimensional size, thickness, depth,
morphology, content, foci of calcification or necrosis, vascularization, exact
location and involvement of adjacent structures (44).
In HFUS, skin cancers, malignant or benign, usually appear as hypoechoic
areas in contrast to the adjacent healthy tissue. In addition to echogenicity, it is
possible to evaluate the lesion shape, the longitudinal, transverse and axial
measures, the edges, the contour and the involvement of the deep layers, such
as muscle, cartilage and bone. The study of the vascularization can be

22
accomplished with the combination of color Doppler or power Doppler, which
allows observation of the distribution, size and nat ure of tumor vessels (45). As
the cutaneous lesions may be asymmetric, the measurements of the tumor
thickness should be based on the site of greater invasion (44).
Basal cell carcinom a is often located in head and neck regions chronically
exposed to the sun. It presents as a heterogenous hypoechoic area, well
defined, with irregular contour usually located on the dermis but may extend to
deep planes, causing destructive lesions sometimes. Often the presence of
characteristic hyperechoic spots inside the tumor is observed. These images
are attributed to the presence of corneal cysts, called pearls,
microcalcifications and clusters of apoptotic cells within the tumor mass. The
intra and peritumoral blood flow is discrete and consists of arteries and veins of
low flow. BCC has a high recurrence rate, and preoperative HFUS is helpful in
reducing the rate of relapse by accurate determination of the area and margins
of the tumor for either surgical excision or nonsurgical treatment with
radiotherapy or cryosurgery (46). It is also helpful in the detection of early
recurrence, especially in the case of incomplete surgical removal or in th e
cases of treatment with radiotherapy or cryosurgery.
The appearance , in HFUS , of the previous lesion described is similar to our
second studied epidermal malignant tumor, squamous cell carcinoma.
Squamous cell carcinoma has a major tendency to local relapse and with
frequent lymph nodal metastases. It presents hyperechoic points within the
tumor and due to its more aggressive behavior, is more likely to invade soft
tissues, cartilage and adjacent bone. It is seen with the help of HFUS as a
lesion with marginal irregularities and inhomogeneous hypoechoic structure. In
color Doppler mapping, there is a mixed pattern with internal and peripheral
vascularization of low -resistance pulsatile flow signals. Keep in mind, SCC
generally presents with hyperkeratosis and to the higher inflammatory process
associated, the tumor area can be over estimated when evaluating by the US

23
and in some cases the hyperkeratotic epidermis may le ad to total reflection of
the ultrasound waves, making the ap preciation of the tumor thickness
impossible.
Talking about benign lesions, Seborrheic keratosis is epidermal in origin, well
delimited and very superficial on the skin and may be misdiagnosed as
melanoma. HFUS shows them just beneath the entry echo as hyp oechoic
lesions with dense echoes (horny pseudocysts), mostly avascular on Doppler.
Various studies reported that seborrheic keratosis was differentiated from
melanoma and other benign nevi, who presented as reflective and irregular
with shadowing, thanks to its high attenuation, prominent entry echo and
irregular surface.
Nevi are polychromic maculopapular or slightly elevated plaque -like
pigmentary lesions with an irregular contour. They are not well identifiable with
probes of 10 -13 MHz frequency but HF US shows them as round -oval
hypoechoic lesions with relatively well -defined borders, usually very thin in
case of junctional and thicker in the case of dermal nevi . The nevic cells are
located at the dermo -epidermal junction, during malignant transformatio n, their
transition goes from radial growth to vertical with progression in depth. HFUS
reveals the epidermal lesions, their regression areas and their degree of
dermal penetration during the malignant transformation into melanomas and
helps in the assessm ent of location and size for the excision with safety
margins (42).
HFUS tool is useful in diagnostic and staging of melanoma, in measuring tumor
thickness, vascularization and margins. The image depicted by ultrasound
corresponds to a solid, well -delimited, homogeneous hypoechoic area, oval or
spindle -shaped with a thin entry echo. In case of ulceration the skin may result
irregular . Color Doppler helps in highlighting the vasculature belonging to the
lesion. Usually, in melanoma the vascularization is more enhanced with
prevalent arterial vessels of low flow compared to benign skin lesions (45).

