We all Know that the most dangerous medical condition in our modern life is cancer! There are two types of this awful condition, BENIGN and MALIGNANT. The first is safe and can be removed by many ways without large effects on the patients, but the last one is very killing and can cause a lot of consequences on the patient, even death. In my report, I will discuss one of the cancer's types that occur in the human body, which is "Melanocytes tumors". I mentioned everything about Melanocytes tumor, starting with signs and symptoms, and finishing with diagnosis and treatment. The Melanocytes are found in two areas of the human body, (Eye and skin). It can be hidden for a lot of time without discovering by patients or doctors, so all people need to be checked every month or years to be sure that they are safe from this killing condition. Also, this condition can be normal without problems and found in all people approximately, such we called it "Nevus" or "Shama" in Arabic language which is one of the beauty sings.

1. UNIVERSIY OF BAGHDAD
COLLEGE OF MEDICINE
MELANOCYTE TUMORS
CLS – Pathology MODULE
By:
MUSTAFA AHMED RAMADHAN
2nd Stage

2. 2
Contents
1. Introduction ………………………………….…...................... 3
2. Search board and discussion:
Types of Melanocytic tumor ……………………………. 4
a. Melanocytic Nevus ……………………………………. 4
b. Melanocytic tumors of uncertain malignant potential 6
c. Melanoma ……………………………………….…….. 7
3. Conjunctiva's Melanocytic tumors …..……………………… 8
4. Summary ……………………………………………………… 8
5. References …………………………………………..………... 9

3. 3
Introduction
We all Know that the most dangerous medical condition in our modern life is cancer!
There are two types of this awful condition, BENIGN and MALIGNANT. The first is safe
and can be removed by many ways without large effects on the patients, but the last
one is very killing and can cause a lot of consequences on the patient, even death.
In my report, I will discuss one of the cancer's types that occur in the human body,
which is "Melanocytes tumors".
I mentioned everything about Melanocytes tumor, starting with signs and symptoms,
and finishing with diagnosis and treatment.
The Melanocytes are found in two areas of the human body, (Eye and skin). It can be
hidden for a lot of time without discovering by patients or doctors, so all people need
to be checked every month or years to be sure that they are safe from this killing
condition.
Also, this condition can be normal without problems and found in all people
approximately, such we called it "Nevus" or "Shama" in Arabic language which is one of
the beauty sings.

4. 4
Types of Melanocytic tumors (Fig1):
1) Melanocytic Nevus
2) Melanocytic tumors of uncertain malignant potential
3) Melanoma
Now we will discuss each one alone:
Fig: 1
Fig: 2

5. 5
1) Melanocytic Nevus:
Classification:
There are many types of nevus depending on the location and appearances[1]
:
 Junctional nevus: the nevus cells are located along the junction of
the epidermis and the underlying dermis. A junctional nevus is flat and brown
to black.[1]
 Compound nevus: a mixture of junctional and intradermal proliferation.
Compound nevi are slightly raised and brown to black. Beauty marks are
usually compound nevi of either the acquired variety or congenital variety.[1]
 Intradermal nevus: the nevus cells are located in the dermis only. Intradermal
nevi are raised; most are flesh-colored (not pigmented).
 Dysplastic nevus (nevus of Clark): usually a compound nevus with cellular and
architectural dysplasia. Like typical moles, dysplastic nevi can be flat or raised.
While they vary in size, dysplastic nevi are typically larger than normal moles
and tend to have irregular borders and irregular coloration. Hence, they
resemble melanoma, appear worrisome, and are often removed to clarify the
diagnosis. Dysplastic nevi are markers of risk when they are numerous
(atypical mole syndrome). According to the National Cancer Institute (NIH),
doctors believe that, when part of a series or syndrome of multiple moles,
dysplastic nevi are more likely than ordinary moles to develop into the most
virulent type of skin cancer called melanoma.[2]
 Blue nevus: It is blue in color as its melanocytes are very deep in the skin. The
nevus cells are spindle shaped and scattered in deep layers of the dermis. The
covering epidermis is normal.
 Spitz nevus: a distinct variant of intradermal nevus, usually in a child. They
are raised and reddish (non-pigmented). pigmented variant, called the 'nevus
of Reed', typically appears on the leg of young women.
 Acquired nevus: Any melanocytic nevus that is not a congenital nevus or not
present at birth or near birth. This includes junctional, compound and
intradermal nevus.[1]
 Congenital nevus: Small to large nevus present at or near time of birth. Small
ones have low potential for forming melanomas, however the risk increases
with size, as in the giant pigmented nevus.[3]
 Giant pigmented nevus: these large, pigmented, often hairy congenital nevi.
They are important because melanoma may occasionally (10 to 15%) appear in
them.[3]
 Intramucosal nevus: junctional nevus of the mucosa of the mouth or genital
areas. In the mouth, they are found most frequently on the hard palate. They
are typically light brown and dome-shaped.[4]
 Nevus of Ito and nevus of Ota: congenital, flat brownish lesions on the face or
shoulder.[5]

