Ophthalmic Pathology Potpourri
Moderators: Dr. Miguel Burnier and Dr. Alexandre Nakao Odashiro
Section 3 -
Alexandre Nakao Odashiro
Lac – Pathology Laboratory
Campo Grande , MS ,
Universidade para o Desenvolvimento do Estado e Região do
Pantanal – UNIDERP
Campo Grande, MS, Brazil
The retina has two functions. The first, performed by the rod and cone photoreceptors, is to
transduce information from an optical image into electrical signals. The second, performed by the neural
circuits of the retina, is to process certain features of the visual world from the photoreceptor signals
and relay this information to the brain via the optic nerve (Rodieck, 1973).
The sensory retina is composed of layers: 1.layer of the photoreceptors of the rods and cones.
2.external limiting membrane. 3.outer nuclear layer. 4.outer plexiform layer. 5.inner nuclear layer.
6.inner plexiform layer. 7.ganglion cell layer. 8.never fiber layer. 9.internal limiting membrane.
It is beyond the scope of this handout to describe the functional role of the retina.
The retinal pigment epithelium (RPE) is a monolayer of cells extending from the optic disc to the ora
serrata, where it is continuous with the pigmented epithelium of the ciliary body. The RPE cells are
essential for photoreceptor health and have several other functions, including vitamin A metabolism,
phagocytosis,, light absorption, heat exchange, and active transport of materials between the
choriocapillare and the subretinal space (Duane, 1994).
RB is the most common intraocular malignancy of childhood, and the incidence is about 1:15.000 to
1:30.000 live births. There are no differences in incidence by sex, race, or right versus left eye. The
mean age of diagnosis is 18 months. RB in adults is extremely rare (Odashiro et al., 2005) .
Knudson (Knudson, 1971) proposed the two hit model after noting the differences in tumor development in
patients with unilateral versus bilateral disease. RB requires 2 complementary tumor inducing genetic
events. The first event for a genetic-induced RB is a germinal or inherited mutation, therefore,
genetic-induced RB requires only one more tumor-inducing event. It represents 1/3 of the cases, is
transmitted as an autosomal dominant trait, and the tumor is frequently bilateral. Non genetic-induced
(sporadic) RB, however, requires 2 tumor-inducing events, represents 2/3 of the cases, is caused by
somatic mutations and is not transmissible.
Retinoblastoma gene : the well-known RB gene is a tumor suppressor
gene, located on the region q14 of the chromosome 13. The gene also encodes the Esterase D, an enzyme
responsible for radiation repair.
|Diagnosed earlier ||Diagnosed later|
|Bilateral or Unilateral ||Unilateral|
|Chromosomal abnormality from germinal mutation or inherited ||Chromosomal abnormality from somatic mutation|
|Offspring affected ||Offspring normal|
|Risk of other malignancies ||No increased risk of other malignancies|
: initially RB presents as a small and transparent mass that gradually becomes more opaque. More
advanced tumors present as an elevated dome-shaped white retinal mass. Leukocoria (white eye) can occur
early or late, and is a clinical characteristic of the tumor.
Growth patterns: the endophytic growth pattern can simulate
endophthalmitis; the exophytic growth pattern can simulate Coat's disease, and there is the
diffuse-infiltrating pattern. Some cases of spontaneous regression have been documented, and it is
believed that it occurs more frequently in RB than in other malignant neoplasm. Ultrasound is very helpful for diagnosis and characteristically shows
Histopathological findings: small, round,
blue, neuroblastic cells compose the tumor. Rosettes are characteristic features:
the Flexner-Wintersteiner rosettes, observed in well- differentiated tumors, are lined by tall cuboidal
cells that circumscribe an apical lumen. In the Homer-Wright
rosettes, that are less specific for RB, cells are not
arranged around a lumen but instead send out cytoplasmatic process that form a tangle within the center
of the rosette. Fleurettes are photoreceptor
differentiation observed in well-differentiated tumors. Areas of necrosis and calcifications are
commonlly observed. Vascular cuffs are spheroid aggregates of viable tumor cells around vessels, with
peripheral necrosis (Burnier et al., 1990).
Demirci et al studied enucleated eyes previously treated with
chemotherapy (Demirci et al., 2003). Histopathologic examination of 10 enucleatedeyes
following chemoreduction alone revealed that the main retinoblastomaregressed in all eyes.
Calcified glialscar and an apical calcified glial scar with a basalresidual
well-differentiated component with retinomalike and/orretinocytomalike features were the main
findings. Fociof mitotically active, viable-appearing malignant retinoblastoma
cells can be present and should be reported. Despite the lack of viable-appearing
retinoblastomawithin the main tumor, enucleation was performed for viable
subretinal and/or vitreous seeds in 7 cases and confirmed histopathologically.
: tumor extension through the optic nerve is the most important histopathological prognostic
factor, when enucleation is performed. The optic nerve is the main route for retinoblastoma to produce
extraocular extension and metastasize. Massive choroidal extension is also a prognostic factor.
The presence of tumor beyond the lamina cribrosa is a risk factorfor metastatic disease,
and although the choroidal invasionhas been considered an important risk factor for
metastaticdisease because it allows for access to sclera and emissaryvessels, it
is not clear whether choroidal invasion alone necessitatesthe use of systemic chemotherapy
(Finger et al., 2002).
