Ocular surface squamous neoplasia in xeroderma pigmentosum: clinical spectrum and outcome

Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-011-1679-8

CORNEA

Ocular surface squamous neoplasia in xeroderma pigmentosum: clinical spectrum and outcome Noopur Gupta & Ritika Sachdev & Radhika Tandon

Received: 1 December 2010 / Revised: 21 February 2011 / Accepted: 8 March 2011 # Springer-Verlag 2011

Abstract Background To study the clinical spectrum and therapeutic outcome of ocular surface squamous neoplasia (OSSN) in patients with xeroderma pigmentosa (XP). Methods The authors performed a retrospective review of records of patients with xeroderma pigmentosa referred to Cornea Services for management of OSSN. Presenting symptoms, clinical features, tumour morphology and location, treatment modalities, recurrence rates and visual outcome were noted. Results Seven patients of XP (six males; one female) with bilateral OSSN were included in the study. All patients were less than 15 years of age at presentation, with 13 of 14 lesions of OSSN (93%) occurring at the limbus. Associated ocular features were limbal stem cell deficiency in nine eyes (64.3%), dry eye in all 14 eyes (100%), conjunctival melanosis in seven eyes (50%), pseudopterygium in two eyes (14.3%), anterior symblepharon in three eyes (21.4%) and conjunctival inflammatory granuloma in one eye (7.1%). Unaided visual acuity in the 14 eyes ranged from 6/6 to 6/36 at presentation. Six of the 14 eyes (42.9%) had histopathological features of invasive squamous cell carcinoma, and eight eyes (57.1%) demonstrated features consistent with conjunctival The authors have full control of all primary data, and agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data upon request. Electronic supplementary material The online version of this article (doi:10.1007/s00417-011-1679-8) contains supplementary material, which is available to authorized users. N. Gupta : R. Sachdev : R. Tandon (*) Cornea & Refractive Surgery Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India e-mail: [email protected]

intraepithelial neoplasia. Recurrence was seen in nine of 14 eyes (64.3%). Conclusions OSSN occurs predominantly in the elderly, but in patients of XP it tends to occur at a younger age (6–22 years). The disease appeared to be more aggressive (recurrence rate = 64.3%) than usual. Awareness and prompt management with close follow up is warranted in these patients. Keywords Xeroderma pigmentosum . Ocular surface squamous neoplasia . Recurrence . Clinical outcome

Introduction Xeroderma pigmentosum (XP) is a rare genetic disorder associated with multiple oculocutaneous and neurological manifestations. It occurs due to deficiency of the enzymes responsible for repairing ultraviolet radiation-induced DNA damage [1]. Persistence of un-repaired DNA results in somatic mutations, leading to neoplasia of the skin and ocular surface [2]. As this condition is rare, only isolated case reports of XP with ocular surface squamous neoplasia (OSSN) are found in literature. Ocular surface squamous neoplasia (OSSN) includes a spectrum of diseases which range from mild dysplasia to conjunctival and corneal intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma (SCC). Pre-invasive OSSN lesions are classified as mild, moderate, or severe, depending on the degree of involvement of the dysplastic epithelium. Mild dysplasia, or CIN grade I, is defined as dysplasia confined to the lower third of the conjunctival epithelial thickness. Moderate dysplasia (CIN grade II) extends into the middle third, and severe dysplasia (CIN III) to the upper third of the conjunctival epithelium. Full-

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thickness dysplasia of the epithelium is also referred to as carcinoma-in-situ. The pathological basis for a diagnosis of pre-invasive OSSN is based on the identification of epithelial disarray and abnormalities in maturation. In general, these conditions show an abrupt demarcation between neoplastic cells and the uninvolved benign epithelium. Invasive OSSN or squamous cell carcinoma shows nests of infiltrating cells that have penetrated the epithelial basement membrane and spread into the conjunctival stroma. OSSN is known to occur in patients with xeroderma pigmentosa, but the clinical course, therapeutic options, recurrence rate and outcome in this subgroup has not been highlighted.

