Recurrence of Ocular Surface Squamous Neoplasia Treated With Excisional Biopsy and Cryotherapy ALBERT S. LI, CAROLYN Y. SHIH, LISA ROSEN, ANNE STEINER, TATYANA MILMAN, AND IRA J. UDELL PURPOSE:
To evaluate the recurrence rate of ocular surface squamous neoplasias (OSSN) after excision and cryotherapy in an academic cornea practice and to determine factors associated with recurrence. DESIGN: Retrospective interventional case series. METHODS: All cases of OSSN from 1998 through 2013 that were treated with excisional biopsy and adjunctive cryotherapy were retrospectively reviewed. Clinical characteristics upon presentation including size of lesion, location, and atypical features were noted. All recurrences of OSSN after excision and cryotherapy were noted and categorized in relation to clinical characteristics, pathologic grade, and margin involvement. RESULTS: Forty-three cases of OSSN from 42 patients were analyzed with a median follow-up of 29 months. A total of 32.6% of subjects had dysplasia and 67.4% had squamous cell carcinoma (SCC). A total of 83.7% of subjects had both corneal and conjunctival involvement while 16.3% had conjunctival involvement only. Overall, 3 recurrences were observed, all of which had margin involvement; nonetheless, the majority of incompletely excised OSSN (25/28) showed no recurrence. The recurrence rate at 6 months was 2.3%. Recurrence at 1 year, 2 years, and 5 years remained stable at 7.1%. CONCLUSIONS: Excision with cryotherapy is an effective treatment for the majority of OSSN cases, even among cases with pathologic evidence of tumor at the margin, with an overall recurrence rate of 7.1% at 1 year, 2 years, and 5 years. (Am J Ophthalmol 2015;160(2):213–219. Ó 2015 by Elsevier Inc. All rights reserved.)
O
CULAR SURFACE SQUAMOUS NEOPLASIAS (OSSN)
are a spectrum of lesions of the corneal or conjunctival epithelium with malignant potential, ranging from dysplasia through carcinoma in situ (CIS) and carcinoma. The average annual incidence of Accepted for publication Apr 20, 2015. From the Department of Ophthalmology (A.S.L., C.Y.S., A.S., I.J.U.), North Shore Long Island Jewish Health System, Great Neck, New York; Feinstein Institute for Medical Research, Biostatistics Unit (L.R.), North Shore Long Island Jewish Health System, Manhasset, New York; and New York Eye and Ear Infirmary (T.M.), New York, New York. Inquiries to Albert S. Li, Department of Ophthalmology, North Shore Long Island Jewish Health System, 600 Northern Boulevard, Suite 214, Great Neck, NY 11021; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.04.027
Ó
2015 BY
OSSN is estimated to be approximately 20 cases per million persons per year.1,2 OSSN predominantly affects older men and affects people of all races.2 Patients often present with a slightly elevated growth interpalpebrally along the limbus, involving the cornea, the conjunctiva, or both, which could have either clearly delineated or ill-defined borders.3 Tumors can appear flat, gelatinous, or papillomatous, with varying degrees of leukoplakia.4 Areas of corneal involvement tend to appear as translucent grayish corneal clouding, with or without a fimbriated leading edge, best observed with slit-lamp examination.2 Frequently ‘‘feeder’’ blood vessels are associated with the mass, and corneal portions can either be avascular or have fine blood vessels.4 Symptoms may include foreign body sensation, redness, irritation, and decrease in visual acuity, especially if the lesion involves the cornea.2 Classically appearing tumors can be diagnosed clinically,5 but presentations of OSSN can be mistaken for many other processes, including an inflammatory picture such as conjunctivitis, keratoconjunctivitis, or scleritis or perhaps a more serious lymphoma or melanoma.2,4,6,7 Traditionally, diagnosis and treatment of OSSN involves excisional biopsy of the clinically apparent tumor with wide margins. Studies looking at simple excision with clear margins have reported recurrence rates from 5% to 33%; however, incomplete excision of the tumor at the margins results in recurrence rates as high as 56%.8,9 Achieving clear margins may be difficult because often the lesion’s borders may be poorly defined and tumors may extend microscopically beyond the macroscopic edge.6,7 In 1994 Shields and Shields described a method involving excisional biopsy with a no-touch technique followed by double freeze-thaw cryotherapy.10 Subsequent studies confirmed that this may be an effective technique, as the average recurrence rate of OSSN with excision and cryotherapy is 12%,1 ranging from 7% to 22% in published studies.1,11,12 Recent surveys of anterior segment surgeons have indicated that practice patterns are evolving now toward using topical chemotherapy such as 5-fluorouracil, mitomycin C, and interferon alpha-2b as monotherapy.3,7,13,14 Topical monotherapy has the advantage of treating the entire ocular surface for subclinical disease; however, unlike a surgical approach, clinical resolution of the tumor is not immediate, with the average time for resolution with topical treatment often requiring months.15,16
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Furthermore, this requires the patient’s continued adherence to a demanding regimen (often 4 times daily), as well as the patient’s shouldering the nontrivial cost of these drugs, estimated to cost hundreds of dollars per treatment;15,17 since the use of these medications for treating OSSN is considered ‘‘off-label,’’ it is not generally covered by insurance. The purpose of this study is to evaluate the efficacy of excisional biopsy with adjuvant cryotherapy as a treatment of the initial presentation of OSSN, as measured by recurrence rate, in the face of increased practice patterns of topical chemotherapeutic monotherapy without concurrent excision and tissue diagnosis.
METHODS STUDY POPULATION:
Approval for this retrospective interventional case series was obtained from the North Shore–Long Island Jewish Health System Institutional Review Board (IRB# 13-368A); informed consent for this study was waived, given the retrospective nature of the chart review. The records of the Department of Ophthalmology at North Shore–Long Island Jewish Health System were searched for diagnoses of benign or malignant neoplasms of the conjunctiva or cornea and for procedures of conjunctival or corneal biopsy from January 1, 1998 through June 30, 2013. Of the 235 available charts, there were 51 cases of OSSN that were identified and retrospectively reviewed, with 43 ultimately being included in this series. Two cases were excluded from this study because cryotherapy was not used in the excision. Six subjects with less than 2 months of follow-up were also excluded from analysis because of insufficient observation time to state that there was no recurrence of disease. Of note, none of these 8 were noted to have had any recurrences during their follow-up.
