Tumors of the eyelid and conjunctiva vary in histology and extent of disease, and which treatments, if any, are needed after surgical excision depends on several factors, including the potential for metastasis.
To help guide treatment decisions, physicians at The University of Texas MD Anderson Cancer Center are using innovative techniques such as sentinel lymph node biopsy (SLNB) to refine the staging of these tumors and are conducting molecular studies of rare tumors to improve the personalized treatment of patients with eyelid and conjunctival tumors.
“Treating cancers of the eyelid and conjunctiva requires a multidisciplinary effort that includes surgeons, nuclear radiologists, pathologists, and radiation and medical oncologists,” said Bita Esmaeli, M.D., a professor of ophthalmology and the director of the Orbital Oncology and Ophthalmic Plastic Surgery Fellowship Program at MD Anderson.
Dr. Esmaeli said that the first-line treatment for eyelid or conjunctival tumors is almost always surgical excision, although radiation therapy may be used as the first-line treatment if surgery is contraindicated. In patients whose tumors are excised, decisions about postoperative treatment are determined by factors such as the type of cancer and the risk of lymph node metastases.
Surgery and reconstruction
Many eyelid and conjunctival tumors are caught early; such tumors often can be excised and the wound repaired using oculoplastic surgical techniques with little or no loss of eye function. Neither enucleation nor orbital exenteration has been shown to improve survival outcomes, so these procedures are unnecessary unless there is orbital extension of the tumor. However, large tumors can endanger function and require extensive reconstruction, and surgeons at tertiary referral centers often encounter such difficult-to-treat cases. “We see rare cancers of the eyelid at an advanced stage, where it is questionable whether we can salvage the eye and its function. Such cases are where complex reconstructive procedures and an innovative but cautious multidisciplinary approach can make a big difference,” Dr. Esmaeli said.
At MD Anderson, reconstructive surgery typically is performed immediately after the tumor is excised. A tumor’s size and location determine the techniques used for reconstruction. “Basal cell carcinoma most often occurs in the lower eyelid, and for the larger tumors the wound from excision is repaired with a tarsoconjunctival flap [Hughes flap]—often with excellent functional and cosmetic outcomes,” Dr. Esmaeli said. “But the more rare cancers—sebaceous carcinoma, melanoma, and Merkel cell carcinoma—tend to occur in the upper eyelid, which is more difficult to reconstruct. Patients with these tumors are more likely to come to a referral center, and as a result we end up doing more of these unusual, upper eyelid reconstructions compared with other settings. Eyelid sharing procedures such as Cutler-Beard bridge flaps are often needed to reconstruct large upper eyelid defects.”
Conjunctival carcinomas and melanomas, which can occur in either the bulbar or palpebral region, typically require microscopic ocular surface reconstruction and sometimes the use of amniotic membrane grafts. Special handling of conjunctival surgical specimens by the pathologist and communication between the eye surgeon and the pathologist are very important for correct diagnosis of conjunctival melanomas and carcinomas and for determining the patient’s prognosis.
For tumors that have a significant risk of regional lymph node metastasis—such as conjunctival or eyelid melanomas that are thicker than 1 mm or demonstrate other high-risk histologic features such as ulceration or high mitotic figures, sebaceous carcinomas of the eyelid, or Merkel cell carcinomas of the eyelid—SLNB is typically done at the time of primary tumor excision.
Sentinel lymph node biopsy
SLNB entails the removal and examination of one or two sentinel lymph nodes (i.e., the draining lymph nodes nearest the tumor) to determine whether they contain metastatic disease. The use of SLNB for eyelid and conjunctival cancers was developed and modified over the past 15 years by Dr. Esmaeli and her colleagues at MD Anderson—including Merrick Ross, M.D., a professor in the Department of Surgical Oncology, and Jeffrey Myers, M.D., Ph.D., a professor in the Department of Head and Neck Surgery. The technique has now been adopted at other centers, mostly outside the United States.
“The chief benefits of SLNB are accurate staging and early diagnosis of metastatic disease. In melanomas and other cutaneous tumors of the eyelid and conjunctiva with a significant risk of nodal metastasis, it is important to identify micrometastases early rather than wait for them to get big enough to be palpable on a physical exam or show up on imaging,” Dr. Esmaeli said. “If we can find metastasis early, we can offer treatments earlier.”
Several decades ago, studies were done of elective neck dissection in patients with head and neck cutaneous melanoma. The procedure was abandoned for patients with no signs of metastasis because the morbidity of such major surgery was not justified by the small proportion of patients who were found to have positive lymph nodes.
Another drawback of elective neck dissection is the number of lymph nodes that must be examined. “The techniques we use to examine lymph nodes are exhaustive and expensive,” said Victor Prieto, M.D., Ph.D., a professor in and chair of the Department of Pathology. “It would be unfeasible to apply them to up to 30 lymph nodes that can be retrieved in a procedure to remove all the lymph nodes of an anatomic region. With SLNB, by examining only the nodes that are most likely to be positive, we can increase our sensitivity.”
Sentinel lymph node(s) typically are removed at the time of primary eyelid/conjunctival tumor excision, although SLNB can also be done later. Before surgery, a radioactive tracer such as technetium-99m is injected into the tissue around the tumor. Preoperative lymphoscintigraphy may be performed to determine which of the region’s multiple nodal basins contains the sentinel node(s). Lymphoscintigraphy can be especially helpful in patients with scarring from prior surgery or radiation therapy.
To remove the sentinel lymph node(s), the surgeon first uses a gamma probe to locate the tracer taken up by the sentinel node(s). A small incision is made, and the sentinel nodes(s) are removed and sent to pathologists for examination.