6. 6
 Mongolian spot: congenital large, deep, bluish discoloration which generally
disappears by puberty. It is named for its association with East Asian ethnic
groups but is not limited to them.[6]
 Recurrent nevus: Any incompletely removed nevus with residual melanocytes
left in the surgical wound. It creates a dilemma for the patient and physician,
as these scars cannot be distinguished from a melanoma.
 Signs and symptoms:
According to the American Academy of Dermatology, the most common types of
moles are skin tags, raised moles and flat moles. Benign moles are usually brown,
tan, pink or black (especially on dark-colored skin). They are circular or oval and
are usually small (commonly between 1–3 mm), though some can be larger than the
size of a typical pencil eraser (>5 mm). Some moles produce dark, coarse hair.
Common mole hair removal procedures include plucking, cosmetic
waxing, electrolysis, threading and cauterization[7]
Causes:
The cause is not clearly understood, but is thought to be caused by a defect in
embryologic development. This is in the first twelve weeks of pregnancy. The defect
is thought to cause a proliferation of melanocytes. This means melanocytes, the cells
in the body in charge of normal skin color, are being produced at an extremely fast
rate. Thus causing the melanocytes to form in clusters instead of spread out, causing
abnormal skin pigmentation in some areas of the body.
Genetics[8]
Genes can have an influence on a person's moles.
Dysplastic nevi and atypical mole syndrome are hereditary conditions which causes a
person to have a large quantity of moles (often 100 or more) with some larger than
normal or atypical. This often leads to a higher risk of melanoma, a serious skin
cancer.[8]
Dysplastic nevi are more likely than ordinary moles to become cancerous.
Dysplastic nevi are common, and many people have a few of these abnormal moles.
Having more than 50 ordinary moles increases the risk of developing melanoma.[9]
In
the overall population, a slight majority of melanomas do not form in an existing
mole, but rather create a new growth on the skin. Somewhat surprisingly, this also
applies to those with dysplastic nevi. They are at a higher risk of melanoma
occurring not only where there is an existing mole, but also where there are
none.[8][9]
Such persons need to be checked regularly for any changes in their moles
and to note any new ones.
Sunlight[10]
Ultraviolet light from the sun causes premature aging of the skin and skin damage
that can lead to melanoma. However, more research is needed to determine the

