REV.CHIM.(Bucharest) 67No. 8 2016 http:www.revistadechimie.ro 1641Malignant Tumors of the Eyeball and its Appendixes [615924]

REV.CHIM.(Bucharest) ♦67♦No. 8 ♦2016 http://www.revistadechimie.ro 1641Malignant Tumors of the Eyeball and its Appendixes
CARMEN TIUTIUCA1, DRAGOS VOICU1*, ISABELLA BRUJBU2, LUANA MACOVEI2, CORINA CUPILAN3, CAMELIA BOGDANICI4,
VIRGIL BULIMAR2
1 Dunarea de jos University of Galati. Faculty of Medicine and Pharmacy, 47, Domneasca Str., 800008, Galati, Romania
2 Gr. T. Popa University of Medicine and Pharmacy, F aculty of Medicine, 16 Universitatii Str., 700115, Iasi, Romania
3 Gr. T. Popa University of Medicine and Pharmacy, Faculty of Medicine, Department of Anatomy, 16 Universitatii Str., 700115, Ia si,
Romania
4 Gr. T. Popa University of Medicine and Pharmacy, F aculty of Medicine, Department of Surgery II, 16 Universitatii Str., 700115, Iasi,
Romania
In pathology of tumors, there are several reasons in favour of immunology. Spontaneous regressions of
malignant tumors and their metastases have been reported, as well as an increased incidence of neoplasia
in immunodepression (in subjects who suffered a renal transplantation, the incidence of neoplasms is 5%,
compared to 0.05% in general population). One of the main functions of the immunity system in neoplastic
pathology consists of detection and purging of the new tumoral cells. The paradox of the immunology is that
often the immunity system favours the tumoral development rather than inhibit it. One of the possible
explanations is the absence or the very low titre of the tumoral antigens (which would “escape” the
immunocompetence), contrary to experimental data. Histologically, we noticed the abundance of
lymphocytes and inflammatory cells around and inside the tumor. Similar to malignant tumors of other
organs and tissues within the body, the malignant tumors of the eye and its appendages must be early
detected and rapidly approached. This is a well-known fact, especially since everyone agrees on the fact that
antitumor therapy is generally relatively effective and the early surgical intervention is the only way to
effectively resolve tumors, supplemented by chemotherapy, radiation and non-specific immunotherapy.
Keywords: orbital tumors, exophtalmos, treatment protocol, enucleation.
Malignant tumors of the eye and its appendages can be
classified, considering certain particularities, as:
·Tumors of epithelial origin (epithelioma). Epithelioma
is a superficial neoformation with a tendency to ulcerate,
neighbouring destructions and superinfections withadenopathy after superinfections, rarely with metastases;
·
Tumors of connective origin (sarcoma), neoformations
with a rapidly expanding evolution, with a high metastaticpotential (local, regional and general metastases). They
can be made of fusiform, globus or polymorphic cells. It is
remarkable that every organ forms its own type of sarcoma,depending on its own connective tissue: myosarcoma,
osteosarcoma, reticulosarcoma, retinoblastoma –
retinocytoma (derived from the visual cell, not having aconnective origin, as initially thought). In general, the term
blastoma is used for tumors developed from precursor
cells (blast cells), therefore with a very high potential forproliferations, but also very sensitive to therapy with
physical agents (radium, cobalt, and especially betatron –
generated high energy electrons).
·
Pigmented tumors (malignant melanomas). Once
considered as epetheliomatous, sarcomatous or mixed
type, nowadays regarded as a particular variant of sarcoma,with the stem cell formed by melanoblast, therefore an
extremely malignant variant of tumors.
Malignant tumors of the appendages
Malignant tumors of the eyelids and conjunctiva
Eyelids and conjunctiva may develop all three types of
malignant tumors: malignant epithelioma, sarcoma, and
melanoma (fig.1).
Epithelioma of the eyelids involves the cutaneous layers;
it is the most frequent malignant tumor in ophthalmology.
Histopathologically speaking, it is classified as basal cell
and squamous cell epithelioma.Basal cell epithelioma clinically presents in ulcerous,
papillomatous form, or as a so-called scarring plane
epithelioma.
