Squamous Carcinoma and Intraepithelial Neoplasia of the Conjunctiva

By Paul T. FInger, MD

Description

Squamous conjunctival neoplasia (SCN) is most commonly found in older white males (76%). The average age of patients affected by SCN is 56. This tumor, said to make up 14% of all primary ocular and orbital tumors is related to sun exposure. Sunlight, particularly ultraviolet-B (UV-B) radiation can cause DNA damage, mutations, and cancerous cells. Though human papillomavirus -16 has been found in conjunctival tumor specimens, it has not been proven to cause this tumor. The immunosuppressed (e.g. elderly, HIV positive) are particularly vulnerable. When conjunctival squamous carcinoma occurs in HIV positive patients, it can be particularly resistant to treatment.

Symptoms

Patients notice a white or yellow-white tumor on the surface of the eye (often with extension onto the cornea).

Diagnosis

Squamous conjunctival neoplasia tends to be found between the eyelids (interpalpebral space), and at the limbus (border of the white sclera and clear cornea). This tumor can extend onto the cornea, around the limbus, and rarely into the eye and orbit. When the tumor extends onto the cornea it can be avascular and opaque in appearance. Commonly, squamous conjunctival neoplasia will contain characteristic corkscrew-shaped blood vessels.

Squamous Conjunctival Carcinoma: Note the white nodular thickening at the limbus.

Nodular Squamous Conjunctival Carcinoma:  There is also a nodular type that is  circumscribed, rapidly growing, and invasive. Since this type more commonly extends beneath the conjunctival epithelium, nodular tumors exhibit increased metastatic potential. All large squamous conjunctival cancers should be examined with high frequency ultrasound. This technique can be used to determine if the tumor has invaded the eye or orbit.

In the image on the middle right, note that a few corkscrew-shaped blood vessels on its surface (arrow).

Diffuse Squamous Conjunctival Carcinoma:

Nodular Squamous Conjunctival Carcinoma: Note that a few corkscrew-shaped blood vessels on its surface (arrow).

There is a diffuse variant that can masquerade as chronic conjunctivitis. Tumor thickening occurs late making it difficult to diagnose. Therefore, a conjunctival biopsy should be considered in cases of conjunctivitis lasting more than 3 months.

The diagnosis of malignant squamous conjunctival neoplasia is typically made by biopsy. Like most squamous epithelial tumors, invasion beneath the epithelium into the substantia propria defines these lesions as carcinoma. This is because, when the tumor is contained within the epithelium it does not have access to the lymphatic system or metastatic potential.

Treatments

Every suspected squamous conjunctival cancer should be photographed and AJCC staged prior to biopsy or excision. Surgical excision (alone) has been associated with high rates

The diagnosis of squamous conjunctival neoplasia is typically made by biopsy.

of recurrence. This is because the tumor’s edges and deep margins are either gray or the same color and the sclera and thus difficult to determine. When the tumors edges are clear and avascular, it leads to a false sense that the tumor is smaller than it is.

Local superficial freezing of the tumor bed, sclera and adjacent conjunctiva (cryotherapy) has improved local control and decreased the incidence of tumor recurrence. Other centers have added radiation therapy to decrease tumor recurrence.

However, topical chemotherapy is becoming the most common method of treatment.

While a large clinical trial is needed to compare the effectiveness of topical chemotherapy to excision and cryotherapy, Dr. Finger now uses topical chemotherapy eye drops to avoid surgery (in most cases).

Additional info

Local Spread:

Intraocular spread of squamous conjunctival neoplasia is rare in developed countries (< 5% of cases). When intraocular penetration occurs it is typically through the limbus. Signs include neovascularization of the iris and cornea as well as glaucoma, and peripheral anterior synechiae. Dr. Finger has found high frequency ultrasound to be particularly helpful in these cases.

High frequency ultrasound is particularly helpful in these cases. Positive findings include: thickening of the ciliary body, uvea and blunting of the iridocorneal angle. Intraocular penetration is typically treated by deep cryotherapy, eye-wall resection or radiation.

