Figure 5-23 Melanoma of the ciliary body with extrascleral extension, presenting as an ocular surface mass. Note that there is no PAM surrounding the nodule, a clue that the lesion might have an intraocular origin. Also note that the lesion does not obscure the overlying conjunctival vessels. This indicates that the lesion is deep to the conjunctiva. (Courtesy of J. William
Harbour, MD.)
Lymphocytic Lesions
The normal conjunctiva is an example of mucosa-associated lymphoid tissue (MALT), and a few small follicles are often visible clinically in the normal inferior fornix. As described previously, the normal lymphoid follicle consists of a germinal center and surrounding corona (see Fig 5-5). The corona is further subdivided into marginal and mantle zones, although these are not well delineated histologically without the use of special stains.
Occasionally in asymptomatic patients (generally children or adolescents), numerous, prominent
follicles may be incidentally found in the inferior fornix bilaterally, a condition called benign lymphoid folliculosis. Lymphoid follicles of the palpebral/forniceal conjunctiva may also become more prominent and increase in number when associated with conjunctival inflammation, that is, follicular conjunctivitis (discussed earlier).
Lymphoid tissue may proliferate in the conjunctiva abnormally, often in the absence of inflammation, and this lymphoid hyperplasia may be benign or malignant. Clinically, both benign and malignant lymphoproliferative lesions of the conjunctiva have a salmon-pink appearance with a smooth surface and are usually soft (Fig 5-24A, B). Both benign and malignant lesions may be unilateral or bilateral. Lymphocytic lesions are often seen in the inferior fornix but may also be seen on the bulbar, tarsal, or caruncular conjunctiva. A lymphocytic lesion involving the forniceal conjunctiva or caruncle may also have an orbital component. As benign and malignant lymphocytic lesions of the conjunctiva may appear similar clinically, incisional biopsy is generally required to make a precise diagnosis.
For biopsy of suspected lymphoid lesions of the conjunctiva, 4–5 mm of tissue is generally sufficient, and the biopsy may usually be performed in the office with topical or subconjunctival anesthetic. The specimen should be submitted in formalin for routine H&E sections and immunohistochemistry. If possible, an additional 4–5 mm of tissue may be harvested and submitted in saline or special flow cytometry medium, on ice.
Figure 5-24 Lymphocytic lesions of the conjunctiva. A, Clinical appearance (“salmon patch”) in the inferior fornix. B, Clinical appearance on the bulbar conjunctiva. C, Histology of benign lymphoid hyperplasia, showing normal follicular architecture,
with well-defined germinal center (G) and corona (C). D, Histology of lymphoma, showing a sheet of lymphocytes infiltrating
the substantia propria, without well-defined follicles. (Part A courtesy of Anthony J. Lubniewski, MD; part B courtesy of Anjali K. Pathak, MD; parts C and D courtesy of George J. Harocopos, MD.)
Histologic features favoring a diagnosis of benign lymphoid hyperplasia on routine H&E sections include the presence of normal-appearing lymphoid follicles with distinct germinal centers and with small, mature coronal lymphocytes (Fig 5-24C). In contrast, lymphoma often demonstrates a solid sheet of lymphocytes in the substantia propria, without well-defined follicles (Fig 5-24D). However, most conjunctival lymphomas are low grade, and these low-grade malignant lesions are sometimes difficult to differentiate from benign lesions on H&E sections. Immunohistochemistry, flow cytometry, and other techniques are useful diagnostically, as discussed later. Also, it should be noted that some patients with “benign” lymphoid hyperplasia eventually develop lymphoma.
Lymphoma
The most common form of lymphoma of the conjunctiva (and also of the orbit), seen in over half of cases, is extranodal marginal zone lymphoma (formerly known as MALToma), so named because the pathogenesis involves expansion of the follicle’s marginal zone. Extranodal refers to the site of the tumor being somewhere other than a lymph node. Conjunctival marginal zone lymphoma may be unilateral or bilateral and often presents in the forniceal conjunctiva but may present on the bulbar conjunctiva. This is a form of low-grade B-cell lymphoma, and histology shows small lymphocytes (Fig 5-25). Immunohistochemistry for B-cell and T-cell markers demonstrates a preponderance of B cells, although a variable proportion of normal T cells will be present. Tissue in situ hybridization (ISH) for immunoglobulin light chains often demonstrates B-cell monoclonality by revealing either κ or λ light-chain predominance. However, ISH is not as sensitive as flow cytometry for detecting κ or λ clonality, and thus flow cytometry is especially useful in cases that fail to show clonality by ISH. Another technique to detect clonality, which can be performed on fresh or formalin-fixed tissue, is IgH (immunoglobulin heavy chain) gene rearrangement testing by PCR. In addition, fluorescence in situ hybridization (FISH) may be performed on fresh or formalin-fixed tissue to test for specific genetic translocations. The t(3;14) translocation, involving the FOXP1 gene, and other translocations have been described in marginal zone lymphoma; and various translocations have been found in other forms of conjunctival lymphoma. Interestingly, the same translocation may be associated with more than one type of lymphoma.
Figure 5-25 Histology of marginal zone lymphoma. A, Higher magnification of the same case shown in Fig 5-24D, showing small lymphocytes. B, CD20 immunostain (brown) for B cells, staining positive in the vast majority of the lymphocytes. C, In situ hybridization (ISH) for λ light chain, exhibiting prominent positivity (blue cells), confirming λ clonality and establishing the
diagnosis of marginal zone lymphoma. (Courtesy of George J. Harocopos, MD.)
Other forms of conjunctival lymphoma include follicular lymphoma (arising from the germinal center) and, less commonly, mantle cell lymphoma (which arises from the mantle zone). Also less common in the conjunctiva are diffuse large B-cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, and plasmacytoma. T-cell lymphomas are rare. High-grade lymphomas such as diffuse large B-cell lymphoma are readily recognized as malignant by virtue of their nuclear features (“coarse clumping” chromatin pattern, that is, multiple nucleoli) and high mitotic rate. Large B-cell lymphoma is relatively rare in the conjunctiva and is more commonly seen in the central nervous system and vitreous (see Chapters 10 and 20 of this volume).
Approximately two-thirds of conjunctival lymphomas are localized to the conjunctiva and not associated with systemic disease. In contrast, nearly two-thirds of lymphomas arising in the preseptal skin eventually show evidence of systemic involvement. However, the likelihood of systemic involvement varies according to the type of lymphoma; that is, marginal zone lymphoma presenting on the conjunctiva has been estimated in some studies to be localized in up to 90% of cases, whereas mantle cell lymphoma often has systemic involvement. The vast majority of cases of conjunctival marginal zone lymphoma present initially to the ophthalmologist, with no known systemic disease; the frequency of known preexisting systemic disease is greater with higher-grade lymphomas. Any