TREATMENT:
After informed consent was obtained from the patient, excisional biopsies were performed by 1 of 3 surgeons (C.S., I.U., or A.S.), following the general approach outlined by Shields and associates.10 A ‘‘no-touch’’ technique was used to excise the lesion using wide excision margins of at least 2 mm. Next, double freeze-thaw cryotherapy was applied to the conjunctival and limbal edges of excision. Specifically, the cryoprobe was placed on the lifted conjunctival margin for 3 seconds and then allowed to thaw. A subsequent 3-second application would be applied adjacent to and slightly overlapping the prior application. Upon reaching the limbal margin, the cryoprobe was placed such that it would freeze the limbus and about 0.5 mm of cornea. Upon completion of treatment of the entire perimeter, this would be performed again for a second cycle to complete the double freeze-thaw cryotherapy. Alcohol epitheliectomy was performed for corneal involvement. At the surgeon’s discretion, a clear amniotic membrane graft
214
was placed over the exposed scleral bed and secured with either glue alone or glue with sutures, according to the surgeon’s preference, to promote healing and to prevent fibrovascular scarring. These grafts were used because they did not obscure the clinician’s view of possible recurrent disease. Patients with OSSN who were not treated with excisional biopsy and adjunctive cryotherapy or alcohol epitheliectomy on initial presentation to our group were excluded. When a recurrence was confirmed, patients were treated with either mitomycin C, 0.02%–0.04%, or interferon alpha-2b, 1-2 million international units per milliliter. DATA COLLECTION:
Demographics, lesion size, location, and whether the lesion was primary or recurrent was recorded. Corresponding patient records were reviewed for age, sex, self-reported smoking status (current, former, never), involved eye, previous history of OSSN lesions, lesion location (superior/inferior, temporal/nasal), size, clinical appearance (adherence/not, leukoplakia/not), date of surgery, and length of follow-up. For patients with less than a year of follow-up with the treating surgeon, the referring ophthalmologist was contacted for more recent information about the patient and whether the OSSN had recurred postoperatively. Tumors were categorized as small (less than 3-clock-hour involvement and less than 5 mm in greatest dimension); medium (3- to 6-clock-hour involvement or greatest dimension between 5 and 10 mm); or large (greater than 6-clock-hour involvement or greatest dimension greater than 10 mm). Data were correlated with presurgical photographs when available. Pathology reports were reviewed for tumor grade, location, and positive or negative tumor at the surgical margins. All specimens were graded according to the American Joint Committee on Cancer’s (AJCC) tumor/node/metastasis (TNM) classification for conjunctival neoplasia or OSSN;18 dysplasias that were less than full thickness (ie, less than squamous cell carcinoma in situ) were also classified as Tis. In addition, lesions were classified as having mild, moderate, or severe dysplasia or being squamous cell carcinoma in situ or frank squamous cell carcinoma. Mild dysplasia (formerly CIN I) denotes atypical cells in less than 25% of the epithelial thickness. Moderate dysplasia (CIN II) denotes atypical cells involving 25%– 75% of the epithelial thickness. Severe dysplasia (CIN III) denotes atypical cells involving more than 75% of the epithelial thickness.2 Full-thickness dysplasia where there are no normal epithelial cells is referred to as carcinoma in situ.3 Squamous cell carcinoma is present when the basement membrane of the epithelium is violated and there is invasion of the substantia propria.19 Cases excised in 2004 or prior were originally read by an ocular pathologist at Montefiore Medical Center, Albert Einstein School of Medicine, Bronx, New York; cases excised from 2005 on were read by ocular pathologists at the New York Eye and Ear Infirmary, New York, New York. For the purposes of this study, cases that were
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recurrent or invasive were reviewed by an ocular pathologist (T.M.), as well as cases in which margin involvement was not clearly stated in the original pathology report. To calculate recurrence rates after surgical excision with cryotherapy, a recurrence was defined as the appearance of a lesion at the same site after excision, having an appearance that was suspicious for OSSN (eg, corneal clouding, conjunctival scarring with atypical vessels, papillomatous or leukoplakic appearance) and later confirmed with biopsy. Further surgeries or adjunctive topical therapies for recurrences were also noted. STATISTICAL ANALYSIS:
All analysis was conducted using SAS version 9.3 (SAS Institute, Cary, North Carolina, USA). Standard methods of survival analysis were applied to the data. The primary outcome variable was progression-free survival (PFS) in OSSN patients, which was defined as the time from surgery to recurrence or progression of disease. The Kaplan-Meier (KM) product-limit method was used to estimate PFS and recurrence rates at 6 months, 1 year, 2 years, and 5 years post surgery. Subjects in whom the outcomes of interest (recurrence) were not observed were considered censored using their last known date of follow-up. The median follow-up time was calculated using the reverse KM method as described by Schemper and Smith.20 The analysis was repeated including the 6 additional subjects with minimal (less than 2 months) follow-up. However, results were qualitatively similar with and without these subjects. Therefore, only results excluding these subjects are reported.
RESULTS THERE WERE A TOTAL OF 43 CASES OF OSSN FROM 42
patients that were treated with excisional biopsy and adjunctive cryotherapy, with amniotic membrane placement used in 16 cases (32.7%). The average age was 68.4 years and 69.8% (30/43) were male. In terms of OSSN risk factors, the majority had no smoking history with only 23.3% (10/ 43) having a former smoking history and 9.3% (4/43) being current smokers in this series. One patient had history of organ transplant. Two patients were referred to us with prior OSSN that had recurred; the remainder were initial presentations of OSSN that were not previously treated. The median follow-up time after surgery was 29.0 months (95% confidence interval [CI]: 18.4, 44.3 months). Tumor characteristics are presented in Table 1. A total of 83.7% of the tumors (36/43) involved both the cornea and conjunctiva; the remainder involved only the conjunctiva. Our series did not have any tumors that initially presented with corneal involvement only. All of the tumors except for 3 (40/43) were classified as small or medium, with greatest dimension less than 1 cm and not involving more than 6 clock hours. VOL. 160, NO. 2
TABLE 1. Series Characteristics of Ocular Surface Squamous Neoplasias Treated with Excisional Biopsy and Cryotherapy N
Age (y), mean (median, range) Sex Male Female Risk factors Current smoker Former smoker Organ transplantation Tissue involvement Cornea & conjunctiva Conjunctiva only Size Small (6 clock hours) Locationa Temporal Inferior Nasal Superior Characteristics Leukoplakic Adherent
%
68.4 (69, 45–85) 30 13
69.8 30.2
4 10 1
9.3 23.3 2.3
36 7
83.7 16.3
22 18 3
51 42 7
16 7 25 1
37.2 14.3 58.1 2.3
16 2
30.2 4.7
a
Total is not equal to 100% for location, given that tumors often involved multiple regions (eg, superotemporal) and were counted in multiple categories (eg, superior and temporal).
Histopathologic examination of biopsied tissues demonstrated squamous cell carcinoma in situ (SCCis) in more than half of biopsies (55.8%, 24/43), invasive squamous cell carcinoma in 5 biopsies (11.6%, 5/43), and varying degrees of dysplasia in the remainder of biopsies (32.6%, 14/43) (Table 2). According to AJCC staging, 6 (14%) were classified as Tis and the remainder as T3 (37/43, 86%) (Table 2). A total of 32.6% (14/43) of tumors that were excised pathologically documented clearance of surgical margins. Of the 28 incompletely excised lesions, half (14/28) had involvement of the corneal margin only; this was expected, given that 36 out of all 43 tumors were conjunctival-corneal neoplasias. Involvement of a noncorneal margin was reported in 9 biopsies, while 5 had tumor present at the margin but the orientation could not be determined. One biopsy had indeterminate involvement of margins on histopathologic review (Table 3). RECURRENCE RATES AFTER EXCISIONAL BIOPSY WITH CRYOTHERAPY: The overall recurrence rate for all
OSSN tumors that were treated was 7.0% (3/43). Kaplan-Meier analysis showed a 97.7% 6-month recurrence-free survival rate (2.3% recurrence rate) and a 92.9% recurrence-free survival rate (7.1% recurrence rate) at both 1 year and 5 years after excision and
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TABLE 2. Histopathologic Classification of Ocular Surface Squamous Neoplasias Treated With Excision and Cryotherapy
AJCC tumor classification Tis T1 T2 T3 T4 N0 N1 M0 M1 Pathology Dysplasia Dysplasia, mild Dysplasia, moderate Dysplasia, severe Dysplasia, not otherwise specified Squamous cell carcinoma Squamous cell carcinoma in situ (SCCis) Squamous cell carcinoma, invasive (SCC)
N
%
6 0 0 37 0 43 0 43 0
14.0 0.0 0.0 86.0 0.0 100.0 0.0 100.0 0.0
14 3 6 4 1 29 24 5
32.6 7.0 14.0 9.3 2.3 67.4 55.8 11.6
TABLE 3. Margin Involvement of Excisional Biopsy With Adjunctive Cryotherapy of Ocular Surface Squamous Neoplasias Margin Involvement
N
%
Negative Positive At corneal margin only At noncorneal margin At unspecified margin Indeterminate
14
32.6
14 9 5 1
32.6 20.9 11.6 2.3
AJCC ¼ American Joint Committee on Cancer.
