Introduction to Part I

The purpose of BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, is to provide a general overview of the fields of ophthalmic pathology and ocular oncology. Although there is some overlap between the 2 fields, it is useful to approach specific disease processes from the standpoint of 2 separate disciplines. This book contains numerous illustrations of entities commonly encountered in an ophthalmic pathology laboratory and in the practice of ocular oncology. In addition, important but less common entities are included for teaching purposes. For more comprehensive reviews of ophthalmic pathology and ocular oncology, the reader is referred to the excellent textbooks listed in Basic Texts at the end of this volume.

Part I of this text provides a framework for the study of ophthalmic pathology, with the following hierarchical organizational paradigm (explained in detail in the next section): topography, disease process, general diagnosis, differential diagnosis. Chapter 2 briefly covers basic principles and specific aspects of wound repair as it applies to ophthalmic tissues, which exhibit distinct responses to trauma, including end-stage processes such as phthisis bulbi. Chapter 3 discusses specimen handling, including orientation and dissection, and emphasizes the critical communication between the ophthalmologist and the pathologist. Although most ophthalmic pathology specimens are routinely processed and slides are stained with hematoxylin and eosin (H&E), special procedures are used in selected cases. Chapter 4 details several of these procedures, including immunohistochemical staining, flow cytometry, polymerase chain reaction (PCR), and electron microscopy. Also discussed are indications in some instances for special techniques in obtaining the specimen, such as fine-needle aspiration biopsy, and special ways of preparing slides for examination, such as frozen sections. Chapters 5 through 15 apply the organizational paradigm to specific anatomical locations.

Organization

Chapters 5 through 15 are each devoted to a particular ocular structure. Within the chapter, the text is organized from general to specific, according to the following hierarchical framework:

topography disease process general diagnosis

differential diagnosis

Topography

The microscopic evaluation of a specimen, whether on a glass slide or depicted in a photograph, should begin with a description of any normal tissue. For instance, the topography of the cornea is characterized by nonkeratinized stratified squamous epithelium, the Bowman layer, stroma, the Descemet membrane, and endothelium. By recognizing a particular structure, such as the Bowman

layer or the Descemet membrane, in a biopsy specimen, an examiner might be able to identify the topography in question as cornea. It may not be possible, however, to identify the specific tissue source from the topography present on a glass slide or in a photograph. For example, a specimen showing the topographic features of keratinized stratified squamous epithelium overlying dermis with dermal appendages may be classified as skin; however, unless specific eyelid structures such as a tarsal plate are identified, that skin is not necessarily from the eyelid. See BCSC Section 2,

Fundamentals and Principles of Ophthalmology, for a review of ophthalmic anatomy.

Disease Process

After identifying a tissue source, the pathologist should attempt to categorize the general disease process. These processes include

congenital anomaly inflammation degeneration and dystrophy neoplasia

Congenital anomaly

Congenital anomalies usually involve abnormalities in size, location, organization, or amount of tissue. An example of congenitally enlarged tissue is congenital hypertrophy of the retinal pigment epithelium (CHRPE) (see Chapter 11, Fig 11-5; and Chapter 17, Fig 17-10). Many congenital abnormalities may be classified as choristomas or hamartomas.

A choristoma consists of normal, mature tissue at an abnormal location. It occurs when 1 or 2 embryonic germ layers form mature tissue that is abnormal for a given topographic location. An example of a choristoma is a dermoid: skin that is otherwise normal and mature present at the abnormal location of the limbus. A tumor made up of tissue derived from all 3 embryonic germ layers is called a teratoma (Fig 1-1).

In contrast, the term hamartoma describes an exaggerated hypertrophy and hyperplasia (abnormal amount) of mature tissue at a normal location. An example of a hamartoma is a cavernous hemangioma, an encapsulated mass of mature venous channels in the orbit.

Inflammation

The next disease process in the schema, inflammation, is classified in several ways. It may be acute or chronic in onset and focal or diffuse in location. Chronic inflammation is subdivided further as either granulomatous or nongranulomatous. For example, a bacterial corneal ulcer is generally an acute, focal, nongranulomatous inflammation, whereas sympathetic ophthalmia is a chronic, diffuse, granulomatous inflammation.

