Cancers Staged Using This Staging System
The classification applies only to carcinoma of the conjunctiva. Other tumors of the conjunctiva, including secondary conjunctival tumors (e.g., intraocular tumors extending through the conjunctiva, such as uveal melanoma or uveal non-Hodgkin lymphoma, and orbital tumors extending into the conjunctiva, such as rhabdomyosarcoma), are not classified using this schema.
Cancers Not Staged Using This Staging System
| These histopathologic types of cancer… | Are staged according to the classification for… | and can be found in chapter… |
|---|---|---|
| Conjunctival lymphoma | Ocular adnexal lymphoma | 71 |
| Conjunctival melanoma | Conjunctival melanoma | 66 |
Summary of Changes
| Change | Details of Change | Level of Evidence |
|---|---|---|
| Definition of Primary Tumor (T) | T1 and T2 definitions have been revised to include invasion of the conjunctival basement membrane. | II |
| Prognostic Factors | Expand ed Emerging Prognostic Factors list | II and III |
ICD-O-3 Topography Codes
| Code | Description |
|---|---|
| C69.0 | Conjunctiva |
WHO Classification of Tumors
This list includes histology codes and preferred terms from the WHO Classification of Tumors and the International Classification of Diseases for Oncology (ICD-O). Most of the terms in this list represent malignant behavior. For cancer reporting purposes, behavior codes /3 (denoting malignant neoplasms), /2 (denoting in situ neoplasms), and in some cases /1 (denoting neoplasms with uncertain and unknown behavior) may be appended to the 4-digit histology codes to create a complete morphology code.
| Code | Description |
|---|---|
| 8010 | Carcinoma, NOS |
| 8070 | Squamous cell carcinoma, NOS |
| 8071 | Squamous cell carcinoma, keratinizing, NOS |
| 8072 | Squamous cell carcinoma, large cell, nonkeratinizing, NOS |
| 8073 | Squamous cell carcinoma, small cell, nonkeratinizing, NOS |
| 8074 | Squamous cell carcinoma, spindle cell |
| 8075 | Squamous cell carcinoma, adenoid |
| 8076 | Squamous cell carcinoma, microinvasive |
| 8090 | Basal cell carcinoma, NOS |
| 8410 | Sebaceous adenocarcinoma |
| 8430 | Mucoepidermoid carcinoma |
| 8560 | Adenosquamous carcinoma |
Histology is not ideal for clinical use in patient care, as it describes an unspecified or outdated diagnosis. Data collectors may use this code only if there is not enough information in the medical record to document a more specific diagnosis.
International Agency for Research on Cancer, World Health Organization. International Classification of Diseases for Oncology. ICD-O-3-Online.http://codes.iarc.fr/home. Accessed August 16, 2017. Used with permission.
The AJCC staging system for conjunctival carcinoma remains largely unchanged from the AJCC Cancer Staging Manual, 7th Edition, apart from a more precisely defined disease extent for early invasive lesions (T1 and T2). This change has implications for management, as emerging studies support adjuvant treatment in some of these patients.
It is acknowledged that the TNM staging system for these tumors would benefit greatly from the establishment of multicenter registries, prospective rand omized trials, and prospective data mining to consolidate and expand the definitions of prognostic significance and to incorporate biomarkers.
Similarly, it is noted that data from a large registry would help provide significance to the currently applied subdivisions of intraepithelial disease (i.e., conjunctival squamous intraepithelial neoplasia, I-III). However, these data currently do not exist.
AJCC staging for conjunctival carcinoma is becoming more important, because the incidence of conjunctival squamous cell carcinoma (SCC) associated with HIV is increasing, especially in younger individuals in developing countries with high incidences of HIV. Such tumors behave more aggressively.
This chapter clearly defines the clinical term ocular squamous surface neoplasia and explains why a histopathologic tissue diagnosis is needed for TNM staging.
