I. DISEASES OF THE CONJUNCTIVA
A. Degenerative. Two benign degenerative lesions on the conjunctiva are the pinguecula and the pterygium, which are manifestations of chronic actinic damage to the interpalpebral bulbar conjunctiva. The pinguecula is confined to the conjunctiva, appearing clinically as a yellowish nodule, whereas the pterygium extends onto the peripheral cornea, appearing clinically as a vascular, wing-shaped lesion. Histologically, a pinguecula shows elastotic (actinic) degeneration and may show variable degrees of chronic inflammation (e-Fig. 5.1).* The pterygium may show these same findings, but the most prominent feature is congested vessels (e-Fig. 5.2).
B. Inflammatory. A variety of infectious and noninfectious conditions may cause conjunctivitis.
1. Sarcoidosis often affects the conjunctiva, manifesting clinically as small, tan nodules in the inferior forniceal conjunctiva, often in non-injected, asymptomatic eyes. Sarcoidosis may also cause symptomatic inflammation in all parts of the eye, including conjunctivitis, uveitis, retinal phlebitis, optic neuritis, and so on. Conjunctival biopsy may provide the most expedient way of diagnosing this systemic disease, even in cases where there are no visible nodules clinically, though the diagnostic yield is highest when an obvious nodule is present. Histology shows noncaseating granulomatous tubercles in the stroma, with a variable (but usually minimal) cuff of lymphocytes and plasma cells (e-Fig. 5.3).
2. Ocular cicatricial pemphigoid (OCP) is a form of cicatrizing conjunctivitis that typically also involves other mucous membranes and sometimes involves the skin. When conjunctival biopsy is performed to establish the diagnosis, half the specimen should be submitted in formalin for routine histology, and half in Michel’s medium or saline for immunofluorescence studies. Histology shows epithelial bullae (or blebs) and a subepithelial band of chronic inflammation composed predominantly of plasma cells (e-Fig. 5.4). Immunofluorescence demonstrates IgG, IgA, and/or IgM immunoglobulins, and complement (C3) positivity in the epithelial basement membrane zone. The sensitivity of immunofluorescence may be as low as 50%, and accordingly, a negative result does not rule out OCP.
C. Neoplasms of the conjunctiva fall mostly into one of the three categories: squamous (surface epithelium), melanocytic, or lymphoid.
1. Neoplasms arising from the surface epithelium range from benign papillomas (e-Fig. 5.5) to ocular surface squamous neoplasia (OSSN) which is further subdivided into conjunctival intraepithelial neoplasia (CIN) (e-Fig. 5.6) versus invasive squamous cell carcinoma (e-Fig. 5.7). Histologic sections of a papilloma show finger-like projections of hyperplastic epithelium draped over fibrovascular cores. The epithelium may exhibit loss of goblet cells and surface keratinization if the lesion was exposed (i.e., not covered adequately by the tear film due to its size).
TABLE 5.1 Carcinoma of the Conjunctiva
Definition of TNM. These definitions apply to both clinical and pathologic staging.
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor <5 mm in greatest dimension
T2
Tumor >5 mm in greatest dimension, without invasion of adjacent structures
T3
Tumor invades adjacent structures, excluding the orbit
T4
Tumor invades orbit with or without further extension
T4a
Tumor invades orbital soft tissues, without bone invasion
T4b
Tumor invades bone
T4c
Tumor invades adjacent paranasal sinuses
T4d
Tumor invades brain
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
Distant metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
Anatomic stage/prognostic groups
No stage grouping is presently recommended.
From: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Used with permission.