24
Skin or subcutaneous metastases are seen as hypoechoic nodules by US.
They are identified as “satellite” metastases when they are found in a range of
2 cm from the primary tumor. When the range goes over 2 cm but not beyond
the reg ional nodal basin, they take the name of “in transit” metastases. These
two types of metastases are confined within the dermal and subdermal
lymphatics before getting in touch with the regional lymph nodes. Evaluation of
these lesions is demonstrated to be superior to any physical exam (42).
In case of metastases spread to regional lymph nodes, several studied have
demonstrated once again that HFUS has a higher sensitivity an d specificity
than clinical exam. Metastatic impregnation of lymph nodes makes these
present in the ultrasound like round, well demarcated, hypoechoic or with an
echolucent center corresponding to necrosis. Reactive lymphadenopathy
shows a different aspect , they have a central type of vascularization, elliptical
shape with hyperechoic center. The physician who conducts the
ultrasonographic exam must keep in mind that some factors as inflammatory
process due to cancer or presence of hyperechoic perilesional glands may
lead to inaccurate increase of the lesion’s size while presence of ulceration
might wrongly underestimate it (45).
Another valuable non-invasive method of examination is offered by
Dermoscopy, even if its use is preferable to be operated by experienced
hands (47). It allows in vivo examination of colors and microstructures of the
epidermis, the dermo -epidermal junction and th e papillary dermis not visible to
naked eye. The specific diagnostic patterns related to the specific distribution
of colors and structure ca n suggest the occurrence of a malignant or benign
pigmented lesion (48). How do the previous lesions analyzed by US look with
dermoscopy?
The dermatoscopic features of non pigmented BCC: arborizing vessels,
superficial fine telangiectasia, ulcer ation, multiple small erosions, shiny white,
red structureless areas and short white streaks (49).

25
Superficial BCCs are characterized by superficial fine telangiectasia, mul tiple
small erosions, shiny white -red struct ureless areas. In the pigmented ones
could be present maple leaf -like structu res, spoke wheel areas, concentric
structures, multiple blue -gray dots and in -focus dots (16).
Non-pigmented nodular BCCs usually, dermoscopically , appe ar as a
translucent pinkish tumor, with arborizing vessels. Another common feature is
ulceration. In pigmented nodular type , it is possible to find the above –
mentioned features plus blue -grey ovoid nests or multiple blue -grey dots and
globules.
The infiltra tive and sclerodermiform BCCs show fine, more scattered and less
branched vessels compared to the nodular type. The infiltrative type shows
white/red structureless areas while the sclerodermiform exhibits a whitish
background, dermoscopically expression of the histopathological fibrosis that
characterizes this kind of BCCs.
Talking about actinic keratosis there are th ree different patterns at
derm oscopy (16). Grade 1 is characterized by red pseudo network pattern and
discrete white scales, grade 2 corresponds to an erythematous background
mixed with white to yellow, keratotic and enlar ged follicular openings and grade
3 characteristics are enlarged follicular openings with keratotic plugs
presenting over a scaly and white -yellow background, marked hyperkeratosis,
or white -yellow areas with no structure . The progression of actinic keratosis
into SCCs is shown by initially dotted or glomerular vessels which evolve into
hairpin and linear vessels resulting in invasive SCCs (17).
There is large varierty of configuration of vascular structures in SCCs .
Dermoscopic descriptors of SCCs are linear irregular and hairpin vessels,
central keratin, white structure -less areas, ulceration and scaly surface that
when too wide could impair the visualization of vessels. Keratin, when present
in the center of the lesion, is the only element that allow s the distinction
between keratoacanthoma and SCC. In fact, t he presence of central keratin

26
was more frequent ly observed in keratoacanthoma in several studies. This
finding meets perfectly the histopathological definition of keratoacanthoma, that
considers the presence of a central keratin plug as an important architectural
criterion for the diagnosis of the lesion (16).

Staging

27
Making the right tre atment decision begins staging , or progression, of the
disease. The stage of skin cancer is one of the most important factors in
evaluating treatment options (50).
Non-melanoma skin cancers, such as basal cell carcinomas rarely spread and
may not be staged. The chance that squamous cell carcinomas will spread is
slightly higher.
The American Joint Commission on Cancer has developed a uniform system
for describing the stages of skin cancer. This sy stem allows doctors to
determine how advanced skin cancer is, and to share that information with
each other in a meaningful way (51)(51).
This system, known as the TNM system, is composed of three key pieces of
information:
T (tumor): This describes the tumor ’s size, location and how deep it has grown
into the skin.
N (node): This indicates whether or not cancer cells have spread to nearby
lymph nodes, or the channels connecting the lymph nodes.
M (metastasis): This refers to whether the cancer cells have spread to distant
organs (51).

