Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

4.Multinucleated tumor cells may be found in retinocytomas.

5.Very rarely, a retinocytoma may undergo malignant transformation.

C.Those areas that show photoreceptor di erentiation usually lack evidence of necrosis and show only occasional calcification.

1.Retinocytoma is most likely to be found in the inherited form, the mutation presumably taking place in a relatively mature retinoblast.

2.There may be an increased possibility of a second primary tumor following the development of retinoma.

D.Developing photoreceptors have apical adherens junctions, mitochondria-filled inner-segment regions, occa-

sional fragments of membranous outer segments, and cilia that contain a 9 + 0 tubular arrangement.

VI. Other histologic features

A.Most tumors show significant areas of necrosis (Fig.

18.10; see also Fig. 18.6).

1.Advanced necrotic retinoblastoma may present as orbital cellulitis.

2.Total necrosis may lead to spontaneous and complete regression in a shrunken, scarred, calcific eye—a rare occurrence.

3.After complete regression, the eye sometimes retains useful vision (Fig. 18.11).

4.The necrosis of the retinoblastoma may be caused by tumor ischemia or host immunologic response to the tumor.

5.Another group of “regressed” retinoblastomas, not found in scarred, calcified eyes, probably represents de novo origin of neural retinal lesions called retinocytomas (see earlier discussion of fleurettes and retinocytoma).

B.Calcification (see Fig. 18.10) is a frequent and important diagnostic feature. It is mainly present in areas of necrosis and may be detected clinically by CT.

Calcification begins in nonviable cells or cells that are undergoing necrosis. The calcification is intracel-

lular and begins in the cytoplasm, probably in the mitochondria.

C.Basophilic areas around blood vessels (Fig. 18.12), and also lying freely within the tumor and on the lens capsule represent deposition of DNA liberated from necrotic retinoblastoma cells.

D.Approximately 1.5% of cases have a di use, infiltrating type of tumor but without a discrete neural retinal mass.

It occurs in a slightly older age group than the usual

type, tends not to be bilateral, and is frequently accompanied by a simulated hypopyon.

VII. Mode of extension

A.Local spread

1.Anteriorly by seeding, into the vitreous and aqueous

(see Figs 18.2B and 18.3)

Aqueous seeding may simulate a hypopyon. Deposits may appear on the iris and in the anterior-chamber angle, and may produce a secondary open-angle glaucoma. Aqueous lactate dehydrogenase (LDH) and neuron-specific enolase levels may be elevated in eyes containing retinoblastoma, especially if the tumor is in the anterior chamber. LDH may also be elevated in Coats’ disease. It is not clear what the neuron-specific enolase level is in normal eyes in children or in eyes that have lesions simulating retinoblastoma (pseudogliomas).

2.Posteriorly (see Fig. 18.4C and D) by direct extension into the subneural retinal space (Fig. 18.13)

After invasion into the choroid, the tumor may gain access to the systemic circulation. By spread into the optic nerve, the tumor may gain access to the subarachnoid space through passage alongside the central retinal vessels to their exit from the nerve into the subarachnoid space.

B.Extraocular extension

1.Orbit (see Fig. 18.4C and D)

2.Brain

Fig. 18.14 Metastases. Retinoblastoma cells are present in bone marrow aspirate.

a.The most common site of metastasis is the central nervous system, and has an extremely poor prognosis, particularly if radiotherapy is not utilized in the treatment.

C.Metastases (Fig. 18.14; see section Prognosis, later)

Prognosis

I.Metastases—four factors appear to be independently associated with the development of metastases:

A.Invasion of the cut end of the optic nerve: 5-year metastatic risk, 67%

B.Invasion of the optic nerve (but not of the cut end): 5- year metastatic risk, 13%

C.Invasion of the choroid: 5-year metastatic risk, 8%

Choroidal invasion is a risk for metastases, especially if the invasion is associated with iris neovascularization, increased intraocular pressure, or optic nerve invasion.

D.Enucleation of the globe more than 120 days after initial diagnosis: 5-year metastatic risk, 4%.

The K-ras oncogene may undergo mutation in one-third of retinoblastomas, probably causing a selective growth advantage. The mutations seem to occur in, or cause, undifferentiated tumors. Mutations of the K-ras gene, therefore, may cause increased aggressiveness of retinoblastomas in which the mutations take place (i.e., increased malignancy).