Table 1 Demographic profile and general features of patients with xeroderma pigmentosa Patient

Current age (years)

Sex

Age at onset of XP (years)

Family history

Consanguinity in parents

1 2 3 4 5 6 7

16 6 17 22 20 12 12

F M M M M M M

14 8 6 14 15 10 8

+ − + + + − −

+ − + + + − −

XP = xeroderma pigmentosa; M = male; F = female; + = present; − = absent

Material & methods Cases diagnosed as xeroderma pigmentosum with OSSN from January 2002 to March 2008 were included in this study. Patient data were analyzed for presenting symptoms, possible etiological factors, clinical features, tumour shape and location, treatment modalities, clinical course, recurrence rates, and visual outcome. Associated ocular features like limbal stem cell deficiency (LSCD), dry eye, conjunctival melanosis, pseudopterygium, etc. were noted. Limbal stem cell deficiency was characterized clinically by loss of limbal architecture & palisades of Vogt and evidence of conjunctivalization of the cornea. It was confirmed histopathologically by impression cytology that demonstrated presence of conjunctival goblet cells at the limbus. Dry eye was defined as Schirmer’s test value of less than 10 mm, performed without anaesthesia. All patients were followed up at monthly intervals in order to ensure prompt detection of recurrence or development of a fresh lesion.

Results Fourteen eyes of seven patients with xeroderma pigmentosum (six males; one female) and ocular surface squamous neoplasia with median age of 12 years (range; 6–22 years) were included in this study. All patients had clinical and dermatological features of xeroderma pigmentosum. The age at onset of skin lesions in these patients ranged from 3– 13 years. All the patients were below 15 years of age at the time of onset of dermatological features of XP. Ten of 14 eyes (71.4%) developed ocular surface squamous neoplasia before the age of 15. Positive family history and consanguineous marriage in parents was reported in four patients (Table 1). On systemic examination, there was no evidence of any neurological disorder, skin malignancies or lymphadenopathy in any of the patients. Parents of all our cases were clinically normal.

Red eye, photophobia, dry eye, foreign body sensation, and reddish, and painless progressive growth were the presenting complaints in four patients, while one patient presented with diminution of vision and photophobia. The other two patients presented to the dermatologist with irregular 1- to 2-mm sized hyperpigmented skin lesions associated with achromic, hypopigmented areas, consistent with the diagnosis of xeroderma pigmentosa. These two patients were referred for routine ophthalmic examination, and were diagnosed to have OSSN by the cornea specialist. Other associated ocular features were limbal stem cell deficiency in nine eyes (64.3%), dry eye in all 14 eyes (100%), conjunctival melanosis in seven eyes (50%), conjunctival xerosis in nine eyes (64.3%), pseudopterygium in two eyes(14.3%), extensive anterior symblepharon in three eyes(21.4%), and conjunctival necrobiotic granuloma (confirmed on histopathological examination) in one eye (7.1%). Lid freckles were present in all eyes (100%), while lower lid ectropion due to scarring was seen in three patients (four eyes). At presentation, unaided visual acuity in the 14 eyes ranged from 6/6 to 6/36 (Table 2). The tumour size in these patients ranged from 1 mm to 11 mm, measured along the longest axis. Morphologically, all lesions showed abundant intrinsic vascularity and dilated episcleral feeder vessels. Out of a total of 14 eyes with OSSN, six tumours were gelatinous and papilliform type, four were nodular, two were leukoplakic and two eyes had diffuse variety of OSSN. Six eyes (42.9%) had histopathological features of invasive SCC without orbital involvement, and eight eyes (57.1%) had CIN. Right eye was involved initially in four patients, left eye in two patients; and in one patient, both eyes were involved simultaneously. There was predominance of temporal (nine eyes; 75%) over nasal (three eyes) location for the well-circumscribed lesions (Table 2). The tumour in two eyes had a diffuse,

Graefes Arch Clin Exp Ophthalmol Table 2 Ocular features and characteristics of OSSN in patients with xeroderma pigmentosa Patient Visiual Type of Location Size & eye acuity at OSSN (mm) presentation

Number of Tumour recurrences free interval (months)

1

2 3

4

5 6 7

Duration BCVA Other ocular of follow up at final findings (months) follow-up

R

6/6

SCC

T

4.9×4.5

0

–

L

6/9

CIN

T

2.0×3.0

1

72

6/9

R L R

6/9 6/24(−3) 6/6(−4)