Basal cell carcinoma stages

There are certain features that are considered to make cancer at higher risk for
spreading or recurrence, and these may also be used to stage basal cell
carcinomas. These include:
 Greater than 2 mm in thickness

28
 Invasion into the lower dermis or subcutis layers of the skin
 Invasion into the tiny nerves in the skin
 Location on the ear or on a hair -bearing lip
After the TNM components and risk factors have been established, the cancer
is given a stage. For basal cell carcinoma staging, the factors are grouped and
labeled 0 to 4. The characteristics and stages of basal cell carcinoma
are(52)(51):
Stage 0: Also called carcinoma in situ, cancer discovered in this stage is only
present in the epidermis (upper layer of the skin) and has not spread deeper to
the dermis.
Stage I (stage 1 basal cell carcinoma): The cancer is less than 2
centimeters, about 4/5 of 2,5 cm across, has not spread to nearby lymph
nodes or organs and has one or fewer high -risk features.
Stage II (stage 2 basal cell carcinoma): The cancer is larger than 2
centimeters across, and has not spread to nearby organs or lymph nodes, or a
tumor of any size with 2 or more high -risk features.
Stage III (stage 3 basal cell carcinoma): cancer has spread into facial bones
or 1 nearby lymph node, but not to other organs.
Stage IV (stage 4 basal cell carcinoma): cancer can be any size and has
spread (metastasized) to 1 or more lymph nodes which are larger than 3 cm
and may have spread to bones or other organs in the body (50)(53).

Squamous cell carcinoma stages

There are certain featu res tha t are considered to make cancer at higher risk for
spreading or recurrence, and these may also be used to stage squamous cell
carcinomas. These include (54)(53):

29
 Greater than 2 mm in thickness
 Invasion into the lower dermis or subcutis layers of the skin
 Invasion into the tiny nerves in the skin
 Location on the ear or on a hair -bearing lip
After the TNM components and risk factors have been established, the cancer
is assigned to one of the five squamous cell carcinoma stages, which are
labeled 0 to 4. The characteristics and stages of squamous cell cancer are:
Stage 0: Also called carcinoma in situ, cancer discovered in this stage is only
present in the epidermis (upper layer of the skin) and has not spread deeper to
the dermis.
Stage I (stage 1 squamous cell carcinoma): The cancer is less than 2
centimete rs, about 4/5 of an inch across, has not spread to nearby lymph
nodes or organs and has one or fewer high -risk features.
Stage II (stage 2 squamous cell carcinoma): The cancer is larger than 2
centimeters across and has not spread to nearby organs or lymph nodes, or a
tumor of any size with 2 or more high -risk features.
Stage III (stage 3 squamous cell carcinoma): cancer has spread into facial
bones or 1 nearby lymph node, but not to other organs.
Stage IV (stage 4 squamous cell carcinoma): cancer can be any size and
has spread (metastasized) to 1 or more lymph nodes which are larger than 3
cm and may have spread to bones or other organs in the body (54).
Melanomas stages

Stage 0 : melanoma in situ, tumor does not penetrate below the epidermis .
Stage I : melanoma penetrates the epidermis into the skin’s next layer, dermis.
Lesion is small and has no high risk of metastasizing to nearby lymph nodes or
beyond .

30
Stage II : melanoma is localized with larger dimensions than 1 mm and can
have traits like ulceration that give high risk of spreading to the nearby lymph
nodes o r beyond. Considered as “high -risk” melanomas.
Stage III and IV : metastasized to other parts of the body .

Breslow classification represents the melanoma thickness measured by a
micrometer and defines the level of invasion of the skin as follows:
0.75 m m or less in skin surface, epide rmis
0.76-1.5 mm in upper dermis
1.51-4 mm in lower dermis
4 mm or more in subcutaneous tissue

Skin cancer treatment option s

Most cases of skin lesions are treated in a dermatologist's office or with
outpatient surgery. In a more serious clinical picture, aggressive skin cancers
may require more extensive treatments, such as surgery, chemotherapy or
immunotherapy.

