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

cellular inhibitor of the p53 tumor suppressor, functionally inactivates p53. The p53 gene encodes a 53-kD nucleophosphoprotein that binds DNA, is involved in the regulation of transcription and the induction of programmed cell death (apoptosis), and negatively regulates cell division, preventing progression from G to S phase. Approximately 25% of adult sarcomas of different types are associated with p53 abnormalities. It also appears to be a marker of tumor progression (i.e., a direct correlation seems to exist between mutations at the p53 locus and increasing histologic grade). The ras proto-oncogene initiates p53-independent apoptosis, but is suppressed through the activation of nuclear factor-κB.

Degeneration and Dystrophy

I.A dystrophy is a primary (bilateral), inherited disorder that has distinct clinicopathologic findings. The individual dystrophies are discussed elsewhere under their individual

tissues.

II.A degeneration (monocular or binocular) is a secondary phenomenon resulting from previous disease. It occurs in a tissue that has reached its full growth.

A.Cloudy swelling is a reversible change in cells secondary to relatively mild infections, intoxications, anemia, or circulatory disturbances. The cells are enlarged and

filled with granules or fluid and probably represent an intracellular edema.

B.Hydropic degeneration is a reversible change in cells also secondary to relatively mild infections, intoxications, anemia, or circulatory disturbances. The cells are enlarged and contain cytoplasmic vacuoles and probably represent an early stage of swelling of the endoplasmic reticulum.

C.Fatty change results when fat accumulates in cells for unknown reasons or after damage by a variety of agents

(e.g., chloroform and carbon tetrachloride).

D.Glycogen infiltration results from diseases such as diabetes mellitus (e.g., lacy vacuolation of iris pigment epithelium; see p. 599 in Chapter 15) and from a lack of nutrition (e.g., in long-standing neural retinal detachment and in proliferating retinal pigment epithelial cells).

E.Amyloid may be found in ocular tissues in primary amyloidosis (see p. 238 in Chapter 7 and p. 488 in Chapter 12), such as in primary familial amyloidosis and lattice corneal dystrophy (in which case it is a dystrophic change) or in secondary amyloidosis (see p. 238 in Chapter 7), in which case it is a degenerative change.

F.Hyaline degeneration is quite common, consists of acellular, amorphous, eosinophilic material, and may be found in places such as the walls of arteriolosclerotic vessels or in the ciliary processes in elderly people.

Necrosis

I.Necrosis occurs when cells die an “accidental” death, such as from severe and sudden injury (e.g., ischemia), sustained hyperthermia, physical or chemical trauma, complement attack, or metabolic poisons.

Necrosis should be differentiated from apoptosis—see later.

Necrosis is accompanied by:

•Swelling of the cytoplasm and organelles (especially the mitochondria) and only mild changes in the nucleus.

•Organelle dissolution and rupture of the plasma membrane.

•Leakage of cellular contents into the extracellular space.

•Inflammatory response to the released cellular debris.

No inflammation occurs in apoptosis—see later.

II.Coagulative necrosis: this is a firm, dry necrosis generally formed in tissue that has been shut o from its blood supply.

A. The gray, opaque clinical appearance of the retina after a central retinal artery occlusion is caused by coagulative necrosis (ischemic necrosis). As seen by electron microscopy, coagulative necrosis (e.g., after a laser burn)

is produced by widespread focal densification of membranes in the necrotic cell.

B.Caseation, characteristic of tuberculosis, is a combination of coagulative and liquefaction (see later) necrosis.

III.Hemorrhagic necrosis: this type is caused by occlusion of venous blood flow but with retention of arterial blood flow, as seen classically in central retinal vein thrombosis.

IV. Liquefaction necrosis: necrosis of this type results from autolytic (see section on autolysis and putrefaction, later) decomposition, usually in tissue that is rich in proteolytic enzymes (e.g., suppuration is a form of liquefaction necrosis in which rapid digestion is brought about by the proteolytic enzymes from the leukocytes, especially

PMNs, present in the area). It also occurs from complete dissolution of all cell components, as in ultraviolet

photocomposition.