If the orbit is invaded, there is a risk of spread into the sinuses and brain. Such invasion is said to be the most common cause of death related to this tumor. When squamous conjunctival neoplasia metastasizes beyond the eye and orbit, it can either be found in the regional lymph nodes (preauricular, submandibular, and cervical), or in the lungs and bone.

In general, early detection allows for removal or destruction of these tumors with excellent local cure rates.

Risk Factors:

  • Fair Skin
  • Tendency to Sunburn
  • Outdoor Occupation
  • Living Close to the Equator
  • History of Actinic Skin Lesions
  • Xeroderma Pigmentosum
  • Immunosuppression
  • Male Gender
  • Older Age

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Pterygium

By Paul T. Finger, MD

Description

A nasal pterygium is noted to extend onto the cornea.
A nasal pterygium is noted to extend onto the cornea.

Pterygium is a vascular pink tissue that can grow from the conjunctiva onto the cornea. If it grows into the line of vision (over the pupillary aperture), it can interfere with vision. Pterygium are most commonly found to originate from on the inner (nasal) surface of the eye, and extend toward the the pupil. They can also occur the on the temporal (towards the ear) side of the eye.
Pterygium are more common in countries near to the equator, where there is long-term exposure to sunlight, particularly ultraviolet (UV) rays. In addition, others believe that chronic eye irritation may play an important role. Therefore, pterygium occur more often in people who spend time outdoors, particularly in sunny climates.
Pterygium are benign (not malignant) tumors. Hence pterygium do not invade the eye, sinuses or brain. Pterygium do not spread to other parts of the body (metastasize).

Symptoms

Pterygium are external to the eye, visibly apparent, and typically noted to grow before they cause symptoms. They can become irritated, causing an itchy, burning sensation. If allowed to grow into the line of vision (pupillary axis), then a pterygium can cause impairment of vision.

Diagnosis

Pterygium is usually diagnosed based on appearance. They are typically a wing-shaped, soft tissue growth from the nasal or less commonly the temporal bulbar conjunctiva toward the cornea. Should growth be documented, excision is usually suggested. When surgery is performed, the excised tissue should be sent to pathology for a histopathologic diagnosis.

Treatments

This pterygium has progressed over the visual (pupillary) axis and is affecting the patient's vision.
This pterygium has progressed over the visual (pupillary) axis and is affecting the patient’s vision.

If a pterygium becomes red and irritated, lubricating eye drops or ointments can be placed onto the eye as to reduce the inflammation. Rarely, anti-inflammatory eye drops may be prescribed.

Pterygium are surgically removed when they affect sight, grow such that your eye care professional expects it to impair vision, or if it is cosmetically unacceptable. Unfortunately, pterygium may return despite proper surgical removal. To help prevent recurrences surface radiation, conjunctival implants (grafts), or chemotherapy medications can be used.

Patients with pterygium should wear ultraviolet (UV) protective sunglasses, use artificial tears, and avoid dry and dusty conditions.

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Pingueculum

By Paul T. Finger, MD

Description

A pingueculum is a yellowish patch on the white (sclera) of the eye. Found between the eyelids, it is most often on the nasal side (closest to the nose), but can be found on the temporal (closest to the ear) side. Pingueculum are not cancer. It is a sun-related alteration of the normal conjunctival tissue.

Pingueculum.
Pingueculum with thickness: Note the lack of intrinsic vascularity or corneal extension.

Symptoms

Pingueculum are usually visible, found on the surface of the eyeball, between the eyelids. They can become a cosmetic problem, rarely become inflammed, irritated and red. When this happens, the patient may have a feeling like there is something (a foreign body) on the eye.

Pingueculum can become thickened. But, it should not have prominent or corkscrew-shaped blood vessels (within the tumor), nor should the pingueculum extend onto the cornea.

 

Diagnosis

An eye care professional can diagnose a pingueculum by clinical “slit-lamp” examination.

 

Treatments

Eye care professionals typically leave pinguecula alone. If it becomes irritated, it can be treated with a topical non-steroidal or steroid eye drop. Artificial tears are also helpful. Surgery is reserved for atypical pingueculum or when another “cancerous” diagnosis is suspected.