CIN SCC CIN

N T T

1.0×1.0 0 10.0×11.0 1 5.8×5.4 4

– 23 20 101; 50;18;24 210

6/12 6/12(−2) 6/12

L

6/9

CIN

T

2.0×2.0

1

38

6/9

R

6/12

SCC

T

5.8×4.6

3

10;70;12

L

6/12

CIN

T

2.1×2.3

0

–

R L R L R L

6/9(−4) 6/12 6/24 6/36 6/9 6/9

SCC CIN SCC SCC CIN CIN

T T T T N N

1.2×2.0 1.1×1.8.0 4.0×4.0 4.0×1.5 7.0×8.0 6.3×7.2

1 0 0 1 0 0

14 – – 14 – –

94

94

6/9

6/9 6/9

72 60 48

6/9 6/9(−2) 6/9 6/9 6/6 6/6

Dry eye; LSCD; conj. melanoses; symblepharon Dry eye; LSCD; ectropion; pseudopterygium Conj. melanosis; dry eye Conj. melanosis; dry eye Dry eye; LSCD; conj. melanoses; pseudopterygium; ectropion Necrobiotic granuloma; dry eye; LSCD; conj. melanosis; Ectropion Conj. melanosis; dry eye; symblepharon Conj. melanosis; dry eye; LSCD; symblepharon; ectropion Dry eye; LSCD Dry eye; LSCD Dry eye Dry eye Dry eye Dry eye

OSSN — ocular surface squamous neoplasia; Visual acuity at presentation — superscripts denote partial visual acuity, and that the patient is unable to read the specified number of letters in that line, e.g., patient no. 2 is unable to read 3 letters of the 6/24 line of the Snellen’s visual acuity chart from his left eye; BCVA — best-corrected visual acuity; R — right; L— left; SCC — squamous cell carcinoma; CIN — conjunctival/corneal intraepithelial neoplasia; T — temporal; N — nasal; Conj. — conjunctival; LSCD — limbal stem cell deficiency

circumferential involvement. The extent of localized lesions in 12 eyes ranged from 1 to 6 clock hours. Corneal involvement (extending 1–4 mm beyond the limbus) due to OSSN was present in only nine eyes at the initial visit, but the cornea infiltration was noted in all 14 eyes at the last follow-up visit. All eyes had a quiet anterior chamber that excluded the possibility of intraocular extension. Intraocular pressure was within normal limits in all eyes. Posterior segment examination was unremarkable in all the patients. Impression cytology was done in all cases preoperatively, and established the presence of dysplastic cells in all cases. Impression cytology was accurate in all eyes (100%) with CIN. Three eyes suspected to be CIN on impression cytology were reported to be SCC on histopathological examination of the biopsy specimen. Treatment options included excision biopsy with triple freeze thaw cryotherapy in ten eyes (71.4%), with no recurrence (Fig. 1a-c) after 80 months of average follow up in three eyes. The patients underwent complete excision biopsy of the tumor with clinically clear margins, with cryotherapy to the resected conjunctival edges. Out of these

ten eyes, six eyes were histopathologically proven SCC, and four eyes had histopathologically proven CIN. Two eyes with small-sized lesions (less than 2 mm) and two eyes with diffuse lesions, all with a preoperative diagnosis of CIN, were treated with topical 0.02% mitomycin C (MMC) four times a day (four cycles). Out of these, the tumour resolved completely in three eyes, and in one eye, excision with cryotherapy was performed as the tumor did not regress following therapy with MMC. Recurrence was noted in nine of 14 eyes (Fig. 2a-c), with an overall recurrence rate of 64.3%. After an average follow-up of nearly 80 months, the rate of new or recurrent tumours was 25% for intraepithelial squamous carcinoma and 83% for invasive squamous cell carcinoma. The average number of recurrences in these eyes with OSSN ranged from none (five eyes) to four recurrences (one eye). Development of a fresh lesion (CIN) was seen in one eye. Tumour-free interval ranged from 3 months to 8 years. At the final follow-up visit, best-corrected visual acuity was 6/9 in ten of 14 eyes (71.4%) and better than 6/24 in all 14 eyes (100%) (Table 2).