cryotherapy (Figure). When categorized by histopathologic diagnosis, there was a 7.7% recurrence rate for dysplasia and a 6.9% recurrence rate for squamous cell carcinoma (in situ and invasive) at 1 year (Table 4). All 3 cases of recurrent OSSN after excision and cryotherapy occurred within 6 months. They occurred in subjects ranging in age from 59 to 75 years, all of whom were male. In all 3 cases, the original excision had positive noncorneal margins. Following repeat biopsies that confirmed persistence of OSSN, all of them were treated with either interferon alpha-2b or both interferon alpha2b and mitomycin C to eliminate the recurrence. The OSSN involving only the conjunctiva (TisN0M0) resolved after 1 month of 4-times-daily interferon treatment (Case 14). The other 2 recurrences, both of which involved both the conjunctiva and the cornea (T3N0M0), had corneal dysplastic recurrences; in both cases, courses of mitomycin C and interferon alpha-2b were attempted separately, but they proved difficult to eliminate even after corneal debridement and re-excision (Table 5). There were 2 patients who had a history of OSSN excised elsewhere and were referred to us for a recurrent lesion. In these 2 patients, the previous lesions had been excised without cryotherapy prior to presentation at our clinic. After treatment with excision and cryotherapy for the recurrence, the pathologic grade of the recurrence was noted to be the same as the initial presentation, consistent with prior observations. One patient’s initial lesion was severe dysplasia, 216
FIGURE. Progression-free survival of ocular surface squamous neoplasia after excisional biopsy with adjunctive cryotherapy. Proportion of recurrence-free cases of ocular surface squamous neoplasia vs time after excision of tumor with adjunctive cryotherapy, in months.
which recurred as squamous cell carcinoma in situ, which implies a higher-grade lesion but has considerable overlap with severe dysplasia. The other case was moderate dysplasia, and the excisional biopsy of the recurrences showed the same. Neither of these 2 referred OSSN cases was noted to have had any further recurrences. ADJUNCTIVE TOPICAL CHEMOTHERAPEUTIC AGENTS:
Overall, topical therapy of either mitomycin C or interferon alpha-2b were used as adjunctive or subsequent treatment in 4 patients, who all underwent excisional biopsy and adjunctive cryotherapy as the first line of treatment. Three patients (numbers 14, 15, 39) received topical therapy after an OSSN recurrence was confirmed by a second biopsy, as described previously (Table 5). The other patient was treated with interferon after biopsy results showed a focus of mucoepidermoid carcinoma after excision with cryotherapy. As mucoepidermoid carcinoma is a rare but aggressive variant of OSSN,3 the patient was treated with topical interferon 4 times a day for 2 months followed by a taper over the next 2 months.
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No resolution at 109 mo Yes Large OD M 74 Moderate dysplasia 39
a
Positive T3N0M0 Leukoplakic Temporal
Gelatinous Nasal
Conjunctiva & cornea Conjunctiva & cornea Medium OS M 75
AJCC ¼ American Joint Committee on Cancer; IFN ¼ topical interferon alpha-2b; MMC ¼ topical mitomycin C; SCCis ¼ squamous cell carcinoma in situ. Resolution is defined as complete disappearance of tumor after further treatment and no recurrence at last follow-up.
Yes
Resolution at 47 mo Yes Yes
9 mo (severe dysplasia) 2 mo (moderate dysplasia) Positive T3N0M0
Resolution at 19 mo No Yes 6 mo (SCCis) Positive TisN0M0
Excision and cryotherapy Excision and cryotherapy Excision and cryotherapy Leukoplakic Temporal Conjunctiva
Margins AJCC Stage Initial Management Characteristic Location Involvement Size
Small OS
SCCis
IN THIS SERIES OF 43 CASES OF OSSN, THERE WAS A 7.1%
15
DISCUSSION
Patient Number in Series
Pathologic Diagnosis
Of note, there was 1 patient that developed OSSN in both eyes. This 71-year-old man, who was a current smoker, was noted to have a small temporal corneal-conjunctival lesion in his right eye; the conjunctival portion measured 3.2 mm in greatest dimension and extended onto the cornea 1.5 mm. The lesion was removed by excisional biopsy with adjunctive cryotherapy and amniotic membrane placement. The pathology was pterygium with microinvasive squamous cell carcinoma; the corneal margin was noted to have presence of tumor, but all other margins were negative. Four months later, the patient had a small, leukoplakic conjunctival lesion located nasally on his left eye, which was also removed via excisional biopsy with adjunctive cryotherapy and amniotic membrane. The pathology was moderate to severe dysplasia, actinic keratosis variety, which was incompletely excised at both corneal and noncorneal margins. The patient was followed for 75 months since the first procedure and has not had any recurrences.
Eye
AJCC ¼ American Joint Committee on Cancer.
Sex
1/6 0/0 0/0 2/37 0/0
Age
0/5
M
6.9
59
2/29 2/24
SCCis
7.7
14
1/14 0/3 1/6 0/4 0/1
MMC
7.1
IFN
3/43 3/41 0/2
Time to Recurrence (Biopsy Diagnosis of Recurrence)
Overall recurrence rate Primary tumors Referred tumors Pathology Dysplasia Dysplasia, mild Dysplasia, moderate Dysplasia, severe Dysplasia, not otherwise specified Squamous cell carcinoma Squamous cell carcinoma in situ (SCCis) Squamous cell carcinoma, invasive (SCC) AJCC tumor classification Tis T1 T2 T3 T4
One-Year Kaplan-Meier Recurrence Rate (%)
TABLE 5. Recurrences of Ocular Surface Squamous Neoplasia After Excisional Biopsy With Adjunctive Cryotherapy
Recurrent Cases/Total Cases
Final Outcomea
TABLE 4. Recurrence Rate of Ocular Surface Squamous Neoplasias After Treatment With Excisional Biopsy With Adjunctive Cryotherapy
overall recurrence rate at 1 year, 2 years, and 5 years, for VOL. 160, NO. 2
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TABLE 6. Summary of Published Recurrence Rates of Ocular Surface Squamous Neoplasias After Excision and Cryotherapy
Series
N
Current study Nanji et al, 201426 Palamar et al, 201424 Crim et al, 201325 Sturges et al, 200821 Peksayar et al, 200322 Sudesh et al, 200011 Tunc et al, 199923
43 49 21 4 14 57 19 60
Excision & Cryotherapy Mean as Initial OSSN Follow-up Treatment (%) Recurrences (%)
29 moa 24 moa 31.0 mo 78 mo 35.6 mo 31.7 mo 37 mo 56 mo
100 100 100 100 100 86 68 66
7.1 6.1 0 0 0 12.3 10.5 5
OSSN ¼ ocular surface squamous neoplasia. Median.