Polymorphonuclear leukocytes (PMNs), eosinophils, and basophils all circulate in the blood and may be present in tissue in early phases of the inflammatory process (Figs 1-2, 1-3, 1-4). The types of leukocytes present at the site of inflammation vary according to the inflammatory response. PMNs, also known as neutrophils, typify acute inflammatory cells and can be recognized by a multisegmented nucleus and intracytoplasmic granules. They may be present in a variety of acute inflammatory processes; for example, they are associated with bacterial infection and found in the walls of blood vessels in some forms of vasculitis. Eosinophils have bilobed nuclei and prominent intracytoplasmic eosinophilic granules. They are commonly found in allergic reactions, although they may also be present in chronic inflammatory processes such as sympathetic ophthalmia. Basophils contain basophilic intracytoplasmic granules. Mast cells are the tissue-bound equivalent of

the bloodborne basophils.

Figure 1-1 Orbital teratoma with tissue from 3 germ layers. Note gastrointestinal mucosa (asterisk) and cartilage (arrows) in

the tumor. (Courtesy of Hans E. Grossniklaus, MD.)

Inflammatory cells that are relatively characteristic of chronic inflammatory processes include monocytes (Fig 1-5) and lymphocytes (Fig 1-6). Monocytes may migrate from the intravascular space into tissue, in which case they are classified as histiocytes, or macrophages. Histiocytes have eccentric nuclei and abundant eosinophilic cytoplasm. In some instances, histiocytes may take on the appearance of epithelial cells, with abundant eosinophilic cytoplasm and sharp cell borders, becoming known in the process as epithelioid histiocytes. Epithelioid histiocytes may form a ball-like aggregate known as a granuloma, the sine qua non for granulomatous inflammation. These granulomas may contain only histologically intact cells (“hard” tubercles, Fig 1-7), or they may exhibit necrotic centers (“caseating” granulomas, Fig 1-8). Epithelioid histiocytes may merge to form a syncytium with multiple nuclei known as a multinucleated giant cell. Giant cells formed from histiocytes come in several varieties, including

Langhans cells, characterized by a horseshoe arrangement of the nuclei (Fig 1-9)

Touton giant cells, which have an annulus of nuclei surrounded by a lipid-filled clear zone (Fig 1-10)

foreign body giant cells, with haphazardly arranged nuclei (Fig 1-11)

Lymphocytes are small cells with round, hyperchromatic nuclei and scant cytoplasm. Circulating lymphocytes infiltrate tissue in all types of chronic inflammatory processes. These cells terminally

differentiate in the thymus (T cells) or bursa equivalent (B cells), although it is not possible to distinguish between B and T lymphocytes with routine histologic stains. B cells may produce immunoglobulin and differentiate into plasma cells, with eccentric “cartwheel,” or “clockface,” nuclei and a perinuclear halo corresponding to the Golgi apparatus. These cells may become completely distended with immunoglobulin and form Russell bodies, which may be extracellular. BCSC Section 9, Intraocular Inflammation and Uveitis, discusses the cells involved in the inflammatory process in depth in Part I, Immunology.

Figure 1-2 Polymorphonuclear leukocyte with multilobulated nucleus. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-3 Eosinophil with bilobed nucleus and intracytoplasmic eosinophilic granules. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-4 Basophil with intracytoplasmic basophilic granules. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-5 Monocyte with indented nucleus. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-6 Lymphocyte with small, hyperchromatic nucleus and scant cytoplasm. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-7 Noncaseating granulomas, or “hard” tubercles, are formed by aggregates of epithelioid histiocytes. (Courtesy of

Hans E. Grossniklaus, MD.)

Figure 1-8 Granulomas with necrotic centers are classified as caseating granulomas. (Courtesy of Hans E. Grossniklaus, MD.)

Figure 1-9 Langhans giant cell.

Figure 1-10 Touton giant cell.

occur in either benign or malignant forms. Examples found in particular tissues include

adenoma (benign) versus adenocarcinoma (malignant) in glandular epithelium topography + oma (benign) versus topography + sarcoma (malignant) in soft tissue

hyperplasia/infiltrate (benign) versus leukemia/lymphoma (malignant) in hematopoietic tissue

Some neoplastic proliferations are called borderline, in that they are difficult to classify histologically as benign or malignant. Although most of the neoplasms illustrated and discussed in this text are classified as benign or malignant, the reader should be aware that tissue evaluation in a particular disease can give only a static portrait of a dynamic process. Thus, it may be impossible to determine whether the process will ultimately be benign or malignant, and in some instances “indeterminate” or “borderline” is a legitimate interpretation. Table 1-1 summarizes the origin, general classification of benign versus malignant, and growth pattern of neoplasms originating in various tissues.

The growth patterns described in Table 1-1 are shown in Figure 1-12. General histologic signs of malignancy include nuclear and cellular pleomorphism, necrosis, hemorrhage, and mitotic activity.

Table 1-1