Orbit

Published on 20/03/2015 by admin

Filed under Pathology

Last modified 22/04/2025

Print this page

This article have been viewed 5456 times

[level-membership-for-pathology-category]

Orbit

Normal Anatomy

I. The orbital volume is approximately 30 ml, and the orbital depth (anterior to posterior) is approximately 4.5 cm (Figs. 14.1–14.5).

A. The medial orbital wall is quite thin (<0.5 mm) and transparent.

B. The roof of the orbit, composed mainly of the orbital plate of the frontal bone, is thinnest anteriorly, where it is adjacent to the frontal sinus, and separates the orbit from the frontal lobes of the brain.

C. The orbital floor is composed of the orbital plates of the maxilla and zygomatic bones and a small contribution from the palatine bone posteriorly. The floor is also thin, 0.5–1 mm, and thus is easily fractured, especially medial to the infraorbital canal.

D. The lateral orbital wall is thick, composed anteriorly by the zygomatic bone and posteriorly by the greater wing of the sphenoid.

Fig. 14.1 Normal orbit. Composite illustration of the seven bones of the orbit. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4, New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993; adapted from Zide B, Jelks G: Surgical Anatomy of the Orbit. New York, Raven Press, 1985.)

Fig. 14.2 Normal orbit. A, Anatomy of the medial orbital wall. B, Anatomy of the orbital floor as viewed from above. (From Wojno TH: Orbital trauma and fractures. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:9.1–9.4. © Elsevier 1993.)

Fig. 14.3 Normal orbit. Right orbital structures and their basic relationships as seen from above. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993.)

Fig. 14.4 Normal orbit—side view. Retrobulbar contents of orbit. (From Levine MR, Larson DW: Orbital tumors. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:10.4–10.13. © Elsevier 1993.)

Fig. 14.5 Normal orbit—front view. Lacrimal gland and surrounding structures. (From Buffam FV: Lacrimal disease. In Podos SM, Yanoff M, eds: Textbook of Ophthalmology, vol. 4. New York, Gower Medical, 1993:7.1–7.6. © Elsevier 1993.)

II. In addition to the bony walls, the eye, and the optic nerve, the orbit contains many soft-tissue structures such as fat, muscle (striated and nonstriated), cartilage, bone, fibrous tissue, nerves, and blood vessels.

A. Other than the epithelia within the eyeball, the lacrimal gland is the only epithelial structure in the orbit.

B. All orbital structures may be involved in disease processes.

C. Orbital disease, whatever its cause, tends to increase the bulk of the orbit, so the main presenting sign is exophthalmos.

Exophthalmos

I. The main clinical manifestation of orbital disease is exophthalmos (ocular proptosis), the extent and direction of which depend on a number of factors ¹: (1) size of lesion, (2) character of lesion (expansile vs. infiltrative growth, rapid vs. slow growth), (3) location of the lesion in the orbit (small lesion in muscle cone causes more exophthalmos than lesion of same size outside the muscle cone; lesions anterior to septum orbitale do not produce exophthalmos unless they also grow posteriorly), and (4) lesion’s effect on the extraocular muscles (complete paralysis of all muscles by itself can cause 2 mm of exophthalmos).

II. Exophthalmos may be simulated by many conditions: lid retraction due to any cause (most commonly Graves’ disease), unilateral enlargement of the globe, high myopia, buphthalmos, sagging lower lid, relaxation of the rectus muscle(s), enophthalmos or microphthalmos of the opposite eye, asymmetry of the bony orbits, and shallow orbits.

III. The most common causes of exophthalmos are thyroid disease (most common for both unilateral and bilateral exophthalmos), hemangioma, inflammatory pseudotumors, and benign and malignant lymphoid tumors (all others are relatively rare).

Although dermoids are one of the most common orbital tumors, if not the most common, they rarely cause exophthalmos because of their position, which is usually anterior to the septum orbitale.

Developmental Abnormalities

Developmental Abnormalities of Bony Orbit

Developmental abnormalities are usually associated with abnormalities of the cranial and facial bones such as tower skull or hypertelorism.

Microphthalmos with Cyst

I. Microphthalmos with cyst (see Fig. 2.10) is usually a unilateral condition, but it may be bilateral.

II. The cyst may be so large as to obscure the microphthalmic eye.

III. Proliferated neuroectodermal tissue (i.e., pseudogliomatous hyperplasia) may simulate an orbital neoplasm.

IV. The condition is caused by incomplete closure of the fetal cleft.

Although microphthalmos with cyst usually has no known cause, it may be associated with the 13q deletion or chromosome 18 deletion defect (partial 18 monosomy). A congenital cystic eye may also be associated with contralateral persistent hyperplastic vitreous and cerebrocutaneous abnormalities, called cranial ectodermopathy.

V. Histologically, the eye may range from relative normality to complete disorder, and it may contain structures such as ectopic smooth muscle and cartilage. The cyst may be lined by gliotic retina, or it may be filled with proliferated glial tissue that can reach massive amounts (massive gliosis) and simulate a glial neoplasm.

Cephaloceles

I. Cephaloceles are caused by a developmental malformation in which brain tissue or meninges or both are present in the orbit.

A. Meningocele—only meninges are present.

B. Encephalocele—only brain tissue is present; hydroencephalocele—considerable fluid is present in the cyst.

C. Meningoencephalocele—meninges and brain tissue are present.

D. All of the preceding may communicate with the brain. Although the initial communication usually closes, it may rarely remain open.

II. Most cephaloceles are developmental displacements of brain tissue and are generally referred to as ectopic brain tissue.

III. Histologically, most cephaloceles show a structure similar to that of the optic nerve (i.e., white matter separated by pial septa).

Congenital Alacrima

I. Hereditary congenital alacrima is part of a systemic disturbance such as the Riley–Day syndrome or anhidrotic ectodermal dysplasia.

II. An isolated case of congenital alacrima, presumably caused by hypoplasia of the lacrimal gland, has been reported.

Orbital Inflammation

Acute

I. Nonsuppurative (see section Nonsuppurative, Chronic Nongranulomatous Uveitis and Endophthalmitis in Chapter 3)—orbital cellulitis is most commonly caused by extension of an inflammation from the paranasal sinuses (Fig. 14.6).

II. Suppurative (see section Suppurative Endophthalmitis and Panophthalmitis in Chapter 3)

A. Purulent infection (e.g., with Staphylococcus) occurs commonly after trauma.

B. Phycomycosis (mucormycosis) is a devastating cause of suppurative orbital inflammation (Fig. 14.7; see Chapter 4).

Fig. 14.7 Orbital phycomycosis. A, Diabetic man had phycomycosis of left orbit, causing B, left central retinal artery occlusion. Systemic antifungal therapy arrested condition. C, Orbital tissue obtained from another patient who died from phycomycosis shows two large thrombosed orbital vessels surrounded by acute suppurative inflammation. Even under this low magnification, large, hematoxylinophilic, nonseptate fungal hyphae (round bodies) can be seen in the wall of the smaller vessel (artery) on the right. D, Increased magnification of another case stained with periodic acid–Schiff clearly shows the organisms. (A and B, Courtesy of Dr. LA Karp; C, courtesy of Dr. H Ring.)

Chronic

I. Nongranulomatous

A. Chronic nongranulomatous inflammation is the most common inflammatory lesion of the orbit and is of unknown cause (see later in this chapter).

B. A rare cause is the benign lymphoepithelial lesion of Godwin ² (Fig. 14.8).

1. It is characterized by painless unilateral or bilateral enlargement of the salivary or, rarely, the lacrimal glands.

2. It may be part of Sjögren’s syndrome (see later).

3. Rarely, it may become malignant.

4. Histologically, two features characterize benign lymphoepithelial lesion: (1) replacement of the glandular parenchyma by a benign lymphoid infiltrate and general preservation of the lobular architecture of the lacrimal gland, and (2) epimyoepithelial islands of proliferation in the glandular ducts.

Fig. 14.8 Benign lymphoepithelial lesion (of Godwin) and Sjögren’s syndrome. Benign lymphoepithelial lesion is characterized by (1) the glandular parenchyma being replaced by benign lymphoid infiltrate (A); (2) general preservation of the glandular lobular architecture (A); and (3) epimyoepithelial islands of proliferation within glandular ducts (B). Note thickened ductal basement membrane. C, Patient who has Sjögren’s syndrome shows bilateral lacrimal gland enlargement caused by Godwin’s lesion and also rheumatoid arthritis (D). (A and B, From Font RL, Yanoff M, Zimmerman LE: Benign lymphoepithelial lesion of the lacrimal gland and its relationship to Sjögren’s syndrome. Am J Clin Pathol 48:365, 1967, with permission; C and D, modified from Meyer D, Yanoff M, Hanno H: Differential diagnosis in Mikulicz’s syndrome, Mikulicz’s disease and similar disease entities. Am J Ophthalmol 71:516. © Elsevier 1971.)

C. Sjögren’s syndrome (see Fig. 14.8)

1. Sjögren’s syndrome is defined as a chronic autoimmune disorder characterized by lymphoid inflammatory infiltration of the lacrimal and salivary glands, destroying acinar tissue.

Autoantibodies to the ribonucleoprotein (RNP) particles SS-A (also called Ro RNA particle) and SS-B (also called La snRNA) are produced systemically. The immune response to 120-kDa α-fodrin may be important in the initial development of Sjögren’s syndrome.

2. The tissue destruction results in the symptoms of keratoconjunctivitis sicca and xerostomia.

3. Indirect support exists for a putative role of the Epstein–Barr virus (see Chapter 3) in the pathogenesis of the disease.

D. Inflammatory pseudotumor (see later in this chapter)

II. Granulomatous

A. Granulomatous inflammations rarely involve the orbit.

B. Causes include tuberculosis, sarcoidosis, syphilis, fungi, parasites (trichinosis, schistosomiasis, etc.), Crohn’s disease, cat-scratch disease, midline lethal granuloma syndrome (polymorphic reticulosis), and giant cell polymyositis (giant cell granulomatous necrotizing myositis).

C. Tolosa–Hunt syndrome is a benign granulomatous orbital inflammation of unknown cause that presents as a painful ophthalmoplegia. Symptoms usually disappear after steroid therapy.

D. Cholesterol granuloma

1. Cholesterol granuloma has also been called cholesteatoma, lipid granuloma of the frontal bone, xanthomatosis of the orbit, hematoma, and chronic hematic cyst.

Some authors incorrectly use the term cholesteatoma interchangeably with epidermoid cyst. The term epidermoid cyst should not be used, or should it be restricted to postinflammatory tumors that contain squamous epithelium and keratin debris; cholesterol granuloma is never associated with any epithelial elements.

2. Cholesterol granuloma of the orbital bones is a rare extraperiosteal condition that usually involves the frontal bone above the lacrimal fossa.

3. The cause seems to be a hemorrhage into the diploë of the bone, probably secondary to trauma but perhaps secondary to an anomaly in the diploë that could initiate a hemorrhage.

4. Histologically, a granulomatous reaction surrounds cholesterol crystals and altered blood.

E. Inflammatory pseudotumor (see later in this chapter)

Injuries

Penetrating Wounds

I. Direct effect on whatever tissue may be wounded by the injury

II. Complications (indirect effect)

A. Infection

1. Organisms may be introduced at the time of injury.

a. Bacteria cause an acute purulent inflammation.

b. Fungi cause a delayed, chronic, granulomatous inflammation.

B. Inflammation

1. The inflammation may be secondary to toxic products of tissue destruction.

2. Orbital thrombophlebitis may result.

3. A retained intraorbital foreign body may induce inflammation.

a. Frequently, cilia and pieces of skin, bone, wood, and so forth may be introduced into the orbit at the time of injury and cause a foreign-body granulomatous inflammatory reaction.

b. Fungi may enter as a coincidental saprophyte along with the penetrating foreign body, which usually causes a granulomatous inflammatory reaction or even superimposed infection if the organism proliferates.

C. Orbital inflammation may lead to other complications, such as cavernous sinus thrombosis, central retinal vein thrombosis, glaucoma, and proptosis.

Nonpenetrating Wounds

The effects of nonpenetrating wounds are those secondary to contusion and concussion, mainly hemorrhage, secondary muscle palsies, and infraorbital nerve involvement.

Vascular Disease

Primary

I. Primary orbital vascular disease is rare.

II. Causes include varices, arteriovenular aneurysm, thrombophlebitis, and cavernous sinus thrombosis.

Orbital varix, also called distensible venous malformation (Fig. 14.9), may occur anterior to the septum orbitale and not cause exophthalmos, or it may occur posterior to the septum orbitale, causing exophthalmos. The exophthalmos may be acute if the varix undergoes thrombosis.