Pigmented Conjunctival Cancers (Primary Acquired Melanosis)

By Paul T. Finger, MD

Description

Malignant melanomas can start as a nevus/freckle or arise as newly formed conjunctival pigmentation called primary acquired melanosis (PAM).

A simple biopsy can determine whether a pigmented conjunctival tumor is a nevus, primary acquired melanosis, or conjunctival melanoma. As seen below, primary acquired melanosis typically affects one eye, in middle-aged, fair-skinned people.

In contrast, darkly pigmented individuals often have naturally occurring pigment on their conjunctiva. When this occurs it is called racial melanosis. Unlike primary acquired melanosis, racial melanosis tends to involve both eyes and is typically present for the entire life of the patient.A simple biopsy can determine whether a pigmented conjunctival tumor is a nevus, primary acquired melanosis, or conjunctival melanoma. As seen above, primary acquired melanosis typically affects one eye, in middle-aged, fair-skinned people.

Symptoms

Pigmentation of the surface of the eye and/or eyelids.

Diagnosis

Most pigmented spots on the eye are benign. Your eye care specialist can take a photograph of them and watch to see if they change prior to consideration of biopsy or treatment.

Pigmented conjunctival tumors that are raised, hypervascular, or extend onto the cornea are considered suspicious. Though suspicious conjunctival tumors can be biopsied after your first visit to the eye cancer specialist, close observation for evidence of growth (prior to biopsy) may also be recommended. Documented tumor growth is a strong indicator that biopsy should be performed.

Once the biopsy is performed, the specimen should be evaluated by an ophthalmic pathologist. If there is no ophthalmic pathologist at your center, the slides can be sent for second opinion.

A pigmented conjunctival nevus can be photographed and followed for evidence of growth prior to biopsy or excision. It is important to note that both benign and malignant tumors can grow (though malignant tumors will grow faster).

Slit-lamp photography of benign conjunctival lesions is helpful in determining if subsequent change has occurred. It is a good idea for the patient to have a copy of the initial photograph because doctors are not required to keep medical records indefinitely, and the lesion can change even years after the initial diagnosis.

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Search the Scientific Literature on Pigmented Conjunctival Tumors

Melanoma In Situ and Invasive Conjunctival Melanoma

By Paul T Finger, MD

Description

Primary acquired melanosis with atypia (biopsy proven).

Malignant melanoma can occur on the surface of the eye (conjunctiva and cornea). It can start on its own, as a pre-existing nevus or arise within newly formed pigmentation.

 

Symptoms

Most patients notice either a nodule forming on, or a darkening of the surface of the eye. Large tumors can bleed resulting in “bloody tears.” The tumor can extend onto the eyelid skin and lymph nodes in front of the ear (preauricular) or neck (cervical). Involved lymph nodes enlarge and can be felt (palpable) during examination.

 

Diagnosis

The doctor will examine your eyes. This includes an examination of all the conjunctival surfaces (including the inside of the eyelids). Pigmented conjunctival tumors are considered suspicious if they have large blood vessels running toward them, if they extend onto the cornea or if they extend into the conjunctival fornices.
Photographs should be taken of all the conjunctival and corneal surfaces at the time of initial examination (prior to any biopsy). This is important because it helps the doctor document the extent of the condition (stage the tumor) and can be used to plan for surgery and aid in follow up. Removing a conjunctival melanoma prior photography and/or referral to an eye cancer specialist can decrease the patients chance for cure.

Biopsy can determine whether a pigmented conjunctival tumor is a nevus, primary acquired melanosis, or conjunctival melanoma. A conjunctival nevus and benign acquired melanosis can be photographed and followed for evidence of change prior to intervention. Malignant conjunctival melanoma and intra-epithelial melanoma (in situ) should be removed or destroyed.

*Note* In a multicenter international effort to develop a staging system for conjunctival melanoma, the authors agreed that the term Primary acquired melanosis with atypia should be abandoned in favor of conjunctival melanoma in situ.

 

Treatments

Most very small areas of conjunctival hyperpigmentation can be photographed and followed for evidence of growth or change prior to treatment. If they are raised, hypervascular or extend onto the cornea a biopsy is reasonable. Small tumors can be completely removed, and if they are found to be malignant additional cryotherapy (freezing) or adjuvant topical chemotherapy may be necessary.