OSSN histologically exhibits epithelial hyperplasia with loss of goblet cells, nuclear hyperchromasia, and cellular pleomorphism, and often shows surface keratinization, dyskeratosis, and increased mitotic figures. In the most severe cases, squamous eddies or keratin whorls/pearls may be seen. There is frequently a subepithelial chronic inflammatory response. The most important distinction histologically in terms of prognosis is whether the lesion is confined by the epithelial basement membrane, (i.e., CIN) versus whether the lesion has broken through the basement membrane and invaded the stroma, (i.e., invasive squamous carcinoma). The staging scheme for conjunctival squamous carcinoma is given in Table 5.1. Treatment options for OSSN include excision with 3 to 4 mm margins and cryotherapy to the edges of excision versus topical chemotherapy with agents such as interferon (IFN) alpha-2b, 5-fluorouracil (5-FU), or mitomycin C (MMC). Topical chemotherapy may also be used as pre- or post-operative adjuvant treatment.
2. Melanocytic lesions of the conjunctiva range from benign to malignant.
a. Conjunctival melanocytic nevi (e-Fig. 5.8) are benign lesions that bear similarities to cutaneous melanocytic nevi. Clinically, they may be pigmented or amelanotic. On histology, as with melanocytic nevi of the skin, the melanocytes are typically arranged in nests which may be junctional, intrastromal, or compound. Another important feature generally seen in conjunctival nevi is epithelial inclusion cysts in association with the melanocytes.
b. Intraepithelial melanocytic lesions of the conjunctiva include benign acquired melanosis (BAM) (also known as racial melanosis) (e-Fig. 5.9),
which appears clinically as bilateral, flat, patchy brown pigmentation in darkly skinned individuals, and primary acquired melanosis (PAM) which has a similar clinical appearance except that it is generally unilateral in Caucasians. Histologically, BAM appears as a lentiginous proliferation of normal-appearing melanocytes confined to the basal layer of the epithelium, similar to lentigo simplex of the skin.
PAM is subdivided into PAM without atypia, which appears histologically identical to BAM (and accordingly has no to minimal risk of future malignant transformation) versus PAM with atypia (e-Fig. 5.10). In PAM with atypia (similar to melanoma in situ of the skin), the melanocytic proliferation extends into the more superficial epithelial layers to varying degrees, and the melanocytes exhibit discohesiveness and may have epithelioid morphology; however, the lesion is still confined by the epithelial basement membrane. There is frequently a subepithelial chronic inflammatory response. In the ophthalmic nomenclature on conjunctival neoplasms, the term melanoma in situ is generally reserved for PAM with severe atypia involving at least 75% of the epithelial thickness. PAM with atypia carries a significant risk of future malignant transformation, with the risk being proportional to the degree of atypia. It is therefore generally treated via complete excision with 4 mm wide margins and cryotherapy to the edges of excision, similar to squamous neoplasms. Topical chemotherapy may also be a treatment option for very extensive lesions deemed too large for excision, though the success rate with this treatment is not as high as with squamous lesions.
c. Melanoma of the conjunctiva (e-Fig. 5.10) generally arises from PAM with atypia, may arise de novo, or, less commonly, may arise from a nevus. When melanoma arises from PAM with atypia, histology demonstrates an area where the melanocytic proliferation violates the epithelial basement membrane and invades the stroma. Particularly when the focus of invasion is relatively small, immunostains such as melanA-red may be helpful in distinguishing the focus of invasion from the surrounding chronic inflammatory response, and in delineating the deep margin of invasion. The staging scheme for melanomas of the conjunctiva is given in Table 5.2. Conjunctival melanoma is generally treated via complete excision with at least 4 mm margins and cryotherapy to the edges of excision.