7. 7
complex interaction between genetic makeup and overall exposure to ultraviolet
light. Some strong indications that this is so (but falling short of proof), are:
 The relative lack of moles on the buttocks of people with dysplastic nevi.
 Freckles (spots of melanin on the skin, and distinct from moles) are known to
be influenced by sunlight.
 Studies have found that sunburns and too much time in the sun can increase
the risk factors for melanoma. This is in addition to those who have dysplastic
nevi being at higher risk of this cancer (the uncertainty is in regard to
acquiring benign moles). To prevent and reduce the risk of melanoma caused
by UV radiation, the American Academy of Dermatology and the National
Cancer Instituterecommends staying out of the sun between 10 a.m. and 4 p.m.
standard time (or whenever one's shadow is shorter than one's height.[9]
Hormones[11]
Hormonal changes during pregnancy and diabetics (i.e. insulin) are often
contributing to mole formation.
 Diagnostic Considerations[12]
Melanoma is one of the great clinical imitators and can manifest with great clinical
diversity. Failure to have a high index of suspicion and failure to evaluate new or
changing lesions that are not unequivocally benign via biopsy, with subsequent
interpretation by a competent, certified dermatopathologist, can lead to liability.
Histopathological overdiagnosis refers to the interpretation of a benign lesion as
melanoma, which is a tendency of some pathologists. Overdiagnosis can prompt
detailed and unwarranted clinical investigation of the patient, can provoke patient
anxiety with respect to longevity, and can trigger unnecessary surgery, including
reexcision and lymph node sampling. Unnecessary surgery and complications such as
chronic lymphedema may result.
Histopathologic underdiagnosis refers to the interpretation of melanoma as a benign
lesion. Underdiagnosis can yield considerable delays that may permit metastatic
spread before appropriate extirpation is possible.
Clinicians and patients can avoid clinical and histopathological misdiagnosis by
adhering closely to standard practices in the evaluation of melanocytic neoplasms
and by seeking appropriate consultations with experienced colleagues.
The prototypical melanoma is readily diagnosable by the ABCDE approach, based
on its asymmetry, irregular border, irregular color, large diameter, and evolution.
However, these clinical parameters are largely useless in three instances, as follows:

8. 8
For amelanotic melanomas, in which pigmentation is largely or entirely absent. For
desmoplastic melanomas, which sometimes manifest without an associated in situ
component and may also lack clinical pigmentation. For ulcerated and inflamed
melanomas, especially nodular lesions, which may clinically simulate common lesions
(eg, basal cell carcinoma, pyogenic granuloma) because of masking by the presence of
ulceration and/or inflammation.
Differential Diagnoses[13]
 Atypical Mole (Clark Nevus or Dysplastic Nevus)
 Cafe Au Lait Spots
 Cockarde nevus
 Cutaneous Melanoma
 Nevi of Ota and Ito
 Nevus spilus
Management:
First, a diagnosis must be made. If the lesion is a seborrheic keratosis, then shave
excision, electrodesiccation or cryosurgery may be performed, usually leaving very
little if any scarring. If the lesion is suspected to be a skin cancer, a skin biopsy must
be done first, before considering removal. This is unless an excisional biopsy is
warranted. If the lesion is a melanocytic nevus, one has to decide if it is medically
indicated or not.
If a melanocytic nevus is suspected of being a melanoma, it needs to be sampled or
removed and sent for microscopic evaluation by a pathologist by a method
called skin biopsy. One can do a complete excisional skin biopsy or a punch skin
biopsy, depending on the size and location of the original nevus. Other reasons for
removal may be cosmetic, or because a raised mole interferes with daily life
(e.g. shaving). Removal can be by excisional biopsy or by shaving. A shaved site
leaves a red mark on the site which returns to the patient’s usual skin color in about
two weeks. However, there might still be a risk of spread of the melanoma, so the
methods of Melanoma diagnosis, including excisional biopsy, are still recommended
even in these instances. Additionally, moles can be removed by laser, surgery or
electrocautery.
In properly trained hands, some medical lasers are used to remove flat moles level
with the surface of the skin, as well as some raised moles. While laser treatment is
commonly offered and may require several appointments, other dermatologists think
lasers are not the best method for removing
moles because the laser only cauterizes or,
in certain cases, removes very superficial
levels of skin. Moles tend to go deeper into
the skin than non-invasive lasers can
penetrate. After a laser treatment a scab is
formed, which falls off about seven days
later, in contrast to surgery, where the
wound has to be sutured. A second concern
about the laser treatment is that if the lesion
is a melanoma, and was misdiagnosed as a
Fig: 3