V. Fat necrosis: necrosis causes liberation of free fatty acids and glycerol that results in a lipogranulomatous reaction.

Apoptosis

I.Apoptosis is “physiologic” or programmed cell death, unrelated to “accidental death” (necrosis)—see earlier.

A.Apoptosis is a spontaneous death of cells that occurs in many di erent tissues under various conditions. Bcl-2 oncogene acts mainly on the pathways of apoptosis (programmed death) and plays a crucial role in the control of cellular growth of lymphoid and nonlymphoid cells.

Two other types of oncogenes are recognized: oncogenes such as myc, ras, and abl act as growth and proliferative regulatory genes; and oncogenes such as Rb and p53 inhibit growth and proliferation.

B.Two steps accompany apoptosis:

1.First, the cell undergoes nuclear and cytoplasmic condensation, eventually breaking up into a number of membrane-bound fragments containing structurally intact organelles.

Cells undergoing apoptosis demonstrate shrinkage, nuclear condensation associated with DNA fragmentation, a relatively intact cell membrane, loss of viability, and absence of inflammation.

2.Second, the cell fragments, termed apoptotic bodies, are phagocytosed by neighboring cells and rapidly (within minutes) degraded.

The apoptotic bodies are membrane-encapsulated, thus preventing exposure of cellular contents to the extracellular space and possible inflammatory reaction.

C.Apoptosis appears to play a major role in regulating cell populations.

D.Defective apoptosis may play a role in the genesis of cancer, AIDS, autoimmune diseases, degenerative and dystrophic diseases of the central nervous system

(including the neural retina), and diabetic retinopathy.

Calcification

I.Dystrophic (degenerative) calcification: this occurs when calcium is deposited in dead or dying tissue (e.g., in long-standing cataracts, in band keratopathy, and in retinoblastoma).

II.Metastatic calcification: this type of calcification occurs when calcium is deposited in previously undamaged tissue [e.g., in the cornea of people with high serum calcium levels (hyperparathyroidism, vitamin D intoxication), where it shows as a horizontal band, and in the sclera, where it shows as a senile plaque].

An unusual cause of metastatic calcification is Werner’s syndrome, a heredofamilial disorder characterized by premature graying and baldness, short stature, gracile build, and “bird face”. Ocular findings include blue sclera, bullous keratopathy, presenile posterior subcapsular cataract, degenerative corneal changes post cataract surgery, retinitis pigmentosalike features, and paramacular degeneration.

Autolysis and Putrefaction

I.Autolysis is partly the self-digestion of cells using their own cellular digestive enzymes contained in lysosomes (“suicide bags”), and partly other unknown factors.

II.When certain bacteria (especially clostridia) invade necrotic

(autolytic) tissue, the changes catalyzed by destructive bacterial enzymes are called putrefaction.

Pigmentation

I.In ocular histologic sections stained with H&E, some commonly found pigments may resemble each other

closely: (1) melanin and lipofuscin; (2) hemosiderin; (3) exogenous iron; and (4) acid hematin.

II.Melanin is found in uveal melanocytes as fine, powdery, brown granules barely resolvable with the light microscope,

and in pigment epithelial cells of the retina, ciliary body, and iris as rather large, black granules. Lipofuscin occurs in aged cells and in the RPE and may be di cult to identify by conventional light microscopy, but by electron micros-

copy di ers considerably in structure and density from melanin.

III.Hemosiderin results from intraocular hemorrhage when hemoglobin is oxidized to hemosiderin.

A.It occurs as an orange-brown pigment in macrophages and, when plentiful in the eye, is called hemosiderosis bulbi.

B.Systemic hemochromatosis (see p. 188 in Chapter 6) consists of portal cirrhosis and elevated iron content in parenchymal cells of multiple organs. When increased amounts of iron are deposited in tissues of multiple

organs but cirrhosis and its complications are lacking, systemic hemosiderosis is present.

C.The distribution of iron in the eye di ers in local ocular

disease (hemosiderosis bulbi and siderosis bulbi) and systemic disease (Table 1.2).