Fig. 14.9 Orbital varix. A, Clinical appearance of varix before removal. Gross appearance of skin (B) and internal (C) side of removed varix. D, Trichrome stains show microscopic appearance of clotted vein.

Part of Systemic Disease

I. Collagen diseases (see Chapter 6 and later in this chapter)

II. Midline lethal granuloma syndrome (natural killer (NK)/T-cell lymphoma, polymorphic or malignant reticulosis; see later this chapter and see Chapter 6)

III. Allergic granulomatosis (vasculitis; see Chapter 6)

IV. Temporal (cranial) arteritis (see Chapter 13)

Ocular Muscle Involvement in Systemic Disease

Graves’ Disease (Fig. 14.10)

I. Classification of eye changes of Graves’ disease (Box 14.1)

II. Mild form (“thyrotoxic” exophthalmos)

A. The mild form of Graves’ ophthalmopathy has its onset in early adult life, with women predominantly affected (approximately 2 : 1).

Smokers have an increased risk for development of both Graves’ disease and thyroid ophthalmopathy. Temporally, the diagnosis of Graves’ ophthalmopathy tends to follow the diagnosis of hyperthyroidism. Treatment of hyperthyroidism with iodine-131 does not seem to alter the course of Graves’ ophthalmopathy.

B. It may present initially with unilateral involvement but usually becomes bilateral.

C. Clinically and chemically, the patient is hyperthyroid.

D. Lid retraction, the most common clinical sign, may simulate exophthalmos.

E. Occasionally exophthalmos is present.

F. Prognosis for vision is good.

III. Severe form (“thyrotropic” or “malignant” exophthalmos; thyroid ophthalmopathy; thyroid orbitopathy)

A. The severe form is an autoimmune disease that affects people in middle age (average age, 50 years).

1. The disease is characterized by an increased percentage of suppressor/cytotoxic T lymphocytes.

2. Circulating T cells are directed against thyroid follicular cell antigens.

B. It is most common in men, especially those older than 50 years of age, is usually bilateral, and is asymmetric.

C. Clinically and chemically, the patient may be hyperthyroid, hypothyroid, or euthyroid.

The term euthyroid Graves’ disease describes ocular manifestations of Graves’ disease in patients who are “euthyroid” and have no past history suggesting hyperthyroidism. The eye signs are frequently asymmetric. The patients may have a family history of thyroid disease or pernicious anemia. All of the euthyroid patients, however, do show some mild thyroid abnormality (e.g., thyroid autoantibodies, negative thyrotropin-releasing hormone test, negative triiodothyronine suppression test, and goiter).

D. Exophthalmos is severe and frequently associated with pretibial myxedema. Chemosis, dilated vessels (especially over the rectus muscles), and limitation of ocular motility often accompany the exophthalmos.

Orbital accumulation of glycosaminoglycans and increased adipogenesis may play an important role in the development of Graves’ ophthalmopathy.

E. Prognosis for vision is poor.

F. Histologically, the orbital tissue is characterized predominantly by extraocular and periorbital muscle involvement by edema, lymphocytic infiltration (mainly CD4⁺ and CD8⁺ T cells along with some focal aggregates of B cells, plasma cells, and mast cells), endomysial fibrosis, and mucopolysaccharide deposition.

1. Positive staining occurs in extraocular and periorbital muscle for immunoglobulin A1 (IgA1) and IgE antibodies and also C3bi (the terminal attack complex) complement component.

2. The inferior rectus muscle is most prone to fibrosis. If the patient is looking up during tonometry, abnormally high readings may be obtained. Therefore, it is important that the patient be looking straight ahead during applanation tonometry.

Fig. 14.10 Graves’ disease. A, In Graves’ disease, exophthalmos often looks more pronounced than it actually is because of the extreme lid retraction that may occur. This patient, for instance, had minimal proptosis of the left eye but marked lid retraction. B, The orbital contents obtained postmortem from a patient with Graves’ disease. Note the enormously thickened extraocular muscle. C, A histologic section shows both fluid and inflammatory cells separating the muscle bundles. The inflammatory cells are predominantly lymphocytes, plus plasma cells. (A, Courtesy of Dr. HG Scheie; B and C, courtesy of Dr. RC Eagle, Jr.; case in B and C reported in Hufnagel TJ, Hickey WF, Cobbs WH et al.: Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with Graves’ disease. Ophthalmology 91:1411. © Elsevier 1984.)

Box 14.1

Eye Changes in Graves’ Disease

CLASS	OCULAR SYMPTOMS AND SIGNS
0	No signs or symptoms
1	Only signs, no symptoms
2	Soft-tissue involvement with symptoms and signs
3	Proptosis of the eyes
4	Extraocular muscle involvement
5	Corneal involvement
6	Sight loss with optic nerve involvement

(Modified from Werner SC: Classification of the eye changes of Graves’ disease. Am J Ophthalmol 68:646, 1969.)

Myasthenia Gravis

I. Myasthenia gravis is an autoimmune disorder (defect on chromosome 19q13.3) that involves the extraocular muscles, especially the levator palpebrae superioris. A reduction in available acetylcholine receptors occurs at the neuromuscular junctions of skeletal muscles.

II. The most common clinical manifestation is ptosis of the eyelid.

As a rough test, the ptosis can often be aggravated by having the patient raise and lower the eyes 10–30 times in rapid succession. The normal patient can do this easily with no ptosis afterward.

III. Histologically, the ocular muscles are edematous and infiltrated by lymphocytes.

Myotonic Dystrophy (Myotonia Dystrophica; Steinert’s Disease)

I. Myotonic dystrophy, an autosomal-dominant condition, is characterized by myotonia (i.e., failure to relax a contracted muscle voluntarily).

Myotonic dystrophy, like Huntington’s disease, is caused by an expansion of a repeated sequence of three nucleotides. In myotonic dystrophy, the expansion occurs in the 3′ untranslated region of the DM gene. Perhaps disrupted activity of a CUG-binding protein induced by repeats in RNA prevents the protein from doing its normal job of splicing a certain family of genes.

A. Its onset is between 20 and 30 years of age, with patients rarely living beyond 40 or 50 years.

B. Frontal baldness and endocrinopathy, especially testicular atrophy, are common.

II. Ocular findings

A. Cataracts showing iridescent dots in the anterior and posterior cortex, and a stellate grouping of opacities at the posterior pole of the lens along the posterior suture lines

B. Foveal dystrophy that hardly affects vision and pigmentary retinopathy

C. Ocular hypotension

III. Histologically, selective atrophy of muscle fibers is seen.

Myotonia Congenita (Thomsen’s Disease)

I. Myotonia congenita, an autosomal-dominant or -recessive condition, is characterized by myotonia.

A. Its onset is early in life and may involve muscles of the face and eyelids.

B. It does not cause death and rarely causes severe disability.

II. Histologically, the muscles are not atrophic; individual muscle fibers may be larger than normal with an increase in sarcolemmal nuclei.

Mitochondrial Myopathies

I. Mitochondrial myopathies (cytopathies) are rare multisystem diseases that mainly affect the central nervous and musculoskeletal systems. Abnormal mitochondria are found in the periphery of skeletal muscle fibers, which have a characteristic “ragged-red” appearance when stained with the modified trichrome stain.

II. Four of these entities are of major ophthalmic importance: Leber’s hereditary optic atrophy; chronic progressive external ophthalmoplegia (CPEO); Kearns–Sayre syndrome (KSS); and the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS).

The inheritance of these point mutations of mitochondrial DNA is from mothers alone because the mitochondrial contribution to the embryo comes only from the maternal ovum.

A. Leber’s hereditary optic atrophy (see Chapter 13)

B. CPEO

1. CPEO is a slowly progressive, bilaterally symmetric, ocular muscle dystrophy that starts in late childhood or adulthood. It is inherited through the maternal transmission of one or more mitochondrial large-deletion DNA mutations.

2. Ptosis, external ophthalmoplegia, and often a pigmentary retinopathy can be seen.

3. Histology of muscle fibers includes atrophy, large variation in diameter, and granular and vacuolar degeneration; absence of glycogen, cross-striations, myofibrillar structure, and succinic dehydrogenase; fibrous and fatty replacement of tissue; and preservation of myelinated nerve fibers and myoneural junctions.

Mitochondria of selective muscle fibers appear abnormal in size, shape, number, and internal structure, whereas others seem normal, resembling the changes found in Leber’s hereditary optic atrophy. Because the modified trichrome stain colors the abnormal muscle fibers red, the fibers have been called ragged-red fibers.

C. KSS

1. KSS consists of the triad of external ophthalmoplegia, pigmentary retinopathy, and heart block. Other findings include mental retardation, hearing loss, endocrinopathy, and cerebellar ataxia.

2. KSS is inherited through the maternal transmission of one or more mitochondrial large-deletion DNA mutations.

3. Histologically, along with the characteristic ragged-red appearance seen under light microscopy with the modified trichrome stain, electron microscopy shows well-preserved, swollen mitochondria containing circular cristae or granular deposits.

D. MELAS (Fig. 14.11)

1. MELAS usually has an abrupt onset before the age of 15 years with symptoms of visual loss, hemiparesis or hemianopia, strokelike episodes, headaches, and convulsions.

2. Patients have short stature and increased serum and cerebrospinal fluid lactate levels.

3. MELAS is inherited through the maternal transmission of one or more mitochondrial point DNA mutations (nucleotide positions 3243 and 3271).

4. Ocular findings include external ophthalmoplegia, atypical pigmentary retinopathy, and nuclear cataract.

5. Histologically, along with the characteristic ragged-red appearance seen under light microscopy with the modified trichrome stain, electron microscopy shows an increased number of mitochondria containing abnormal cristae.

a. The eyes show abnormalities of the macular photoreceptor–retinal pigment epithelium (RPE)–choriocapillaris complex, namely absent or degenerated outer segments and hyperpigmented and hypopigmented RPE.

1) The cytoplasm of RPE cells show ballooned, structurally abnormal (“giant”) mitochondria.

2) The photoreceptor inner segments demonstrate markedly altered mitochondria (increased number, loss of cristae, circular cristae, ballooned mitochondria, and paracrystalline inclusions).

b. Abnormal mitochondria are also found in choriocapillaris endothelial cells and smooth muscle cells of choroidal and retinal blood vessel walls.

Fig. 14.11 Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome. A, Complete external ophthalmoplegia present in 20-year-old woman. B, Fundus shows a fine, dustlike, “salt-and-pepper” appearance. C, Microscopic section of degenerated extraocular muscles stained with trichrome shows “ragged-red” fibers. D, Cytoplasm of retinal pigment epithelial cells packed with many ballooned, structurally abnormal (“giant”) mitochondria. (Case presented by Dr. R Folberg to the meeting of the Verhoeff Society, 1993, and reported in Rummelt V, Folberg R, Ionasescu V et al.: Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation. Ophthalmology 100:1757. © Elsevier 1993.)

Dermatomyositis

I. Dermatomyositis is a collagen disease of unknown cause with a poor prognosis; death is a frequent outcome.

II. Men predominate and may acquire the disease in childhood.

III. Conjunctivitis, iritis, ptosis, paralysis of external ocular muscles, horizontal nystagmus, and exophthalmos may be present.

Erythematous, edematous patches of skin are frequently seen. A predilection for the face and periorbital region exists, where a violaceous heliotrope may occur around the eyes, on the lids, and on the cheeks.

IV. A retinitis may be seen with superficial whitish exudates in the macula, and round and flame-shaped hemorrhages.

V. Histologically, lymphocytes are present in the muscles (myositis) and in the walls of blood vessels (vasculitis), giving a picture of a nonspecific chronic nongranulomatous inflammation.

Neoplasms and Other Tumors³

See Box 14.2 for classification of neoplasms and other tumors.