9. 9
benign mole, the procedure might delay diagnosis. If the mole is incompletely
removed by the laser, and the pigmented lesion regrows, it might form a recurrent
nevus.[14]
Electrocautery (fig:4) is available as an alternative to laser cautery. Electrocautery is
a procedure that uses a light electrical current to burn moles, skin tags, and warts off
the skin. Electric currents are set to a level such that they only reach the outermost
layers of the skin, thus reducing the problem of scarring. Approximately 1-3
treatments may be needed to completely remove a mole. Typically, a local anesthetic
is applied to the treated skin area before beginning the mole removal procedure.[14]
For surgery, many dermatologic and plastic surgeons first use a freezing solution,
usually liquid nitrogen, on a raised mole and then shave it away with a scalpel. If the
surgeon opts for the shaving method, he or she usually
also cauterizes the stump.[15]
Because a circle is difficult to close with stitches,
the incision is usually elliptical or eye-shaped. However, freezing should not be done
to a nevus suspected to be a melanoma, as the ice crystals can cause pathological
changes called "freezing artifacts" which might interfere with the diagnosis of the
melanoma.[15]
 Mole removal risks[16]
Mole removal[30]
risks mainly depend on the type of mole removal method the patient
undergoes. First, mole removal may be followed by some discomfort that can be
relieved with pain medication. Second, there is a risk that a scab will form or that
redness will occur. However, such scabs and redness usually heal within one or two
weeks. Third, as in other surgeries, there is also risk of infection or an anesthetic
allergy or even nerve damage. Lastly, the mole removal may imply an
uncomfortable scar depending on the mole size.[16]
Fig: 4

10. 10
2) Melanocytic tumors of uncertain
malignant potential:
are melanocytic lesions in the dermis that cannot be classified by morphology as
either benign naevi (moles) or malignant melanomasbecause the mass shows features
of both.
Several lesion types may be classified as MELTUMPs: these include atypical
melanocytic proliferations with features that may overlap with atypical Spitz
naevi/tumors, dysplastic naevi, pigmented epithelioid melanocytoma, deep
penetrating naevi, congenital neavi, cellular nodules in congenital naevi, possible
naevoid melanomas, and cellular blue naevi.[18][19]
A related category of melanocytic proliferation is superficial atypical melanocytic
proliferations of uncertain significance (SAMPUS). This category, unlike MELTUMP,
which implies as yet undetermined potential for metastases even after complete
excision, signifies lesions without metastatic potential at time of excision but with
potential to progress upon incomplete excision. The SAMPUS category includes
certain atypical junctional melanocytic proliferations and proliferations in both
the epidermis and papillary dermis that are not accompanied by intradermal
tumorigenic architecture or cell mitosis.[18]
Fig: 5

11. 11
3) Melanoma
Malignant melanoma in children and adolescents is a rare disease; nevertheless it is
the most common type of skin cancer in this age group. Only 1–4% of all the
cutaneous malignant melanoma in the population consists of patients younger than
20 years. Pediatric melanoma is generally defined as melanoma occurring in the age
from birth until the age of 21 years of age. According to the age melanoma is divided
into four groups[20]
:
1. congenital melanoma ( diagnosed in utero prenatally and at the birth)
2. neonatal/infantile melanoma (from the birth to 1 year of the age)
3. pediatric melanoma (from 1 year to 13 years)
4. adolescent melanoma ( from 13 to 21 years)
Epidemiology[21]
Malignant melanoma is among the tumors with fastest rising incidence of tumors and
occurrence is shifted to younger age groups.
For children under 15 years is an annual melanoma incidence increase of about 1%
per year, in adolescents 7% a year and in young adults up to 24 years the annual
incidence increase is of 12%.
According to the WHO definition for rare tumors (incidence less than 5 : 100 000)
include melanoma in children below 12 years of a rare cancer, but melanoma in
adolescents has not.
In adolescents is a significant predominance of melanoma in girls with predominant
localization on the upper and lower extremities and trunk.
For children under 5 years of age, melanoma is more common in boys, in which
dominates the appearance of the head and neck.
Etiology[22]
The causes of cutaneous malignant melanoma in children are mostly unknown. More
vulnerable are the children of low skin phototype (white skin, freckles, blond or red
hair). Malignant transformation may occur spontaneously. Several risk factors may
be associated with melanoma development.
1. ultraviolet solar radiation: is the best known risk factor for cutaneous
malignant melanoma due to genotoxic effect of UV rays. More than a
cumulative dose applies to the quantity and size of the intermittent sunbathing.
Most at risk are individuals with skin phototype I and II. Child's skin is more
sensitive to UV radiation, it is thinner than adult skin and can therefore be
considered a risk phototype. For these reasons, infants under 6 months of age
not to be exposed to UV solar radiation. Older children should use a suncream
with a high UV filter.

