Intraocular Spread of Ocular Surface Squamous Neoplasia Presenting as a Postoperative Anterior Chamber Opacity after Excisional Biopsy

Abstract

We describe a rare case of ocular surface squamous neoplasia (OSSN) with intraocular spread after excisional biopsy which presented as a postoperative anterior chamber (A/C) opacity, initially thought to be a hypopyon. A 60-year-old female with history of a right (OD) conjunctival mass involving the cornea, surgically excised and diagnosed as OSSN, presented 2 months postoperatively with an A/C opacity concerning for infection. The patient was prescribed prednisolone acetate and ofloxacin drops postoperatively; topical chemotherapy was not given. When the opacity did not respond to 3 weeks of topical treatment, they were referred to an ocular oncologist for management. Intraoperative records from biopsy were unavailable; use of cryotherapy is unknown. On presentation, the patient had reduced vision OD. On slit-lamp exam, a white plaque in the A/C was seen, obscuring the iris. Given concern for postoperative intraocular cancer spread and extent of disease, enucleation with extended conjunctival excision was done. Gross pathology revealed an A/C mass with a diffuse hazy membrane. Histopathology diagnosed moderately differentiated OSSN with extensive intraocular invasion; a full-thickness limbal defect was visualized. Disease was confined to the globe, without residual conjunctival malignancy. This case emphasizes the importance of taking surgical precaution when excising conjunctival lesions, especially large lesions which obscure ocular anatomy, to maintain scleral integrity and Bowman’s layer with limbal lesions. Intraoperative cryotherapy and postoperative chemotherapy should also be employed. If a patient with history of ocular surface malignancy displays symptoms concerning postoperative infection, this case highlights the importance of considering invasive disease.

Introduction

Ocular surface squamous neoplasia (OSSN), a tumor of the conjunctiva, is the most common ocular tumor, with a yearly incidence of 0.03–1.9 per 100,000 people [1]. It typically affects older individuals due to prolonged ultraviolet-B radiation exposure, but the risk of development is increased in immunocompromised patients and those with cutaneous human papilloma virus [1–3]. The term OSSN includes a spectrum of diseases, ranging from mild dysplasia to invasive squamous cell carcinoma [3, 4]. Patients with OSSN typically experience nonspecific symptoms, most commonly pain and redness, accompanied by a growing mass [1, 2, 4]. The mass usually arises from the interpalpebral part of the conjunctiva and can be nodular, gelatinous, or plaque-like in appearance [2]. OSSN may be discovered on routine ocular examination in an asymptomatic patient and can be confused with a benign conjunctival growth [2, 5].

If OSSN is suspected on examination, the diagnosis can be established via biopsy with histopathologic confirmation, anterior segment optical coherence tomography, or impression cytology [1]. Management of OSSN can be done both surgically and medically. The current gold standard for OSSN surgical excision utilizes the “no touch” technique to prevent seeding of malignant cells into adjacent tissues, accompanied by cryotherapy for improved marginal control [3]. However, for multiple reasons, medical management may be preferred. This includes topical chemotherapy including mitomycin C, 5-fluorouracil, and interferon [3], all of which have similar outcomes [1]. Surgery is typically the method of choice for tumors involving four or fewer clock hours from the limbus, while topical chemotherapy is often chosen for tumors greater in size [1]. Additionally, topical chemotherapy is often employed after surgical excision in cases without clear margins [1]. In large tumors or those with intraocular invasion, surgical removal of the eye may be necessary depending on extent of disease [1]. Rates of recurrence for appropriately treated OSSN are low [2, 6–8].

Intraocular extension of OSSN is a rare phenomenon, reportedly due to direct scleral invasion, spread of malignant cells through a surgical incision, or spread along the anterior ciliary vessel tract [4, 5, 7–11]. In intraocular OSSN, patients may have the characteristic symptoms of pain and redness in addition to anterior chamber (A/C) inflammation, iris neovascularization, or secondary glaucoma from ciliary body invasion [4, 5, 11]. Here, we report a rare case of intraocular OSSN that presented after excisional biopsy as an A/C opacity, initially thought to be postoperative hypopyon.