a
primary and recurrent OSSN treated with excisional biopsy and adjunctive cryotherapy, the technique employed by all surgeons in our group. This is in line with the recent reports in which recurrence data were explicitly reported after excision and adjunctive cryotherapy11,21–26 (Table 6). Overall, these recurrence rates are considerably lower than the 53%–56% recurrence rate that is commonly cited for a surgical approach to OSSN. These higher recurrence rates reflect an era in which the lesion was excised without adjunctive cryotherapy and tumor was present at the surgical margin; the recurrence rate of OSSN with excision only and negative margins was lower, ranging from 5% to 33%,8,9 and we continue to observe a low recurrence rate with excisional biopsy and cryotherapy in our experience. This study contributes to the existing evidence favoring excision with cryotherapy over excision only, when considering surgical approaches for OSSN. There was no recurrence observed in the majority (25/28) of incompletely excised OSSN in this series of tumors treated with excision and cryotherapy. When compared to the much higher 53% recurrence rate reported among lesions treated with surgical excision alone with margin involvement,8 this supports the adjunctive role of cryotherapy in effectively treating the residual microscopic disease that may be left behind after surgical excision and reducing subsequent recurrence. A retrospective review by Sudesh and associates that directly compared the two in 2002 showed a 7.7% recurrence rate when excision was used with cryotherapy, compared to 28.5% for simple excision.11 Furthermore, in their study looking at predictors of OSSN recurrence after excision, Galor and associates identified a significant 0.51-fold decreased risk of recurrence when excising with cryotherapy compared to excising with no cryotherapy.27 This series of 43 cases is one of the largest studies in which every case was treated with excision with cryotherapy upon 218
presentation to our group (Table 6); the 2 cases that were not initially treated with excision and cryotherapy were treated with excision only by another ophthalmologist before referral to our group for excision and cryotherapy of the recurrent OSSN lesion. Concurrently in the last 2 decades, topical therapies have been introduced alongside excisional biopsy with cryotherapy in the armamentarium against OSSN; a range of recurrence rates have been reported, with some observing low recurrence rates with topical monotherapy, even as low as 0%.16,21,26,28,29 Based on such reports in the literature, ophthalmologists have shifted away from surgery toward topical agents in treating OSSN (according to a 2005 survey of the Ocular Microbiology and Immunology Group),14 especially with the advent of treatments such as interferon alpha-2b with minimal side effects. When this subject was revisited more recently in 2013, it was shown that 79% of ophthalmologists think there is enough evidence for topical monotherapy, with 58% reporting they have employed topical monotherapy.13 In response to the question of how often biopsies of suspected OSSN were performed before starting topical monotherapy, 51% of respondents always performed a biopsy before prescribing topical treatment, while about 10% of respondents never did, with the remainder of ophthalmologists performing biopsies some of the time before starting topical therapy.13,14 While there has been a report of a few cases with full clinical resolution and no recurrences in 12 months after interferon alpha-2b treatment for OSSN diagnosed by clinical appearance,5 employing topical monotherapy for suspected OSSN on appearance alone without pathologic confirmation is less than ideal, given that a variety of more common lesions could be mistaken for the comparatively rarer OSSN. In fact, benign lesions such as conjunctival papillomata have also resolved with the same treatment of interferon alpha-2b,30 emphasizing that clinical disappearance after topical treatment does not prove that the lesion was OSSN. Having a low threshold for instituting topical treatment of an OSSN-like conjunctival tumor comes at a great cost of unnecessarily treating entities that do not require it, regardless of the benign side effect profile. Our series of OSSN shows that resolution with minimal recurrence is achievable with the gold standard of excision and cryotherapy, which also provides a pathologic diagnosis. Without an excisional biopsy, the nature, severity, and grade of the lesion is unknown, and physicians are left without a definitive diagnosis should there be future recurrences. Although the idea of avoiding surgery altogether is quite attractive, only a prospective randomized trial would sufficiently determine if a topical monotherapy such as interferon alpha-2b could replace the existing gold standard of excisional biopsy with cryotherapy. Based on these data, a cost-effective analysis can be done to guide recommendations for the initial course of treatment for patients presenting with OSSN.
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: A.S.L.: reviewer, Academic Press/Elsevier, San Diego, California (no relationship to study); I.J.U.: consultant, Alcon, Fort Worth, Texas (no relationship to study). The authors indicate no funding support. All authors attest that they meet the current ICMJE requirements to qualify as authors.
REFERENCES 1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39(6):429–450. 2. Hamam R, Bhat P, Foster CS. Conjunctival/corneal intraepithelial neoplasia. Int Ophthalmol Clin 2009;49(1): 63–70. 3. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol 2004;49(1):3–24. 4. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:283–306. 5. Schechter BA, Schrier A, Nagler RS, Smith EF, Velasquez GE. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea 2002;21(1):6–11. 6. Basti S, Macsai MS. Ocular surface squamous neoplasia: a review. Cornea 2003;22(7):687–704. 7. Kiire CA, Srinivasan S, Karp CL. Ocular surface squamous neoplasia. Int Ophthalmol Clin 2010;50(3):35–46. 8. Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmology 1986;93(2):176–183. 9. Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997;104(3):485–492. 10. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115(6):808–815. 11. Sudesh S, Rapuano CJ, Cohen EJ, Eagle RC Jr, Laibson PR. Surgical management of ocular surface squamous neoplasms: the experience from a cornea center. Cornea 2000;19(3): 278–283. 12. Yousef YA, Finger PT. Squamous carcinoma and dysplasia of the conjunctiva and cornea: an analysis of 101 cases. Ophthalmology 2012;119(2):233–240. 13. Adler E, Turner JR, Stone DU. Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to 2012. Cornea 2013;32(12):1558–1561. 14. Stone DU, Butt AL, Chodosh J. Ocular surface squamous neoplasia: a standard of care survey. Cornea 2005;24(3): 297–300. 15. Sepulveda R, Pe’er J, Midena E, Seregard S, Dua HS, Singh AD. Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2010;94(5): 532–535. 16. Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface squamous neoplasia. Curr Opin Ophthalmol 2013;24(4):336–342.