IV. Exogenous iron results from an intraocular iron foreign body. The resultant ocular iron deposition is called siderosis bulbi (see Table 1.2).

V.Acid hematin is an artifact produced by action of acid fixatives, particularly formaldehyde, on hemoglobin.

VI. Di erentiation of the pigments.

A. Only acid hematin is birefringent to polarized light.

TABLE 1.2 Deposition of Iron in the Eye of Local* and Systemic (Hemo) Siderosis

*With local iron foreign body, iron is usually deposited in all adjacent (contiguous) tissues.

(Modified from Roth AM, Foos RY: Arch Ophthalmol 87:507, 1972. © American Medical Association.)

B.Only melanin bleaches with oxidizing agents, such as hydrogen peroxide.

C.The cathepsin-D reaction is helpful in identifying lipofuscin.

D.Only iron stains positively with the common stains for iron.

Hemosiderin and exogenous iron cannot be differentiated on their staining properties and sometimes may not be differentiated on structural grounds.

Growth and Aging

I.In general, ocular tissue in infants and young people is quite cellular. Cellularity decreases with aging as the collagenization of tissues increases.

II.The eye is at least two-thirds of its adult size at birth, and usually reaches full size by the end of the second decade of life.

Although the eyeball reaches full size, the lens, an inverted epithelial structure, continues to grow throughout life. Nuclear cataract results from the increased density of the central (unclear) lens cells (and other factors) and can be considered an aging change.

III.Certain chemicals may be deposited in ocular tissues

during the aging process, including calcium in the insertion of the rectus muscles (senile plaque; Fig. 1.28) and in Bruch’s membrane (calcification of Bruch’s membrane),

and sorbitol in the lens.

IV. The important growth and aging changes of individual tissues are taken up in the appropriate sections in the remaining chapters.

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PHAKOMATOSES (DISSEMINATED HEREDITARY HAMARTOMAS)

General Information

I.The phakomatoses are a heredofamilial group of congenital tumors having disseminated, usually benign, hamartomas in common.

The term phakomatosis (Greek: phakos = “mother spot” or “birthmark”) was introduced by van der Hoeve in 1923.

II. In each type of phakomatosis, the hamartomas tend to a ect one type of tissue predominantly (e.g., blood vessels in angiomatosis retinae and neural tissue in neurofibromatosis).

A hamartoma is a congenital tumor composed of tissues normally found in the involved area, in contrast to a choristoma, which is a congenital tumor composed of tissues not normally present in the involved area.

Angiomatosis Retinae [von Hippel’s

Disease (VHL)]

I.General information

A.The onset of ocular symptoms is usually in young adulthood.

B.Retinal capillary hemangiomas (hemangioblastomas) occur in over 50% of patients (Fig. 2.1), and central nervous system lesions occur in 72% of patients.

C.VHL disease is an inherited cancer syndrome

(autosomal-dominant) characterized by a predisposition to development of multiple retinal angiomas, cer-

ebellar “hemangioblastomas,” bilateral renal cysts and carcinomas, bilateral pheochromocytomas, pancreatic cysts, and epididymal cysts.

The combination of retinal and cerebellar capillary hemangiomas (and capillary hemangiomas of medulla and spinal cord) is called von Hippel–Lindau disease. The retinal component, von Hippel’s disease, was the first to be described. The responsible VHL gene resides at human chromosome 3 (band 3p25.5–p26). Genetically, the disease gene behaves as a typical tumor suppressor, as defined in Knudson’s theory of carcinogenesis.

II.Ocular findings

A.A retinal capillary hemangioma (see p. 544 in Chapter

14), usually supplied by large feeder vessels, may occur in the optic nerve or in any part of the retina.

Unusual retinal hamartomas may be seen in the inner retina, usually adjacent to a retinal vein, and are characterized by small, moss fiberlike, relatively flat, vascular lesions with smooth or irregular margins but without enlarged afferent and efferent vessels.

B.Retinal exudates, often in the macula even when the tumor is peripheral, result when serum leaks from the abnormal tumor blood vessels.

C.Ultimately, organized fibroglial bands may form and neural retinal detachment may develop. Secondary closed-angle glaucoma may also be found.

