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Review

Conjunctival Squamous Cell Carcinoma: A Clinical Review of Diagnostic Features, Genetics, Current Management and an Update on Targeted and Immunotherapies

by
Murad Mir
1,
Hardeep Singh Mudhar
2,
Mandeep S. Sagoo
3,4,
Stephen Gichuhi
5,6 and
Yamini Krishna
1,7,*
1
Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, Liverpool L7 8TX, UK
2
National Specialist Ophthalmic Pathology Service Sheffield, Department of Histopathology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
3
NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital, University College London Institute of Ophthalmology, London EC1V 2PD, UK
4
Royal London Hospital, London E1 1FR, UK
5
Department of Ophthalmology, Faculty of Health Sciences, University of Nairobi, Nairobi 00100, Kenya
6
Department of Clinical Research, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, University of London, London WC1E 7HT, UK
7
National Specialist Ophthalmic Pathology Service Liverpool, Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Liverpool L7 8YE, UK
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(6), 940; https://doi.org/10.3390/cancers18060940
Submission received: 8 February 2026 / Revised: 1 March 2026 / Accepted: 11 March 2026 / Published: 13 March 2026
(This article belongs to the Special Issue Clinical Research in Ocular Oncology)
Browse Figures
Versions Notes

Simple Summary

Conjunctival squamous cell carcinoma (CSCC) is an eye surface cancer that can cause visual loss mortality. It is rare in temperate climates but is common in the tropics, particularly in India and Africa. Global number of new cases is on the rise. There is no standard treatment for CSCC, and management varies between eye cancer centres. This review aims to present current knowledge of CSSC development, clinical presentation, diagnosis, management and outcomes, and finally summarise novel therapies and future directions for research in CSCC. Immune checkpoint inhibitors, particularly anti-PDL1 therapies, offer a less invasive and globe sparing alternative for advanced SCC treatment. Future directions should focus on earlier detection and personalised approaches which integrate immunotherapy and other targeted treatments.

Abstract

Invasive conjunctival squamous cell carcinoma (CSCC) is an aggressive, ocular surface malignancy. The mean annual age-standardised incidence rate of 0.45 cases per million per year is increasing with an average annual percent rise of 4.5% and occurs mainly in over 65-year-olds in temperate climates but in a younger demographic in the tropics. Invasive CSCC can lead to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. There is no standardised treatment and not all cases are referred to a specialist ocular oncology centre. Recent progress in cancer immunology and genetics has revolutionised the treatment of cutaneous and head and neck SCCs, which share some similarities to invasive CSCC. A better understanding of invasive CSCC and its preinvasive intraepithelial lesions is required to lead to the development of novel targeted and immunotherapies both for local tumour control, globe sparing alternatives and to prevent disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding CSSC, its epidemiology, pathogenesis, presentation, diagnosis, management, recent advances in targeted and immunotherapies for personalised treatment of this disease, and early diagnosis strategies to improve patient outcomes.