Ulcerated epithelioma presents as a profound cutaneous
ulceration, hardened at the base, with a tendency to heal
on one side and extend on the other side (it spreads itself
like prairie fire ).
The treatment of noninfiltrating epitheliomas which are
not prone to metastases is based on the plain resection
with the scalpel or the laser scalpel with CO2, followed by
the suture. Epitheliomas in general, especially the small
ones, are sensitive to contact radiotherapy.
A particular form of this tumor is epithelioma terebrans,
which spreads itself in depth, rather than in surface, being
able to propagate on the eyeball and the orbit. The palpebral
ulceration is always covered by dirty gray tissue detrituses.Despite its evolution, the ulcerated epithelioma does not
develop remote metastases; it might involve the ganglia a
result of suprainfection, therefore satellite adenopathy, butit doesn’t develop ganglionic metastase.
Papillomatous epithelioma presents as a small
papilloma with a hardened base, sometimes pigmented;its evolution is much slower than the evolution of the
ulcerated form. If treated as a plain wart and destroyed by
diathermy, it relapses.
*Tel: (+40)336130109
Fig.1.
Basocellular
epithelioma of
the upper eyelid
– suture

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦67♦No. 8 ♦2016 1642Scarring plane epithelioma presents as a keratosis area,
surrounded by a reddish halo, hardened, with a tendency
to spontaneously heal and relapse.
Squamous cell epithelioma shows as a cutaneous
protuberance, hard during palpation, with a tendency to
spontaneously ulcerate and bleed. It evolves both on thesurface and in depth. The superinfection leads to pre-
auricular satellite adenopathy. Only the histopathologic
examination can definitely differentiate between this formand the basal cell epithelioma.
Conjunctival epithelioma is a rare tumor, mostly located
on the sclerocorneal limbus. The clinical appearanceconsists of papillomatous formations of 2-3 mm in
diameter, with a bleeding surface, possible pigmented. At
palpation, the formation feels hard. It evolves at the surface,being able to spread on the cornea and very rare, in depth.
Conjunctival epithelioma can rarely develop ganglionic
metastases (in pre-auricular or maxillary ganglia).
Palpebral sarcoma is a rare tumor that develops in
extreme ages, especially in young or old subjects. It arises
as a nodular formation of the upper eyelid, adherent totarsus and the overlying skin, prone to ulceration. It has a
high evolutionary potential, invading the bulbar conjunctiva
and spreading to the eyeball and orbit, developingmetastases via the blood. In the initial stage, it can be
easily mistaken for chalazion, while in chalazion, the skin
is free at the surface of the tumor. It differs from chalazionby the fact that the eyelid cannot be rolled on Desmarres
roller.
Conjunctival sarcoma is an extreme rare tumor, located
on the tarsal conjunctiva in the proximity of the cul-de-sac
with the appearance of small white-yellowish formation.
Melanic tumors of the eyelid are cutaneous pigmented
nevi which, in certain situations (traumas, surgical
interventions, inflammation without an obvious reason)
expand, become pruruginous, surround themselves by an
intensely vascularised halo and exulcerate; these are
symptoms of malignancy. Before ulceration, surgicalexeresis of at least 0.5 cm is indicated, either with electric
scalpel, or with laser scalpel with CO
2. Infiltration with local
anaesthesia is not recommended, due to the possibility ofdissemination of melanic cells. In case of lack of a larger
substance, replacement plasty is necessary. Melanoma is
radioresistant to X-Rays, but not to Cobalt or Radium; if theresult of anatomic-pathological examination is abnormal,
a nonspecific desensitising treatment with BCG vaccine
and cytostatic is used.
Treatment principles of palpebral cutaneous malignant
tumors
In mutilations after cancerous exeresis and the outer
half of the lower eyelid, the upper eyelid is dualized, by
suturing its tarsus in colobomatous area. Pediculated plastyfrom the upper eyelid, with excessive skin (fig.2).treated by tarsal-conjunctival and cutaneous plasty from
the opposite eyelid (fig.3).
In the exeresis of the inner half of the lower eyelid, after
the external release of the eyelid, there will be a completeplasty through gliding, obturating the initial coloboma.
