Recurrence of Ocular Surface Squamous Neoplasia Treated With Excisional Biopsy and Cryotherapy




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.


Ocular 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 OSSN is estimated to be approximately 20 cases per million persons per year. OSSN predominantly affects older men and affects people of all races. 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. Tumors can appear flat, gelatinous, or papillomatous, with varying degrees of leukoplakia. 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. Frequently “feeder” blood vessels are associated with the mass, and corneal portions can either be avascular or have fine blood vessels. Symptoms may include foreign body sensation, redness, irritation, and decrease in visual acuity, especially if the lesion involves the cornea. Classically appearing tumors can be diagnosed clinically, 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.


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%. 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. In 1994 Shields and Shields described a method involving excisional biopsy with a no-touch technique followed by double freeze-thaw cryotherapy. Subsequent studies confirmed that this may be an effective technique, as the average recurrence rate of OSSN with excision and cryotherapy is 12%, ranging from 7% to 22% in published studies.


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. 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. 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; 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. 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 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; 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. Full-thickness dysplasia where there are no normal epithelial cells is referred to as carcinoma in situ. Squamous cell carcinoma is present when the basement membrane of the epithelium is violated and there is invasion of the substantia propria.


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 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. 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.



Table 1

Series Characteristics of Ocular Surface Squamous Neoplasias Treated with Excisional Biopsy and Cryotherapy



































































































N %
Age (y), mean (median, range) 68.4 (69, 45–85)
Sex
Male 30 69.8
Female 13 30.2
Risk factors
Current smoker 4 9.3
Former smoker 10 23.3
Organ transplantation 1 2.3
Tissue involvement
Cornea & conjunctiva 36 83.7
Conjunctiva only 7 16.3
Size
Small (<5 mm or <3 clock hours) 22 51
Medium (5–10 mm or 3–6 clock hours) 18 42
Large (>10 mm or >6 clock hours) 3 7
Location a
Temporal 16 37.2
Inferior 7 14.3
Nasal 25 58.1
Superior 1 2.3
Characteristics
Leukoplakic 16 30.2
Adherent 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 ).



Table 2

Histopathologic Classification of Ocular Surface Squamous Neoplasias Treated With Excision and Cryotherapy




















































































N %
AJCC tumor classification
Tis 6 14.0
T1 0 0.0
T2 0 0.0
T3 37 86.0
T4 0 0.0
N0 43 100.0
N1 0 0.0
M0 43 100.0
M1 0 0.0
Pathology
Dysplasia 14 32.6
Dysplasia, mild 3 7.0
Dysplasia, moderate 6 14.0
Dysplasia, severe 4 9.3
Dysplasia, not otherwise specified 1 2.3
Squamous cell carcinoma 29 67.4
Squamous cell carcinoma in situ (SCCis) 24 55.8
Squamous cell carcinoma, invasive (SCC) 5 11.6

AJCC = American Joint Committee on Cancer.


Table 3

Margin Involvement of Excisional Biopsy With Adjunctive Cryotherapy of Ocular Surface Squamous Neoplasias
































Margin Involvement N %
Negative 14 32.6
Positive
At corneal margin only 14 32.6
At noncorneal margin 9 20.9
At unspecified margin 5 11.6
Indeterminate 1 2.3


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 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 ).




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.


Table 4

Recurrence Rate of Ocular Surface Squamous Neoplasias After Treatment With Excisional Biopsy With Adjunctive Cryotherapy
















































































Recurrent Cases/Total Cases One-Year Kaplan-Meier Recurrence Rate (%)
Overall recurrence rate 3/43 7.1
Primary tumors 3/41
Referred tumors 0/2
Pathology
Dysplasia 1/14 7.7
Dysplasia, mild 0/3
Dysplasia, moderate 1/6
Dysplasia, severe 0/4
Dysplasia, not otherwise specified 0/1
Squamous cell carcinoma 2/29 6.9
Squamous cell carcinoma in situ (SCCis) 2/24
Squamous cell carcinoma, invasive (SCC) 0/5
AJCC tumor classification
Tis 1/6
T1 0/0
T2 0/0
T3 2/37
T4 0/0

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Jan 7, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Recurrence of Ocular Surface Squamous Neoplasia Treated With Excisional Biopsy and Cryotherapy

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