12. 12
2. familial occurrence of pediatric melanomas is expected in a case with positive
family history and age <6 years of the child. Familial melanomas are autosomal
dominant with incomplete penetrance, occur at younger age. 10-25% of familial
melanomas demonstrated germline mutations in the genes CDKN2A (cyclin
dependent kinase inhibitor 2A) or CDK4 (cyclin dependent kinase 4).
3. pigmented nevi: there is a wide spectrum of pigmented skin nevi in childhood,
undergoing constantly changes in size, color and surface from birth to puberty.
o Intradermal nevi without breaking the junctional zone are the most
common. In the course of life are fixed with no risk of malignant
transformation, and they should not be removed. Excision is indicated only
in a case of traumatized nevus.
o Juvenile Spitz nevus is a special form of nevus occurs in children aged 3-13
years, arises from normal skin. It is hemispheric, rigid, smooth with a
relatively fast growth (2-3 months). A typical Spitz nevus does not pose any
risk, but there are also atypical Spitz nevi and malignant or transitional
forms. The distinction between atypical Spitz nevus and spitzoid malignant
melanoma is difficult.
4. genetic factors: some hereditary disorders associated with high risk of
melanoma
o Xeroderma pigmentosum is autosomal recessive hereditary disease
characterized by excessive photosensitivity to ultraviolet radiation. Multiple
skin tumors and melanomas are frequent in young age. Median of
melanoma occurrence is 19 years typically localised on the head and neck.
o germinal mutation RB1 gene is associated with higher risk of skin
melanoma
o Werner syndrome is autosomal recessive hereditary syndrome cause by
mutation of WRN gene. Characterized is by unusual localization of
melanoma (nasal cavity, sole of the foot)
o Dysplastic nevi syndrome is je autosomal dominant hereditary disorder
characterized by dozens of skin dysplastic nevi (50 and more) and/or 5 and
more atypical melanocytic nevi and melanoma in family history.
o neurocutaneous melanosis is rare disease characterized by large congenital
melanocytic nevus (> 9cm) or multiple congenital nevi (>3) and
leptomeningeal proliferation of melanocytes. Neurology symptoms occur
within 2 years of the age. Leptomeningeal melanoma with poor prognosis
develops in 64% of patients.
o Li Fraumeni syndrom is autosomal dominant hereditary syndrome, cause
by mutation of tumor suppressor gene TP53 (17p13). Patients are at high
risk to develop different types of malignancies including melanoma.
5. immunodeficiency: patients with congenital immunodeficiency, childhood
cancer survivors or patients on immunosuppressive therapy due to organ
transplantation are 2 – 6 times higher risk of developing melanoma
Most malignant melanomas in prepubertal children and adolescents arises de novo in
healthy individuals who have any of these risk factors.