Box 14.2

Classification of Neoplasms and Other Tumors

PRIMARY ORBITAL TUMORS

Choristomas

Epidermoid cyst ^†

Dermoid cyst ^† (see Figs. 14.12 and 14.13)

Teratoma ^‡ (see Fig. 14.14)

Ectopic lacrimal gland ^‡ (see Fig. 14.15)

Hamartomas

Phakomatoses ^† (see Chapter 2)

Hemangioma

Capillary hemangioma ^† (see Figs. 14.16 and 14.17)

Cavernous hemangioma ^† (see Fig. 14.18)

Arteriovenous communication ^‡ (see Chapter 2)

Telangiectasia ^‡ (see Chapter 2)

Lymphangioma ^† (see Fig. 14.19)

Mesenchymal Tumors

Vascular

Hemangiopericytoma ^‡

Glomus tumor ^‡ (see Fig. 14.20)

Hemangiosarcoma ^‡

Kaposi’s sarcoma ^‡ (see Fig. 14.21)

Fatty

Lipoma ^† (see Fig. 14.22)

Liposarcoma ^‡ (see Fig. 14.23)

Fibrous

Reactive fibrous proliferations

Nodular fasciitis ^†

Juvenile fibromatosis ^‡

Neoplastic fibrous proliferations

Fibrous histiocytoma ^† (see Fig. 14.24)

Fibroma ^‡ and fibrosarcoma^‡ (see Fig. 14.25)

Solitary fibrous tumor ^‡

Giant cell angiofibroma ^‡

Muscle

Leiomyoma (see Fig. 14.26)^‡ and leiomyosarcoma^‡

Mesectodermal leiomyosarcoma ^‡ (see Chapter 9)

Rhabdomyoma ^‡

Rhabdomyosarcoma ^† (see Figs. 14.27 and 14.28; see also Fig. 17.29)

Cartilage

Chondroma ^‡ and chondrosarcoma^‡

Bone

Aneurysmal bone cyst ^‡

Fibrous dysplasia ^† (see Fig. 14.29)

Giant cell tumor ^‡

Juvenile fibromatosis ^‡

Leontiasis ossea ^‡

Osteitis Fibrosa Cystica ^†

Osteopetrosis ^‡

Paget’s disease ^†

Osteoma ^‡ and osteogenic sarcoma (osteosarcoma)^‡

Neural Tumors

Amputation neuroma ^‡

Neurofibromas ^† (see Chapter 2)

Neurilemmoma ^† (see Figs. 14.30 and 14.31)

Juvenile pilocystic astrocytoma ^† (see Chapter 13)

Peripheral primitive neuroectodermal tumors (PNETs)^‡ (see Fig. 14.32)

Miscellaneous Tumors

Meningioma ^† (see Chapter 13)

Nonchromaffin paraganglioma ^‡

Granular cell tumor ^‡ (see Fig. 14.33)

Alveolar soft-part sarcoma ^‡ (see Fig. 14.34)

Malignant melanoma ^‡ (see Chapter 17)

Endodermal sinus tumor ^‡

Epithelial Cysts and Neoplasms of Lacrimal Gland

Lacrimal ductal cysts ^†

Benign mixed tumor ^† (see Fig. 14.35)

Malignant mixed tumor ^† (see Fig. 14.36)

Adenoid cystic carcinoma ^† (see Fig. 14.37)

Other types of carcinoma ^‡ (see Fig. 14.38)

Reticuloendothelial System, Lymphatic System, and Myeloid System

Reticuloendothelial system

Langerhans’ granulomatoses (histiocytosis X)^†

Eosinophilic granuloma ^† (see Fig. 14.39)

Hand–Schüller–Christian disease ^†

Letterer–Siwe disease ^‡ (see Fig. 14.40)

Juvenile xanthogranuloma ^† (see Chapter 9)

Sinus histiocytosis ^‡ (see Fig. 14.41)

Inflammatory pseudotumor ^† (see Fig. 14.42)

Malignant lymphoma ^† (see Figs. 14.44, 14.45, 14.48, and 14.49)

Leukemia ^† (see Fig. 14.50)

Multiple myeloma ^‡ (see Fig. 14.51)

Monoclonal and polyclonal gammopathies ^‡

SECONDARY ORBITAL TUMORS

Direct Extension ^† (see Fig. 14.52)

Metastatic ^†

^† The tumor is common, important, or both.

^‡ The tumor is uncommon, unimportant, or both.

Primary Orbital Tumors

I. Choristomas—these are congenital tumors not normally present at the involved site.

A. Epidermoid cyst ^†

1. An epidermoid cyst is composed of epidermis (i.e., stratified squamous epithelium with no epidermal appendages in the wall of the cyst) and contains desquamated keratin in the cyst, which appears as a cheesy material.

a. An epidermoid cyst tends to occur in the superotemporal aspect of the orbit, often anterior to the septum orbitale.

Rarely, an epidermoid cyst may originate in the diploic space of the orbital bone, called an intradiploic epidermoid cyst. Also rarely, squamous cell carcinoma may develop in an epidermoid or dermoid cyst.

b. A much rarer type of congenital epithelial cyst is called primary nonkeratinized epithelial cyst (“conjunctival cyst”; see Figs. 14.12D and 14.12E). It is usually found in the superonasal aspect of the orbit, is lined by nonkeratinizing epithelium that resembles conjunctival epithelium, contains no adnexal structures in its wall, and is filled with clear fluid.

Fig. 14.12 Dermoid cyst. A, A dermoid tumor is present in its most common location: the superior temporal portion of the orbit. B, Gross examination of the cut surface of the tumor shows a cyst filled with “cheesy” material. C, A histologic section, viewed using polarized light, shows a cyst lined by stratified squamous epithelium. Hair follicles (which contain birefringent hair shafts) and other epidermal appendages are contained in the wall of the cyst. The cyst itself contains keratin debris (k) and hair shafts (s) that are birefringent in the polarized light (f, hair follicle; w, wall of cyst). D and E, A much rarer type, found in the superonasal quadrant, containing clear fluid, and lined by nonkeratinizing epithelium, is called primary nonkeratinized epidermoid cyst (“conjunctival cyst”). The cyst in D and E contained adnexal structures in its wall. (A, Courtesy of Dr. JA Katowitz.)

2. Histologically, a congenital epidermoid cyst and an acquired (usually secondary to trauma) epithelial inclusion cyst appear identical.

B. Dermoid cyst ^† (Fig. 14.12)

1. A dermoid cyst is probably a result of the sequestration of surface ectoderm pinched off at bony suture lines or along lines of embryonic closure.

a. It is most often found in the superotemporal quadrant of the orbit (rarely, a dermoid may occur in the lateral rectus muscle).

b. A dermoid may have a pedicle attached to the periorbita and may produce bony changes detectable on radiography.

c. A much rarer type, which is lined by nonkeratinizing epithelium (resembling conjunctival epithelium), contains adnexal structures in its wall and is filled with clear fluid; it is called primary nonkeratinized epidermoid cyst (“conjunctival cyst”).

Primary nonkeratinized epidermoid cysts probably represent developmental sequestrations of forniceal or caruncular conjunctival epithelium. They are found in the superonasal quadrant (see Figs. 14.12D and 14.12E) and are not associated with an osseous defect. They constitute approximately 75% of the superonasal dermoids, the other 25% being the typical dermoids lined by keratinizing squamous epithelium.

2. Histologically, a dermoid cyst, derived from ectoderm, is composed of a wall surrounding a cavity.

a. The wall is lined by keratinizing, stratified squamous epithelium and contains epidermal appendages (e.g., hair follicles, sebaceous glands, and sweat glands).

Rupture of a dermoid cyst can cause a chronic granulomatous inflammatory reaction (Fig. 14.13). Rarely, squamous cell carcinoma may develop in an epidermoid or dermoid cyst.

Fig. 14.13 Dermoid cyst. Rupture of the dermoid cyst has caused a chronic granulomatous inflammatory reaction.

b. The cavity contains desquamated keratin, hair shafts, and debris.

C. Teratoma ^‡ (Fig. 14.14)

1. An orbital teratoma is an embryonic tumor composed of all three embryonic germinal cell layers (ectoderm, endoderm, and mesoderm).

A rare teratoma has been reported in an intraocular location. A teratoma can also have both an orbital and an extraorbital (limited intracranial extension) or periorbital (beneath the skin and scalp) location.

2. It characteristically causes massive exophthalmos at birth and may contain structures such as stratified squamous epithelium, colonic mucosa, and central nervous system tissue.

3. It has malignant potential and may also involve the eye.

Fig. 14.14 Teratoma. A, Child presented with a cystic eyeball protruding between the left eyelids. B, Computed tomography scan shows cystic structures extending back into brain. C, Removal of left orbital cystic contents showed a large teratoma, which was behind an atrophic eyeball. The teratoma contained many choristomatous structures, including intestinal tract lined by colonic mucosa. (A and B, Courtesy of Dr. JA Katowitz.)

D. Cholesterol granuloma and cholesteatoma (see previously in this chapter)

E. Ectopic lacrimal gland ^‡ (Fig. 14.15)

1. Ectopic lacrimal gland consists of lacrimal gland tissue found anywhere except in the lacrimal fossa. It may be associated with other choristomatous tissues such as muscle, nerve, cartilage, or various dermal appendages, or it may occur alone.

2. It usually causes symptoms only when inflamed; the origin of the inflammation is unknown.

3. Histologically, it is composed of relatively normal-looking lacrimal gland tissue with a mild inflammatory infiltrate of lymphocytes and plasma cells.

Fig. 14.15 Ectopic lacrimal gland. A, Proptosis of left eye. B, Biopsy of retrobulbar mass, which was not connected to the lacrimal gland, shows glandular tissue that resembles lacrimal gland, with foci of chronic nongranulomatous inflammation. (A, Courtesy of Dr. HG Scheie.)

II. Hamartomas—these are congenital tumors normally found at the involved site.

A. Phakomatoses (see Chapter 2)

B. Hemangioma

1. Capillary hemangioma (“cherry” hemangioma)^† (Fig. 14.16)

a. Capillary hemangioma, the most common periocular vascular tumor in infancy and childhood, is usually solitary, bright red, and smooth.

Another form occurs in middle-aged or older people, often those with cardiovascular problems.

b. Usually, a capillary hemangioma begins before two months of age, reaches maximum size by 6–12 months, and then tends to regress (involute) spontaneously by 4–7 years. Although it usually regresses, it can cause deprivation or anisometropic amblyopia, strabismus, and other problems before regression is attained.

c. A form of capillary hemangioma is found in angiomatosis retinae (see Chapter 2).

d. A variant of capillary hemangioma, often called hemangioendothelioma (Fig. 14.17), is observed at birth (20%), infancy, or early childhood. Typically, it appears suddenly, grows rapidly, and is characterized by relatively solid cords of round, multilayered endothelial cells with little or no evidence of lumen.

The tumor has also been called benign hemangioendothelioma and strawberry, infantile, and juvenile hemangioma. The lesion, although benign, may arise in a number of areas simultaneously and thereby simulate invasion and malignancy. The tumor almost always regresses spontaneously. Histologically, it consists mainly of plump endothelial cells, some of which form a capillary lumen.

e. Histologically, the capillary hemangioma is composed primarily of capillaries lined by plump endothelial cells.

Fig. 14.16 Capillary hemangioma. A, Clinical appearance of tumor. B, Tumor composed of blood vessels of predominantly capillary size. C, High magnification shows capillaries and endothelial cells.

Fig. 14.17 Hemangioendothelioma variant of capillary hemangioma. A, Child shows diffuse thickening of right upper lid. B, Biopsy shows tumor composed primarily of endothelial cells and occasional capillaries. C, High magnification shows endothelial cells. (A, Courtesy of Dr. RE Shannon.)

2. Cavernous hemangioma ^† (orbital cavernoma) (Fig. 14.18)

a. Cavernous hemangioma is the most common primary orbital tumor producing exophthalmos.

b. It may press on the coats of the eye and cause chorioretinal striae.

c. It is a well-encapsulated tumor, usually within the muscle cone, and can often be shelled out easily with little or no bleeding.

Rarely, the tumor may arise in the orbital bones. Even more rarely, the tumor may be associated with the blue rubber bleb nevus syndrome (multiple cutaneous and visceral bluish-red, rubbery hemangiomas; may be autosomal dominant but most cases are sporadic). If bilateral orbital hemangiomas are present, they may be part of the blue rubber bleb nevus syndrome or Maffuci’s syndrome (nonhereditary disease characterized by hemangiomas and enchondromas).

d. No feeder vessels are demonstrated by dye study techniques.

Rarely, a cavernous hemangioma may bleed and give rise to a hematic cyst. The cyst contains birefringent crystals and altered blood that seem to initiate a granulomatous inflammation (similar to a cholesterol granuloma; see previously in this chapter). Other causes of hematic cyst include blunt trauma, spontaneous orbital hemorrhage, blood dyscrasias, vascular disease, and lymphangioma.

e. Histologically, it is composed of large, blood-filled spaces, lined by endothelium and separated by fibrous septa ranging from quite thin to fairly thick. The endothelial cells of hemangiomas give a strong reaction for factor VIII-related antigen (FVIII-RAG).

Fig. 14.18 Cavernous hemangioma. A, Clinical appearance of left exophthalmos. B, Pressure of tumor on optic nerve has caused optic disc edema. C, Magnetic resonance imaging shows optic nerve stretched over tumor in T1-weighted image. D, Tumor “lights up” in T2-weighted image, characteristic of a hemangioma. E, Gross appearance of surgically removed hemangioma. F, Histologic section shows large, blood-filled spaces of tumor lined by endothelium and separated by fibrous septa of different thicknesses. (Case presented by Dr. WC Frayer to the meeting of the Verhoeff Society, 1989.)