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17. Esquenazi S, Fry CL, Holley E. Treatment of biopsy proved conjunctival intraepithelial neoplasia with topical interferon alfa-2b. Br J Ophthalmol 2005;89(9):1221. 18. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. Carcinoma of the conjunctiva. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:531–533. 19. Kiire CA, Dhillon B. The aetiology and associations of conjunctival intraepithelial neoplasia. Br J Ophthalmol 2006;90(1):109–113. 20. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17(4):343–346. 21. Sturges A, Butt AL, Lai JE, Chodosh J. Topical interferon or surgical excision for the management of primary ocular surface squamous neoplasia. Ophthalmology 2008;115(8): 1297–1302.1302.e1. 22. Peksayar G, Altan-Yaycioglu R, Onal S. Excision and cryosurgery in the treatment of conjunctival malignant epithelial tumours. Eye (Lond) 2003;17(2):228–232. 23. Tunc M, Char DH, Crawford B, Miller T. Intraepithelial and invasive squamous cell carcinoma of the conjunctiva: analysis of 60 cases. Br J Ophthalmol 1999;83(1):98–103. 24. Palamar M, Kaya E, Egrilmez S, Akalin T, Yagci A. Amniotic membrane transplantation in surgical management of ocular surface squamous neoplasias: long-term results. Eye (Lond) 2014;28(9):1131–1135. 25. Crim N, Fornies-Paz ME, Monti R, Esposito E, Maccio JP, Urrets-Zavalia JA. In situ carcinoma of the conjunctiva: surgical excision associated with cryotherapy. Clin Ophthalmol 2013;7:1889–1893. 26. Nanji AA, Moon CS, Galor A, Sein J, Oellers P, Karp CL. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology 2014;121(5):994–1000. 27. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology 2012;119(10):1974–1981. 28. Shah SU, Kaliki S, Kim HJ, Lally SE, Shields JA, Shields CL. Topical interferon alfa-2b for management of ocular surface squamous neoplasia in 23 cases: outcomes based on American Joint Committee on Cancer classification. Arch Ophthalmol 2012;130(2):159–164. 29. Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea 2013;32(3):248–256. 30. Schechter BA, Rand WJ, Velazquez GE, Williams WD, Starasoler L. Treatment of conjunctival papillomata with topical interferon Alfa-2b. Am J Ophthalmol 2002;134(2): 268–270.
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Biosketch Albert S. Li, MD, received his undergraduate degree in chemical and physical biology from Harvard College, where he was elected to The Phi Beta Kappa Society. During college, he received the Thomas Temple Hoopes Prize for his undergraduate research thesis. Subsequently, Dr. Li attended New York University School of Medicine, where he received his Doctorate of Medicine. Dr. Li is currently an ophthalmology resident at North Shore-Long Island Jewish Health System in Long Island, NY.
219.e1
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To evaluate the recurrence rate of ocular surface squamous neoplasias (OSSN) after excision and cryotherapy in an academic cornea practice and to determine factors associated with recurrence. DESIGN: Retrospective interventional case series. METHODS: All cases of OSSN from 1998 through 2013 that were treated with excisional biopsy and adjunctive cryotherapy were retrospectively reviewed. Clinical characteristics upon presentation including size of lesion, location, and atypical features were noted. All recurrences of OSSN after excision and cryotherapy were noted and categorized in relation to clinical characteristics, pathologic grade, and margin involvement. RESULTS: Forty-three cases of OSSN from 42 patients were analyzed with a median follow-up of 29 months. A total of 32.6% of subjects had dysplasia and 67.4% had squamous cell carcinoma (SCC). A total of 83.7% of subjects had both corneal and conjunctival involvement while 16.3% had conjunctival involvement only. Overall, 3 recurrences were observed, all of which had margin involvement; nonetheless, the majority of incompletely excised OSSN (25/28) showed no recurrence. The recurrence rate at 6 months was 2.3%. Recurrence at 1 year, 2 years, and 5 years remained stable at 7.1%. CONCLUSIONS: Excision with cryotherapy is an effective treatment for the majority of OSSN cases, even among cases with pathologic evidence of tumor at the margin, with an overall recurrence rate of 7.1% at 1 year, 2 years, and 5 years. (Am J Ophthalmol 2015;160(2):213–219. Ó 2015 by Elsevier Inc. All rights reserved.)
O
CULAR SURFACE SQUAMOUS NEOPLASIAS (OSSN)
are a spectrum of lesions of the corneal or conjunctival epithelium with malignant potential, ranging from dysplasia through carcinoma in situ (CIS) and carcinoma. The average annual incidence of Accepted for publication Apr 20, 2015. From the Department of Ophthalmology (A.S.L., C.Y.S., A.S., I.J.U.), North Shore Long Island Jewish Health System, Great Neck, New York; Feinstein Institute for Medical Research, Biostatistics Unit (L.R.), North Shore Long Island Jewish Health System, Manhasset, New York; and New York Eye and Ear Infirmary (T.M.), New York, New York. Inquiries to Albert S. Li, Department of Ophthalmology, North Shore Long Island Jewish Health System, 600 Northern Boulevard, Suite 214, Great Neck, NY 11021; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.04.027
Ó
2015 BY
OSSN is estimated to be approximately 20 cases per million persons per year.1,2 OSSN predominantly affects older men and affects people of all races.2 Patients often present with a slightly elevated growth interpalpebrally along the limbus, involving the cornea, the conjunctiva, or both, which could have either clearly delineated or ill-defined borders.3 Tumors can appear flat, gelatinous, or papillomatous, with varying degrees of leukoplakia.4 Areas of corneal involvement tend to appear as translucent grayish corneal clouding, with or without a fimbriated leading edge, best observed with slit-lamp examination.2 Frequently ‘‘feeder’’ blood vessels are associated with the mass, and corneal portions can either be avascular or have fine blood vessels.4 Symptoms may include foreign body sensation, redness, irritation, and decrease in visual acuity, especially if the lesion involves the cornea.2 Classically appearing tumors can be diagnosed clinically,5 but presentations of OSSN can be mistaken for many other processes, including an inflammatory picture such as conjunctivitis, keratoconjunctivitis, or scleritis or perhaps a more serious lymphoma or melanoma.2,4,6,7 Traditionally, diagnosis and treatment of OSSN involves excisional biopsy of the clinically apparent tumor with wide margins. Studies looking at simple excision with clear margins have reported recurrence rates from 5% to 33%; however, incomplete excision of the tumor at the margins results in recurrence rates as high as 56%.8,9 Achieving clear margins may be difficult because often the lesion’s borders may be poorly defined and tumors may extend microscopically beyond the macroscopic edge.6,7 In 1994 Shields and Shields described a method involving excisional biopsy with a no-touch technique followed by double freeze-thaw cryotherapy.10 Subsequent studies confirmed that this may be an effective technique, as the average recurrence rate of OSSN with excision and cryotherapy is 12%,1 ranging from 7% to 22% in published studies.1,11,12 Recent surveys of anterior segment surgeons have indicated that practice patterns are evolving now toward using topical chemotherapy such as 5-fluorouracil, mitomycin C, and interferon alpha-2b as monotherapy.3,7,13,14 Topical monotherapy has the advantage of treating the entire ocular surface for subclinical disease; however, unlike a surgical approach, clinical resolution of the tumor is not immediate, with the average time for resolution with topical treatment often requiring months.15,16
ELSEVIER INC. ALL
RIGHTS RESERVED.
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Furthermore, this requires the patient’s continued adherence to a demanding regimen (often 4 times daily), as well as the patient’s shouldering the nontrivial cost of these drugs, estimated to cost hundreds of dollars per treatment;15,17 since the use of these medications for treating OSSN is considered ‘‘off-label,’’ it is not generally covered by insurance. The purpose of this study is to evaluate the efficacy of excisional biopsy with adjuvant cryotherapy as a treatment of the initial presentation of OSSN, as measured by recurrence rate, in the face of increased practice patterns of topical chemotherapeutic monotherapy without concurrent excision and tissue diagnosis.