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Fig. 1 Clinical photograph of left eye of patient 4 (22-year-old male) showing: a ocular surface squamous neoplasia (OSSN) located temporally and measuring 2.1×2.3 mm (14×), b progress of OSSN to invole the cornea. Dilated episcleral feeder vessels and conjunctival melanosis is evident (10×). c No recurrence noted in left eye after 94 months of follow up following excision

Discussion Xeroderma pigmentosum is inherited as an autosomal recessive disorder with a prevalence rate of 1:250,000. It

Fig. 2 Slit-lamp photograph of left eye of patient 2 (6-year-old boy) with OSSN showing: a temporal, nodular, elevated mass measuring 10×11 mm. The lesion shows abundant intrinsic vascularity & dilated episcleral feeder vessels (10×) . b Excision of neoplastic mass followed by the triple freeze thaw technique cryotherapy at the conjunctival edges of the lesion (10×). Conjunctival melanosis is evident at 5 o’clock limabal region. c Recurrence of OSSN after 20 months (10×)

is characterized by multiple pigmented spots, called ‘freckles’ and larger atrophic lesions, and a glossy white thinning of the skin [2]. This study presents the ocular features of seven cases of XP, with particular reference to development and management of OSSN in these patients.

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Conjunctival and corneal epithelial malignancies are seen more commonly in elderly and male patients, but may develop at a younger age, especially in association with xeroderma pigmentosum or immunodeficiency. OSSN predominantly occurs in older males with an average age of 56 years [3]. All patients in our series presented with OSSN at less than 22 years of age. Patients with XP are unable to repair the DNA that is damaged by ultraviolet rays. This can lead to somatic mutations and development of cancerous cells. This inherent defect accounts for the increased susceptibility to OSSN and the younger age at presentation [4]. Some reports have noted a younger age in intraepithelial cases compared with invasive squamous cell carcinoma [5]. Likewise, patients in our series presented with pre-invasive OSSN (CIN) at a younger age group, but developed an invasive form of squamous neoplasia (SCC) when they grew older, in the form of a recurrence or development of a new lesion. Bilateral affliction is encountered very frequently in patients of XP. All cases in our series presented with OSSN in both eyes either simultaneously or sequentially. In line with previous reports, we noted a male preponderance, probably due to increased exposure to sunlight. OSSN most commonly occurs at the limbus, as it is a transition zone and is prone to development of dysplasia [3]. Limbal location was noted in all our patients. Temporal lesions were more common than nasal lesions in our cases. We did not come across cutaneous and visceral malignancies in association with conjunctival epithelial tumours in our cases of XP. Four of the seven patients in our series (57.1%) presented with the primary complaint of an ocular mass. Irritation may not always be a consistent symptom in patients of XP developing OSSN or recurrence of the tumor [6]. Concomitant ocular pathologies such as dry eye or limbal stem cell deficiency may lead to foreign body sensation and photophobia in patients of XP without OSSN. Two of the seven patients were diagnosed with OSSN on routine ophthalmic examination. This emphasizes the need of routine ophthalmic examination and regular follow-up of all patients with XP. Conjunctival squamous cell neoplasms can cause significant ocular morbidity. Early diagnosis and intervention can prevent extensive visual morbidity. Simple excision of

conjunctival intraepithelial or invasive neoplasia has been reported to be associated with a 24–50% recurrence rate [3, 7]. Excision with intraoperative control of the surgical margins and adjunctive cryotherapy has been reported to reduce recurrence rates to 12% [8, 9]. In our series, a high overall recurrence rate of 64.3% was seen; the rate of new or recurrent tumours was 25% for intraepithelial squamous carcinoma and 83% for invasive squamous cell carcinoma. Up to four recurrences were noted in a single patient. Development of a fresh lesion (CIN) was noted in one eye. Our series highlights the increased susceptibility of patients of XP with OSSN to develop fresh or recurrent lesions. A majority of the patients of XP with OSSN develop recurrence of the tumor despite a meticulous tumor excision and adjunctive cryotherapy. Fresh lesions may also be encountered during the follow-up examination of these patients. The increased risk of recurrence of OSSN in patients of XP warrants a regular, meticulous follow-up with an ophthalmologist. Recurrent lesions were noted as long as 8 years after the initial excision. We recommend a regular, lifelong follow-up in all these patients to monitor any recurrence.

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