This staging system applies to conjunctival carcinoma comprising predominantly SCC and corneal squamous intraepithelial neoplasia, along with other histologic subtypes (see ICD-O-3 Histology Codes). Nonepithelial tumors of the conjunctiva are not staged using these criteria. Biopsy is required for tumor staging.
Risk factors for the disease are exposure to sun and ultraviolet B light, as well as light-colored skin. Other risk factors include radiation exposure, smoking, human papillomavirus (HPV) infection, chemical exposures, immunosuppression, and particular syndromes (e.g., xeroderma pigmentosum). In developed countries, this condition is more common in men, with a peak incidence in the seventh decade of life. At diagnosis, it is typically localized to the corneal limbus. Conjunctival carcinoma also is associated with HIV infection, and this association is particularly prevalent in developing countries, where it may be considered an AIDS-defining illness, especially in younger patients.1-10
Ocular surface squamous neoplasia is a clinical term encompassing the continuum of disease from mild epithelial dysplasia to SCC. Because this term includes overlapping histopathologic grades and entities, it is imprecise and should be avoided in histopathology reports. The precise morphologic changes should be documented using terminology applied in pathology. 11,12
After clinical and pathological diagnosis, excisional treatment typically is supplemented by adjunctive double freeze-thaw cryotherapy to the conjunctival margins and sclera base at the time of primary resection.13 Additional adjuvant and /or alternative treatments include topical chemotherapy (mitomycin C, 5-fluorouracil, or interferon alfa-2b). Radiation therapy (teletherapy or brachytherapy) may be used when complete resection is not possible or as salvage treatment to avoid orbital exenteration.14-20
Anatomically, the conjunctiva consists of stratified epithelium that contains mucus-secreting goblet cells. These cells are most numerous in the fornices. Palpebral conjunctiva lines the eyelid; bulbar conjunctiva covers the eyeball. Conjunctival epithelium merges with that of the cornea at the limbus.2 Conjunctival squamous carcinomas are most likely to arise from the exposed bulbar limbal location.
Conjunctival squamous intraepithelial neoplasia embraces all forms of intraepithelial dysplasia, including SCC in situ. Spread occurs initially by direct local extension radially into the adjacent conjunctiva and cornea, and ultimately vertically into the conjunctival stroma, Tenon's capsule, and the sclera. Perineural invasion may occur at an earlier stage, typically in more aggressive histologic subtypes (e.g.,mucoepidermoid carcinoma), leading to orbital extension. Larger lesions may develop the capacity for metastatic spread to regional lymph nodes following invasion into lymphatic vessels in the conjunctiva. Intraocular spread may occur through the sclera, particularly if weakened by prior surgery.2,4,5,21-28
Advanced tumors may directly invade the eyelid, eye, nasolacrimal system, orbit, adjacent paranasal sinus structures, or brain.26,28,29
Regional Lymph Nodes
The regional lymph nodes are preauricular (parotid), submand ibular, and cervical nodes (Figure 63.1).
Initial and subsequent clinical assessments of conjunctival carcinoma are based on inspection, slit lamp examination, and palpation of the regional lymph nodes. All conjunctival surfaces should be inspected, measured, documented, and photographed (including eversion of the upper eyelid) (Figure 63.2). Tumor photography should pay particular attention to the lesion margins, evidence of pagetoid spread, corneal epithelial extension, and involvement of the punctum. Gonioscopy should be performed with photography (for limbal disease), particularly when intraocular extension is suspected. Examination of the ipsilateral sinuses is indicated (particularly if punctal involvement has been noted).