METHODS STUDY POPULATION:
Approval for this retrospective interventional case series was obtained from the North Shore–Long Island Jewish Health System Institutional Review Board (IRB# 13-368A); informed consent for this study was waived, given the retrospective nature of the chart review. The records of the Department of Ophthalmology at North Shore–Long Island Jewish Health System were searched for diagnoses of benign or malignant neoplasms of the conjunctiva or cornea and for procedures of conjunctival or corneal biopsy from January 1, 1998 through June 30, 2013. Of the 235 available charts, there were 51 cases of OSSN that were identified and retrospectively reviewed, with 43 ultimately being included in this series. Two cases were excluded from this study because cryotherapy was not used in the excision. Six subjects with less than 2 months of follow-up were also excluded from analysis because of insufficient observation time to state that there was no recurrence of disease. Of note, none of these 8 were noted to have had any recurrences during their follow-up.
TREATMENT:
After informed consent was obtained from the patient, excisional biopsies were performed by 1 of 3 surgeons (C.S., I.U., or A.S.), following the general approach outlined by Shields and associates.10 A ‘‘no-touch’’ technique was used to excise the lesion using wide excision margins of at least 2 mm. Next, double freeze-thaw cryotherapy was applied to the conjunctival and limbal edges of excision. Specifically, the cryoprobe was placed on the lifted conjunctival margin for 3 seconds and then allowed to thaw. A subsequent 3-second application would be applied adjacent to and slightly overlapping the prior application. Upon reaching the limbal margin, the cryoprobe was placed such that it would freeze the limbus and about 0.5 mm of cornea. Upon completion of treatment of the entire perimeter, this would be performed again for a second cycle to complete the double freeze-thaw cryotherapy. Alcohol epitheliectomy was performed for corneal involvement. At the surgeon’s discretion, a clear amniotic membrane graft
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was placed over the exposed scleral bed and secured with either glue alone or glue with sutures, according to the surgeon’s preference, to promote healing and to prevent fibrovascular scarring. These grafts were used because they did not obscure the clinician’s view of possible recurrent disease. Patients with OSSN who were not treated with excisional biopsy and adjunctive cryotherapy or alcohol epitheliectomy on initial presentation to our group were excluded. When a recurrence was confirmed, patients were treated with either mitomycin C, 0.02%–0.04%, or interferon alpha-2b, 1-2 million international units per milliliter. DATA COLLECTION:
Demographics, lesion size, location, and whether the lesion was primary or recurrent was recorded. Corresponding patient records were reviewed for age, sex, self-reported smoking status (current, former, never), involved eye, previous history of OSSN lesions, lesion location (superior/inferior, temporal/nasal), size, clinical appearance (adherence/not, leukoplakia/not), date of surgery, and length of follow-up. For patients with less than a year of follow-up with the treating surgeon, the referring ophthalmologist was contacted for more recent information about the patient and whether the OSSN had recurred postoperatively. Tumors were categorized as small (less than 3-clock-hour involvement and less than 5 mm in greatest dimension); medium (3- to 6-clock-hour involvement or greatest dimension between 5 and 10 mm); or large (greater than 6-clock-hour involvement or greatest dimension greater than 10 mm). Data were correlated with presurgical photographs when available. Pathology reports were reviewed for tumor grade, location, and positive or negative tumor at the surgical margins. All specimens were graded according to the American Joint Committee on Cancer’s (AJCC) tumor/node/metastasis (TNM) classification for conjunctival neoplasia or OSSN;18 dysplasias that were less than full thickness (ie, less than squamous cell carcinoma in situ) were also classified as Tis. In addition, lesions were classified as having mild, moderate, or severe dysplasia or being squamous cell carcinoma in situ or frank squamous cell carcinoma. Mild dysplasia (formerly CIN I) denotes atypical cells in less than 25% of the epithelial thickness. Moderate dysplasia (CIN II) denotes atypical cells involving 25%– 75% of the epithelial thickness. Severe dysplasia (CIN III) denotes atypical cells involving more than 75% of the epithelial thickness.2 Full-thickness dysplasia where there are no normal epithelial cells is referred to as carcinoma in situ.3 Squamous cell carcinoma is present when the basement membrane of the epithelium is violated and there is invasion of the substantia propria.19 Cases excised in 2004 or prior were originally read by an ocular pathologist at Montefiore Medical Center, Albert Einstein School of Medicine, Bronx, New York; cases excised from 2005 on were read by ocular pathologists at the New York Eye and Ear Infirmary, New York, New York. For the purposes of this study, cases that were
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recurrent or invasive were reviewed by an ocular pathologist (T.M.), as well as cases in which margin involvement was not clearly stated in the original pathology report. To calculate recurrence rates after surgical excision with cryotherapy, a recurrence was defined as the appearance of a lesion at the same site after excision, having an appearance that was suspicious for OSSN (eg, corneal clouding, conjunctival scarring with atypical vessels, papillomatous or leukoplakic appearance) and later confirmed with biopsy. Further surgeries or adjunctive topical therapies for recurrences were also noted. STATISTICAL ANALYSIS:
All analysis was conducted using SAS version 9.3 (SAS Institute, Cary, North Carolina, USA). Standard methods of survival analysis were applied to the data. The primary outcome variable was progression-free survival (PFS) in OSSN patients, which was defined as the time from surgery to recurrence or progression of disease. The Kaplan-Meier (KM) product-limit method was used to estimate PFS and recurrence rates at 6 months, 1 year, 2 years, and 5 years post surgery. Subjects in whom the outcomes of interest (recurrence) were not observed were considered censored using their last known date of follow-up. The median follow-up time was calculated using the reverse KM method as described by Schemper and Smith.20 The analysis was repeated including the 6 additional subjects with minimal (less than 2 months) follow-up. However, results were qualitatively similar with and without these subjects. Therefore, only results excluding these subjects are reported.
RESULTS THERE WERE A TOTAL OF 43 CASES OF OSSN FROM 42
patients that were treated with excisional biopsy and adjunctive cryotherapy, with amniotic membrane placement used in 16 cases (32.7%). The average age was 68.4 years and 69.8% (30/43) were male. In terms of OSSN risk factors, the majority had no smoking history with only 23.3% (10/ 43) having a former smoking history and 9.3% (4/43) being current smokers in this series. One patient had history of organ transplant. Two patients were referred to us with prior OSSN that had recurred; the remainder were initial presentations of OSSN that were not previously treated. The median follow-up time after surgery was 29.0 months (95% confidence interval [CI]: 18.4, 44.3 months). Tumor characteristics are presented in Table 1. A total of 83.7% of the tumors (36/43) involved both the cornea and conjunctiva; the remainder involved only the conjunctiva. Our series did not have any tumors that initially presented with corneal involvement only. All of the tumors except for 3 (40/43) were classified as small or medium, with greatest dimension less than 1 cm and not involving more than 6 clock hours. VOL. 160, NO. 2
TABLE 1. Series Characteristics of Ocular Surface Squamous Neoplasias Treated with Excisional Biopsy and Cryotherapy N
Age (y), mean (median, range) Sex Male Female Risk factors Current smoker Former smoker Organ transplantation Tissue involvement Cornea & conjunctiva Conjunctiva only Size Small (6 clock hours) Locationa Temporal Inferior Nasal Superior Characteristics Leukoplakic Adherent
%
68.4 (69, 45–85) 30 13
69.8 30.2
4 10 1
9.3 23.3 2.3
36 7
83.7 16.3
22 18 3
51 42 7
16 7 25 1
37.2 14.3 58.1 2.3
16 2
30.2 4.7
a
Total is not equal to 100% for location, given that tumors often involved multiple regions (eg, superotemporal) and were counted in multiple categories (eg, superior and temporal).