Lungs, bones and brain are the main sites of metastases. Metastases usually occur 1-2 years after
the treatment. Later metastases are so rare that should raise the possibility of a new independent
Trilateral retinoblastoma (TRb) is
represented by a bilateral retinoblastoma plus pinealoblastoma or parasellar tumor. It occurs in the
first 3 years of life, and is often a fatal tumor. Marcus et al (Marcus et
al., 1998) evaluated the histopathologic findings, clinical features, treatment modalities, and survival
rates from 80 cases of RB with intracranial tumors. Histopathologic findings from intracranial
malignancies demonstrated primitive neuroectodermal tumors in 61.5% of cases. Various degrees of
neuronal or photoreceptor differentiation were seen in the other 38.5% of cases. The findings suggest
that more likely arises from a germinal layer of predisposed primitive subependymal neuroblasts that are
not necessarily destined for pineal or photoreceptor differentiation. TRb is usually fatal, with an
average survival time of 11.2 months. Therapies include radiation, systemic chemotherapy, intrathecal
chemotherapy, and surgical resection/craniotomy in combination with radiation and/or chemotherapy.
Survival may be prolonged with combination chemotherapy (24.6 months) and if neuroradiologic screening
identifies TRb before symptoms are present (23.5 months). Recent success with platinum-based
chemoreduction of intraocular retinoblastoma may indicate a similar role for platinum-based chemotherapy
in the treatment of TRb. Routine central nervous system imaging should be considered in the management
Treatment: treatment for retinoblastoma has
changed in the past few years. Enucleation is reserved for selected cases and conservative forms of
treatment have gained popularity. Such measures include external beam irradiation, episcleral plaque
brachytherapy, cryotherapy, laser photocoagulation, and chemotherapy.
In an attempt to preserve vision and avoid enucleation and thecomplications associated
with external beam radiation therapy, new drug regimens were developed,and chemotherapy is
currently considered to be an importantmodality for the treatment of Rb. Chemotherapeutic
drugsinduce tumor regression and therefore allow for focal treatmentssuch as
photocoagulation, thermotherapy, and cryotherapy. However, intraocular or local Rb recurrence continues
to bea major problem, even with the use of multidrug regimens. Local tumor recurrence in
such cases could suggest a lack ofresponse to chemotherapy also known as tumor resistance
(Filho et al., 2005).
A recent publication described the histopathological featuresof Rb treated with
chemotherapy and observed that several tumorsshowed residual areas of well-differentiated
cells (Demirci et al., 2003). RB recurrence after chemotherapy continues to be a major problem, even
with the use of multidrug regimens. Tumor recurrence in such cases suggests inherent insensivity of RB
to chemotherapy (Souza Filho et al., 2005) .
Overall, the 3-year follow-up survival in the USA is about 90% (Filho et al., 2005). Genetic counseling for families of retinoblastoma patients is complex and
Secondary tumors can develop in patients with
genetically induced RB, due to the esterase D defect. The most common are osteogenic sarcomas of the
skull and long bones, soft tissue sarcomas, pinealoblastomas, cutaneous melanomas, brain tumors,
Hodgkin's disease, lung and breast cancer.
Differential diagnosis : the clinical
differential diagnosis includes other causes of leukocoria such as toxocariasis, coats disease,
persistent hyperplastic primary vitreous, and retinopathy of prematurity. The most important
histopathological differential diagnosis is Medulloepithelioma (see below).
Important feature to the diagnosis is the highly malignant small blue cells with
irregular chromatin and several mitotic figures.
Tumors of the Ciliary Epithelium
Primary tumors of the pigmented or non-pigmented ciliary epithelium arerare. Zimmerman
proposed dividing these tumours into two classes — congenital (embryonic)and acquired
(non-embryonic). Congenital tumours arise in the embryonic or earlypostnatal period, and
include medulloepithelioma and glioneuromas.The acquired tumours are seen in adulthood and
include Fuch'sadenoma, adenoma, and adenocarcinoma (McLean et al., 1994).
Intraocular medulloepithelioma is a rare embryonal neoplasmthat occurs predominantly in
children and arises from the primitivemedullary epithelium of the optic cup.
Medulloepitheliomas thatcontain heterotopic elements or tissues such as brain,
cartilage,or rhabdomyoblasts are classified as teratoid, and tumors lackingthese
elements are classified as nonteratoid medulloepitheliomas.Both nonteratoid and teratoid
medulloepitheliomas may be benignor malignant.
Clinically and histopathologically the tumor shows cystic areas intermixed with solid areas in the
ciliary body area.
The histopathological criteriafor malignancy includes the presence of poorly
differentiatedneuroblastic cells, numerous mitoses, pronounced pleomorphism,
sarcomatous areas, or invasion of other ocular structures withor without extraocular
extension (Font & Rishi, 2005). Different from RB, the neuroblastic cells of the medulloepitheliomas
are elongated with a fusiform nuclei.
Adenoma and Carcinoma of the Ciliary Epithelium
These are rare tumors. As Medulloepitheliomas, they are also tumors of the ciliary epithelium and
can be benign (adenoma) or malignant (adenocarcinoma). However, they are acquiredlesions
that occur after embryonic development, in adult patients.
Primary Retinal Lymphoma (PRL)
PRL is a non-Hodgkin large B cell lymphoma (high grade) also called non-Hodgkin's lymphoma of the
central nervous system (Whitcup et al., 1993). It represents 1% of all lymphomas and may involve the
retina, vitreous, optic nerve and central nervous system. It occurs in elderly patients that may have a
misdiagnosis of chronic uveitis for a long period. Immunocompromised patients, especially AIDS patients,
have a high-risk predisposition for this tumor. Vitreous aspiration biopsy and cytological examination
can establish the diagnosis (Lopez et al., 1991). Prognosis is generally poor.
Other Retinal Tumors
Other retinal tumors include astrocytic tumors like astrocytomas and vascular tumors.
Vascular tumors: the retinal capillary hemangioma can be present in the von Hippel-Lindau syndrome;
the cavernous hemangioma is a rare congenital malformation.
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