There will be an external palpebral lack, which will beFig.2. Surgical
lower
paracantal
subtotal
coloboma
Fig.3. Surgical subtotal and inner coloboma of the lower eyelid
An original method when lacking the palpebral
substance consists of blepharoptosis by Teflonimplantation (fig.4).
Fig.4. 2/3 palpebral lack,
grasping the entire tarsus –
Teflon plasty dressed in upper
conjunctiva and pediculated
cutaneous plasty
Other types of plasty can be performed on the lower
eyelid or mixed – upper palpebral translation towards the
middle and pediculated plasty on the opposite eyelid,entirely, completing the remaining upper coloboma (fig.5).
Fig.5. Revealed
coloboma, total
post-exeresis in
the middle area ofthe upper eyelid –
graft of the lower
eyelid towards
the upper
In bilateral ablepharia, reconstructive surgery is even
more urgent, since the eye with dehiscence is exposed to
dryness. That is why, after a protective conjunctival
movement of the eyeball, cutaneous plasty by sliding fromproximity or pediculated plasty are performed (fig.7).
Fig.6. Total mild degree
coloboma of the upper
eyelid; Esser-Abbe-
Mustarde method
Fig.7. Reconstruction of bilateral ablepharia (blepharoptosis) –
Teflon graft covered by cutaneous sliding from neighbouring area
after incision clearance and free upper eyebrow autograft; with
frontal pediculated flap.

REV.CHIM.(Bucharest) ♦67♦No. 8 ♦2016 http://www.revistadechimie.ro 1643Malignant melanoma of conjunctiva occurs by
malignant degeneration of conjunctival pigmented nevusor of a conjunctival melanosis. Malignization of a
pigmented
nevus consists of growth, signs of acute inflammation,intensified pigmentation
, and abnormal neovascularization.
The preferred localition of the melanoma of conjunctiva
is on the sclerocorneal limbus or on caruncle. The tumor
easily bleeds if touched. It has an extremely high evolutionpotential, with frequent metastases in liver and brain.
The tumors of conjunctiva and eyelids benefit from wide
surgical exeresis, in healthy tissue, preferable with electricscalpel to prevent the spread of tumor cells via
hematogenic path and then cutaneous grafts via sliding,
pediculated or free grafts. In eyelid plasty, with integrationof the inner angle, the cul-de-sac will be removed in the
same session, to prevent the breaking of the suture wires
by proximity suprainfection.
In case of corneal damage, besides the conjunctival
pasty, lamellar corneal homograft is practised. In advanced
stages with expansion to orbit of the proximity areas, oneneeds to cooperate with the ENT specialist, maxillofacial
surgeon and the neurosurgeon. If needed, also the
damaged ganglia can be removed.
After surgery, especially in melanic tumors, de-
sensitization with increasingly higher doses of BCG, and
immunostimulation with levasimole and even interferonare recommended.
Noli me tangere principle is applicable to all pigmented
formations of the eyelids or conjunctiva, as long as they donot show signs of activity and progress; in these situations,
one should monitor the lesion, intervening surgically only
in obvious signs of progress.
Malignant tumors of the lacrimal glands
Even if the tumors of the lacrimal glands are quite
frequent, only some of them are malignant. Clinically, the
tumors of the lacrimal glands show unilateral
exophtalmos, pushing the eyeball downwards and towardsthe inner side, and limiting the movement of the globe
upwards and on the outer side. Palpation of the
superexternal angle of the orbit is sensitive, painful and itshows a renitent or even hard formation. Other symptoms
are diplopia and excessive unilateral production of tears.
The diagnosis is complete by echography, orbitalscintigraphy, and computer tomodensitometry. From an
anatomopathological point of view, there are adenoid cystic
carcinoma, mucoepidermoid carcinoma, infiltrativecarcinoma and, rarely, lymphoreticular sarcoma. Sarcoma
shows acute inflammation.
The tumors of the lacrimal gland are easier approached
when they reach the palpebral area or by means of Kronlein
approach, when the orbital part is involved. The treatment
with cytostatics and immunostimulants is bothrecommended and useful, since the recurrences are quite
frequent.Tumors of the orbit
Tumors of the orbit have epithelial or conjunctival origin,
with a clear development towards sarcoma . The presence
of several tissues in the orbit – vessels, muscles, cellular
tissue – create the possibility to develop several types of
sarcoma: fibrosarcoma, myosarcoma, lymph sarcoma,osteosarcoma, etc.