Histopathologic examination of biopsied tissues demonstrated squamous cell carcinoma in situ (SCCis) in more than half of biopsies (55.8%, 24/43), invasive squamous cell carcinoma in 5 biopsies (11.6%, 5/43), and varying degrees of dysplasia in the remainder of biopsies (32.6%, 14/43) (Table 2). According to AJCC staging, 6 (14%) were classified as Tis and the remainder as T3 (37/43, 86%) (Table 2). A total of 32.6% (14/43) of tumors that were excised pathologically documented clearance of surgical margins. Of the 28 incompletely excised lesions, half (14/28) had involvement of the corneal margin only; this was expected, given that 36 out of all 43 tumors were conjunctival-corneal neoplasias. Involvement of a noncorneal margin was reported in 9 biopsies, while 5 had tumor present at the margin but the orientation could not be determined. One biopsy had indeterminate involvement of margins on histopathologic review (Table 3). RECURRENCE RATES AFTER EXCISIONAL BIOPSY WITH CRYOTHERAPY: The overall recurrence rate for all
OSSN tumors that were treated was 7.0% (3/43). Kaplan-Meier analysis showed a 97.7% 6-month recurrence-free survival rate (2.3% recurrence rate) and a 92.9% recurrence-free survival rate (7.1% recurrence rate) at both 1 year and 5 years after excision and
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TABLE 2. Histopathologic Classification of Ocular Surface Squamous Neoplasias Treated With Excision and Cryotherapy
AJCC tumor classification Tis T1 T2 T3 T4 N0 N1 M0 M1 Pathology Dysplasia Dysplasia, mild Dysplasia, moderate Dysplasia, severe Dysplasia, not otherwise specified Squamous cell carcinoma Squamous cell carcinoma in situ (SCCis) Squamous cell carcinoma, invasive (SCC)
N
%
6 0 0 37 0 43 0 43 0
14.0 0.0 0.0 86.0 0.0 100.0 0.0 100.0 0.0
14 3 6 4 1 29 24 5
32.6 7.0 14.0 9.3 2.3 67.4 55.8 11.6
TABLE 3. Margin Involvement of Excisional Biopsy With Adjunctive Cryotherapy of Ocular Surface Squamous Neoplasias Margin Involvement
N
%
Negative Positive At corneal margin only At noncorneal margin At unspecified margin Indeterminate
14
32.6
14 9 5 1
32.6 20.9 11.6 2.3
AJCC ¼ American Joint Committee on Cancer.
cryotherapy (Figure). When categorized by histopathologic diagnosis, there was a 7.7% recurrence rate for dysplasia and a 6.9% recurrence rate for squamous cell carcinoma (in situ and invasive) at 1 year (Table 4). All 3 cases of recurrent OSSN after excision and cryotherapy occurred within 6 months. They occurred in subjects ranging in age from 59 to 75 years, all of whom were male. In all 3 cases, the original excision had positive noncorneal margins. Following repeat biopsies that confirmed persistence of OSSN, all of them were treated with either interferon alpha-2b or both interferon alpha2b and mitomycin C to eliminate the recurrence. The OSSN involving only the conjunctiva (TisN0M0) resolved after 1 month of 4-times-daily interferon treatment (Case 14). The other 2 recurrences, both of which involved both the conjunctiva and the cornea (T3N0M0), had corneal dysplastic recurrences; in both cases, courses of mitomycin C and interferon alpha-2b were attempted separately, but they proved difficult to eliminate even after corneal debridement and re-excision (Table 5). There were 2 patients who had a history of OSSN excised elsewhere and were referred to us for a recurrent lesion. In these 2 patients, the previous lesions had been excised without cryotherapy prior to presentation at our clinic. After treatment with excision and cryotherapy for the recurrence, the pathologic grade of the recurrence was noted to be the same as the initial presentation, consistent with prior observations. One patient’s initial lesion was severe dysplasia, 216
FIGURE. Progression-free survival of ocular surface squamous neoplasia after excisional biopsy with adjunctive cryotherapy. Proportion of recurrence-free cases of ocular surface squamous neoplasia vs time after excision of tumor with adjunctive cryotherapy, in months.
which recurred as squamous cell carcinoma in situ, which implies a higher-grade lesion but has considerable overlap with severe dysplasia. The other case was moderate dysplasia, and the excisional biopsy of the recurrences showed the same. Neither of these 2 referred OSSN cases was noted to have had any further recurrences. ADJUNCTIVE TOPICAL CHEMOTHERAPEUTIC AGENTS:
Overall, topical therapy of either mitomycin C or interferon alpha-2b were used as adjunctive or subsequent treatment in 4 patients, who all underwent excisional biopsy and adjunctive cryotherapy as the first line of treatment. Three patients (numbers 14, 15, 39) received topical therapy after an OSSN recurrence was confirmed by a second biopsy, as described previously (Table 5). The other patient was treated with interferon after biopsy results showed a focus of mucoepidermoid carcinoma after excision with cryotherapy. As mucoepidermoid carcinoma is a rare but aggressive variant of OSSN,3 the patient was treated with topical interferon 4 times a day for 2 months followed by a taper over the next 2 months.
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No resolution at 109 mo Yes Large OD M 74 Moderate dysplasia 39
a
Positive T3N0M0 Leukoplakic Temporal
Gelatinous Nasal
Conjunctiva & cornea Conjunctiva & cornea Medium OS M 75
AJCC ¼ American Joint Committee on Cancer; IFN ¼ topical interferon alpha-2b; MMC ¼ topical mitomycin C; SCCis ¼ squamous cell carcinoma in situ. Resolution is defined as complete disappearance of tumor after further treatment and no recurrence at last follow-up.
Yes
Resolution at 47 mo Yes Yes
9 mo (severe dysplasia) 2 mo (moderate dysplasia) Positive T3N0M0
Resolution at 19 mo No Yes 6 mo (SCCis) Positive TisN0M0
Excision and cryotherapy Excision and cryotherapy Excision and cryotherapy Leukoplakic Temporal Conjunctiva
Margins AJCC Stage Initial Management Characteristic Location Involvement Size
Small OS
SCCis
IN THIS SERIES OF 43 CASES OF OSSN, THERE WAS A 7.1%
15
DISCUSSION
Patient Number in Series
Pathologic Diagnosis
Of note, there was 1 patient that developed OSSN in both eyes. This 71-year-old man, who was a current smoker, was noted to have a small temporal corneal-conjunctival lesion in his right eye; the conjunctival portion measured 3.2 mm in greatest dimension and extended onto the cornea 1.5 mm. The lesion was removed by excisional biopsy with adjunctive cryotherapy and amniotic membrane placement. The pathology was pterygium with microinvasive squamous cell carcinoma; the corneal margin was noted to have presence of tumor, but all other margins were negative. Four months later, the patient had a small, leukoplakic conjunctival lesion located nasally on his left eye, which was also removed via excisional biopsy with adjunctive cryotherapy and amniotic membrane. The pathology was moderate to severe dysplasia, actinic keratosis variety, which was incompletely excised at both corneal and noncorneal margins. The patient was followed for 75 months since the first procedure and has not had any recurrences.