Melanomas can be difficult to treat if they occur at multiple spots on the eye. In these cases, surgical removal with freezing therapy may not control this tumor. Then chemotherapy eye-drops can be used for patients with conjunctival melanoma. Chemotherapy eye drops treat the entire surface of the eye, and is less dependent upon defining the tumors edges.

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Lymphoma of the Conjunctiva

By Paul T Finger, MD

Description

Lymphoma can occur in the conjunctiva. These tumors typically look like “salmon-patches.” Red colored tumors on the eye can be a presenting sign of systemic lymphoma. Eye cancer specialists usually biopsy lymphoid tumors and the pathologist is requested to perform special immunologic and genetic studies on the tumor cells. These techniques are used to determine if the tumor is benign or malignant as well as define the subtype of lymphoid malignancy.

Symptoms

The "Salmon-Patch" of Conjunctival Lymphoma.
The “Salmon-Patch” of Conjunctival Lymphoma.

Most patients notice the reddish discoloration of the surface of the eyeball (conjunctiva). As the tumor enlarges, patients seek medical attention. Conjunctival lymphomas can become large enough to displace the eyeball, and restrict eye movement. Eye movement restriction can cause diplopia (double-vision).

If the tumor extends behind the eyeball, it can be pushed forward (proptosis). Rarely, and if large enough, orbital lymphoma can press on the optic nerve and cause loss of vision. If discovered early, prompt treatment offers the best chance for recovery of vision.

Diagnosis

Pathology analysis of biopsied tissue allows your eye cancer specialist to determine if the  lymphoma is a less aggressive MALT (mucosa associated lymphoid tissue) or the more malignant-behaving non-MALT lymphomas. Clinical differentiation between these types of cancers can be difficult.

In either case, patients with lymphoid conjunctival tumors (ocular adnexal lymphoma) should have a complete medical check up and be followed by both their eye cancer specialist and a hematologist-oncologist.

Treatments

Treatment depends on whether or not systemic lymphoma is detected. If the patient is found to have systemic lymphoma, they are likely to receive systemic immunotherapy or chemotherapy, no additional eye treatment may be necessary. However, if the conjunctival tumor is the only site of disease, most patients with malignant conjunctival lymphoma at The New York Eye Cancer Center are treated with low dose external beam radiation therapy.

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Epibulbar Dermoid

By Paul T. Finger, MD

Description

This epibulbar dermolipoma is found to infiltrate the peripheral cornea and extend back to the lacrimal gland.

Epibulbar dermoids are benign tumors. They tend to be firm, white-yellow or pinkish tumors straddling the limbus in the temporal (primarily inferotemporal) quadrants. They are located both over the cornea and sclera. They can range from several millimeters to over a centimeter in size. They are typically unilateral (found on one eye), but can be bilateral.

Dermoids are choristomas (normal tissues that are in the wrong place). Made up of cutaneous and subcutaneous tissue, it is not uncommon for dermoids to contain hair and other skin structures. These tumors can be found on the eye, adnexa and orbit.

Dermolipomas are more commonly found in the superotemporal quadrant extending to the lacrimal gland and/or orbit.

 

Symptoms

Most patients with epibulbar dermoid or dermolipomas have no symptoms unless hairs or other dermal structures cause local irritation. The lesions do cause a cosmetic defect.

 

Diagnosis

The diagnosis of dermoid and dermolipoma is made by ophthalmic examination. These lesions are typically present at birth and do not progress. Though ultrasound and radiographic imaging may be required to investigate the extent of the tumor, biopsy is not necessary.

Dermoids or dermolipomas are more likely to be associated with Goldenhar’s Syndrome if they are multiple or bilateral. Goldenhar Syndrome is associated with dermoid tumors at the tragus of the ear and facial dysostosis.

 

Treatments

It is very important to make sure your child does not have a secondary astigmatism related to corneal tumor involvement. Early treatment of astigmatism can prevent amblyopia (loss of vision).

Surgery can be performed to limit the cosmetic defect, but there are many reports of secondary complications related to thinning of the scleral “eye wall” and corneal astigmatism.