1. Introduction

Invasive conjunctival squamous cell carcinoma (CSCC) has a worldwide incidence rate of 0.02 to 3.5 per 100,000, showing increasing incidences in recent decades [1,2,3,4,5]. It typically presents at 60–70 years of age, occurring more commonly in fair-skinned males, of increasing age, and following significant sunlight exposure, but presents at 30–40-year-old females in the tropics [2,4,5,6,7]. It has a high recurrence rate and local spread is common. Distant metastasis occur less commonly [8].
Conjunctival squamous intraepithelial neoplasia (CSIN) [also clinically known as ocular surface squamous neoplasia (OSSN)] is a preinvasive lesion and encompasses a spectrum of intraepithelial squamous dysplasia, from mild to severe, and can progress to in situ squamous carcinoma. Most cases of invasive CSSC develop from CSIN and in situ squamous carcinoma [8,9].
Invasive CSCC usually involves the interpalpebral conjunctiva and limbus (especially the nasal limbus) and can extend onto the cornea. It can also less frequently occur in the caruncle, tarsal, or forniceal conjunctiva. Invasive CSCC presents as a well-demarcated pinkish-grey nodule with keratinisation or ulceration [10]. In the African and Asian population, it often presents with brown surface pigmentation and feeder vessels [11]. It originates from conjunctival epithelium, shows squamous differentiation, and breaches the basement membrane to invade the underlying substantia propria/stroma [6,12,13].
Ultraviolet (UV) radiation and impaired immune surveillance are well known risk factors. Immunosuppression (e.g., due to HIV infection or post-transplant therapy) and oncogenic viruses such as HPV and Epstein–Barr virus (EBV) are important co-factors [2,4,13,14,15,16,17].
Mutations in TP53, TERT, EGFR, titin, HER2 and DNA repair genes and overexpression of matrix metalloproteinases have been identified in invasive CSCC [13,18,19,20,21,22,23,24,25,26,27,28,29].
The treatment for invasive CSCC varies considerably between centres but mainly includes surgical excision and/or adjuvant cryotherapy, topical chemotherapy, brachytherapy, proton beam radiotherapy or external beam radiation. In advanced cases with orbital invasion, orbital exenteration is required [1,6,30,31,32]. Invasive CSCC has a high rate of local recurrence (approx. 10–40%), incidence of up to 24% in regional lymph node metastases and distant metastases of ~6–18% [8,33,34,35,36].
Despite recent successes with targeted and immunotherapies in SCCs elsewhere, data on invasive CSCC treated with similar therapies (EGFR inhibitors, anti-VEGF, anti-PDL1) are promising but limited, often stemming from a single patient or small case series with inoperable or advanced disease prior to surgery [37,38,39,40,41,42,43,44,45,46,47].
This review aims to provide a comprehensive clinical overview of the current understanding of CSCC, its epidemiology, pathogenesis, clinical presentation, diagnosis, and treatments, and explore the recent advances in novel biological therapies and future management.

2. Epidemiology

In situ conjunctival squamous carcinoma is the most common preinvasive ocular surface malignancy and if untreated can progress to invasive CSCC. Its incidence varies geographically: in the UK, it is estimated at 0.4 cases/million/year, whereas both Australia and North America show incidences of 19–35 cases/million/year [48,49]. The mean age-standardised incidence rate worldwide is 0.18 and 0.08 cases/year/100,000 among males and females, respectively. However, the highest age-standardised incidence rate reported from Zimbabwe is 3.4 and 3.0 cases/year/100,000 population for males and females, respectively [2].
Invasive CSCC, although rare compared to SCCs of other sites, is a common ocular surface malignancy. It is the most prevalent ocular surface carcinoma representing approximately 4% to 29% of tumours found in the ocular region, depending on the population or tumour registry records [50,51]. There has been a disconcerting increase in incidence in recent decades with markedly advanced cases presenting following the COVID-19 pandemic. Worldwide the incidence is 2–35 per million [1,2,3,4] occurring more commonly in fair-skinned males (with a ratio of 1.83:1 compared with females), of increasing age, and following significant sunlight exposure [4,5,7]. Ultraviolet (UV) radiation is the strongest environmental etiological factor with incidence rate decreasing by 49% per each ten-degree increase in latitude [3].
In the African continent, the disease mainly affects women at a younger age and is strongly associated with human immunodeficiency virus (HIV) infection. It is variable with human papillomavirus (HPV) infection [2,17,52]. The combination of low latitude and high prevalence of HIV and HPV infections most likely explains the higher incidence of invasive CSCC observed in Africa.
A higher prevalence of CSCC is also seen in patients with impaired immune surveillance, certain autoimmune conditions (atopy, ocular cicatricial pemphigoid and xeroderma pigmentosum) and/or immunosuppression with susceptibility to oncogenic viruses HPV and Epstein–Barr Virus (EBV) [2,13,14,15,16]. Iatrogenic immunosuppression is also a risk factor.