The clinical picture of the intraorbital tumors overlaps
the clinical picture of
unilateral exophtalmos .Fig.8. Malignant
melanoma
Fig.9. Structure of
the orbit (f-frontal
bone, gs – great
wing of the
sphenoid bone,
ls – little wing of
the sphenoid bone,
p – palatine bone, m
– maxillary bone,
e – ethmoid bone)
Fig.10. Cross
section of the two
orbits
Fig.12. Orbital tomodensitometry
A – T.D.T scanner; B – image of the normal orbit – axial section; C-
frontal section of the eyes; D – retrobulbar frontal section Fig.11.
Topography of
the orbit –
Benedict
division
If the bilateral exophtalmos is usually the expression of
an endocrine disease – Graves’ disease and rarely the
expression of other diseases like lymphoma, leukemia,
scurvy – diseases which are easy to diagnose and whichdo not raise issues to the physician, it is caused by a wide
array of conditions, some of them extremely difficult to be
diagnosed and which need to be treated as emergencies.
Checking a patient with unilateral exophtalmos must
follow the scheme: complete anamnesis, thorough clinical,
ENT, maxillo-facial, and neurological examination, simpleradiography, and echography.
When there are suspicions of an orbital tumor, perform
tomodensitometry or NMR, orbital arteriography, orbitalphlebography, orbital scintigraphy, cutaneous
thermography.

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦67♦No. 8 ♦2016 1644The tumor shows tumoral exeresis with anatomo-
pathological examination and by scanning electron
microscopy. For malignant tumors, perform chemotherapy,radiation and immunotherapy (non-specific BCG
desensitization and immunostimulation with Levasimole).
The anamnesis of the patient suffering from unilateral
exophtalmos should monitor: onset circumstances;
presence or absence of the pain, changes in visual acuity
or visual field, presence or absence of diplopia, chronologyof the symptoms, progress of the exophtalmos (progressive
or remittent).
Attention should be paid to ocular-orbital or cranial
traumas, inflammatory or tumoral processes of the facial
sinuses, endocrine diseases (especially thyroid diseases),
and neurologic conditions.
In terms of therapy, cancer of the orbit asks for
neurosurgery, by means of a transfrontal flap.
The patients showing signs that lead to the suspicion of
a malignant tumor should be immediately referred to a
specialty service.
Malignant tumors of the eyeball
Malignant tumors of the eyeball include malignant
tumors of the retina, optic nerve and uvea. Unlike othertumors, intraocular tumors have a special status, given by
the particular structure of the eyeball, with its fibrous tunic,
sclera, which makes the programming of the tumordifficult and late. The extraocular propagation of the
intraocular tumor via lymphatic path is practically
neglectable, due to little lymph tissue within the eyeball.
Intraocular tumors can propagate via hematogenic path
or step by step. Situated inside the sclerotic coat, intraocular
tumors spread very late, step by step.
Sclera has three areas of minimal resistance: orbital
lamina, where the fibers of the optic nerve exit the eyeball;
the equatorial area, where the sclera is pierced by the four
vortex veins; the perilimbal area, with numerous piercing
vessels that make the anastomosis between the episcleralcirculation and the great irian circle.
For tumors situated in the neighbourhood of these places
of minimal resistance, the expansion risk is much higherthan for the ones located further.
As long as the macular area is not involved and the
patient is not alarmed by a poor vision, early detection ofthe intraocular tumors is extremely difficult.
Early detection of the extramacular tumor is completely
random, usually it happens only late, even whencomplications arise.
Malignancy of intraocular tumors (retinal, uveal, made
of very young cells, with an extremely high power ofproliferation) has a special status.
Malignant tumors of the retina
Retinoblastoma
Next to the uveal malignant melanoma, retinoblastoma
is the most frequent intraocular tumor of childhood.Heredity plays an important part in the onset of
retinoblastoma; most of the cases are or appear unilateral
and erratic.
The tumor arises in children with normal eyeballs, more
frequent in posterior pole. The typical pattern consists of
multiple burning points of variable sizes, sometimes alarger tumor surrounded by several smaller ones, probably
independent, in most of the cases.