III.Systemic findings

A.A retinal capillary hemangioma may occur in the cerebellum, brainstem, and spinal cord.

B.Cysts of pancreas and kidney are commonly found.

C.Hypernephroma and pheochromocytoma (usually bilateral) occur infrequently.

A B

D E

IV. Histology

A.The basic lesion is a capillary hemangioma (hemangioblastoma) (see p. 544 in Chapter 14).

1.The tumor, a capillary hemangioma, is composed of endothelial cells and pericytes.

2.Between the capillaries are foamy stromal cells that appear to be of glial origin.

a.Immunohistochemical studies show that the foamy stromal cells stain positively for glial fibrillary acid protein and neuron-specific enolase.

b.The VHL gene deletion may be restricted to the stromal cells, suggesting that the stromal cells are the neoplastic component in retinal hemangiomas and induce the accompanying neovascularization.

B.Secondary complications may be found, such as retinal exudates and hemorrhages, fixed retinal folds and organized fibroglial membranes, neural retinal detachment, iris neovascularization, peripheral anterior synechiae, and chronic closed-angle glaucoma.

Meningocutaneous Angiomatosis

[Encephalotrigeminal Angiomatosis; Sturge–

Weber Syndrome (SWS)]

I.General information

A.SWS (Fig. 2.2) usually consists of unilateral (rarely bilateral) meningeal calcification, facial nevus flammeus (port-wine stain, phakomatosis pigmentovascularis), frequently along the distribution of the trigeminal nerve, and congenital glaucoma.

C

Fig. 2.1 Angiomatosis retinae. A, Fundus picture of peripheral retinal capillary hemangiomas in 16-year-old patient.

B, Retinal capillary hemangioma of optic nerve head, shown with fluorescein in C. D, Capillary hemangioma (hemangioblastoma) replaces full thickness of retina. E, High magnification shows capillary blood-filled spaces intimately associated with characteristic pale, foamy, polygonal stromal cells. (B and C, Courtesy of Dr. GE Lang; D and E, courtesy of Dr. DH Nicholson.)

B.The condition is congenital (heredity does not seem to be an important factor).

II.Ocular findings

A.The most common intraocular finding is a cavernous hemangioma (see p. 544 in Chapter 14) of the choroid on the side of the facial nevus flammeus.

Extremely rarely, the choroidal nevus can be bilateral even with unilateral facial nevus flammeus.

B.A cavernous hemangioma or telangiectasis (see pp. 544 and 545 in Chapter 14) of the lids on the side of the facial nevus flammeus is common.

C.Congenital glaucoma is associated with ipsilateral hemangioma of the facial skin in approximately 30% of patients.

When nevus flammeus and congenital oculodermal melanocytosis occur together, especially when each extensively involves the globe, a strong predisposition exists for the development of congenital glaucoma.

1.The lids, especially the upper, are usually involved.

2.The cause of the glaucoma is unclear, but in most instances it is not related to the commonly found ipsilateral choroidal hemangioma.

III.Systemic findings

A.Cavernous hemangioma or telangiectasis of the skin of the face (“birthmark” or port-wine stain) is the most common visible sign.

B.Hemangioma of the meninges and brain on the side of the facial hemangioma is usually present.

D

Meningeal or intracranial calcification allows the area of the hemangioma to be located radiographically.

C. Seizures and mental retardation are common.

IV. Histology

A.The basic lesion in the skin of the face (including lids), the meninges, and the choroid is a cavernous hemangioma (see p. 544 in Chapter 14).

The vascular dermal lesion in the SWS differs, however, from a non-SWS, “garden-variety” cavernous hemangioma in that the vascular wall in the SWS lesion lacks a multilaminar smooth muscle. The vascular abnormality in SWS, therefore, as suggested by Lever, would be better termed a vascular malformation or nevus telangiectaticus, rather than cavernous hemangioma.

1.In addition, telangiectasis (see p. 545 in Chapter

14)of the skin of the face may occur.