Eye
AJCC ¼ American Joint Committee on Cancer.
Sex
1/6 0/0 0/0 2/37 0/0
Age
0/5
M
6.9
59
2/29 2/24
SCCis
7.7
14
1/14 0/3 1/6 0/4 0/1
MMC
7.1
IFN
3/43 3/41 0/2
Time to Recurrence (Biopsy Diagnosis of Recurrence)
Overall recurrence rate Primary tumors Referred tumors Pathology Dysplasia Dysplasia, mild Dysplasia, moderate Dysplasia, severe Dysplasia, not otherwise specified Squamous cell carcinoma Squamous cell carcinoma in situ (SCCis) Squamous cell carcinoma, invasive (SCC) AJCC tumor classification Tis T1 T2 T3 T4
One-Year Kaplan-Meier Recurrence Rate (%)
TABLE 5. Recurrences of Ocular Surface Squamous Neoplasia After Excisional Biopsy With Adjunctive Cryotherapy
Recurrent Cases/Total Cases
Final Outcomea
TABLE 4. Recurrence Rate of Ocular Surface Squamous Neoplasias After Treatment With Excisional Biopsy With Adjunctive Cryotherapy
overall recurrence rate at 1 year, 2 years, and 5 years, for VOL. 160, NO. 2
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TABLE 6. Summary of Published Recurrence Rates of Ocular Surface Squamous Neoplasias After Excision and Cryotherapy
Series
N
Current study Nanji et al, 201426 Palamar et al, 201424 Crim et al, 201325 Sturges et al, 200821 Peksayar et al, 200322 Sudesh et al, 200011 Tunc et al, 199923
43 49 21 4 14 57 19 60
Excision & Cryotherapy Mean as Initial OSSN Follow-up Treatment (%) Recurrences (%)
29 moa 24 moa 31.0 mo 78 mo 35.6 mo 31.7 mo 37 mo 56 mo
100 100 100 100 100 86 68 66
7.1 6.1 0 0 0 12.3 10.5 5
OSSN ¼ ocular surface squamous neoplasia. Median.
a
primary and recurrent OSSN treated with excisional biopsy and adjunctive cryotherapy, the technique employed by all surgeons in our group. This is in line with the recent reports in which recurrence data were explicitly reported after excision and adjunctive cryotherapy11,21–26 (Table 6). Overall, these recurrence rates are considerably lower than the 53%–56% recurrence rate that is commonly cited for a surgical approach to OSSN. These higher recurrence rates reflect an era in which the lesion was excised without adjunctive cryotherapy and tumor was present at the surgical margin; the recurrence rate of OSSN with excision only and negative margins was lower, ranging from 5% to 33%,8,9 and we continue to observe a low recurrence rate with excisional biopsy and cryotherapy in our experience. This study contributes to the existing evidence favoring excision with cryotherapy over excision only, when considering surgical approaches for OSSN. There was no recurrence observed in the majority (25/28) of incompletely excised OSSN in this series of tumors treated with excision and cryotherapy. When compared to the much higher 53% recurrence rate reported among lesions treated with surgical excision alone with margin involvement,8 this supports the adjunctive role of cryotherapy in effectively treating the residual microscopic disease that may be left behind after surgical excision and reducing subsequent recurrence. A retrospective review by Sudesh and associates that directly compared the two in 2002 showed a 7.7% recurrence rate when excision was used with cryotherapy, compared to 28.5% for simple excision.11 Furthermore, in their study looking at predictors of OSSN recurrence after excision, Galor and associates identified a significant 0.51-fold decreased risk of recurrence when excising with cryotherapy compared to excising with no cryotherapy.27 This series of 43 cases is one of the largest studies in which every case was treated with excision with cryotherapy upon 218
presentation to our group (Table 6); the 2 cases that were not initially treated with excision and cryotherapy were treated with excision only by another ophthalmologist before referral to our group for excision and cryotherapy of the recurrent OSSN lesion. Concurrently in the last 2 decades, topical therapies have been introduced alongside excisional biopsy with cryotherapy in the armamentarium against OSSN; a range of recurrence rates have been reported, with some observing low recurrence rates with topical monotherapy, even as low as 0%.16,21,26,28,29 Based on such reports in the literature, ophthalmologists have shifted away from surgery toward topical agents in treating OSSN (according to a 2005 survey of the Ocular Microbiology and Immunology Group),14 especially with the advent of treatments such as interferon alpha-2b with minimal side effects. When this subject was revisited more recently in 2013, it was shown that 79% of ophthalmologists think there is enough evidence for topical monotherapy, with 58% reporting they have employed topical monotherapy.13 In response to the question of how often biopsies of suspected OSSN were performed before starting topical monotherapy, 51% of respondents always performed a biopsy before prescribing topical treatment, while about 10% of respondents never did, with the remainder of ophthalmologists performing biopsies some of the time before starting topical therapy.13,14 While there has been a report of a few cases with full clinical resolution and no recurrences in 12 months after interferon alpha-2b treatment for OSSN diagnosed by clinical appearance,5 employing topical monotherapy for suspected OSSN on appearance alone without pathologic confirmation is less than ideal, given that a variety of more common lesions could be mistaken for the comparatively rarer OSSN. In fact, benign lesions such as conjunctival papillomata have also resolved with the same treatment of interferon alpha-2b,30 emphasizing that clinical disappearance after topical treatment does not prove that the lesion was OSSN. Having a low threshold for instituting topical treatment of an OSSN-like conjunctival tumor comes at a great cost of unnecessarily treating entities that do not require it, regardless of the benign side effect profile. Our series of OSSN shows that resolution with minimal recurrence is achievable with the gold standard of excision and cryotherapy, which also provides a pathologic diagnosis. Without an excisional biopsy, the nature, severity, and grade of the lesion is unknown, and physicians are left without a definitive diagnosis should there be future recurrences. Although the idea of avoiding surgery altogether is quite attractive, only a prospective randomized trial would sufficiently determine if a topical monotherapy such as interferon alpha-2b could replace the existing gold standard of excisional biopsy with cryotherapy. Based on these data, a cost-effective analysis can be done to guide recommendations for the initial course of treatment for patients presenting with OSSN.
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: A.S.L.: reviewer, Academic Press/Elsevier, San Diego, California (no relationship to study); I.J.U.: consultant, Alcon, Fort Worth, Texas (no relationship to study). The authors indicate no funding support. All authors attest that they meet the current ICMJE requirements to qualify as authors.
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Biosketch Albert S. Li, MD, received his undergraduate degree in chemical and physical biology from Harvard College, where he was elected to The Phi Beta Kappa Society. During college, he received the Thomas Temple Hoopes Prize for his undergraduate research thesis. Subsequently, Dr. Li attended New York University School of Medicine, where he received his Doctorate of Medicine. Dr. Li is currently an ophthalmology resident at North Shore-Long Island Jewish Health System in Long Island, NY.
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