II.Over the last two decades, the prognosis for life has improved considerably because of earlier diagnosis and improved methods of treatment. Nevertheless, a 2005 study of childhood cancer survival trends in Europe found no improvement for 5-year survival for retinoblastoma diagnosed under the age of 15 years during the period

1983 to 1994

Bilateral and unilateral cases have the same fatality rate.

III.Histologic correlation

A.Cellular di erentiation

1.A patient whose tumor has abundant Flexner– Wintersteiner rosettes has approximately a sixfold better prognosis than one whose tumor has no rosettes.

2.A tumor that is completely di erentiated (retinocytoma) is believed to augur a better prognosis than an undi erentiated retinoblastoma; the prognosis is even better than for a tumor with abundant Flexner–Wintersteiner rosettes but no di erentiation (i.e., no fleurettes).

B.When choroidal invasion is slight (most cases with choroidal invasion), the mortality rate appears not to be a ected; when the invasion is massive (Fig. 18.15), the mortality rate is approximately 60%.

C.Optic nerve involvement (see Fig. 18.15B)

1.When the optic nerve is not invaded, the mortality rate is approximately 8%.

2.Grade I: when it is invaded up to, but not involving, the lamina cribrosa (superficial involvement of the optic nerve head only), the mortality rate is approximately 10%.

3.Grade II: when the invasion is up to and including the lamina cribrosa, the mortality rate is approximately 29%.

4.Grade III: when the invasion is beyond the lamina cribrosa, but not to the surgical margin, the mortality rate is approximately 42%.

5.Grade IV: when the invasion is to the line of transection or to the posterior point of exit of the central retinal vessels from the optic nerve, the mortality rate is approximately 67%.

D.The presence of iris neovascularization (rubeosis iridis) is a poor prognostic sign.

E.The clinical prognosis is determined by the location and size of the tumor.

F.Probably only retinoblastoma patients with the genetic (familial) tumor or sporadic tumors with germinal cell gene mutations have a definite predilection for the development of fatal second malignancies (with or without radiation therapy for the initial lesion) despite adequate control of their original eye tumor.

1.Patients who have bilateral retinoblastomas have a 26% chance of dying from a second primary neoplasm after 40 years; the risk is increased if the patient received radiation therapy for the initial lesion.

2.Osteosarcoma of the femur is the most common second malignancy; other tumors include fibrosarcoma, skin carcinoma, cutaneous melanoma, rhabdomyosarcoma, leukemia, Ewing’s sarcoma, peripheral neuroepithelioma, benign and malignant neoplasms of brain and meninges, Langerhans’ granulomatosis, and sinonasal carcinoma. Sebaceous carcinoma of the eyelid may occur in patients with hereditary retinoblastoma regardless of the

primary treatment, especially within the field 5 to

15 years after radiotherapy.

A primary osteosarcoma displaying a rosette-like appearance has developed 24 years after bilateral retinoblastoma at age 1 year. Also, orbital malignant fibrous histiocytoma has occurred 17 years following radiation therapy and systemic chemotherapy for retinoblastoma at age 5 months.

4.A pineal gland tumor plus bilateral retinoblastoma is called trilateral retinoblastoma.

Pineal cyst may simulate pinealoblastoma in patients with retinoblastoma.

5.The second tumor is not necessarily related to prior radiation therapy of the primary retinoblastoma.

6.Cell proliferation may be more important than apoptosis and angiogenesis in determining tumor size. Higher apoptotic index (over 2.4%) appears to be related to decreased metastasis and lower proliferative index.

G.Angiogenesis is important in tumor survival.There is no di erence in blood vessel density between unilateral and bilateral tumors; however,higher vessel density is associated with choroid and/or optic nerve invasion, and with metastasis at the time of presentation.The relative vascular area of a retinoblastoma may help to identify patients at higher risk for disease metastasis after enucleation.

PSEUDOGLIOMA

General Information

I.Terminology

A.The term pseudoglioma, introduced by Collins in 1892, designates a heterogeneous group of pathologic entities that may be confused with retinoblastomas.