13. 13
Clinical presentation and symptoms[23]
Clinical symptoms of melanoma are non-specific and there are a number of skin
lesions in children that may mimic malignant melanoma (benign nevi, dysplastic
nevi, atypical blue nevus, hemangioma, pyogenic granuloma, verrucas, Spitz nevus
etc.). Prepubertal melanoma has not always typical appearsance of melanoma, as is
known from the adult oncology.
In preexisting pigmented skin affections the most common symptoms of melanoma
are known ABCDE criteria. These criteria pediatric melanoma may not always apply
and can sometimes be misleading. Benign nevi can grow with the child and is
increasing, while at the same time healthy skin may appear a tiny little melanoma.
Conversely, a dark pigmented nevus, which has a child from birth, it can vary in its
deeper parts change and melanoma may be visible on the surface.
Local symptoms: ABCD criteria for preexisting nevus. Itching, tingling,
enlargement of nevus, ulceration, bleeding.
Systemic symptoms: are caused by metastatic spread (anorexia, weight loss,
unexplained fever, lymphadenopathy, caugh, hepatosplenomegaly.
Diagnosis pediatric melanoma, even when appearance of clinical symptoms (itching,
tingling, a gradual rise or ulceration) is often unexpected and surprising.
 Diagnostic procedures[24]
Diagnosis of pediatric melanoma is arduous due to the rare occurrence, the absence
of well-known risk factors, atypical presentation and many other skin nevi. In
comparison with the adult population have melanoma in children and patients under
20 years of age usually greater size and thickness.
Nearly 80% of pediatric patients are diagnosed with localized disease. The lymph
nodes is demonstrated in 15-30% of patients, and less than 5% of patients have
distant metastases at the time of diagnosis.
Clinical examination: for correct diagnosis is mandatory a detailed examination of
the entire skin surface including the scalp
and photodocumentation of all suspicious
lesions. Dermatoscopic examination of
suspected lesion is crucial.

14. 14
Imaging studies and laboratory tests for
pediatric melanoma do not differ from
the examination of adult patients.
Imaging studies are focused not only on
locoregional extent of disease, but also
to detect metastatic disease. Extent of
locoregional disease is crucial for
further treatment. Whole-body 18FDG
PET examination significantly
contributed to a more accurate
diagnosis in fusion with CT scans.
Histopathology of pediatric
melanoma: pediatric melanocytic
tumors should be divided in to 3 categories:
1. conventional skin melanoma
2. melanoma origin from the large congenital melanocytic nevus (risk of
transformation to melanoma is 5–10% usually within the first 10 years of the
life
3. spectrum of spitzoid melanocytic tumors:
o typical (benign) Spitz nevus
o atypical Spitz nevus
o MELTUMP
o spitzoid melanoma
Definitive diagnosis of melanoma is in the hands of pathologist and molecular
biologist.
Histopathology report evaluates:
 type of melanoma (nodular, superficially spread melanoma, lentigo maligna or
acrolentiginous melanoma). For pediatric age is typical nodular or superficially
spread melanoma
Fig: 6
Fig: 8
Fig: 7

15. 15
 safe surgical margins ( at least 0.5–1 cm)
 thickness (Breslow), microscopic invasion according to Clark
 ulceration, lymphangioinvasion, microsatellites
 tumor microenvironment ( tumor infiltrating lymphocytes CD8, CD4, CD3,
macrophages, microvascular density, PD-L1 expression) is important for decision
regarding immunotherapy
Molecular genetic examination: Malignant melanoma is a tumor with the broadest
spectrum of signaling pathways mutations. Molecular genetic factors influencing the
biological behavior of melanoma in different age groups. Typical genetic mutations
described for melanoma are germline mutations CDKN2A gene, RB1 gene, CDK4
and MC1R (melanocortin-1 receptor) gene, TP53 and somatic mutations of BRAF,
RAS, KIT.
Molecular genetic examination is important for:
1. exact diagnosis of pediatric melanoma: biological studies can help in the
differential diagnosis of melanocytic lesions and spitzoid forms of melanoma in
a case of unclear histopathological examination
2. to determinate the exact origin of pediatric melanoma:
o total absence of B-RAF mutation in spitzoid lesions contrasts with the high
incidence of this mutation in conventional melanoma (53–80%)
and melanocytic nevi (25 - 50%). This fact also supports the theory of a
different developmental path of spitzoid lesions.
o NRAS mutations occur in adult melanoma in 15–20% . In children are
more frequent in melanoma origin from congenital melanocytic nevus
3. to determine use of targeted therapy for advanced melanoma.