It is believed that the disease is the result of the loss or
mutation of RB1 gene, a suppressor oncogene located in
chromosome 13q14. Genetics of retinoblastoma also
influences the therapy ways.When the tumor is larger, the clinical picture differs,
depending on the development type, leading to several
clinical forms: endophytic, exophytic, diffuse infiltrative,and combined forms.
Retinoblastoma has a heritable (40% cases) and a non-
heritable form (60%). Heritable cases imply mutations ofthe germinal line, while the non-heritable ones imply
somatic mutations.
Histologically, there are two types of retinoblastoma,
undifferentiated with cells with reduced cytoplasm and
hyperchromatic nuclei, and differentiated, with large cells,
with Flexner-Wintersteiner rosettes.
The indications of the clinical diagnosis of retino-
blastoma are: leukocoria (white pupillary reflex), amaurotic
cat’s eye, strabismus, secondary glaucoma, changes ofthe pupil or iris, hypopyon or hypema, and mydriasis.
Early diagnosis is crucial for an effective treatment, that
could preserve the vision as much as possible.
Pre-therapy studies in retinoblastoma should describe
the extension of intraocular tumor, the presence or absence
of orbital extension, as well as the presence or absence ofmetastatic disease.
The treatment is complex, depending on several factors.
It must be combined with the family’s genetic counsellor,as well as with early detection of new cases in families at
risk; it depends on the site, size and number of tumors,
laterality, histological form, association with other eyeconditions, age and heath of the child and her compliance
to treatment or the parents’ understanding of the treatment.
There are conservative treatment methods: external
radiotherapy, scleral plaque radiotherapy, laser
photocoagulation, thermotherapy, transscleral cryo-
coagulation, local chemotherapy, systemic chemotherapy,and genic therapy.
Enucleation is a radical treatment method used for
patients with extensive retinoblastoma.
Malignant tumors of the uvea
Involving the iris, ciliary body or choroid, malignant uveal
melanoma is the most frequent tumor; its preferred
location is the choroid, then the ciliary body and rarely, theiris.
Malignant iris melanoma is an emergency, since the
surgical intervention – sectorial iridectomy – performed intime leads to the preservation of the eyeball and the patient’s
survival, a favourable chance.
Malignant choroidal melanoma or choroidal mean-
sarcoma is the most frequent and severe tumor of the eye.
Angiography allows the differentiation of the melanoma
from the choroidal pigmented nevus, but it can hardlydifferentiate it from the appearance of the hemangioma.
Enucleation seems to be the best solution when
intraocular tumors are believed to be malignant.
Although choroidal metastases are rare, there are
certain forms of cancer, especially liver and breast
carcinoma, as well as uterine, and pulmonary cancer, whichlead quite frequently to choroidal metastases; they can be
bilateral or, more frequent, unilateral; but if the patients
survive, the cases with unilateral metastases usuallydevelop neoplastic buds also in the second eye.
Choroidal metastases are unique or multiple tumors,
preferably located in the posterior pole, in the proximity ofthe optic nerve papilla or at the inferonasal periphery of
the fundus. They are round or oval, with margins that are
difficult to define, and are little pigmented.
Their angifluorographic picture resembles the one or
primary melanoma. Almost always there is a certain
element, difficult to define, that differentiates a primitive

REV.CHIM.(Bucharest) ♦67♦No. 8 ♦2016 http://www.revistadechimie.ro 1645choroidal tumor from a choroidal metastase; alternating
the hyperfluoroscence phenomenon with hypo-
fluorescence reveals the kaleidoscope of choroidalmetastases. Investigations on the general health of the
body might guide the diagnosis towards a primitive tumor
of another organ with metastases in the eye.
Unlike the approach of a choroidal melanoma, in
metastatic tumors, enucleation is not indicated; perform
treatment with cytostatics, immunostimulants, eventuallyphysiotherapy, but the results are not encouraging due to
the reserved chances.
Conclusions
The main goal of the treatment of a tumor, regardless of
location or sometimes evolution, is to remove, as much aspossible, the entire tumor mass. To reach this goal,
advanced tumors need more complex and numerous
interventions.
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Manuscript received:20.01.2016