TABLE 18.1 Classification of Conditions That Can

Simulate Retinoblastoma

HEREDITARY CONDITIONS

Norrie’s disease

Juvenile retinoschisis

Incontinentia pigmenti

Dominant exudative vitreoretinopathy

DEVELOPMENTAL ABNORMALITIES

Persistent hyperplastic primary vitreous

Congenital cataract

Coloboma

Retinal dysplasia

Congenital retinal fold

Myelinated nerve fibers

Morning-glory syndrome

Congenital corneal opacity

Congenital nonattachment of retina

Retinal heterotopic brain tissue

INFLAMMATORY DISORDERS

Ocular toxocariasis

Congenital toxoplasmosis

Congenital cytomegalovirus retinitis

Herpes simplex retinitis

Peripheral uveoretinitis

Metastatic endophthalmitis

Orbital cellulites

TUMORS

Retinal astrocytic hamartoma

Medulloepithelioma

Glioneuroma

Choroidal hemangioma

Retinal capillary hemangioma

Combined hamartoma

Leukemia

MISCELLANEOUS

Coats’ disease

Retinopathy of prematurity

Rhegmatogenous retinal detachment

Vitreous hemorrhage

Perforating ocular injury

(Adapted from Shields JA et al.: Retina 11:232, 1991.)

B.The term pseudoretinoblastoma is preferred, but has not gained wide acceptance.

II.The clinical presentation of pseudoglioma is similar to retinoblastoma in that it may present with leukokoria (whitish pupil) or with a small endophytic or exophytic tumor.

Leukokoria (Table 18.1)

I.Persistent hyperplastic primacy vitreous (PHPV) (Fig. 18.16)

A.PHPV [also called persistent fetal vasculature (PFV)] is a congenital, unilateral condition recognizable at birth; rarely, it is bilateral.

1.PHPV has been found in association with chromosome 6p25 terminal deletion resulting in karyotype 46,XX, del (6) (p25.1) and associated with Axen- feld–Rieger syndrome. It has occurred with neurofi- bromatosis-2, and with urogenital anomalies accompanying varicella syndrome. Focal dermal hypoplasia or Goltz syndrome,which has cutaneous, skeletal, dental, ocular, central nervous system, and soft-tissue defects,has been reported with sclerocornea in one eye and anterior PHPV in the fellow eye.

Bilateral PHPV has been reported in association with protein C deficiency, an autosomal-recessive disorder. Nonsyndromic, autosomal-recessive PHPV was studied in a six-generation consanguineous family and localized to chromosome 10q11–q21. It can also be an isolated finding.

2.PHPV is the most common lesion simulating retinoblastoma.

B.It is unrelated to prematurity.

C.PHPV exists in a microphthalmic eye having a shallow anterior chamber. Long ciliary processes are frequently seen around the periphery of a small lens.

Buphthalmos may accompany PHPV if the eye becomes glaucomatous.

D.Rarely, PHPV and retinoblastoma have been reported together in microphthalmic eyes.

E.A lens capsule dehiscence is often present posteriorly. Rarely, the lens is cataractous.

Lenticular fibroxanthomatous nodule consisting of vascularized collections of foamy histiocytes, multinucleated cells, lens capsule, and lens epithelium that had undergone fibrous metaplasia has been found in one patient with PHPV and another with a history of trauma.

F.The condition is the result of persistence of the embryonic primary vitreous and hyaloid vasculature system.

Preretinal glial nodules may occur with PHPV. The preretinal nodules are thought to represent neuroectodermal proliferations.

G.PHPV may cause angle closure glaucoma even in individuals 40 years of age or younger.

II.Retinal dysplasia (see Fig. 2.9)

A.Retinal dysplasia is congenital, usually bilateral, and recognizable at birth but is unrelated to prematurity.

B.Bilateral retinal dysplasia is most often part of trisomy

13(see p. 38 in Chapter 2). It may be unilateral and then is not associated with systemic anomalies and trisomy 13.

C.Histologically, tubular and rosette-like structures form the dysplastic neural retina; four general types of rosettes are recognized.

1.Three-layer rosettes, that have the appearance of mature neural retina that has been thrown into folds secondarily

2.Two-layer rosettes, in which the innermost layer resembles a photoreceptor cell layer with an external limiting membrane and a relatively large lumen that often contains undi erentiated cells. Surrounding the rosette is a more peripheral layer of bipolar-like cells or poorly di erentiated cells.

3.One-layer rosettes with a single layer of moderately well-di erentiated neural cells, usually several cells in thickness, having an external limiting mem- brane-like structure and surrounding a lumen. In the lumen, larger undi erentiated cells are usually observed.