Case Report

A 60-year-old female with previous history of a right (OD) nasal conjunctival lesion, pathologically diagnosed as conjunctival squamous cell carcinoma after excisional biopsy, was referred to our hospital system for management of a postoperative nasal A/C opacity OD, initially thought to be a hypopyon. Two months before referral to our institution, the patient presented to an emergency room with a nasal conjunctival lesion involving the cornea (Fig. 1a), endorsing pain and irritation of the right eye; the patient first noticed the conjunctival mass several months prior. The mass was believed to be a large benign conjunctival lesion, so the patient was referred to an outside provider, and surgical excision was pursued 10 days after initial presentation. It is unknown how the biopsy was performed, including whether cryotherapy was done, as intraoperative records are unavailable. Pathology of the tissue specimen diagnosed well-differentiated OSSN with positive conjunctival margins. After biopsy, the patient was prescribed topical prednisolone acetate 1% and ofloxacin 0.3% OD with reported medication compliance; topical chemotherapy was not given. Postoperatively, the patient developed an A/C opacity OD, with suspicion for infectious hypopyon. When the opacity did not respond to approximately 3 weeks of topical treatment, the patient was referred to an ocular oncologist at our institution for further management.

Fig. 1.

Series of ocular photographs of the affected right eye. a A preoperative patient photograph of the right eye, highlighting the original nasal conjunctival lesion (image provided by patient, only preoperative image available). The mass is large, gelatinous, and opaque. Additionally, it appears to cross the limbus onto the cornea. b–d Slit-lamp examination photos of the right eye taken at postoperative evaluation. Pronounced nasal conjunctival injection and edema are seen, extending from the conjunctiva to the sclera. Additionally, a small bleb on the nasal conjunctiva is visible in (b, c) (black arrows). d Image highlighting the large, white opacity occupying the nasal half of the A/C.

On presentation, the patient endorsed light sensitivity and chronic watery eyes bilaterally but denied pain and burning OD. They had no pertinent past medical history including no known immunocompromising conditions such as human immunodeficiency virus and no history of known human papilloma virus. The patient’s only pertinent surgical history was the conjunctival lesion excision OD. Patient did not report family history of ocular diseases or cancers. They denied smoking, alcohol, substance use, and prolonged ultraviolet-B exposure. On examination, vision was 20/300 + 2 in the right eye and 20/70 + 2 in the left eye (OS). Intraocular pressure (IOP) was 21 OD and 15 OS.

Slit-lamp examination was performed. The right conjunctiva had significant nasal injection with a visible bleb and thin sclera (Fig. 1b, c). Corneal examination was clear OU. A/C examination OD revealed a large, white plaque with scattered pigment occupying the nasal half of the chamber (Fig. 1d). The nasal iris was not visible OD due to the A/C mass, but a white membrane adherent to the mass was noted temporally, extending superiorly around the pupillary margin. The lens OD could not be visualized due to the A/C mass, but possible nuclear sclerosis was noted superiorly. Slit-lamp examination OS was within normal limits. On posterior segment examination, view was limited OD due to the A/C mass. Posterior structures were normal OS. All branches of the bilateral trigeminal nerves were intact on examination, and no lymphadenopathy was appreciated.