Pathologists cut the lymph node into multiple slices, like a bread loaf, rather than in half longitudinally. “In 2002 we proved that the two techniques are equivalent,” Dr. Prieto said. “The advantage of the bread loaf technique is that you can put more tissue in one cassette, so it’s less expensive and requires less time to process.”
Next, the pathologists look at a slide stained with standard hematoxylin and eosin. If they find tumor cells, the lymph node is positive and no further tests are needed. If hematoxylin and eosin staining is negative, more sensitive immunohistochemical analysis is employed using antigens against the patient’s cancer type. For example, antigens against keratin are used for carcinoma and antigens against melanocytes for melanoma. “The test is sensitive enough to detect one cancer cell among thousands of benign cells,” Dr. Prieto said.
The utility of SLNB goes beyond merely stating whether the node is positive or negative: the size of a metastasis and its location within the lymph node also affect the patient’s prognosis. “The bigger the metastasis, the worse the prognosis,” Dr. Prieto said. A metastasis deep inside the lymph node’s parenchyma carries a worse prognosis than does one on the periphery of the node. Likewise, a metastasis that extends beyond the node’s outer capsule carries a worse prognosis than does one contained within the capsule. “If any of the three applies—large size, parenchymal location, or extracapsular extension—the patient has a worse prognosis,” Dr. Prieto said.
If the SLNB result is negative, many eyelid cancers require no further treatment after surgery.
However, some conjunctival and eyelid cancers are treated postoperatively (or receive primary or neoadjuvant treatment) with topical chemotherapy drops—mitomycin C for melanoma or sebaceous carcinoma and interferon or 5-fluorouracil for squamous cell carcinoma on the ocular surface—regardless of lymph node status.
In addition, certain tumor characteristics warrant postoperative radiation therapy regardless of lymph node status. Patients with basal cell carcinoma or squamous cell carcinoma may undergo adjuvant external-beam radiation therapy to the periocular region if their primary tumors have high-risk features such as microscopic perineural invasion. Postoperative external-beam radiation therapy is also often recommended for patients with Merkel cell carcinoma of the eyelid to reduce the likelihood of local recurrence, as long as radiation therapy is not expected to endanger the eye. Radiation therapy is generally avoided for tumors of the upper eyelid due to concerns about toxic effects to the eye.
Patients with any type of eyelid or conjunctival cancer whose SLNB results are positive typically undergo a parotidectomy and completion neck dissection. If such dissection yields three or more positive lymph nodes, radiation therapy to the lymph nodal basin may be recommended. Adjuvant chemotherapy may be recommended for patients with one or more positive nodes.
Positive lymph node status changes a patient’s cancer stage, which may make the patient eligible for clinical trials of new agents. Even in the absence of immediate treatment, patients with positive lymph nodes and no evidence of distant metastases are monitored closely so that any metastases that develop can be caught early. “Finding early metastasis may be especially of interest in patients with melanoma since the advent of immune modulating drugs such as immune checkpoint inhibitors that can be used to treat metastatic disease with a reasonable toxicity profile,” Dr. Esmaeli said.
Dr. Esmaeli and her colleagues continue to search for ways to improve their patients’ outcomes. Toward this end, two clinical trials at MD Anderson are under way to refine the use of SLNB. One trial recently completed its enrollment of patients with melanoma of the eyelid or conjunctiva, and the other is currently enrolling patients with sebaceous carcinoma of the eyelid. The primary endpoints of both trials are to determine the true-positive and false-negative rates of the procedure.
Data from the trials may also clarify which patients should undergo SLNB. “We currently use the criteria for SLNB in cutaneous melanomas—any lesion greater than 1 mm thick—in patients with eyelid or conjunctival melanomas.” Dr. Esmaeli said. “But in conjunctival melanomas, for example, we’ve never seen a primary tumor less than 2 mm thick that had a positive sentinel lymph node. Conjunctival melanomas are rare, so our patient numbers are not large enough to draw a definitive conclusion; but it seems likely that the cutoff point for SLNB in conjunctival melanomas should be 2 mm.”
Likewise, data from the trial of SLNB in sebaceous carcinoma of the eyelid could confirm clinical observations. “Sebaceous carcinoma is a rare cancer, but I’ve treated 80 patients with it in my 17 years here at MD Anderson,” Dr. Esmaeli said. “Based on the natural history of that cancer and our observations to date, eyelid sebaceous carcinomas of category T2b or higher—based on the American Joint Committee on Cancer seventh edition criteria for eyelid carcinomas—seem to have the highest risk of nodal metastasis.”
Related studies by Dr. Esmaeli—in collaboration with Michael Tetzlaff, M.D., Ph.D., an assistant professor in the Department of Pathology, and other colleagues—seek to refine the treatment of sebaceous carcinoma of the eyelid. “We’ve done some RNA sequencing of sebaceous carcinoma, and we’re doing mutational analysis to look for mutations that are potentially targetable in patients with metastatic disease,” Dr. Esmaeli said.
Together, these studies are adding to a body of research that, combined with clinical experience, is elucidating the understanding and treatment of cancers of the eyelid and conjunctiva.
For more information, contact Dr. Bita Esmaeli at 713-792-4457 or Dr. Victor Prieto at 713-792-3187. For more information about clinical trials of sentinel lymph node biopsy in conjunctival and eyelid tumors, visit www.clinicaltrials.org and select study GSP00-106 or 2008-0266.
OncoLog, November-December 2015, Volume 60, Issue 11-12