3. Aetiology and Pathogenesis

The aetiology of CSCC is classically understood to be triggered by UV radiation exposure and immunosuppression (due to HIV infection or post organ transplantation) [4]. Mutations in TP53, TERT, EGFR, titin, and DNA repair genes and overexpression of matrix metalloproteinases, Human Epidermal growth factor Receptor 2 (HER2) and programmed death ligand1 (PD-L1) have been identified in invasive CSCC [18,19,20,21,22,23,24,25,26,27,28,29]. However, none of these are pathognomonic, and have been reported in other conjunctival epithelial neoplasms, e.g., pterygia and pingueculae.
The vulnerability of limbal stem cells to the oncogenic effects of UV radiation and certain viruses is postulated to give rise to most invasive CSCC [13]. UVB exposure may induce preinvasive disease by an increase in pyrimidine dimers, which damage DNA and disrupt its repair pathways. Proliferation of unrepaired DNA by continued excess UVB exposure or immunosuppression can manifest CSIN/in situ carcinoma (preinvasive disease) of the conjunctiva [21,53]. UV exposure also activates c-Jun N-terminal kinase 1 (JNK1), which plays a role in tumour development through phosphorylation and oncogenic signal transduction pathways [54].
UVB radiation has also been implicated in upregulated expression of matrix metalloproteinases (MMPs) (particularly MMP-9 and -11) and tissue inhibitors of metalloproteinases (TIMPs) such as TIMP-2 and -3, which promote the tumourigenesis via antiapoptotic, proliferative, invasive and metastatic properties [21].
UV-mediated driver mutations in telomerase reverse transcriptase (TERT) promoter and TP53 have been reported in up to 48% of in situ and invasive CSCC cases. Telomerase overexpression in the conjunctival epithelium increases telomere length with proliferative and anti-apoptotic functions [20,55]. TP53 mutations disrupt pyrimidine dimer repair pathways [53]. TP53 mutations were the most frequent, followed by CDKN2A and PIK3CA [28]. The role of stratifin acting as a p53-mediated inhibitor is also implicated in UV-induced p53 pathogenesis [56].
Titin and EGFR mutations have been reported in both in situ and invasive CSCC. Structural disturbances in nuclear proteins and EGFR translocation from the membrane into the cytoplasm, respectively, are thought to facilitate oncogenic activity [18]. The cytoplasmic staining of EGFR compared with membranous staining has been shown to be an inverse prognostic marker with increased number of orbital exenteration cases [19].
Overexpression of HER2 has been documented in high-grade CSIN and invasive CSCC suggesting its main role in tumour progression rather than early oncogenic initiation. Anti-HER2 therapy may therefore be a considered in select patients with advanced disease when conventional topical or surgical treatments are contraindicated [24]. However, there are no clinical trials investigating the role of anti-HER2 treatment on invasive CSCC.
Increased vascular endothelial growth factor (VEGF) and alpha-B crystallin protein expression has also been shown in invasive CSCC. VEGF is an established potent angiogenic factor and alpha-B crystallin is known to promote angiogenesis as a molecular chaperone of VEGF. Furthermore, treatment of invasive CSCC with topical mitomycin C reduced the expression of both [57].
PD-L1 is expressed in around 47% of CSSC, with higher expression levels correlating with invasive and advanced stage (≥T3) tumours with increased densities of tumour-infiltrating lymphocytes [58,59]. These results are encouraging and may potentially mirror some success in a subset of invasive CSCC as established targeted therapies and PD-L1 targeted treatment blockades used in head and neck and cutaneous SCC.
Since the 1990s, increased incidence rate of invasive CSCC in Africa has been strongly associated with the high prevalence of HIV primarily as well as EBV and HPV (particularly HPV-16 and -18 subtypes, and less commonly HPV-5 and -8) in patients with HIV. HIV has an immunosuppressive effect on the limbal stem cells, making them vulnerable to oncogenic viruses and leading to aggressive invasive CSCC at a younger age with worse prognosis [60]. HPV-driven invasive CSCC in immunocompetent patients has been controversial but a recent meta-analysis concluded an eight-fold increase in development of CSIN or invasive CSCC in HPV-infected patients compared to healthy control subjects [61]. HPV-16 with early gene expression (active HPV mRNA transcripts confirmed via RNAscope) has been implicated in in situ carcinoma in a subset of patients who had atopy [62]. Comparison of these HPV-positive tumours with HPV negative tumours showed that HPV-positive tumours were very often located in an inferomedial location under the lower eyelid, were not leukoplakic and had higher recurrence rates and were resistant to topical chemotherapy, when compared to HPV negative tumours. Another study further confirmed that patients with HPV-positive tumours were significantly younger and had a higher recurrence rate compared to patients with HPV-negative tumours. The HPV-positive tumours showed a non-keratinising histomorphology [63].
Other risk factors include cigarette smoking, chronic inflammation and vitamin A-deficiency. Also there is an increased risk of CSIN/invasive CSCC with autoimmune ocular surface disorders such as ocular cicatricial pemphigoid/mucous membrane pemphigoid, and genetic conditions including and xeroderma pigmentosum [2,14,15]. Please see Figure 1.