Additional imaging was performed for better characterization of the mass OD. Ultrasound biomicroscopy revealed a highly reflective mass in the inferonasal A/C involving the ciliary body, thickened conjunctiva, and an area of low reflectivity, suggesting possible scleral invasion (Fig. 2a). Anterior segment optical coherence tomography of the right eye showed focal, inner scleral thinning with an adjacent inner mass along the endothelium (Fig. 2b). Given examination and imaging findings, the leading differential diagnosis in this case was intraocular spread of OSSN. The patient was sent for urgent systemic metastatic workup, including positron emission tomography, which confirmed that pathology was confined to the right globe. Due to the severity of intraocular disease and poor visual potential, the patient was offered an enucleation with extended conjunctival excision, and they decided to proceed. The right eye was successfully removed utilizing modified aspects of the “no touch” technique [3] including excision of the conjunctiva adjacent to the initial surgical site along with the globe (there was no clear residual conjunctival mass), and use of cryotherapy at the margins of this area prior to placement of a 20-mm orbital implant. Additionally, before closure, the conjunctival margins were treated with 3 freeze-thaw cycles of cryotherapy, and additional cryotherapy was applied to the nasal conjunctiva at the original surgical excision site. The procedure was completed without complications, and the enucleated globe was sent for pathologic evaluation.

Fig. 2.

Imaging of the right eye. a An ultrasound biomicroscopy image of the right A/C, notable for irregular A/C morphology and a highly reflective mass in the inferonasal component (red arrow). This mass appears to be rooted in the angle with possible ciliary body involvement. Thickened and elevated conjunctiva with low reflectivity is seen, suggesting possible scleral excavation (green arrow). b An anterior segment optical coherence tomography image of the nasal lesion, emphasizing the nasal conjunctival irregularity. Focal inner scleral thinning is seen with an adjacent inner mass that traces along the endothelium (red arrow).

Gross pathology of the enucleated right eye revealed a white mass partially filling the A/C measuring 8.5 × 6.5 mm, with a mild hazy membrane covering the nasal angle, iris, pupillary space, and posterior cornea. The A/C was noted to be shallow. The nasal pars plicata was covered in a white and powdery material, and this same material was found between the lens and ciliary body. Microscopic pathology diagnosed moderately differentiated squamous cell carcinoma of the conjunctiva with extensive intraocular invasion including the sclera, posterior corneal surface, trabecular meshwork, iris, ciliary body, and lens (Fig. 3). Notably, a full-thickness nasal limbal defect was identified, plugged by keratinous debris (Fig. 3a). The optic nerve was negative for tumor, and no perineural or vascular invasion was identified. Due to the extent of intraocular cell spread in this case, disease pathology was comparable to epithelial downgrowth, malignant version, where epithelial cells are introduced into the inner structures of the eye through a traumatic or surgical wound and spread over contiguous structures, impeding vision and aqueous outflow [12]. At postoperative follow-up 2 weeks after enucleation, the conjunctiva OD was noted to be healing appropriately. Vision, IOP, anterior segment exam, and posterior segment exam OS were within normal limits. Although disease in this patient’s case was confined to the globe without residual conjunctival malignancy, given the degree of local disease progression, there is a high risk of cancer relapse in the head and neck. The patient will continue following with both a systemic and ocular oncologist every 6 months for monitoring.

Fig. 3.

Histopathologic specimen from the enucleated right eye. a The nasal limbal full-thickness open defect, partially plugged by keratinous debris (black arrow), with focal mild dysplastic change in the surface epithelium along the wound edge. Eosinophilic material partially fills the anterior chamber (A/C). Epithelial cells line the posterior corneal (c) surface, the angle area, and the anterior iris (I) surface. The sclera (s) is disrupted and infiltrated by chronic inflammatory cells, which are also present in the ciliary body (cb) and iris (×2). b The nasal limbal defect; at the bottom of the photo, a cluster of tumor (t) cells invading the iris is seen, and tumor cells cover the inner corneal surface, iris surface, and ciliary body (black arrows) (×4). In (c), tumor is seen invading the sclera and ciliary body (×4). d Tumor cells on the iris pigment epithelium (IPE) and along the ciliary epithelium (×10). e Tumor cells on the opposite ciliary process (cp), in the posterior chamber admixed with neutrophils, and growing on lens (L) anterior surface. In (f), malignant tumor cells can be seen on anterior iris surface, crawling around the pupillary edge of the iris and into the posterior iris surface. Keratinized and degenerated cells are visualized in A/C with dystrophic calcifications (black arrow) (×10). g A higher magnification image of the tumor cells on the iris surface (×20). Polygonal tumor cells have large nuclei with prominent nucleoli, moderately abundant dense eosinophilic cytoplasm, and intercellular bridges indicating squamous differentiation. Degenerating keratinized cells and keratinous debris admixed with neutrophils are present in the A/C (top of photo). h A higher magnification of the tumor cells along the corneal edge (×20); this defect is presumably one entry point of the tumor cells. All images are stained with H&E.