3. Arteriovenous (AV) communication ^‡

a. AV communication (arteriovenous or varix aneurysm; tumor cirsoides; angiomatous malformation; cirsoid, serpentine, plexiform, racemose, or cavernous angioma) is a rare malformation or developmental anomaly between the arterial and venous systems.

b. It occurs in AV communication of retina and brain or as an incidental finding.

c. Histologically, it is composed of mature blood vessels that may be hypertrophied. The malformation seems to be a mature artery (albeit hypertrophied) that is becoming a mature vein (also often hypertrophied) without passing through a vascular (i.e., capillary) bed.

4. Telangiectasia ^‡

a. Telangiectasia of the orbit is rare.

b. Telangiectasia is found in meningocutaneous angiomatosis (see Chapter 2), ataxia–telangiectasia (see Chapter 2), and Osler–Rendu–Weber disease (see Chapter 7).

c. Histologically, it is composed of dilated and tortuous capillaries.

C. Lymphangioma ^† (Fig. 14.19)

Often, lymphangiomas contain both venous and lymphatic components; hence, another term for the lesions is combined venous lymphatic malformations. The lesions may be associated with noncontiguous intracranial vascular anomalies.

1. Frequently, the clinical onset of lymphangioma is in children younger than 10 years of age.

2. It may diffusely involve the orbit, conjunctiva, and lids, and it tends to be invasive and slow-growing.

a. Clinically at presentation, proptosis occurs in 85% of cases, blepharoptosis in 73%, and restriction of eye movements in 46%.

b. Although retinal folds may be seen, compressive optic neuropathy is rare.

3. The tumor probably regresses somewhat in time but easily becomes infected.

4. Histologically, it is composed of lymph-filled spaces of different sizes, lined by endothelium and separated by thin, delicate walls. Hemorrhage in the lesion produces a “chocolate cyst.”

Fig. 14.19 Lymphangioma. A, Patient developed acute proptosis of right eye. B, Computed tomographic appearance of retrobulbar tumor. C, Histologic section of surgically removed specimen shows tumor composed of lymph-filled spaces of varying sizes (some of the spaces contain blood). Note lymphoid collections in walls of tumor. D, Other areas show older blood (hemosiderin) in the lumen and septum that stains positively with Perl’s stain for iron (blue color in E). Presumably, a hemorrhage into the lymphangioma caused the acute exophthalmos.

III. Mesenchymal tumors

A. Vascular

1. Hemangiomas and lymphangioma (see previously under discussion of hamartomas)

2. Hemangiopericytoma ^‡

a. This rare orbital tumor is most common in the fourth decade.

b. It may be malignant in 12–57% of cases (varies according to authors’ series—it seems that the longer the follow-up, the greater the mortality rate from the tumor).

c. The clinical course cannot always be predicted from the histologic appearance, especially when the cytology “appears” benign.

d. The tumor probably arises from pericytes.

“Angioblastic type” of meningioma, once thought to be of meningeal origin, is now generally accepted to be a hemangiopericytoma of the central nervous system.

e. Histologically, an increased number of thin-walled vascular channels are separated by tumor cells in a network of extracellular material.

1) Perivascular massing of pericytes is present. The cell morphology is uniform.

2) Silver-stained material reveals reticulin characteristically segregating cells into groups.

The tumor is more likely to be malignant if the following occur: increased mitotic activity (>4 mitotic figures per 400 field), necrotic foci, pleomorphism, S-phase greater than 9, and a proliferative index greater than 11 (the last two determined by cell cycle analysis). Hemangiopericytoma resembles the vascular form of fibrous histiocytoma (FH; see later in this chapter).

3) Focal staining for vimentin, CD34, and factor XIIIa occurs.

3. Glomus tumor (glomangioma ^‡; Fig. 14.20)

a. The tumor, composed of smooth muscle-derived glomus cells, is a very rare tumor and occurs in two forms: a solitary form and a familial form that shows multiple tumors involving face, palate, eyelid, and anterior orbit.

b. Histologically, small vessels lined by a single layer of endothelial cells are surrounded by one or more layers of glomus cells.

1) The cells are round and have small, round nuclei and clear cytoplasm.

2) Immunohistochemically, the cells are positive for muscle-specific actin and vimentin, and they are negative for factor VIII and other endothelial markers.

Fig. 14.20 Glomus tumor. A, A bluish tumor is present in the right lower lid. B, Histologic section shows vascular spaces lined by a single layer of endothelial cells and surrounded by layers of glomus cells. (Presented by Dr. NC Charles to the meeting of the Eastern Ophthalmic Pathology Society, 1975, and reported in Charles NC: Multiple glomus tumors of the face and eyelid. Arch Ophthalmol 94:1283, 1976. © American Medical Association. All rights reserved.)

4. Hemangiosarcoma ^‡ (angiosarcoma, malignant hemangioendothelioma)

a. This is a rare orbital tumor.

Intravascular papillary endothelial hyperplasia, a benign lesion, has been confused with hemangiosarcoma. Another benign lesion, probably a reactive or immunologic inflammatory process, angiolymphoid hyperplasia with eosinophilia (Kimura’s disease; see later in this chapter), has also been mistaken for hemangiosarcoma.

b. Histologically, it is composed of intercommunicating channels or irregular vascular spaces lined by atypical endothelial cells confined in a thin reticulin network.

1) The endothelial cells may form a single layer, proliferate in focal areas, or produce papillary projections. The endothelial cells stain positively for FVIII-RAG and Ulex europaeus agglutinin I.

2) Marked histologic variation is seen in the tumor and from tumor to tumor.

5. Kaposi’s sarcoma (KS ^‡; Fig. 14.21)

a. KS, previously a disease of elderly men of Mediterranean or Eastern European Jewish ancestry, young black African men, or chemotherapy-immunosuppressed patients, now is mostly associated with acquired immunodeficiency syndrome (AIDS).

Approximately 20% of patients who have AIDS also have KS (second only to Pneumocystis carinii infection as a presenting manifestation). In addition to AIDS, an association exists between KS and other cancers such as malignant lymphoma (especially Hodgkin’s disease), leukemia, or a primary carcinoma with a separate histogenesis.

b. KS is a multicentric vascular neoplasm that affects skin, mucous membranes, internal organs, and lymph nodes. It may present in the bulbar conjunctiva as the initial clinical manifestation of AIDS.

Herpesvirus-like DNA sequences (KSHV) have been found in classic, endemic, and AIDS-associated KS. KSHV is also associated with lesions other than KS in non-AIDS-immunosuppressed patients, and it may be involved in the pathogenesis of the various forms of proliferative skin lesions in organ transplant recipients. The human herpesvirus 8 (HHV-8) is the infectious agent responsible for KS in patients with or without human immunodeficiency virus infection. The latent nuclear antigen-1 (LNA-1) of HHV-8 is a nuclear antigen expressed in all cells latently infected by the virus.

c. Characteristically, it originates as a bluish-red skin macule, often on the lower extremities, that multiplies, coalesces, and eventually spreads to internal viscera.

d. Approximately 22% of patients with AIDS have involvement of the lids and conjunctiva, often as multifocal tumors.

e. Histologically, it is composed of many foci of capillary clusters in a stroma of malignant spindle cells. KSHV is a reliable marker (by polymerase chain reaction) to distinguish KS, particularly at its early stage, from other vascular lesions.

1) Type I consists of a flat lesion with thin, dilated vascular channels lined by flat endothelial cells with lumen-containing erythrocytes.

2) Type II consists of a flat lesion with plump, fusiform endothelial cells, often containing hyperchromic nuclei, and foci of immature spindle cells and occasionally slit vessels.

3) Type III consists of a nodular (>3 mm in height) lesion with large aggregates of densely packed spindle cells containing hyperchromic nuclei, occasional mitotic figures, and abundant slit vessels, often with erythrocytes in between.

Commonly, the tumor is admixed with lymphocytes, hence the term malignant granulation tissue. The endothelial cells lining well-formed tumor blood vessels give a strong reaction with immunohistochemical staining for FVIII-RAG when the peroxidase–antiperoxidase technique is used. The proliferating spindle cells that form the capillary clusters (“vascular slits”), however, give a negative reaction.

Fig. 14.21 Kaposi’s sarcoma. A, A patient who was subsequently found to have the acquired immunodeficiency syndrome presented with a conjunctival tumor. B, Biopsy shows neoplastic cells that contain spindle-shaped nuclei and conspicuous nucleoli that are forming bundles or are lining vascular clefts. C, A mitotic figure is seen. (Case reported by Bedrick JJ, Savino PJ, Schatz NH: Conjunctival Kaposi’s sarcoma in a patient with myasthenia gravis. Arch Ophthalmol 99:1607, 1981. © American Medical Association. All rights reserved.)

B. Fatty

1. Lipoma ^† (Fig. 14.22)

a. It is easier to determine clinically than histologically whether a tumor is a primary orbital lipoma or herniated orbital fat.

Variants of benign lipoma include angiolipoma, angiomyolipoma, spindle cell lipoma, pleomorphic lipoma, benign lipoblastoma, and hibernoma (multivacuolar brown fat cells).

b. Histologically, a lipoma is composed of groups of mature, univacuolar, white, fat cells separated from other groups by delicate fibrovascular septa.

1) Coarser septa divide the tumor into lobules.

2) A true lipoma usually has a thin, fibrous capsule.

Fig. 14.22 Lipoma. A, Clinical appearance of lipoma of right brow. B, Gross specimen of another case in a 14-year-old girl has “fatty” appearance. C, Microscopic section shows that the tumor is composed of lobules of mature fat separated from each other by delicate fibrovascular septa. (A, Courtesy of Dr. WR Green; B and C, presented by Dr. CJ Lee Jr to the meeting of the Eastern Ophthalmic Pathology Society, 1989.)

2. Liposarcoma ^‡ (Fig. 14.23)

a. This extremely rare orbital tumor may be primary or secondary to radiation therapy.

b. It may be part of the Li–Fraumeni syndrome, an autosomal dominantely inherited tumor-suppressor (p53) gene mutation.

c. Histologically, liposarcomas tend to be well differentiated or myxoid.

1) The tumors are composed of univacuolar signet-ring lipoblasts.

2) Scattered, bizarre, hyperchromatic cells without prominent lipidization may also be present.

Fig. 14.23 Liposarcoma. A, A 78-year-old man has swelling and ptosis of the left upper lid. B, Computed tomography scan shows a mass superior to the globe. C, Appearance of gross specimen. D, Microscopic section shows bizarre lipoblasts. (Presented by Dr. CJ Lee Jr to the AOA–Armed Forces Institute of Pathology Alumni meeting, 1989.)

C. Fibrous–histiocytic–reactive

1. Nodular fasciitis ^† (also called subcutaneous pseudosarcomatous fibromatosis, pseudosarcomatous fasciitis, and nodular fibrositis)

a. This is a benign proliferation of connective tissue that clinically presents as a rapidly growing mass.

b. Histologically, it is composed of nodular proliferations of plump, stellate, or spindle-shaped fibroblasts arranged in parallel bundles or haphazardly (the cells resemble tissue culture fibroblasts).

1) A variable amount of intercellular myxoid ground substance is present.

2) Abundant reticulin fibers and moderate numbers of collagen fibers can be demonstrated.

3) Proliferation of slitlike vascular spaces or well-formed capillaries is characteristic.

2. Juvenile fibromatosis ^‡ (psammomatoid ossifying fibroma)

a. This is usually seen in children.

The group of tumors includes keloids, desmoids, fibromatoses of palmar and plantar fascias and of sternomastoid muscle, radiation fibromatosis, and congenital progressive polyfibromatosis.

b. It may recur after excision and is frequently mistaken for fibrosarcoma.

c. Histologically, it is composed of fibrous tissue interlacing with numerous mature capillaries.

A rare tumor in infants contains both fibroblastic and smooth muscle elements and is called infantile myofibromatosis.

D. Fibrous–histiocytic–neoplastic

1. Fibrous histiocytoma (FH)^† (xanthoma; Fig. 14.24)

Xanthoma consists of an intracellular accumulation of fat, as opposed to a lipogranuloma, which is composed of an extracellular accumulation of fat.

a. FH is the most common primary mesenchymal orbital tumor of adults.

FH has been misdiagnosed as hemangiopericytoma, sclerosing hemangioma, dermatofibrosarcoma protuberans (DFSP), and even neurofibroma. When associated with multinucleated giant cells and lipid-filled histiocytes, it has been misdiagnosed as synovial giant cell tumor and villonodular synovitis.

b. FH may involve ocular structures such as orbit (most commonly), lids, conjunctiva, and corneoscleral limbus.

c. Although its cell of origin has been thought to be the histiocyte or the fibroblast, it is most probably a primitive mesenchymal cell that shows divergent lines of differentiation, expressing fibroblastic, histiocytic, and even myofibroblastic phenotypes.

d. A variant of FH that forms no fibers at all and is entirely composed of histiocytes is called a histiocytoma.

e. FH has a malignant potential.