The diagnosis of conjunctival squamous carcinoma typically requires excisional biopsy because histolopathologic examination allows for the assessment of vertical tumor extent, which is needed to determine the levels required for TNM staging. In contrast, cytologic techniques have been found to be useful in determining cytologic atypia. Cytology has been particularly helpful as an adjunct to clinical diagnosis and in evaluation for recurrent disease.11
Anterior segment ultrasound imaging and optical coherence tomography are useful for measuring tumor thickness and evaluating invasion of adjacent structures (e.g., the sclera, uvea, and anterior orbit). Ultrasound biomicroscopy (UBM) findings suspicious for intraocular invasion include angle blunting and uveal thickening.30 Low-frequency posterior segment ultrasonography also may be used to evaluate for choroidal and orbital invasion.31
Radiologic evaluation may be necessary to stage locally invasive and nodal disease and may include computed tomography (CT), magnetic resonance imaging, and positron emission tomography/CT. Metastatic survey typically includes a physical examination as well as hematologic screening and radiologic evaluations of the head, chest, and abdomen.
For pathological staging, complete resection of the primary site is indicated, if possible.
To obtain the best histopathologic information, it is important to send the conjunctival specimen to the laboratory, spread evenly on a piece of filter paper with orientation marks on the paper. These measures prevent the specimen from curling and enable orthogonal sections to be taken from the tissue, allowing assessment of the depth of tumor penetration. Histopathologic evaluation for negative peripheral or deep margins should be performed. If mapping biopsy samples are sent to the laboratory, they should be placed in separate containers labeled with the appropriate anatomic location. Sentinel lymph node biopsy is investigational.32
As stated earlier, the clinical term ocular squamous surface neoplasia is imprecise and may even include benign growths; thus, it should be avoided in surgical pathology reports.12
For pN, histologic examination of regional lymphadenectomy specimens, if performed, will include one or more regional lymph nodes.28,32
Prognostic Factors Required for Stage Grouping
Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping.
Additional Factors Recommended for Clinical Care
For more information, see references 2-7, 10, and 33.
Presence or absence of subepithelial invasion, as determined by histopathologic examination
Tumor size as determined by clinical measurement, clock hour evaluation, and UBM
Local invasion as assessed by gonioscopy, ultrasound, and radiologic testing
The following factors are associated with higher recurrence rates after treatment. For more information, see references 2-7, 10, 14, 21-29, 34, and 35.
SCC vs. spindle cell carcinoma and mucoepidermoid carcinoma, the latter being more aggressive variants of conjunctival carcinoma and associated with higher recurrence rates and worse prognosis due to a tendency for intraocular extension
Presence or absence of lymphatic or vascular invasion
Ki-67 is reported as percentage of positive tumor cells
The following factors are prognostically significant potential therapeutic targets. For more information, see references 2-7,10,14,21-29,34, and 35.
The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use.36 Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.
Definition of Primary Tumor (T)
Adjacent structures include the cornea (3, 6, 9, or 12 clock hours), intraocular compartments, forniceal conjunctiva (lower and /or upper), palpebral conjunctiva (lower and /or upper), tarsal conjunctiva (lower and /or upper), lacrimal punctum and canaliculi (lower and /or upper), plica, caruncle, posterior eyelid lamella, anterior eyelid lamella, and /or eyelid margin (lower and /or upper).
| T Category | T Criteria |
|---|---|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ |
| T1 | Tumor (less than or equal to 5 mm in greatest dimension) invades through the conjunctival basement membrane without invasion of adjacent structures |
| T2 | Tumor (greater than 5 mm in greatest dimension) invades through the conjunctival basement membrane without invasion of adjacent structures |
| T3 | Tumor invades adjacent structures (excluding the orbit) |
| T4 | Tumor invades the 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 |
Definition of Regional Lymph Node (N)
| N Category | N Criteria |
|---|---|
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
Definition of Distant Metastasis (M)
| M Category | M Criteria |
|---|---|
| M0 | No distant metastasis |
| M1 | Distant metastasis |
Registry Data Collection Variables
| G | G Definition |
|---|---|
| GX | Grade cannot be assessed |
| G1 | Well differentiated |
| G2 | Moderately differentiated |
| G3 | Poorly differentiated |
| G4 | Undifferentiated |