16. 16
Treatment[25]
Treatment of pediatric MM is built on the experience of treatment of melanoma in
the adult population and is not different from guidelines recommended in adult
oncology. Challenge in pediatric oncology is almost absolute lack of pediatric clinical
studies and the lack of any reduction in the age limit for enrollment to adult studies.
Surgery[26]
Localized melanoma is surgical disease and radical surgery with safe margins is
treatment of choice.
Thickness of primary melanoma lesion determinates the width of safe margins (for
melanoma thickness <2 mm safe margin is 1cm, for thickness of > 2 mm is safe
margin 2 cm). These principles apply to all ages.
Resection of sentinel lymph node in children is realized for melanoma with thickness
below 1 cm, if the surface is ulcerated and melanoma with high proliferative activity
For spitzoid melanocytic lesions surgical guidelines are similar or same as for
melanoma
In a case of positive sentinel lymph node dissection of regional lymph nodes is
recommended
Chemotherapy[26]
Malignant melanoma is considered to be a chemoresistant tumor and the role of
chemotherapy is limited.
Monotherapy (dacarbazine) historically reached overall therapeutic response in less
than 20% of patients with no effect to overall survival.
Combination of chemotherapeutic agents (combination DTIC + VBL or DTIC +
Cisplatina) reach response rate only in 10–20%, of patients. Duration of response do
not exceed 4–6 months
For advanced pediatric melanoma temozolomide was under clinical
study.
 Targeted biology therapy
Identification of specific oncogenic mutations leads to the development of targeted
biology therapy.
The most frequent mutation (positive in > 55%) in conventional melanoma is BRAF
V600E mutation. Specific monoclonal antibodies (vemurafenib, dabrafenib) are
approved for advanced melanoma since 2011. Antibodies demonstrated in a
randomized trial of advanced melanomas significantly longer survival (84% vs.
64%). Currently there is only one pediatric clinical trial with vemurafenib for
children with advanced melanoma, lower age limit is 12 years.

17. 17
Sorafenib, multikinase inhibitor (BRAF,CRAF,VEGF and PDGF) has been tested in
adult oncology, but no studies were realized for pediatric population.
Immunotherapy
Interferon alfa: is the longest used method of immunotherapy for stage III melanoma.
It has been a standard treatment of adult melanoma for years, but with limited
effect. The overall response rate was around 15 - 20%. According to current
guidelines of COG (Children's Oncology Group) it is still considered the standard
method of treatment for advanced pediatric melanoma
Interleukin 2 was used for metastatic melanoma with response rate 10–20%. Its
utilization for pediatric patients limited poor tolerance and severe toxicity.
Tumor vaccines were assumed to increase immunological detection of tumor cells and
strengthen the anti-tumor immune response. Different types of vaccines have been
tested (anti-idiotypic vaccines, DNA vaccines, dendritic cells). Their preparation is
required highly individual approach, financial demands and strict laboratory
conditions. In pediatric oncology vaccines are not yet a part of standard therapy.
Immune checkpoint inhibitors:
Ipilimumab (human anti CTLA4 antibody, CTLA-4 = cytotoxic T lymphocyte-
associated antigen 4) showed in a prospective randomized study significant
prolongation of life in metastatic melanoma. Its use in pediatric oncology have been
delayed nearly 4 years, currently four pediatric clinical studies have been open for
pediatric advanced melanoma.
Anti PD-1 monoclonal antibody (nivolumab, pembrolizumab) are humanized
monoclonal antibodies against receptor PD-1 (programmed death receptor).
Prognosis and outcome[27]
Prognosis of pediatric malignant melanoma is difficult to predict. Extent of disease
(clinical stage) is an independent prognostic factor regardless of age.
Negative prognostic factors in children are:
 clinical factors:
o age (infantile melanoma and age > 10 years)
o central localization (head and neck, trunk)
 pathology factors:
 type of melanoma (nodular melanoma, amelanotic melanoma)
 thickness (Breslow)
 ulceration, lymphovascular invasion
 high proliferative aktivity (high Ki67 index)
 positive sentinel lymph node
 negative BRAF mutation

18. 18
 biology factors:
10-year overall survival:
 stage 1 is 94%
 stage 2 is 79%
 stage 3 is 77%
 stage 4 is less than 10%
Figure (9)