4.Primitive unilayer rosettes in which a single layer of undi erentiated neural retinal cells surrounds a lumen with a tangle of fibrils seen centrally.

III.Retinopathy of prematurity (ROP; retrolental fibroplasia; Figs 18.17 and 18.18): ROP is the fourth most common lesion simulating retinoblastoma.

Despite a decrease in mean gestational age and birth weight, a British survey found a reduced incidence of ROP from 1989 to 1998 and attributed the finding to improvements in ventilation techniques and overall care of the neonate, in particular, the use of steroids and surfactant.*

A.ROP is bilateral and not present at birth.

A number of cases of “congenital ROP” (e.g., in Potter’s

syndrome) have been reported. Although ROP is rare in children who have not had oxygen therapy or who were

*Rowlands E, Ionides AC, Chinn S et al. Reduced incidence of retinopathy of prematurity. Br J Ophthalmol 85:933, 2001.

not premature, it does seem to occur. In some conditions, retinal neovascularization can simulate ROP. Missense mutations in the Norrie’s disease gene may play a role in the development of severe ROP in premature infants.

B.It occurs in premature infants, most weighing less than 1.5 kg, who have a history of oxygen therapy.

1.The degrees of early retinal vessel development and iris vessel dilatation are significant predictors of outcome from ROP.

The retinal vessels must be immature to be affected by increased oxygen tension. If the infant is premature but the retinal vessels are mature, oxygen therapy will not cause ROP; conversely, if the infant is full-term but the retinal vessels are immature, oxygen therapy may cause ROP.

2.ROP develops in approximately 66% of infants weighing less than 1251 g at birth, and in approximately 82% weighing less than 1000 g.

3.An association exists between the incidence and severity of ROP, and the duration of exposure to arterial oxygen levels of 80 mmHg or higher, as measured transcutaneously.

4.Hyperoxia causes neural retinal vascular closure, obliteration, and hypoxia, then induces neural retinal vasoproliferation; finally, after relief of hypoxia, normalization occurs.

5.Based on data such as racial and sexual di erences in the incidence of ROP, it has been suggested that genetic factors may predispose some individuals to develop ROP.

6.In neonatal cats, the interaction of vascular endothelial growth factor and degenerating retinal astrocytes creates conditions for the growth of preretinal blood vessels.

C.The eyes are normal in size at birth but may become microphthalmic with development of shallow anterior chambers.

C

D.Ciliary processes may be seen in the periphery of the retrolental mass.

E.The classification includes five stages (the process can arrest at any stage):

1.Stage 1: demarcation line

a.The demarcation line separates the avascular neural retina anteriorly from the vascular neural retina posteriorly.

b.The retinal vessels leading to the line have brush-like endings.

2.Stage 2: ridge

a.Extraretinal neovascularization results from growth in width and height of the demarcation line.

b.Small, isolated tufts of new vessels may be seen lying on the surface posterior to the ridge.

3.Stage 3: ridge with extraneural retinal fibrovascular proliferation

a.Fibrovascular proliferation occurs posterior to the ridge.

b.Mild, moderate, and severe grades exist.

4.Stage 4: partial neural retinal detachment

a.Stage 4a: partial extrafoveal neural retinal detachment

b.Stage 4b: partial neural retinal detachment involving fovea

c.Progressive stage 4 retinopathy requiring surgical intervention is predicted by the absence of clear vitreous, ridge elevation of six or more clock-hours, and two or more quadrants of plus disease, but not by neovascularization.

5.Stage 5: total neural retinal detachment

Subretinal organization in stage 5 retinopathy is most frequently identified as subretinal band formation, has been found in about 10% of stage 5 eyes, and is associated with incomplete retinal reattachment.

F.Plus disease is typified by increasing dilatation and tortuosity of the retinal vessels, iris engorgement, pupillary rigidity, and vitreous haze or hemorrhage, or both.

G.Regressed ROP is the common outcome of ROP.

H.A fulminant type of ROP may occur.

I.Histology

1.Early, a sheet of spindle cells of mesenchymal origin—the precursors of the inner retinal endothelial cells—proliferate in the peripheral neural retina, associated with the development of retinal vessels.

2.Behind the proliferating spindle cells are newly formed capillaries in an area of di erentiating endothelium.