Discussion

Here, we report a rare case of invasive intraocular OSSN with diffuse A/C involvement. The patient presented to our institution after excision of an irregular conjunctival mass with a postoperative A/C opacity, thought to be infection that was not responsive to topical antibiotics and steroids. Though originally thought to be a benign mass of the conjunctiva, pathology diagnosed the mass as well-differentiated conjunctival squamous cell carcinoma with positive tumor margins. OSSN is typically a nonaggressive cancer with low rates of recurrence; size >5 mm in diameter, extension onto the cornea of >2 mm, local tumor invasion, higher grade malignancy, positive pathologic margins, and inadequate initial treatment are all associated with an increased recurrence risk and poorer overall prognosis [6, 7, 9, 13]. This tumor had multiple poor prognostic risk factors. Although original tumor dimensions are unknown, as seen in a preoperative photograph provided by the patient (Fig. 1a), the lesion was large and crossed the limbus. Also, pathology diagnosed the mass as OSSN with positive pathologic margins. In cases of OSSN with positive surgical margins, adjuvant therapy with surgical cryotherapy and topical chemotherapy is typically used to reduce risk of recurrence [1]. Our case is limited by a lack of intraoperative biopsy records, so the use of cryotherapy during initial biopsy is unknown, but there is no record of postoperative topical chemotherapy. A lack of adjuvant therapy may have therefore increased the risk of recurrence for this patient.

Though intraocular invasion of OSSN is a rare phenomenon, review of the existing literature suggests that surgical intervention can create a route for tumor cells to enter the eye and is therefore a risk factor for intraocular cancer spread [4, 9]. This patient experienced intraocular spread post-excision biopsy, and a full-thickness limbal defect was noted on pathologic examination between the area of the original lesion and the area of histopathologic cellular spread. Therefore, we hypothesize that during initial biopsy of this large lesion (which likely distorted ocular anatomy), an iatrogenic defect was introduced which prompted tumor cell seeding into the eye. This breach would have allowed the malignant cells to invade in a manner pathologically reminiscent of epithelial downgrowth, spreading diffusely throughout the A/C [12]. This case emphasizes the importance of taking surgical precaution when excising any conjunctival lesion, especially those which are atypical or have poor prognostic risk factors including large size and corneal involvement, as were features of this case. When excising a conjunctival lesion, the surgeon should pay special attention not to create a potential track for cells to enter the globe and also employ intraoperative cryotherapy to ensure clear surgical margins [14]. Most reported cases of intraocular invasion of OSSN have a history of prior excision of a limbal lesion which, as per Shields et al. [11], should serve as a “clue” for the underlying diagnosis. Employing the “no touch” technique [3] with cryotherapy reduces risk of intraocular invasion, as does the use of postoperative chemotherapy [15] which was not done for this patient.