Malignant FH (MFH) is considered to be a sarcoma having an undifferentiated mesenchymal cell origin that differentiates along a broad fibroblastic and histiocytic (fibrohistiocytic) spectrum and usually has a predominant “fibroblastic” component. It may be difficult to differentiate from other pleomorphic soft-tissue tumors, such as pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant schwannoma, leiomyosarcoma, and epithelioid sarcoma—a very rare orbital malignancy presumably of tendon sheath origin, having both epithelial and mesenchymal features. KP-1 (CD68), a recently described monoclonal antibody to a cytoplasmic epitope present on tissue histiocytes and macrophages, may have specific marker properties to help identify MFH. Vimentin also is usually positive. Finally, molecular assays for specific gene fusion provide a genetic approach to the differential diagnosis of soft-tissue sarcomas.

f. Histologically, FH shows a characteristic, diphasic pattern with mainly “storiform” (matted) areas composed of fibrous spindle cells along with scattered areas showing single or grouped foamy histiocytes.

1) FH can be richly vascularized and then easily confused with hemangiopericytoma.

2) MFH shows a mixture of storiform and pleomorphic features.

Fig. 14.24 Fibrous histiocytoma. A, This is the fourth recurrence of an orbital tumor that had first been excised 10 years previously. The histology of the primary lesion and of the four recurrences appears identical. B, A histologic section shows the diphasic pattern consisting of a histiocytic component (h) (mainly on far left) and a fibrous component (f). C, Increased magnification shows that the fibrous component forms a storiform or matted pattern. Controversy exists as to whether the tumor arises from histiocytes or fibroblasts (most of the evidence points toward a primitive mesenchymal cell origin). (Case reported in Jones WD III, Yanoff M, Katowitz JA: Recurrent facial fibrous histiocytoma. Br J Plast Surg 32:46, 1979. © 1979 with permission from Elsevier.)

2. Atypical fibroxanthoma (AFX)^‡

a. AFX usually occurs in the sun-damaged skin of the head and neck in the elderly.

b. Histologically, spindle cells and pleomorphic polyhedral cells occur with many giant cells and mitotic figures.

1) Despite its anaplastic appearance, AFX is regarded as a low-grade malignant tumor, usually acts benign, but rarely may metastasize.

2) Immunohistochemically, AFX and dermatofibrosarcoma (DFSP) (see later) stain nearly identically: negative for cytokeratin, desmin, S-100 protein, and melanoma antibodies HMB-45 and HMB-50; strongly positive for vimentin and NKI/C3; and variable positivity for muscle-specific actin (HHF-35).

Although AFX and DFSP can be confused with spindle cell, squamous cell carcinoma and desmoplastic malignant melanoma, the absence of cytokeratin, HMB-45, and HMB-50 staining easily distinguishes AFX and DFSP from the others.

3. Dermatofibrosarcoma (DFSP)^‡

a. DFSP usually occurs in young or middle-aged persons as large cutaneous nodules.

b. Histologically, DFSP is composed of relatively uniform spindle cells with a conspicuous storiform pattern (similar to FH except for the lack of a histiocytic component).

1) DFSP is regarded as a low-grade malignant tumor, usually acts benign, but extremely rarely may metastasize.

2) Immunohistochemically, DFSP and AFX (see previously) stain nearly identically.

4. Fibroma ^‡ and fibrosarcoma^‡

a. True orbital fibroma is rare.

An even rarer tumor is the elastofibroma, which consists of a fibrous proliferation of abundant elastinophilic polymorphic structures.

Histologically, orbital fibroma is composed of scattered spindle-shaped cells, sometimes showing a herringbone pattern, but lacking atypia and mitotic figures.

b. Fibrosarcoma (Fig. 14.25) is a very rare, slow-growing, orbital, spindle-cell tumor.

Fig. 14.25 Fibrosarcoma. A, A 60-year-old man presented with exophthalmos of left eye. B, Histologic section of removed orbital tumor shows well-differentiated fibrosarcoma with “herringbone” pattern and bland spindle nuclei. C, Recurrent tumor excised three years later by exenteration is much more cellular and less well differentiated than primary (shown with increased magnification in D). At time of death nine years later from a heart condition, two small tumors had developed (presumably recurrences)—one at temple over removed eye and other on cheek on same side. (From Yanoff M, Scheie HG: Fibrosarcoma of the orbit: Report of two cases. Cancer 19:1711, 1966. © American Cancer Society. Reproduced by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Histologically, fibrosarcoma is composed of interlacing bundles of spindle-shaped cells forming a herringbone pattern, often with atypical cells and mitotic figures.

5. Solitary fibrous tumor ^†

a. Solitary fibrous tumor is a rare tumor of mesenchymal origin that most often involves the pleura; rarely, the orbit is involved.

The tumor may arise from mesenchymal cells that show fibroblastic differentiation.

b. Although usually benign, it can recur locally and rarely metastasizes.

c. Histologically, usually strong CD34- and vimentin-positive spindle cells with elongated, wavy nuclei and inconspicuous nucleoli in hypocellular collagen-rich areas form a characteristic “patternless pattern.”

Solitary fibrous tumor resembles giant cell angiofibroma but lacks multinucleated giant cells and pseudovascular spaces.

6. Fibrous hamartoma of infancy ^‡

a. Benign solitary tumor (0.5–4.0 cm) present at birth or at a very young age and tends to grow slowly with age without malignant transformation.

b. Male to female ratio is 2 : 1.

c. Histologically, it consists of well-defined bundles of dense fibrocollagenous tissue, immature and primitive mesenchyme arranged in nests, concentric whorls or bands, and mature adipose tissue intimately admixed with the other components.

7. Giant cell angiofibroma ^‡

a. Giant cell angiofibroma, probably a benign tumor, occurs mainly in men from the third to the eighth decades.

b. Although most occur in the orbit, they can also occur in the lids and, rarely, conjunctiva.

c. Histologically, the tumors are richly vascularized and contain a patternless proliferation of spindle cells, numerous multinucleated giant cells, and some pseudovascular spaces, all embedded in variably collagenized stroma.

1) Myxoid stromal deposition may be present.

2) The spindle cells and multinucleated giant cells stain intensely positive with CD34 and vimentin.

Solitary fibrous tumor, which resembles giant cell angiofibroma, lacks multinucleated giant cells and pseudovascular spaces. Stains for KP1 (CD68) are negative, unlike in FH, in which they are positive.

E. Muscle

1. Leiomyoma ^‡ and leiomyosarcoma^‡ are very rare orbital tumors.

An even rarer tumor, composed of myofibroblasts surrounding a hemangiopericytoma-like stroma, is infantile myofibromatosis.

Histologically, leiomyoma (Fig. 14.26) consists of interlacing fascicles of smooth muscle cells.

a. Immunohistochemistry shows strong positivity for the sensitive marker muscle-specific actin and focal positivity for desmin.

b. Electron microscopy shows the characteristic findings for smooth muscle, namely cytoplasmic filaments associated with dense bodies, plasmalemmal densities, and pinocytotic vesicles, and investing thin basement membrane.

c. Leiomyosarcoma, in addition, shows atypical nuclei and mitotic figures.

Fig. 14.26 Leiomyoma. A, Tumor present in sclera of right eye. B, Histologic section shows fascicles of spindle cells against a vascular background. Spindle cells are positive for muscle-specific actin (C) and smooth muscle actin (D). (Presented by Dr. CL Shields to the meeting of the Eastern Ophthalmic Pathology Society, 1989; case reported in Shields CL, Shields JA, Varenhorst MP: Transscleral leiomyoma. Ophthalmology 98:84. © Elsevier 1991.)

2. Mesectodermal leiomyoma ^‡ (see Chapter 9) and leiomyosarcoma^‡ are very rare orbital tumors whose origin seems to be from tissue derived from neural crest.

3. Malignant rhabdoid tumor ^‡

a. Malignant rhabdoid tumor is a rare, highly aggressive renal tumor of infants.

1) The tumor rarely involves extrarenal sites in children and adults, and even more rarely involves the orbit.

2) Although its name, malignant rhabdoid tumor, implies a muscle origin, more likely the tumor arises from epithelium.

b. Histologically, the tumor is composed of dyscohesive, globoid, and eosinophilic cells, often containing cytoplasmic inclusions.

1) Immunohistochemically, the inclusions consist of whorls of vimentin-positive (intermediate) filaments, and the cells express epithelial membrane antigen and cytokeratin positivity (evidence of epithelial origin).

2) Electron microscopy shows intercellular junctions and interrupted segments of thin basement membrane material—further evidence of epithelial origin.

4. Rhabdomyoma ^‡ is a very rare, benign orbital tumor.

Histologically, well-differentiated rhabdomyoblasts are present.

5. Rhabdomyosarcoma ^†

a. Rhabdomyosarcoma is the most common malignant mesenchymal orbital neoplasm, and it is the most common primary malignant orbital tumor in children.

b. Although found in many parts of the body, rhabdomyosarcoma has a predilection for the orbit. It can also rarely occur in the eyelid, conjunctiva, and uveal tract.

c. The average age of onset is approximately 6 years, with most children younger than 10 years of age; it is extremely rare after 25 years of age.

d. The tumor is characterized clinically by a very rapid onset, often simulating an orbital cellulitis.

e. Three types exist: embryonal, differentiated, and alveolar.

f. Embryonal type (Fig. 14.27) is the most common type.

An undifferentiated tumor that resembles rhabdomyosarcoma, but without demonstrable rhabdomyoblasts, should be classified as embryonal sarcoma. Many of the metastases, however, show rhabdomyoblasts with cross-striations; then the classification embryonal rhabdomyosarcoma (or alveolar rhabdomyosarcoma, according to pattern) is appropriate.

1) When it arises in the submucosa of the conjunctiva, it is identical to the vaginal submucosal tumor of infancy, sarcoma botryoides.

2) Histologically, it is composed of malignant embryonal cells, rhabdomyoblasts, in a loose syncytial arrangement of fascicles of spindle cells running in a haphazard arrangement, usually showing frequent mitotic figures.

a) The cells are round, oval, elongate, or stellate, with nuclei rich in chromatin and cytoplasm rich in glycogen. A ribbon of eosinophilic cytoplasm may be seen around the nucleus.

Usually, only undifferentiated embryonal cells with large hyperchromic nuclei and a scant amount of cytoplasm are present. In some areas, however, cells with a ribbon of pink cytoplasm can be seen. Cross-striations are most likely to be found in these latter areas.

b) Cross-striations may sometimes be present in the metastases even though they were not found in the primary tumor.

c) Immunohistochemistry shows positivity for vimentin, myosin, myoglobin, muscle-specific actin, and desmin.

Insulin-like growth factor-2, which acts as an autocrine growth and motility factor, may be operating in rhabdomyosarcomas. The expression of the myogenic determination gene MyoD, a member of the helix–loop–helix family of transcription factors, is the most sensitive marker for rhabdomyosarcoma. Rhabdomyosarcomas seem to be deficient in a factor required for MyoD activity.

d) Electron microscopy shows, in better-differentiated tumors, the characteristic findings for striated muscle (formed sarcomeres containing interdigitated thick myosin and thin actin filaments outlined by transverse Z-bands), but in primitive cases it may show only focal myofilamentary differentiation.

Fig. 14.27 Embryonal rhabdomyosarcoma. A, The patient has a unilateral right ocular proptosis of very recent onset. Often, rhabdomyosarcoma presents rapidly, causes lid redness, and is mistaken for orbital inflammation. B, A histologic section shows a marked embryonic cellular pattern, hence the term embryonal rhabdomyosarcoma (a, relatively acellular area; b, blood vessels; c, relatively cellular area). C, Increased magnification of a cellular area shows the primitive nature of the rhabdomyoblasts; these tend to cluster in groups, separated by relatively acellular areas. D, A trichrome stain shows characteristic cross-striations (c) in the cytoplasm of some of the rhabdomyoblasts. Cross-striations, although not abundant in embryonal rhabdomyosarcoma, can be seen in sections stained with hematoxylin and eosin but are easier to see with special stains.

g. Differentiated type

1) The differentiated form of rhabdomyosarcoma is the least common type, but it seems to have the best prognosis.

2) Cross-striations are easily found in the differentiated type.