2.The choroidal hemangiomas in SWS show a di use angiomatosis and involve at least half the choroid, often a ecting the episcleral and intrascleral perilimbal plexuses.

3.SWS hemangioma shows infiltrative margins, making it di cult to tell where hemangioma ends and normal choroid begins.

Hemangioma of the choroid unrelated to SWS, conversely, is usually well circumscribed, shows a sharply demarcated pushing margin, often compresses surrounding melanocytes and choroidal lamellae, and usually (in 70% of cases) occurs in the region of the posterior pole (area centralis).

B.Congenital glaucoma may be present.

C.Secondary complications such as microcystoid degeneration of the overlying retina (see p. 422 in Chapter

11)and leakage of serous fluid (see p. 422 in Chapter

11)are common.

Neurofibromatosis (Figs 2.3–2.5)

I.Neurofibromatosis type 1 (NF-1: von Recklinghausen’s disease or peripheral neurofibromatosis)

A.General information

1.Diagnosis of NF-1 is made if two or more of the

following are found: six or more café-au-lait spots

>5 mm in greatest diameter in prepubertal persons and 15 mm in postpubertal persons; two or more neurofibromas of any type or one plexiform neurofibroma; freckling in the axillary, inguinal, or other intertriginous region; optic nerve glioma; two or more Lisch nodules; a distinctive osseous lesion (e.g., sphenoid bone dysplasia); a first-degree relative who has NF-1.

2.Multiple tumors are found that are derived from Schwann cells of peripheral and cranial nerves and glial cells of the central nervous system.

3.A superimposed malignant change (fibrosarcoma, neurofibrosarcoma, malignant schwannoma) may occur.

4.NF-1 is transmitted as an irregular autosomaldominant trait (prevalence approximately 1 in 3000 to 4000). The responsible gene is located on chromosome 17 (band 17q11.2).

B.Ocular findings

1.Café-au-lait spots

A

C

2.Neurofibromas

a.Fibroma molluscum, the common neurofibroma, results from proliferation of the distal end of a nerve and produces a small, localized skin tumor.

b.Plexiform neurofibroma (“bag of worms”) is a di use proliferation in the nerve sheath and produces a thickened and tortuous nerve.

c.Elephantiasis neuromatosa is a di use proliferation outside the nerve sheath that produces a thickening and folding of the skin.

3.Thickening of corneal and conjunctival nerves and congenital glaucoma

If a plexiform neurofibroma of the eyelid is present (especially upper eyelid), 50% will have glaucoma.

4.Hamartomas in trabecular meshwork, uvea, neural retina, and optic nerve head

a.Melanocytic nevi in trabecular meshwork and uvea

Clinically, the multiple, small, spider-like, melanocytic iris nevi (Lisch nodules) are the most common clinical feature of adult NF-1, found in 93% of adults. Rarely, Lisch nodules may be found in NF-2.

c

n

B

Fig. 2.5 Neurofibromatosis. A and B, Gross and microscopic appearance of hamartomatously, markedly thickened choroid (c). Sclera contains thickened, abnormal nerves (n). C, High magnification of diffuse choroidal hamartoma shows structures resembling tactile nerve endings and cells resembling nevus cells. (A and C, Courtesy of Dr. RC Eagle, Jr.; B, courtesy of Dr. L Calkins.)

b.Glial hamartomas in neural retina and optic nerve head

c.Retinal capillary hemangiomas and combined pigment epithelial and retinal hamartomas

5.Sectoral neural retinal pigmentation (sector retinitis pigmentosa of Bietti)

6.Optic nerve glioma (juvenile pilocytic astrocytoma)

About 25% of patients who have optic nerve gliomas have neurofibromatosis, almost exclusively type 1. NF-1 patients who have negative neuroimaging studies of the optic pathways may later develop optic nerve gliomas.

7.Orbit: plexiform neurofibroma; neurilemmoma (schwannoma); absence of greater wing of sphenoid; enlarged optic foramen; pulsating exophthalmos

The pulsating exophthalmos may be associated with an orbital encephalocele.

C.Histology

1.In the skin and orbit, a di use, irregular proliferation of peripheral nerve elements (predominantly