The intraocular spread of this patient’s tumor first appeared as a nasal A/C opacity and was thought to be postoperative infectious hypopyon. Acute postoperative endophthalmitis is defined as an intraocular infection within 6 weeks of ocular surgery [16]. It is most widely reported in cataract surgeries, given their frequency, and has only rarely been reported in external ocular surgeries [16, 17]. In postoperative endophthalmitis, patients often present with pain, decreased vision, and redness or edema of the conjunctiva; on examination, patients can have hypopyon or A/C cell [16, 17]. This patient’s A/C opacity was reminiscent of inflammation, and they presented with compromised vision and an injected edematous conjunctiva (Fig. 1b–d), all suggestive of postoperative infection. However, the patient had been newly diagnosed with OSSN when the A/C opacity was discovered, and the dense focal nature of the mass, without shifting or layering as is usual with hypopyon, pointed to another diagnosis. As per the limited existing literature reporting intraocular spread of OSSN, the most common presenting symptoms include intraocular inflammation, secondary glaucoma, and a white mass in the A/C [5, 11]. However, in some reports, secondary glaucoma and A/C cell were less frequently seen [4]. Here, our patient presented with signs of intraocular inflammation, in the absence of frank glaucoma. Our case emphasizes the importance of considering intraocular spread of disease in OSSN patients that display symptoms of endophthalmitis after extraocular surgery, even in the absence of significantly elevated IOP, especially given the rarity of postoperative intraocular infection after extraocular procedures.

Here, we describe a case of intraocular OSSN that presented postoperatively as an A/C opacity non-responsive to topical antibiotic and steroid treatment. While rare, external tumors can invade the intraocular space. An iatrogenic mechanism such as breach of an anatomic barrier including Bowman’s layer or the sclera often plays a role. Large lesions, even if benign, can distort the ocular anatomy. This case emphasizes that extra surgical precaution should be taken with these lesions to prevent iatrogenic breaching of the eye, with the use of intraoperative cryotherapy and postoperative chemotherapy; or, the patient may be referred to a center well versed in the appropriate surgical techniques. Additionally, endophthalmitis after extraocular surgery, such as the setting of conjunctival excision, is rare. If an excised conjunctival lesion is pathologically diagnosed as malignant and the patient presents with symptoms of postoperative infection, this should raise concern for intraoperative tumor spread. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000530335).

Statement of Ethics

Ethics and consent for this retrospective review of patient data were approved by the Institutional Review Board at the University of Southern California (No. HS-17-00108). In approving this research, the IRB determined that all of the requirements under 45 CFR 46.111 were satisfied. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The research was conducted ethically in accordance with the Declaration of Helsinki.

Conflict of Interest Statement

The following authors have no financial disclosures: S.P., S.B.E., M.E.S.S., A.J.M., and G.K.I. J.L.B. has financial support not directly related to the scope of this report from the National Cancer Institute of the National Institute of Health Award Number K08CA232344, the Wright Foundation, Children’s Oncology Group/St. Baldrick’s Foundation, the Knights Templar Eye Foundation, Hyundai Hope On Wheels, Childhood Eye Cancer Trust, Children’s Cancer Research Fund, the Berle & Lucy Adams Chair in Cancer Research, the Larry and Celia Moh Foundation, the Institute for Families, Inc., Children’s Hospital Los Angeles, an unrestricted departmental grant from Research to Prevent Blindness, and the National Cancer Institute P30CA014089. J.L.B has filed a provisional patent application entitled Aqueous Humor Cell-Free DNA for Diagnostic and Prognostic Evaluation of Ophthalmic Disease 62/654,160 (Berry, Xu, Hicks).

Funding Sources

No funding or grant support was received for this article.

Author Contributions

S.P. collected patient data and was the primary manuscript author. J.L.B. was primary in patient management, provided clinical photographs, and was a major contributor to manuscript writing, editing, and final manuscript approval. S.B.E. and G.I.K. participated in working up and caring for the patient, as well as manuscript editing and final manuscript approval. A.J.M. and M.E.S.S. provided a pathologic diagnosis for the case and were involved with manuscript editing and final manuscript approval.

Funding Statement

No funding or grant support was received for this article.

Data Availability Statement

All data that support the findings of this study are included in this article and its online supplementary material. Further inquiries can be made to the corresponding author.