The adult pleomorphic form of rhabdomyosarcoma rarely, if ever, involves the orbit.

h. Alveolar type (Fig. 14.28)

1) The alveolar form of rhabdomyosarcoma seems to have the worst prognosis.

a) The diagnosis of alveolar rhabdomyosarcoma depends heavily on the presence of rearrangement of the FKHR (forkhead) gene located on chromosome 13q14. The tumor is characterized by a tumor-specific translocation, t(2;13)(q35;q14) and t(1;3)(p36;q14).

b) Molecular confirmation of alveolar rhabdomyosarcoma is important in the treatment of this tumor.

2) The individual cell type is similar to that seen in the embryonal type, but the tumor has a distinct alveolar pattern.

3) Some rhabdomyoblastic cell processes fuse to form the walls of the alveoli, whereas other rhabdomyoblasts lie free in the alveolar lumen.

4) It is the most difficult tumor in which to find cross-striations.

Molecular assays for specific gene fusion provide a genetic approach to the differential diagnosis of soft-tissue sarcomas.

Fig. 14.28 Alveolar rhabdomyosarcoma. A, This 21-year-old man presented with marked chemosis and proptosis of his left eye. B, A reticulin stain shows delicate septa, which give the tumor an alveolated appearance (hence the term alveolar rhabdomyosarcoma). C, Increased magnification shows that the cytoplasm of the rhabdomyoblasts makes up part of the septa (s, septa made up of cytoplasm of rhabdomyoblasts; a, “alveolus”; r, rhabdomyoblast nuclei). D, A trichrome stain shows typical cross-striations (c). Cross-striations are least abundant and most difficult to find in alveolar rhabdomyosarcoma. In the third type of rhabdomyosarcoma (differentiated), unlike in embryonal and alveolar types, most of the cells are differentiated, and cross-striations are easy to find.

i. Prognosis

1) If the tumor is confined to the orbit, the survival rate is 90% with a combination of chemotherapy and radiation.

2) If there is bone destruction and extension beyond the orbit exist, the survival rate decreases to 65%.

3) Most deaths occur within the first three years so that a five-year cure probably is a valid one.

4) DNA content is an important variable in predicting prognosis. DNA hyperdiploid and tetradiploid rhabdomyosarcomas have a favorable prognosis, whereas DNA diploid and polyploid tumors have a poor prognosis.

F. Cartilage—chondroma ^‡ and chondrosarcoma^‡

1. Chondroma and chondrosarcoma are extremely rare orbital tumors.

2. Chondrosarcoma may be congenital or may arise primarily without antecedent cause, but most frequently it follows radiation for retinoblastoma or pre-existing Paget’s disease.

Enchondroma, a tumor that originates from misplaced islands of cartilage in the intramedullary canal of bone, is extremely rare.

G. Bone (all are extremely rare orbital tumors)
Nonneoplastic and neoplastic diseases of bone usually cause exophthalmos by decreasing orbital volume.

1. Aneurysmal bone cyst ^‡

2. Fibrous dysplasia ^† (Fig. 14.29)

Fig. 14.29 Fibrous dysplasia. A (fundus OD) and B (fundus OS): A 13-year-old girl had a vision of 20/20 OD and 20/30 OS, a left afferent pupillary defect, and mild optic nerve pallor OS. C, Histologic section of sphenoid bone shows highly characteristic bone structure composed of moderately cellular and loosely textured fibrous connective tissue, enclosing poorly formed bone spicules, demonstrating both formative and resorptive changes, shown with increased magnification in D.

3. Giant cell tumor ^‡

4. Giant cell reparative granuloma ^‡

5. Juvenile fibromatosis ^‡ (psammomatoid ossifying fibroma)

6. Cholesterol granuloma ^‡ and cholesteatoma^‡ (see previously in this chapter)

7. Leontiasis ossea ^‡

8. Osteitis fibrosa cystica (brown tumor)^†

9. Osteopetrosis ^‡

10. Paget’s disease ^†

11. Osteoma,^‡ osteoblastoma,^‡ and osteogenic sarcoma (osteosarcoma)^‡

Osteomas may occur in Gardner’s syndrome, an autosomal-dominant disorder characterized by intestinal polyposis, various skin and soft-tissue tumors, retinal pigment epithelial hypertrophy, and osteomas. Osteogenic sarcoma (osteosarcoma)^‡ may rarely be primary, may be associated with Paget’s disease of bone, or may follow radiation for retinoblastomas.

12. Benign osteoblastoma ^‡

13. Ameloblastoma ^‡

IV. Neural tumors

A. Amputation neuroma ^‡

1. An amputation neuroma is rare in the orbit.

2. Histologically, it is composed of a haphazard entanglement of regenerated nerve fibers from the cut end of the peripheral ciliary nerve(s).

B. Neurofibromas ^† (see Figs. 2.3–2.5)

C. Neurilemmoma (schwannoma ^†; Figs. 14.30 and 14.31)

1. A neurilemmoma is a rare orbital tumor composed of neoplastic Schwann cells.

Even more rarely, the tumor may occur in the uveal tract or in the conjunctiva.

2. Histologically, nuclei of spindle-shaped Schwann cells show a tendency toward palisading.

a. When the texture is compact and composed of interwoven bundles of long bipolar spindle cells, often with ribbons of palisading cells alternating with relatively acellular areas, the Antoni type A pattern is present.

1) Areas of the tumor may mimic tactile corpuscles and are called Verocay bodies.

2) The tumor may have a haphazard arrangement, a loose texture, and mucinous and microcystoid areas of necrosis; this type of degenerative pattern is called the Antoni type B pattern.

b. The tumor is usually encapsulated in the perineurium of the originating nerve.

c. Immunohistochemistry shows positivity for human nerve growth factor (NGF), laminin, the major glycoprotein of basement membranes, HMB-45, and S-100 protein.

Immunohistochemistry may be quite helpful in differentiating the very rare melanotic neurilemmoma from a malignant melanoma, especially if the former arises in the choroid. A rare histologic variant of neurilemoma, called ancient schwannoma, shows distinctive areas of hypercellularity and hyperchromic nuclei suggesting fibrosarcoma, as well as hypocellular areas containing considerable fibrosis; the clinical course, however, tends to be benign.

d. Electron microscopy may show Luse bodies (see Fig. 14.31C; i.e., aggregates of long-spaced collagen).

3. Malignant peripheral nerve sheath tumor (malignant schwannoma, malignant neurilemmoma, neurofibrosarcoma, perineural fibrosarcoma, and neurogenic sarcoma)^‡ is extremely rare, but when present it is associated with neurofibromatosis in 50% of cases.

S-100 protein and NGF positivity and electron microscopic evidence of basement membrane material and mesaxon or pseudomesaxon formation help to identify these often poorly differentiated tumors.

Mutations in the p53 tumor suppressor gene, located on the short arm of chromosome 17 at position 17p13.1, represent the most frequent genetic alteration detected in human solid malignancies. In approximately half of all cancer cases, p53 is inactivated by mutations and other genomic alterations; in many of the remaining cases, p53 is functionally inactivated by the binding of the cellular MDM2 oncoprotein, a cellular inhibitor of the p53 tumor suppressor. The p53 gene encodes a 53-kDa nucleophosphoprotein that binds DNA and negatively regulates cell division, preventing progression from G₁ 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). This correlation may be especially applicable to malignant peripheral nerve sheath tumors.

4. Juvenile pilocytic astrocytoma (glioma) of optic nerve ^† (see Chapter 13)

Fig. 14.30 Neurilemmoma. A, Proptosis of the patient’s left eye had been present for many months and was increasing in size. An orbital tumor was removed. B, A histologic section shows ribbons of spindle Schwann cell nuclei, which show a tendency toward palisading. Areas of relative acellularity, mimicking tactile corpuscles, are called Verocay bodies. This pattern is called the Antoni type A pattern. C, Oil red-O stain shows that the cytoplasm of the tumor cells is clearly lipid-positive. D, In this area of necrosis, inflammatory cells and microcystoid degeneration are present, a pattern called the Antoni type B pattern.

Fig. 14.31 Neurilemmoma. A, A 61-year-old patient had decreased vision in the right eye for eight months. The computed tomography scan shows a right orbital mass. B, Histologic section was characteristic of neurilemmoma and, as seen in this figure, is positive for S-100 protein. C, Electron microscopy shows a Luse body (i.e., an aggregate of long-spaced collagen, arrow), often found in neurilemmomas. (Case presented by Dr. HE Grossniklaus to the meeting of the Verhoeff Society, 1994.)

D. Peripheral primitive neuroectodermal tumors (PNETs ^‡; Fig. 14.32)

1. PNETs are a group of soft-tissue tumors of presumed neural crest origin arising outside the central and sympathetic nervous system.

a. PNETs include adult neuroblastoma, neuroepithelioma, primitive neuroectodermal tumor of bone, and malignant small cell tumors of the thoracopulmonary region (Askin’s tumor).

b. All share in a chromosomal aberration translocation (11;22)(q24]2).

Ewing’s sarcoma also has the same genetic abnormality and may represent the opposite end of the same spectrum. However, despite their genetic and antigenic similarity, most authors recognize PNET and extraosseous Ewing’s sarcoma as separate entities, a distinction based primarily on the more neural differentiation of PNET and its graver prognosis.

c. Histologically, scattered nests of small tumor cells containing an even chromatin pattern, similar to Ewing’s sarcoma cells, are set in a highly desmoplastic stroma.

Ewing’s sarcoma stains positively for periodic acid–Schiff (PAS) stain, vimentin, and especially terminal deoxynucleotidyl transferase and MIC-2 (CD99), a cell surface glycoprotein encoded by genes on chromosomes X and Y. The histologic differentiation includes other small cell tumors such as lymphomas, rhabdomyosarcoma, neuroblastoma, PNET, nephroblastoma, small cell variant of osteosarcoma, and carcinomas with various degrees of neuroendocrine differentiation.

d. Immunohistochemically, the cells are positive for low-molecular-weight cytokeratin, epithelial membrane antigen, and neuron-specific enolase.

e. Electron microscopically, cytoplasmic processes, cytoplasmic glycogen, cytoplasmic filaments, and occasional neurosecretory granules are seen.

2. Adult neuroblastoma (one of the PNETs)

a. Adult neuroblastoma most rarely involves the orbit as a primary tumor.

b. The two-mutation model of tumorigenesis applies to neuroblastoma as well as to retinoblastoma.

c. More commonly, it is a childhood metastatic disease (see previously in this chapter).

Fig. 14.32 Peripheral primitive neuroectodermal tumor. A, Computed tomogram in a four-year-old child shows a large, homogeneous orbital mass behind the left eye. B, Biopsy shows small tumor cells containing an even chromatin pattern. C, The tumor cells stain positively for neuron-specific enolase. D, Electron microscopy demonstrates cytoplasmic neurosecretory granules.

V. Miscellaneous tumors

A. Meningioma ^† (see Chapter 13)

B. Nonchromaffin paraganglioma (carotid body tumor)^‡

1. Nonchromaffin paraganglioma is a rare, benign tumor, probably of neurogenic origin, that occurs mainly outside the orbit at the bifurcation of the common carotid artery, but it may occur in the orbit.

2. Histologically, it is composed of clusters of relatively clear (epithelioid) or dark (chief) cells surrounded by a vascularized connective tissue stroma.

a. Typically, silver stains show that reticulin separates or surrounds tumor cell clusters but does not surround individual cells.

b. By electron microscopy, two cellular elements are present: (1) central chief cells containing membrane-bound neurosecretory granules in great abundance and (2) fibroblast-like sustentacular cells at the periphery of cell clusters.

C. Granular cell tumor (granular cell myoblastoma ^‡; Fig. 14.33)

1. Granular cell tumor is a rare, benign orbital tumor.

The histogenesis of the tumor is uncertain, and skeletal muscle, fibroblasts, undifferentiated mesenchymal cells, histiocytes, and neural or Schwann cells have all been proposed as cells of origin. Most of the evidence suggests that the Schwann cell is the cell of origin. Rarely, the tumor can occur in the epibulbar region or in the ciliary body.

2. Histologically, it is composed of round to polygonal cells in solid groups and cords and occasionally in alveolated collections.

a. The cells are frequently contiguous to adjacent skeletal muscle. The nuclei are round and relatively small in relation to the voluminous, finely granular, eosinophilic cytoplasm, which is PAS-positive and diastase-resistant.

b. Silver stains frequently show reticulin surrounding individual cells.

c. Electron microscopy reveals oval and round membrane-bound cytoplasmic bodies.

Fig. 14.33 Granular cell tumor. A, A 48-year-old woman had a hard tumor of the right lower lid. B, Histologic section shows solid groups and cords of cells. C, Increased magnification of small nuclei and granular eosinophilic cytoplasm of round and polygonal cells.