Surgical removal of dermolipomas (that can extend into the lacrimal gland and orbit) can be associated with lacrimal gland dysfunction (dry eye) and double vision. Care must be taken to preserve the overlying conjunctiva and lacrimal gland.

 

Additional Info

Dermoids and dermolipomas can be associated with Goldenhar Syndrome or Linear Nevus Sebaceous Syndrome.

Conjunctival Kaposi’s Sarcoma

By Paul T. Finger, MD

Description

Slit-lamp photograph of a Kaposi’s sarcoma affecting the medial aspect of the conjunctiva into the fornix (arrow).

Kaposi’s sarcoma (KS) can affect the conjunctiva and eyelids. It is a red to pink conjunctival tumor and a blue to purple eyelid tumor. In North America, it is typically found in patients with HIV acquired immunodeficiency syndrome (AIDS), but can occur in the elderly and immunocompromised (e.g. transplant patients). Classic Kaposi’s sarcoma also occurs in the elderly and is slowly progressive.

Diagnosis

If the doctor suspects that a conjunctival tumor is Kaposi’s sarcoma, the patient’s skin and lymph nodes should be examined. Blood should be tested for HIV, lymphocytes, and other opportunistic diseases. One can make a tissue diagnosis based on a biopsy, or a presumptive diagnosis in patients with a history of Kaposi’s. One problem with a presumptive diagnosis (in this group of patients) is that these patients are particularly vulnerable to developing squamous and lymphoid conjunctival tumors.

Your eye care professional is more likely to suggest an incisional biopsy for diagnosis. In most cases, this can be performed in a treatment room with local anesthetic. Sterile technique, HIV precautions, and proper labeling of the specimen are required. In order to biopsy, it is not necessary to completely excise the Kaposi’s sarcoma (unless it is small and unifocal).

Treatments

Histopathology of the excised Kaposi's sarcoma reveals myriads of vascular channels.
Histopathology of the excised Kaposi’s sarcoma reveals myriads of vascular channels.

Treatment depends on the patient’s age, and the status of his or her general health, current medications and immune status. Small Kaposi’s sarcomas can be removed at biopsy. Larger and multifocal tumors are biopsied, proven Kaposi’s sarcoma by pathologic analysis, and treated (systemically or regionally).

Chemotherapy, radiation therapy and biologic therapy can be employed. In cases of HIV-AIDS related Kaposi’s sarcoma, we tend to avoid any treatment that would further suppress the patient’s immune system. If treatment of the patient’s underlying HIV-AIDS does not halt the progression of the Kaposi’s sarcoma, this tumor has been found to be very sensitive to external beam radiation therapy.

Additional Info

For the ophthalmologist who discovers conjunctival Kaposi’s sarcoma, it is important to coordinate care with a team consisting of a medical oncologist (and/or HIV-specialist), and radiation oncologist.

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Conjunctival Tumors: General Information

By Paul T. Finger, MD

Description

Conjunctival melanoma in situ (biopsy proven).

Malignant cancers can grow on the surface of the eye. They usually start from the membrane that covers most of the eye called the conjunctiva. The most common conjunctival cancers are squamous carcinoma, malignant melanoma and lymphoma.

Malignant melanoma used to be called PAM with atypia, but the newest AJCC staging system authors suggest we stop using the term PAM with atypia and call it melanoma in situ. This was because PAM with atypia doesn’t define it as a cancer. Pathologists call these specimens Tumor in situ or Tis.

Squamous carcinoma of the conjunctiva can form a nodule or diffusely spread out over the surface of the eye. Only very large squamous conjunctival cancers and those in patients who are immunosuppressed metastasize to other parts of the body. But they can invade into and around the eye, into the orbit and sinuses.

Malignant melanoma can start as a conjunctival nevus, arise as newly formed pigmentation (or variably pigmented) within the conjunctiva or onto the cornea. A simple biopsy can determine whether a pigmented conjunctival tumor is a benign nevus, primary acquired melanosis, or conjunctival melanoma.