4. Clinical Presentation and Assessment

CSIN and invasive CSCC most commonly occur in the interpalpebral conjunctiva and limbus (usually nasal limbus). Invasive CSCC frequently invades into the cornea. The caruncle, tarsal, or forniceal conjunctiva are less frequently involved. Advanced or recurrent invasive CSCC may extend to the tarsal and forniceal conjunctiva. The latter locations are also seen in immunosuppressed/immunocompromised patients and in those with atopy-associated squamous carcinoma [62].
Most CSIN lesions appear as unilateral, gelatinous and are minimally elevated but can also be papilliform or a leukoplakic plaque (due to keratinisation). However, intraepithelial lesions can be clinically indistinguishable from the invasive disease and hence histopathological diagnosis remains the ‘gold’ standard. Invasive CSCC usually presents as a unilateral, elevated, immobile, well-demarcated pearly pink-to-grey nodule, which can be ulcerated, leukoplakic, gelatinous, or papilliform. They often have feeder blood vessels and intrinsic vasculature (Figure 2). Pigmentation is variable, depending on the Fitzpatrick skin type. Patients may present on noticing a mass with/without pigmentation on their eye but can also have significant visual morbidities, such as irritation/burning with redness and reflex tearing, dry eye, pain, vision disturbance, double vision or even vision loss [35,36,64,65,66,67].
Differential diagnoses of invasive CSCC, include sebaceous cell carcinoma, naevus, melanoma, lymphoma, or eyelid basal cell or squamous cell carcinoma invading the conjunctiva. CSIN can develop in pinguecula, pterygium, viral squamous papillomas and other inflammatory conjunctival conditions. Diagnosis is confirmed on histopathological assessment. Histological assessment in a specialist centre regularly reporting ophthalmic specimens is recommended for accurate diagnosis and grading [8,50,68].
Clinical examination involves slit lamp biomicroscopy and regular colour photograph-documentation of the anterior segment (including with eversion of eyelids). Toluidine blue (0.05%) vital stain has been shown to be a good screening tool for OSSN/CSIN and can assist in identifying the tumour borders, but is not in widespread use due to high false positive rates [69]. Anterior segment optical coherence tomography (AS-OCT) has been used to distinguish OSSN from other conjunctival lesions. In OSSN/CSIN, the AS-OCT features are those of a hyperreflective lesion that has thickened epithelium, and an abrupt transition between normal and abnormal tissue [70]. However, squamous metaplasia is indistinguishable from OSSN on AS-OCT, highlighting the need for biopsy and histopathological analysis of lesions especially where there is overlap [71]. Other modalities such as ultrasound biomicroscopy and confocal microscopy can be helpful in clinical assessment and when looking for intraocular invasion. Magnetic resonance imaging is required to assess orbital invasion. Diffusion and perfusion-weighted MR imaging can help in differentiating invasive CSCC from other eyelid masses [70,72,73,74].