TABLE 5.2 Malignant Melanoma of the Conjunctiva
Definition of TNM
Clinical classification (cTNM)
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T(is)
Melanoma confined to the conjunctival epithelium
T1
Malignant melanoma of the bulbar conjunctiva:
T1a
Less than or equal to 1 quadrant
T1b
More than 1 but <2 quadrants
T1c
More than 2 but <3 quadrants
T1d
Greater than 3 quadrants
T2
Malignant melanoma of the nonbulbar (palpebral, forniceal, caruncular) conjunctiva:
T2a
No caruncular, <1 quadrant
T2b
No caruncular, >1 quadrant
T2c
Any caruncular, with <1 quadrant
T2d
Any caruncular, with >1 quadrant
T3
Any malignant conjunctival melanoma with local invasion:
T3a
Globe
T3b
Eyelid
T3c
Orbit
T3d
Sinus
T4
Tumor invades the central nervous system
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0a (biopsied)
No regional lymph node metastasis, biopsy performed
N0b (not biopsied)
No regional lymph node metastasis, biopsy not performed
N1
Regional lymph node metastasis
Distant metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
Pathologic classification (pTNM)
Primary tumor (pT)
pTX
Primary tumor cannot be assessed
pT0
No evidence of primary tumor
pT(is)
Melanoma of the conjunctiva confined to the epithelium
pT1a
Melanoma of the bulbar conjunctiva not more than 0.5 mm in thickness with invasion of the substantia propria
pT1b
Melanoma of the bulbar conjunctiva more than 0.5 mm but not more than 1.5 mm in thickness with invasion of the substantia propria
pT1c
Melanoma of the bulbar conjunctiva >1.5 mm in thickness with invasion of the substantia propria
pT2a
Melanoma of the palpebral, forniceal, or caruncular conjunctiva not more than 0.5 mm in thickness with invasion of the substantia propria
pT2b
Melanoma of the palpebral, forniceal, or caruncular conjunctiva more than 0.5 mm but not >1.5 mm in thickness with invasion of the substantia propria
pT2c
Melanoma of the palpebral, forniceal, or caruncular conjunctiva >1.5 mm in thickness with invasion of the substantia propria
pT3
Melanoma invading the eye, eyelid, nasolacrimal system, sinuses, or orbit
pT4
Melanoma invading the central nervous system
Regional lymph nodes (pN)
pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
pN1
Regional lymph node metastasis present
Distant metastasis (pM)
cM0
No distant metastasis
pM1
Distant metastasis
Anatomic stage/prognostic groups
No stage grouping is presently recommended.
From: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Used with permission.
3. Lymphocytic lesions of the conjunctiva include lymphoid hyperplasia and lymphoma, either of which may be unilateral or bilateral. Lymphomas can range from primary localized lesions (even if bilateral), to lesions associated with systemic disease. Most conjunctival/orbital lymphomas are low-grade B-cell lymphomas, with the single most common type being extranodal marginal zone lymphoma (e-Fig. 5.11), which is generally localized to the conjunctiva. Histologically, marginal zone lymphoma shows a sheet of lymphocytes infiltrating the subepithelial region of the substantia propria (stroma) without well-defined follicles; scattered lymphocytes may extend into the epithelium. Immunohistochemistry for B- and T-cell markers (e-Fig. 5.12) as well as in situ hybridization (ISH) for kappa and lambda light chains (e-Fig. 5.13) are very helpful diagnostically. Other techniques for establishing clonality such as IgH gene rearrangement testing by PCR and flow cytometry are also useful, particularly in cases where ISH proves insufficient. Fluorescence in situ hybridization (FISH) may also be used if needed to test for specific genetic translocations.
Follicular and mantle cell lymphomas are also seen in the conjunctiva. More rarely, diffuse large B-cell, Burkitt, Hodgkin, plasmacytoma, or T-cell lymphoma may also occur. Lower-grade lymphomas are more often localized to the conjunctiva, whereas higher-grade lymphomas are more likely to be associated with systemic disease. If the lymphoma is localized to the conjunctiva, the treatment is generally orbital radiation. Another treatment option is subconjunctival injections of IFN or intravenous rituximab. In contrast, if systemic lymphoma is present, then it is treated accordingly with chemotherapy; if systemic remission is achieved, the conjunctival lesion(s) will likewise resolve. The staging scheme for conjunctival/orbital lymphoma is given in Table 5.3.
4. Other neoplasms. Oncocytoma, also known as apocrine cystadenoma or oxophilic cystadenoma (e-Fig. 5.14), is a benign lesion that arises most commonly in the caruncle of elderly females. Histologically, it is an adenoma composed of apocrine or accessory lacrimal gland epithelial cells which exhibit distinctive eosinophilic cytoplasm and surround gland-like spaces.