Lymphoma can also occur in the conjunctiva. These tumors look like red or salmon-colored patches on the eye and can be the first sign of systemic lymphoma. Eye cancer specialists usually biopsy lymphoid tumors so that a pathologist can perform special immunologic and genetic studies on the tumor cells. These techniques are used to determine if the tumor is benign or malignant. Patients with lymphoid conjunctival tumors should have a complete medical check up and be examined by a hematologist-oncologist. Other “less common” conjunctival cancers are reviewed in this section.

Symptoms

Most conjunctival tumors do not cause symptoms. Patients typically seek medical attention because they notice a discoloration on the eye or extension of the tumor onto the cornea. Conjunctival tumors can also be found by an eye care specialist during a routine eye examination.

Diagnosis

Most small benign-appearing conjunctival tumors can be photographed and followed for evidence of growth prior to biopsy or treatment. If they are raised, hypervascular or extend onto the cornea a biopsy is more reasonable. At The New York Eye Cancer Center we typically obtain an office-based cytology specimen for squamous carcinoma. This lets us know the tumor is squamous and avoids a trip to the operating room. In contrast, both melanoma and lymphoma require more histopathology and special pathology analysis. Therefore, those tumors require surgical biopsy or if small, excision.

Conjunctival melanomas require special treatment. The natural history of these tumors has been characterized as presenting with multiple tumors or non-pigmented skip areas.

Therefore, it is difficult and some think impossible to define the extent of the tumor on clinical examination.

 

The So-Called “No Touch Technique”

The natural skip areas of pigmentation, multifocal presentation and high rates of recurrence have led some eye cancer specialists think that handling conjunctival melanoma promotes spread. They fear that tumor cells get stuck on the instruments that if reused, implant tumor on other, unaffected parts of the globe.

However, Dr. Finger disagrees with this theory and its so called “no touch technique” that requires surgeons to get new instruments after each time they touch the tumor (to prevent transplantation). However, there are no other cancers where surgeon-related transplantation has been found. More likely, these eye cancer specialists operate on one area, thinking that the pigmented portion of the tumor is the complete extent of disease. Unaware, there are other non-pigmented or small tumors that are not yet visible and later grow. Then they think they transplanted the tumor.

At The New York Eye Cancer Center, when conjunctival melanoma is suspected, Dr. Finger utilizes his specially designed cryotherapy devices “Finger-tip” cryotherapy probes” to make sure the tumor and a surround of normal appearing tissue is treated before he touches the tumor. Then the tumor can be safely removed without fear of transporting tumor cells or invaginating the edges of the wound rendering tumor too deep to treat with chemotherapy eye drops. At The New York Eye Cancer Center, topical chemotherapy eye drops are used for treatment of both squamous and melanoma cancers. These drops have been found to reduce or more commonly eliminate the need for extensive surgery.

Evaluation of the biopsy specimen should be performed by an experienced ophthalmic pathologist. If there isn’t an ophthalmic pathologist in your area, you can request that the histopathology slides be sent for second opinion.

Treatment: General Guidelines

Small tumors can be completely removed, and if they are found to be either squamous carcinoma or malignant melanoma, additional cryotherapy (freezing) is likely to improve local tumor destruction and thus prevent recurrence. Dr. Finger has developed specialized “Finger-tip” cryotherapy probes to uniformly freeze large surfaces of the eye with minimal intraocular penetration (see innovations section). 

Chemotherapy Eye Drops:

Conjunctival melanoma and squamous carcinoma can be difficult to treat if they are “mulitfocal” – occur in multiple spots on the eye. In these cases, even surgical removal with freezing therapy may not control the tumor. Dr. Finger has found that “Chemotherapy eye-drops can be used for and are often better than surgery for most patients with conjunctival cancers.” Chemotherapy eye-drops treat the entire surface of the eye, are less dependent upon defining the tumors edges, and decreases the chance of scarring (symblepharon) after surgery. Researchers at The New York Eye Cancer Center recently published on treatment of “Giant Conjunctival Squamous Carcinoma’ with chemotherapy eye drops alone (no surgery).

Systemic lymphoma can usually be treated with standard chemotherapy that is also likely to cure malignant ocular lymphomas. If the eye is the only site of malignant lymphoma, low dose external beam radiation therapy is commonly employed.

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