D. Alveolar soft-part sarcoma ^‡ (Fig. 14.34)

1. An alveolar soft-part sarcoma is a rare, malignant orbital tumor.

Another entity, malignant mesenchymoma, a very rare orbital tumor, was thought to be a subtype of alveolar soft-part sarcoma, but it probably represents a separate entity, although this is controversial. The tumor, which usually affects patients older than 60 years, is composed of two or three distinct malignant components (e.g., rhabdomyosarcoma, chondrosarcoma, and osteogenic sarcoma).

2. Histologically, it is composed of alveolated groups of round and polygonal cells circumscribed by bands of connective tissue, some of which contain delicate vascular channels in a distinct organoid pattern.

a. Cytoplasm of tumor cells contains scattered eosinophilic and PAS-positive, diastase-resistant, crystalline granules as well as larger refractile bodies.

b. Immunohistochemistry shows positive staining with desmin, myoglobin, muscle actin, S-100 protein, and NKI/C3 (melanoma marker) but negative staining with HMB-45 (melanoma-specific marker), vimentin, and synaptophysin (neuroendocrine marker), suggesting a muscle cell origin rather than nerve cell or paraganglionic origin.

c. Electron microscopy reveals intracytoplasmic crystalline inclusions that exhibit a variety of geometric configurations.

The cytoplasmic crystalloids are similar to the rods observed in benign rhabdomyoma cells. The tumor, therefore, has been thought by some to be a unique type of rhabdomyosarcoma instead of being of neural derivation.

Fig. 14.34 Alveolar soft-part sarcoma. A, Clinical appearance of right exophthalmos. B, Computed tomography scan shows tumor in nasal orbit. C, Histologic section stained with periodic acid–Schiff (PAS) shows alveolated groups of round and polygonal cells circumscribed by bands of connective tissue. D, Increased magnification demonstrates PAS-positive, diastase-resistant crystalline granules and larger refractile bodies. E, Electron microscopy reveals intracytoplasmic crystalline inclusions exhibiting a variety of geometric configurations. (Case presented by Dr. VT Curtin to the meeting of the Eastern Ophthalmic Pathology Society, 1990.)

E. Malignant melanoma ^‡ (see Chapter 17)

F. Endodermal sinus tumor (parietal yolk sac carcinoma)^‡

1. Always malignant, endodermal sinus tumor usually arises in the gonads but rarely can arise primarily from ectopic, extraembryonic germ cells in the orbit.

2. Histologically, the tumor is composed of a meshwork of spaces and cords lined by flat to cuboidal primitive epithelium, scant myxomatous stroma, and frequent mitotic figures.

The tumors may contain Schiller–Duval bodies (i.e., pseudopapillary formations that contain a central vascular core that resembles a glomerulus).

G. Myxoma ^‡

1. Myxoma may arise in orbital bones as a benign solitary lesion or be part of Carney’s syndrome (see Chapter 7).

2. Histologically, stellate spindle cells, some of which contain PAS-positive, diastase-resistant intracytoplasmic inclusions, are present within a myxoid stroma.

VI. Epithelial cysts and neoplasms of lacrimal gland

A. Lacrimal ductal cysts (dacryops)^†

1. Cysts (dacryops) can occur in any location where lacrimal gland is present and account for 6% of all epithelial lesions of the lacrimal gland—that is, palpebral lobe cysts, orbital lobe cysts, cysts of the accessory lacrimal glands of Krause and Wolfring, and cysts of ectopic lacrimal gland.

2. Histologically, the cysts are lined by a double layer of epithelium.

B. Localized amyloidosis of the lacrimal gland ^‡

1. Localized amyloidosis of the lacrimal gland can occur unilaterally or bilaterally.

2. Characteristic amyloid (see Chapter 7) is found by light and electron microscopy and by immunohistochemistry (monoclonal λ light chains).

C. General information on neoplasms

1. Characteristically, lacrimal gland tumors cause a “down and in” type of exophthalmos.

2. The lacrimal gland is composed exclusively of serous cells, entirely lacking mucinous cells. Myoepithelial cells surround the secretory cells of the acini.

3. Although “classic teaching” states that epithelial and nonepithelial lacrimal gland lesions occur with equal frequency, actually, approximately 25% of lacrimal gland tumors are epithelial, and the remaining 75% are nonepithelial (mainly lymphoid tumors or inflammatory pseudotumors).

The lymphoid tumors and pseudotumors are identical to those occurring elsewhere in the orbit (see later in this chapter). Küttner tumor consists of a unilateral sclerosing, follicular, lymphoid hyperplasia of the submandibular gland sometimes associated with idiopathic inflammatory masses of the lacrimal gland.

4. Pleomorphic adenoma (benign mixed tumor) is the most common benign neoplasm of the salivary glands and of the lacrimal gland.

5. Mucoepidermoid carcinoma, the most common carcinoma of the salivary gland, is uncommon in the lacrimal gland and also can arise from the conjunctiva and the caruncle.

6. Simplified classification of tumors of the lacrimal gland

a. Lymphoid tumors and inflammatory pseudotumors: 75% (most benign)

b. Epithelial and cystic lesions: 25%

1) Benign epithelial lesions: approximately 78% (approximately two-thirds pleomorphic adenomas and one-third dacryops)

2) Malignant epithelial tumors (carcinomas): approximately 22% (slightly greater numbers of adenoid cystic carcinoma than malignant mixed tumor, along with a rare adenocarcinoma, mucinous carcinoma, mucoepidermoid carcinoma, or undifferentiated carcinoma)

Aside from malignant lacrimal gland tumors, the only other malignant epithelial tumor that may occur primarily in the orbit is the carcinoid tumor.

7. Prognosis

a. Pleomorphic adenomas: the mortality rate is well under 10%, with the deaths due mainly to multiple recurrences and intracranial extension.

b. All malignant tumors: the mortality rate is 50% or more.

D. Pleomorphic adenoma (benign mixed tumor)^† (Fig. 14.35)

1. Pleomorphic adenoma occurs in young adults, with a median age of 35 years. Males predominate 2 : 1.

2. It is a locally invasive tumor and may infiltrate its own pseudocapsule to involve adjacent periosteum.

a. Acute pain and progression are rare.

b. With incomplete removal, the tumor may recur in the soft tissues or the bony wall. Also if removed in piecemeal fashion, multiple recurrences may occur.

3. Histologically, the tumor shows marked structural variation from patient to patient and within the same tumor.

a. Almost all, at least in some areas, have tubular structures arranged in an irregularly anastomosing pattern, lying in a myxoid stroma.

The juxtaposition of highly cellular epithelial areas with the relatively acellular myxomatous areas gives the tumor its characteristic diphasic pattern. The stroma is rich in a hyaluronidase-resistant acid mucopolysaccharide. A pleomorohic adenoma has occurred primarily in the choroid.

b. A double layer of epithelium lines the tubes or ducts: (1) the inner layer of epithelium may secrete mucus or undergo squamous metaplasia, and (2) the outer layer of epithelium may undergo metaplasia to form a myxoid, fibrous, or cartilaginous stroma.

c. Pressure of the tumor on surrounding tissue forms a pseudocapsule. The tumor almost always infiltrates its pseudocapsule in some area.

d. Positive immunohistologic staining with cytokeratin, muscle-specific actin, and glial fibrillary acidic protein, in both benign and malignant mixed tumors, suggests that ductal epithelium develops into the epithelial component and some cells in the stroma, and myoepithelium develops into some cells in the stroma.

Fig. 14.35 Benign mixed tumor. A, The patient had proptosis of the left eye for a long time. It had gradually increased in severity. B, A histologic section shows the characteristic diphasic pattern, consisting of a pale background that has a myxomatous stroma and a relatively amorphous appearance, contiguous with quite cellular areas that contain mainly epithelial cells (s, surface of tumor; m, myxomatous stroma; c, cellular epithelial areas). C, Increased magnification shows the characteristic epithelial ductal structures lined by two layers of epithelium. The outer layer often undergoes myxoid and even cartilaginous metaplasia, whereas the inner layer may secrete mucus or may undergo squamous metaplasia, both of which are present here (c, area resembling cartilage; m, mesenchymal component; d, ducts filled with mucin; e, epithelial component; s, squamous metaplasia).

E. Other types of benign tumors (all are rare)

1. Hemangioma ^‡

2. Warthin’s tumor ^‡

F. Malignant mixed tumor ^† (Fig. 14.36)

1. Malignant mixed tumor occurs in an older age group than pleomorphic adenoma, with a median age of 51 years. No sex predilection exists.

2. It arises from a pleomorphic adenoma.

3. Histologically, areas resembling a pleomorphic adenoma are seen along with adenocarcinomatous areas.

Fig. 14.36 Malignant mixed tumor. A, Computed tomography shows large anterior orbital tumor arising from lacrimal gland. B, Histologic section shows areas resembling benign mixed tumor. C, High magnification of another area shows sheets of malignant epithelial cells. (Case presented by Dr. HE Grossniklaus to the meeting of the Eastern Ophthalmic Pathology Society, 1989.)

G. Adenoid cystic carcinoma ^† (malignant cylindroma; Fig. 14.37)

1. The tumor occurs in young adults, with a median age of approximately 38 years. No sex predilection exists.

Rarely, the tumor occurs in young people (6.5–18 years of age) and seems to have a more favorable prognosis in this young group. Also, the tumor can occur in the nasal orbit, presumably from ectopic lacrimal gland.

2. The tumor soon invades perineural lymphatics and has an extremely poor prognosis.

3. Acute pain and progression are common.

4. Histologically, under lower power it has a characteristic “Swiss-cheese” pattern.

a. Aggregates or islands of poorly differentiated, small, tightly packed epithelial cells are sharply outlined against the surrounding typical, hyaline-like stroma.

1) Aggregates may be very small, moderate, or quite large, but they are always sharply outlined.

2) Aggregates contain mucin-filled cystic spaces of different sizes, hence the Swiss-cheese pattern.

b. Hyaline stroma surrounding the nests of neoplastic cells is an important finding in differentiating adenoid cystic carcinoma from similarly appearing basal cell or adnexal cell carcinomas. Instead of a hyaline, relatively acellular stroma, the basal cell and adnexal cell carcinomas have a highly cellular, sarcomatous-like, “desmoplastic” stroma surrounding the nests of neoplastic cells.

c. Some tumors have solid sheets or nests of basaloid cells in addition to the typical cribriform or Swiss-cheese pattern.

Patients who have a basaloid pattern in their tumor have a five-year survival rate of 21%, compared with a 71% survival rate when no basaloid pattern is present. “Bad” prognostic signs include a basaloid (solid) pattern, the presence of tumor at resection margins, and the presence of abnormal S-phase (proliferative) fraction. A basaloid pattern in an adenoid cystic carcinoma must be differentiated from the entity basal cell adenocarcinoma (see later), which has a lower degree of malignancy and a more favorable prognosis than adenoid cystic carcinoma.

Fig. 14.37 Adenoid cystic carcinoma. A, The patient had a rapidly progressing proptosis of the left eye. B, A histologic section shows the characteristic “Swiss-cheese” pattern (s) of adenoid cystic carcinoma. The Swiss-cheese pattern is also present in the perineural sheath around a ciliary nerve (c). Adenoid cystic carcinoma is noted for its rapid invasion of ciliary nerves. C, The tumor may superficially resemble a basal cell carcinoma, but it tends to have a relatively acellular hyalin-like stroma between the islands of poorly differentiated, tightly packed, small, dark, epithelial cells. A basal cell carcinoma tends to have a very cellular desmoplastic stroma between the nests of malignant basal cells. D, In this area, a more solid pattern (basaloid pattern) is seen [l, lobules of solid (basaloid) tumor]. This type of pattern is present in approximately 50% of tumors. If no basaloid pattern is present, the five-year survival rate is 71%; with a basaloid pattern, the five-year survival rate is 21%.

H. Other types of carcinomas (all are rare and all have a very poor prognosis)^‡

1. Mucoepidermoid carcinoma, adenocarcinoma (including the less malignant subtypes salivary duct carcinoma, epithelial–myoepithelial carcinoma, and polymorphous low-grade adenocarcinoma), mucinous carcinoma, undifferentiated carcinoma, myoepithelioma (spindle cell variety), lymphoepithelial carcinoma, primary cystadenocarcinoma, undifferentiated large cell carcinoma, and carcinoid tumor occur.

2. Median age group is approximately 53 years, with a 3 : 1 male predominance.

3. Mucoepidermoid carcinoma (Fig. 14.38) is the most common primary carcinoma of the major salivary glands, but it is rare in the lacrimal gland. The tumor contains both epidermoid (squamous) and mucin-producing cells.