19. 19
Conjunctiva's
Melanocytic tumors
Conjunctival melanocytic tumors comprise benign and malignant neoplasms. Nevi
are congenital benign melanocytic tumors that can be further classified into
junctional, subepithelial, compound, and blue nevus as well as congenital
melanocytosis. In the text, the term “nevus” refers to the most common form of nevi,
the compound nevus (a nevus with a junctional and a subepithelial component). For
further information regarding blue nevus, congenital melanocytosis, and other kinds
of nevi ophthalmological textbooks are recommended. Primary acquired melanosis
(PAM) can either be regarded as benign (PAM without atypia) or represent a
precancerous lesion (PAM with atypia), whereas a melanoma is per definition a
malignant melanocytic tumor[28]
.
Patients usually present for an eye examination when they recognize a new or growth
of a preexisting lesion.
The clinical diagnostic process comprises slit lamp and fundus examination,
sonography or anterior segment OCT (if necessary), and photo-documentation.
Conjunctival melanocytic lesions can appear pigmented (brown), tan, or non-
pigmented.
Nevi (Fig:11) exhibit usually cysts (that can be detected on slit lamp examination and
with sonography/anterior segment OCT) and are
reported by the patient to exist for a long time (as
they are congenital).
usually occurs in middle-aged individuals
(mostly Caucasians). The lesions appear
pigmented, are usually unilateral, and may
become thickened over time. Biopsy is
recommended to define the appropriate
treatment strategy dependent on the
histological picture and the extent of the
disease (fig:11).
Conjunctival melanomas may arise from
PAM (most common) (fig:12), nevi, or de
novo. Increased vascularity and adherence to
the underlying sclera may be present.
Melanomas are like PAM more frequently
observed in Caucasians and exhibit a nodular
or diffuse growth. Suspicious lesions have to
Fig: 10
Fig: 11

20. 20
be completely excised and submitted for
histopathological investigation. Once the
diagnosis is confirmed, systemic work-up is
required.
Inspection of all ocular structures is
mandatory as multicentric lesions can occur,
especially if associated with PAM. Lesions
consisting of PAM and melanoma are also not
uncommon (especially as a melanoma can
arise in PAM), thus all suspicious lesions have
to be excised and submitted for histopathological investigation[29]
.
Nevi may be excised when growth or change in color is noted. These changes do not
necessarily - but can - indicate the development of a melanoma as hormonal changes,
inflammation or even growth of the mucinous inclusion cysts can be mostly accused
for these changes. In most cases nevi can just be followed including photo-
documentation.
Lesions suspicious for PAM should be carefully biopsied (incisional, excisional, or
map biopsy using a “dry” technique) allowing for histological examination.
Dependent on the clinical impression, the surgical margins can be treated with
cryotherapy. Treatment with topical mitomycin or interferon alpha 2b can be
considered for histology-proven PAM with atypia including residual lesions - but
only for lesions confined to the epithelium as these local treatment strategies are not
proper for melanomas[30]
.
Malignant melanomas should be completely excised using “no touch” techniques.
Extensive resection may be required. Adjunctive cryotherapy and additional
treatment (e.g. brachytherapy) can be also employed. Sentinel lymph node biopsy
should be considered for lesions thicker than 2 mm (Breslow equivalent) [30]
.
Fig: 12

21. 21
The Summary
Finally, I have done the research. I hope you take a benefit from this report and
know clearly what are Melanocytes tumors.
Melanocytes tumors are three types:
1. Nevus
2. Melanoma
3. Melanocytic tumor of uncertain malignant potential
The first one is benign and have little damage to the skin or eyes. The second one is
very damaging the body and can be metastasized. The last one is between them.
The treatment is not always success because it is a cancer and can go throughout the
whole body so the best therapy is chemotherapy and stem cells which are under
examination till now.
The diagnosis' ways are very wide and can give us a clear photos for the case without
problem of risks.
The signs and symptoms are varied among the three types but are shared in some.
The prognosis is very high on the world and the percentage is increasing yeas after
years.

22. 22
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