Surgery
Surg ery is the primary treatment option for most skin cancers. Basal cell or
squamous cell carcinomas can be removed by a dermatologist or other
qualified doctor performing an outpatient procedure using a local anesthetic. In

31
these procedures, like with most skin cancer surgeries, the cancer cells are
removed, with a small amount of surrounding skin, known as the margin. For
skin cancers that have not spread, surgery may be performed to remove the
entire tumor, and no other treatment may be needed. More aggres sive skin
cancers such as melanoma may require more extensive surgeries following
protocols based on spreading index like mitotic index, Breslow and Clark’s. If
cancer has spread to the regional lymph nodes or furthers, dissection of them
has to be perform ed.
Mohs surgery:
Developed in the 1930s by Dr. Frederick Mohs, this technique removes skin
cancer tumors preserving as much healthy tissue as possible using simple
local anesthesia. In this procedure, cancerous cells are removed from the skin
layer by lay er until no trace is left. This approach is most often used on more
visible areas, such as the head and neck or hands, to avoid and reduce
unpleasant scarring. It may also be used on recurrent skin
cancers (55)(25)(56).
Excision
The surgeon performs an excision of growth of the skin, by scalpel or sharp
razor after numbing the area of interest with a local anesthetic. E xcisions may
leave a scar (57).
Types of excisions:
A simple excision is created with a scalpel, removing the skin growth with a
small perimeter of surrounding tissue.
Shave excision is a procedure in which growth is shaved or peeled off the
surface of the skin with a sharp razor -like tool.

32
Wide excision is typically used on melanomas and Merkel cell carcinoma
extending deeper than a simple excision. In this technique as the name
suggests skin tumor and a wider perimeter of healthy tissue is removed.
Curettage and electrodes iccation
In this procedure, a s kin lesion is removed with a curette, a long, thin surgical
tool with a small, sharp hoop or scoop on the end for scraping. The scraped
area is treated through electrodes iccation, an electric current through a needle –
like electrode desig ned to kill remaini ng cancer cells and reduce bleeding. This
process can be repeated more than once . It may require a local anesthetic and
may leave a scar (58)(59).
Cryotherapy
Cancer cells are destroyed by freezing using liquid nitrogen several t imes. The
treated area may swell and blister and may be scarred after the wound heals.
This is usually only used for small skin cancers or pre -cancerous lesions like
actinic keratosis (22)(15).
Laser surgery
This technique uses a laser beam, an intense, narrow beam of light, to destroy
cancer cells. L aser surgery may be used to treat very superficial skin
cancers (60).
Surgery for metastatic skin cancer
Basal cell and squamous cell carcinomas, which comprise more than 95
percent of all skin cancers, usually don't metastasize. But melanoma, which
accounts for about 2 percent o f all skin cancers, may travel to the brain, bones,
liver and lungs. When that occurs, surgery may be performed to remove
tumors from those locations. Surgery may need to be combined with other

33
treatments, such as immunotherapy or chemotherapy, to treat me tastatic
cancer. In some cases, surgery for metastatic melanoma may be required to
relieve symptoms of the disease (25).
The extension of the procedure determines the occurrence of side effects .
Even though surgery for basal cell or squamous cell carcinomas is typically
minimally invasive, it may produce some side effects: pain, scarring or
disfigurement, swelling or bruising, nerve damage or numbness, bl eeding,
infection, fatigue and lymphedema .
Topical treatments
In some cases, nonsurgical forms of therapy may be used to remove or
destroy localized skin cancer cells. These techniques may be used, either
alone or in combination with other treatments, to treat early -stage basal cell or
squamous cell carcinomas or noncancerous or pre -cancerous lesions. Topical
treatments include:
Photodynamic therapy uses photosensitive medication combined with light in
an effort to kill cancer cells. In this technique, a l ight-sensitive substance,
usually aminolevulinic acid, is applied directly on the tumor. Up to 18 hours
later, the treated area is exposed to a special blue light that activates the
medication, targeting cancer cells on the skin. This type of treatment is most
often used on actinic keratosis (61).
Topical chemotherapy applying a chemotherapy cream, usually fluorouracil,
directly on the skin tumor. The a pplication may be prescribed twice daily for a
minimum of three weeks to a maximum of 12. Topical chemotherapy may be
used to treat basal cell carcinoma or actinic keratosis. The drug, also known as
5-FU, is generally used for very superficial skin cancers due to its impossibility
to penetrate deep into the skin (62).