Fig. 14.38 Mucoepidermoid carcinoma. A, Both epidermal cells (mainly on left) and clear cells (mainly on right) are present. B, Clear cells stain positively with mucicarmine. (Case courtesy of Dr. LE Zimmerman and reported in Byers RM, Berkeley RG, Luna M et al.: Combined therapeutic approach to malignant lacrimal gland tumors. Am J Ophthalmol 79:53. © Elsevier 1975.)

4. Myoepitheliomas can occur in a spindle form or clear cell form; the latter needs to be differentiated from clear cell variants of oncocytoma, mucoepidermoid carcinoma, carcinoid tumor, and others.

5. Acinic cell carcinoma is rare in the parotid gland (2–4% of tumors) and even rarer in the lacrimal gland.

6. Basal cell adenocarcinoma, a very rare neoplasm of the lacrimal gland, has a similar appearance to those adenoid cystic carcinomas that have a large basaloid component, but it is less malignant and has a more favorable prognosis than the latter.

VII. Reticuloendothelial system

A. Langerhans’ cell histiocytosis (LCH; Langerhans’ granulomatosis, histiocytosis X)^† (Tables 14.1 and 14.2)

1. LCH occurs primarily in children, adolescents, and young adults. It is characterized by a proliferation of Langerhans’ cells in an inflammatory background, often containing many eosinophils.

a. Bone is involved in approximately 80% of cases; other common sites include skin, liver, lymph nodes, spleen, bone marrow, lungs, eyes, and ears.

b. 80% of patients with orbital involvement are male, have unifocal, unisystem disease, and present with periorbital swelling and/or mass.

1) Langerhans’ cells, found primarily in skin and mucosa (including conjunctiva), bear human leukocyte antigen-DR antigens, leukocyte common antigen (CD45-positive in frozen sections but negative in paraffin sections), and express CD1a and S-100 protein. CD 207 is directed against a transmembrane protein associated with Birbeck granules, and it may be more sensitive and specific for Langerhans’ cells than CD1a.

[/level-membership-for-pathology-category][not-level-membership-for-pathology-category]

Orbit

Normal Anatomy

I. The orbital volume is approximately 30 ml, and the orbital depth (anterior to posterior) is approximately 4.5 cm (Figs. 14.1–14.5).

A. The medial orbital wall is quite thin (<0.5 mm) and transparent.

D. The lateral orbital wall is thick, composed anteriorly by the zygomatic bone and posteriorly by the greater wing of the sphenoid.

A. Other than the epithelia within the eyeball, the lacrimal gland is the only epithelial structure in the orbit.

B. All orbital structures may be involved in disease processes.

C. Orbital disease, whatever its cause, tends to increase the bulk of the orbit, so the main presenting sign is exophthalmos.

Exophthalmos

Although dermoids are one of the most common orbital tumors, if not the most common, they rarely cause exophthalmos because of their position, which is usually anterior to the septum orbitale.

Developmental Abnormalities

Developmental Abnormalities of Bony Orbit

Developmental abnormalities are usually associated with abnormalities of the cranial and facial bones such as tower skull or hypertelorism.

Microphthalmos with Cyst

I. Microphthalmos with cyst (see Fig. 2.10) is usually a unilateral condition, but it may be bilateral.

II. The cyst may be so large as to obscure the microphthalmic eye.

III. Proliferated neuroectodermal tissue (i.e., pseudogliomatous hyperplasia) may simulate an orbital neoplasm.

IV. The condition is caused by incomplete closure of the fetal cleft.

Cephaloceles

I. Cephaloceles are caused by a developmental malformation in which brain tissue or meninges or both are present in the orbit.

A. Meningocele—only meninges are present.

B. Encephalocele—only brain tissue is present; hydroencephalocele—considerable fluid is present in the cyst.

C. Meningoencephalocele—meninges and brain tissue are present.

D. All of the preceding may communicate with the brain. Although the initial communication usually closes, it may rarely remain open.

II. Most cephaloceles are developmental displacements of brain tissue and are generally referred to as ectopic brain tissue.

III. Histologically, most cephaloceles show a structure similar to that of the optic nerve (i.e., white matter separated by pial septa).

Congenital Alacrima

I. Hereditary congenital alacrima is part of a systemic disturbance such as the Riley–Day syndrome or anhidrotic ectodermal dysplasia.

II. An isolated case of congenital alacrima, presumably caused by hypoplasia of the lacrimal gland, has been reported.

Orbital Inflammation

Acute

II. Suppurative (see section Suppurative Endophthalmitis and Panophthalmitis in Chapter 3)

A. Purulent infection (e.g., with Staphylococcus) occurs commonly after trauma.

B. Phycomycosis (mucormycosis) is a devastating cause of suppurative orbital inflammation (Fig. 14.7; see Chapter 4).

Chronic

I. Nongranulomatous

A. Chronic nongranulomatous inflammation is the most common inflammatory lesion of the orbit and is of unknown cause (see later in this chapter).

B. A rare cause is the benign lymphoepithelial lesion of Godwin ² (Fig. 14.8).

1. It is characterized by painless unilateral or bilateral enlargement of the salivary or, rarely, the lacrimal glands.

2. It may be part of Sjögren’s syndrome (see later).

3. Rarely, it may become malignant.

C. Sjögren’s syndrome (see Fig. 14.8)

1. Sjögren’s syndrome is defined as a chronic autoimmune disorder characterized by lymphoid inflammatory infiltration of the lacrimal and salivary glands, destroying acinar tissue.

2. The tissue destruction results in the symptoms of keratoconjunctivitis sicca and xerostomia.

3. Indirect support exists for a putative role of the Epstein–Barr virus (see Chapter 3) in the pathogenesis of the disease.

D. Inflammatory pseudotumor (see later in this chapter)

II. Granulomatous

A. Granulomatous inflammations rarely involve the orbit.

C. Tolosa–Hunt syndrome is a benign granulomatous orbital inflammation of unknown cause that presents as a painful ophthalmoplegia. Symptoms usually disappear after steroid therapy.

D. Cholesterol granuloma

1. Cholesterol granuloma has also been called cholesteatoma, lipid granuloma of the frontal bone, xanthomatosis of the orbit, hematoma, and chronic hematic cyst.

2. Cholesterol granuloma of the orbital bones is a rare extraperiosteal condition that usually involves the frontal bone above the lacrimal fossa.

3. The cause seems to be a hemorrhage into the diploë of the bone, probably secondary to trauma but perhaps secondary to an anomaly in the diploë that could initiate a hemorrhage.

4. Histologically, a granulomatous reaction surrounds cholesterol crystals and altered blood.

E. Inflammatory pseudotumor (see later in this chapter)

Injuries

Penetrating Wounds

I. Direct effect on whatever tissue may be wounded by the injury

II. Complications (indirect effect)

A. Infection

1. Organisms may be introduced at the time of injury.

a. Bacteria cause an acute purulent inflammation.

b. Fungi cause a delayed, chronic, granulomatous inflammation.

B. Inflammation

1. The inflammation may be secondary to toxic products of tissue destruction.

2. Orbital thrombophlebitis may result.

3. A retained intraorbital foreign body may induce inflammation.

a. Frequently, cilia and pieces of skin, bone, wood, and so forth may be introduced into the orbit at the time of injury and cause a foreign-body granulomatous inflammatory reaction.

C. Orbital inflammation may lead to other complications, such as cavernous sinus thrombosis, central retinal vein thrombosis, glaucoma, and proptosis.

Nonpenetrating Wounds

The effects of nonpenetrating wounds are those secondary to contusion and concussion, mainly hemorrhage, secondary muscle palsies, and infraorbital nerve involvement.

Vascular Disease

Primary

I. Primary orbital vascular disease is rare.

II. Causes include varices, arteriovenular aneurysm, thrombophlebitis, and cavernous sinus thrombosis.

Part of Systemic Disease

I. Collagen diseases (see Chapter 6 and later in this chapter)

II. Midline lethal granuloma syndrome (natural killer (NK)/T-cell lymphoma, polymorphic or malignant reticulosis; see later this chapter and see Chapter 6)

III. Allergic granulomatosis (vasculitis; see Chapter 6)

IV. Temporal (cranial) arteritis (see Chapter 13)

Ocular Muscle Involvement in Systemic Disease

Graves’ Disease (Fig. 14.10)

I. Classification of eye changes of Graves’ disease (Box 14.1)

II. Mild form (“thyrotoxic” exophthalmos)

A. The mild form of Graves’ ophthalmopathy has its onset in early adult life, with women predominantly affected (approximately 2 : 1).

B. It may present initially with unilateral involvement but usually becomes bilateral.

C. Clinically and chemically, the patient is hyperthyroid.

D. Lid retraction, the most common clinical sign, may simulate exophthalmos.

E. Occasionally exophthalmos is present.

F. Prognosis for vision is good.

III. Severe form (“thyrotropic” or “malignant” exophthalmos; thyroid ophthalmopathy; thyroid orbitopathy)

A. The severe form is an autoimmune disease that affects people in middle age (average age, 50 years).

1. The disease is characterized by an increased percentage of suppressor/cytotoxic T lymphocytes.

2. Circulating T cells are directed against thyroid follicular cell antigens.

B. It is most common in men, especially those older than 50 years of age, is usually bilateral, and is asymmetric.

C. Clinically and chemically, the patient may be hyperthyroid, hypothyroid, or euthyroid.

Orbital accumulation of glycosaminoglycans and increased adipogenesis may play an important role in the development of Graves’ ophthalmopathy.

E. Prognosis for vision is poor.

1. Positive staining occurs in extraocular and periorbital muscle for immunoglobulin A1 (IgA1) and IgE antibodies and also C3bi (the terminal attack complex) complement component.

Box 14.1

Eye Changes in Graves’ Disease

CLASS	OCULAR SYMPTOMS AND SIGNS
0	No signs or symptoms
1	Only signs, no symptoms
2	Soft-tissue involvement with symptoms and signs
3	Proptosis of the eyes
4	Extraocular muscle involvement
5	Corneal involvement
6	Sight loss with optic nerve involvement

(Modified from Werner SC: Classification of the eye changes of Graves’ disease. Am J Ophthalmol 68:646, 1969.)

Myasthenia Gravis

II. The most common clinical manifestation is ptosis of the eyelid.

As a rough test, the ptosis can often be aggravated by having the patient raise and lower the eyes 10–30 times in rapid succession. The normal patient can do this easily with no ptosis afterward.

III. Histologically, the ocular muscles are edematous and infiltrated by lymphocytes.

Myotonic Dystrophy (Myotonia Dystrophica; Steinert’s Disease)

I. Myotonic dystrophy, an autosomal-dominant condition, is characterized by myotonia (i.e., failure to relax a contracted muscle voluntarily).

A. Its onset is between 20 and 30 years of age, with patients rarely living beyond 40 or 50 years.

B. Frontal baldness and endocrinopathy, especially testicular atrophy, are common.

II. Ocular findings

A. Cataracts showing iridescent dots in the anterior and posterior cortex, and a stellate grouping of opacities at the posterior pole of the lens along the posterior suture lines

B. Foveal dystrophy that hardly affects vision and pigmentary retinopathy

C. Ocular hypotension

III. Histologically, selective atrophy of muscle fibers is seen.

Myotonia Congenita (Thomsen’s Disease)

I. Myotonia congenita, an autosomal-dominant or -recessive condition, is characterized by myotonia.

A. Its onset is early in life and may involve muscles of the face and eyelids.

B. It does not cause death and rarely causes severe disability.

II. Histologically, the muscles are not atrophic; individual muscle fibers may be larger than normal with an increase in sarcolemmal nuclei.

Mitochondrial Myopathies

The inheritance of these point mutations of mitochondrial DNA is from mothers alone because the mitochondrial contribution to the embryo comes only from the maternal ovum.

A. Leber’s hereditary optic atrophy (see Chapter 13)

B. CPEO

2. Ptosis, external ophthalmoplegia, and often a pigmentary retinopathy can be seen.

C. KSS

1. KSS consists of the triad of external ophthalmoplegia, pigmentary retinopathy, and heart block. Other findings include mental retardation, hearing loss, endocrinopathy, and cerebellar ataxia.

2. KSS is inherited through the maternal transmission of one or more mitochondrial large-deletion DNA mutations.

D. MELAS (Fig. 14.11)

1. MELAS usually has an abrupt onset before the age of 15 years with symptoms of visual loss, hemiparesis or hemianopia, strokelike episodes, headaches, and convulsions.

2. Patients have short stature and increased serum and cerebrospinal fluid lactate levels.

3. MELAS is inherited through the maternal transmission of one or more mitochondrial point DNA mutations (nucleotide positions 3243 and 3271).

4. Ocular findings include external ophthalmoplegia, atypical pigmentary retinopathy, and nuclear cataract.

1) The cytoplasm of RPE cells show ballooned, structurally abnormal (“giant”) mitochondria.