Any neoplasm seen in the orbit may also occasionally arise in the conjunctiva, including neural, vascular, fibrous, and muscular tumors. Additionally, metastatic lesions to the conjunctiva rarely occur.
II. DISEASES OF THE CORNEA. The host tissue from a corneal transplant procedure is traditionally referred to as a corneal “button”; the surgical procedure itself is a keratoplasty (KP). Most often, full-thickness cornea is removed, (i.e., penetrating keratoplasty or PKP). More recently, however, surgical techniques have been developed such that, for certain disorders, only the diseased layer(s) of the cornea need be transplanted, for example, deep anterior lamellar keratoplasty (DALK), in which only the epithelium and stroma are removed, versus Descemet’s stripping endothelial keratoplasty (DSEK), in which only Descemet’s membrane and endothelium are removed. In the gross room, corneal buttons are bisected, and each half is embedded with the cut side down. The most common reasons for keratoplasty to be performed are Fuchs endothelial dystrophy, pseudophakic/aphakic bullous keratopathy, keratoconus, infectious keratitis (especially herpetic), and graft failure.
A. Fuchs endothelial dystrophy (e-Fig. 5.15) exhibits an autosomal dominant inheritance pattern or may be sporadic, generally becoming symptomatic in middleaged to older individuals. The corneal endothelial cells diminish in number significantly faster than is normal for aging, ultimately leading to chronic edema of the cornea. If conservative therapy is unsuccessful, then keratoplasty (either PKP or DSEK) is necessary. Histologically, Fuchs dystrophy demonstrates loss of the endothelial cells and the presence of anvil-shaped excrescences, known
as guttae, along a thickened Descemet’s membrane. Often secondary epithelial bullae are seen (i.e., bullous keratopathy).
TABLE 5.3 Ocular Adnexal Lymphoma
Definition of TNM. These definitions apply to both clinical and pathologic staging.
Primary tumor (T)
TX
Lymphoma extent not specified
T0
No evidence of lymphoma
T1
Lymphoma involving the conjunctiva alone without orbital involvement:
T1a
Bulbar conjunctiva only
T1b
Palpebral conjunctiva +/− fornix +/− caruncle
T1c
Extensive conjunctival involvement
T2
Lymphoma with orbital involvement +/− any conjunctival involvement:
T2a
Anterior orbital involvement (+/− conjunctival involvement)
T2b
Anterior orbital involvement + lacrimal involvement (+/− conjunctival involvement)
T2c
Posterior orbital involvement (+/− conjunctival involvement +/− anterior involvement +/− any extraocular muscle involvement)
T2d
Nasolacrimal drainage system involvement (+/− conjunctival involvement but not including nasopharynx)
T3
Lymphoma with preseptal eyelid involvement +/− orbital involvement +/− any conjunctival involvement
T4
Orbital adnexal lymphoma extending beyond orbit to adjacent structures such as bone and brain:
T4a
Involvement of nasopharynx
T4b
Osseous involvement (including periosteum)
T4c
Involvement of maxillofacial, ethmoidal, and/or frontal sinuses
T4d
Intracranial spread
Regional lymph nodes (N)
NX
Involvement of lymph nodes not assessed
N0
No evidence of lymph node involvement
N1
Involvement of ipsilateral regional lymph nodes (preauricular, submandibular, or cervical)
N2
Involvement of contralateral or bilateral regional lymph nodes
N3
Involvement of peripheral lymph nodes not draining ocular adnexal region
N4
Involvement of central lymph nodes
Distant metastasis (M)
M0
No evidence of involvement of other extranodal sites
M1a
Noncontiguous involvement of tissues or organs external to the ocular adnexa (e.g., parotid glands, submandibular gland, lung, liver, spleen, kidney, breast, etc.)
M1b
Lymphomatous involvement of the bone marrow
M1c
Both M1a and M1b involvement
Anatomic stage/prognostic groups
No stage grouping is presently recommended.
From: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Used with permission.
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The Eye
The Eye
George J. Harocopos