34
Immune response modifier : The topical cream imiquimod may be used to treat
actinic keratosis or superficial basal cell carcinomas. It can be prescribed for 2
to 8 weeks with an application of several times a day. Imiquimod is designed to
activate the immune system to attack cancer cells, works by stimulating the
body to produce interferon, a natural protein that fights fo reign invaders and
cancer cells (63).
Radiation therapy
It is used following surgery in the area where lymph nodes were removed, to
eliminate any remaining cancer cells. It may also be used in case of
recurrence, to reduce the size of the metastases and to relieve symptoms,
particularly if cancer has spread to the brain or bones.
Radiation therap y techniques used to treat skin cancer include:
External beam radiation therapy directs a beam of radiation from outside the
body to cancerous tissues inside the body. Tumors are reduced in size by
radiations therapy . Advantages of using EBRT to treat skin cancer are
multiples. Being an outpatient procedure does not carry standard risks or
complications associated with major surgery mentioned above. It is painless
and has no risk of radioactivity, allowing a normal lifestyle.
Intensity -modulated radiation t herapy uses higher radiation doses than
traditional ther apies would allow in same areas . At the same time, IMRT helps
to spare more of the surrounding healthy skin tissue from harmful doses of
radiation and it results very efficient in case of recurrence a nd previous
radiotherapy treated skin areas.
TomoTherapy results in intensity modulated radiation therapy (IMRT), with the
accuracy of computed tomography (CT) scanning technology in one . It is able
to confirm the precise shape and location of a skin tumor before starting the

35
treatment. It targets hard to reach skin tumors by powerful and precise beams
from a full 360 degrees, reduces damage and radiation exposure to nearby
healthy tissue like muscles, spine, lungs and other sensitive organs.

Targeted therapy

It works by seeking out specific characteristics in cancer cells, such as gene
mutations or proteins. Targeted therapy drugs are designed to attach
themselves to those cells, to kill them or help other therapies, such as
chemotherapy, work better. A certai n type of targeted therapy drug approved to
treat rare cases of advanced basal cell carcinoma is called hedgehog pathway
inhibitors because they target the hedgehog pathway, a signaling mechanism
critical to healthy cell growth in the fetus. The pathway ty pically goes dormant
by adulthood, but cancer cells may re -activate the hedgehog pathways in
adults, promoting tumor growth in some cases. Because of the pathway’s
importance to developing fetuses, these drugs are teratogenic.

Prognosis

Survival for most non -melanoma skin cancers is excellent. The 5 -year relative
survival for BCC is 100%, tumors enlarge slowly and tend to be locally
destructive. This means that, on average, all of the people diagnosed with BCC
are just as likely to live a t least 5 years after their diagnosis as people in the
general population. If BCC is not treated in time, it could result in significant
morbidity and cosmetic disfigurement. Mortality occurs in the group of patients
dealing with immunosuppression or metas tatic BCC (metastatic incidence less

36
than 0.1%) with aggressive histopathologic patterns as morpheaform,
infiltrating, basosquamous. Although treatment is curative in more than 95% of
cases, BCC may recur, especially in the first year, or develop in new si tes.
Therefore, regular skin screenings are recommended (64).
The 5 -year relative survival for SCC is slightly less at 95%, having significantly
higher risks of metastasis (2 -6%) and tumor death. Tumor thickness is a good
indicator of prognosis. Thick ness greater than 2 mm is an independent
determinant for local recurrence and metastasis. A tumor size 2 cm or larger
triples the risk of metastasis. Desmoplasia is the most important histologic
feature for local recurrence (24% vs 1% for similar but nond esmoplastic SCC).
Perineural invasion occurs in 3 -14% of lesions and correlates with local
recurrence, spindle cell histology, and increasing tumor size. Mohs surgery
with removal of perineural spread has significantly improved the prognosis
from a metasta tic rate as high as 47% to 8% (65).
However, in large cohorts of people with distant metastatic SCC, about 70%
die from their disease.
The prognosis in melanoma like in any other cancer looks better in the earliest
tumor’s stage diagnosis .
The 5 -year relative survival rate is reported, for the years going fr om 2008 to
20014, to be 98% in SEER stage Localized, 64% survival in Regional, 23% in
Distant and 92% in all SEER stages combined.
Understanding the numbers, they just apply to the stage of the cancer when
was diagnosed taking in account how far the cance r has spread without
looking at the patient’s age. Studies underline the age factor as an important
marker, seeing young people having a better outlook regardless the stage.
People newly diagnosed with melanoma or any other skin cancer have a better
outloo k than all these number reported due to treatments improvement over
time.

37

38

39
Special Review

40
Approach considerations

Materials and Methods

Results

Discussion

Conclusion

Bibliography

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