5. Histomorphological Features

Macroscopically CSIN lesions look as flat, cream/white epithelial thickenings/plaques. They may also be papillomatous. Invasive CSCC are gelatinous grey/white nodular, papilliform or ulcerated/erythematous masses. Lesions in the tropics can be brown and have a lot more surface keratinisation [11,35,36]. Depending on the specimen type, invasion of the cornea and other ocular structures and/or orbital soft tissue can be seen on macroscopic examination.
Microscopically CSIN lesions show a range of epithelial dysplasia (cytological atypia, architectural atypia and lack of maturation), which is graded mild (confined to lower third of epithelium), moderate (involves up to middle third), and severe (extends to upper third but surface differentiation preserved). In situ squamous carcinoma shows full-thickness epithelial dysplasia. CSIN, including in situ carcinoma, do not breach the epithelial basement membrane (Figure 3). At low magnification, an abrupt demarcation with the background normal conjunctival epithelium, and with goblet cell loss can be appreciated. At higher magnification, cytological atypia comprises nuclear enlargement and pleomorphism with increased nuclear-to-cytoplasmic ratio, hyperchromatic chromatin and prominent nucleoli. Abnormal mitotic figures are seen at varying levels of the epithelium. Dyskeratosis and apoptotic cells may also be present. Architecturally, the epithelium shows abnormal stratification with loss of normal polarity, and surface keratosis or parakeratosis. The underlying substantia propria/stroma often shows elastotic degeneration from chronic sun exposure. UV-associated cases can resemble skin actinic keratoses [35,36,75,76,77,78,79,80,81,82,83]. High-risk HPV-associated cases usually lack surface keratinisation or parakeratosis, show full thickness epithelial dysplasia and have a basaloid appearance [62,63].
Invasive CSCC usually arises from conjunctival in situ squamous carcinoma but breaches the basement membrane invading the underlying stroma (Figure 3). The invasive carcinoma can be infiltrative or exhibit pushing borders and show stromal desmoplasia. Perineural and lymphovascular invasion may be present. Histological classification of invasive CSCC includes: conventional (showing various degrees of keratinisation); basaloid (poorly differentiated with pleomorphic cells with scant basophilic cytoplasm); spindle cell (poorly differentiated with pleomorphic spindled cells); pigmented (CSCC with melanosis and melanophages); acantholytic (acantholytic and dyskeratotic cells with apoptotic debris); and with mucinous differentiation (intracytoplasmic and extracellular mucin but no true gland formation, overlying in situ component with mucinous differentiation). Immunohistochemistry is usually only required for diagnosis in poorly differentiated tumours, such as basaloid or spindle cell subtypes. For intraepithelial lesions, p53 is expressed in the dysplastic cells. In poorly differentiated invasive carcinomas, CSCC is positive for broad-spectrum/pan and high molecular weight cytokeratins (e.g., AE1/3 or MNF116 and 34βE12 or CK5/6, respectively). Diffuse nuclear and cytoplasmic ‘block-like’ p16 positivity can be predictive of high-risk HPV infection but requires molecular techniques to confirm HPV DNA or RNA presence by either polymerase chain reaction or in situ hybridisation [35,36,62,63,65,69,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91].
In situ conjunctival squamous carcinoma and invasive CSSC are staged by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) T (tumour size), N (nodal spread), and M (metastasis) eighth edition classification system, which has been validated for the risk of tumour recurrence, development of metastasis and survival [92,93].

6. Treatment and Prognosis

There is no standard of care treatment and little trial evidence for the therapies in use for in situ conjunctival squamous carcinoma or invasive CSCC; consequently, management varies considerably between ophthalmic and specialised ocular oncology centres. For localised, solitary tumours, this includes surgical excision (wide local) +/− amniotic membrane allograft and +/− adjuvant cryotherapy, topical chemotherapy (mitomycin C, 5-fluorouracil or interferon alpha-2b), radiotherapy (brachytherapy, proton beam or photon external beam), enucleation, or radical orbital exenteration for advanced cases with local tissue invasion [6,12,30,31,32,94].
Surgical excision with a ‘no touch’ technique and wide margins of smaller localised tumours (<5 mm) is the most frequent approach. Alcohol application allows resection of the corneal component by corneal epitheliectomy. Adjunct cryotherapy usually applied in double- or triple-freeze–thaw cycles to the margins and base of the tumour after resection limits spread. In diffuse recurrences, for example of the tarsal conjunctiva, cryotherapy spray can be applied to limit regrowth. Eyes with intraocular invasion may be salvaged with localised radiotherapy, such as proton beam or plaque brachytherapy. If tumour control cannot be achieved, enucleation may become necessary. For advanced cases of invasive CSCC with periocular and orbital invasion, radical orbital exenteration is performed, which leads to considerable facial disfigurement [95,96,97].
Topical chemotherapy agents, such as interferon alpha 2b (IFNa-2b), 5-fluorouracil (5-FU), or mitomycin C (MMC), can be used as adjuncts to surgery or even as monotherapies in certain cases. IFNa-2b has immunomodulatory mechanisms and inhibits cell proliferation and can be administered as single subconjunctival injection or a regime of topical eye drops. MMC utilises its DNA alkylating properties to inhibit RNA synthesis and tumour growth. Antimetabolite 5-FU blocks DNA synthesis by inhibiting thymidylate sulphate [96,97,98,99,100]. In a multicentre, randomised, placebo-controlled trial, Gichuhi et al. showed that a surgical ‘no touch’ technique together with 5-FU drops four times a day for 4 weeks reduced recurrence at 1 year from 36% to 11% [101].
The HPV vaccine has been used to treat recalcitrant conjunctival in situ squamous carcinoma [102]. In this case, four intramuscular doses of a 9-valent HPV vaccine resulted in a dramatic reduction in the size of the tumour, though not full resolution. This approach has also been used in conjunctival papillomas [103,104].
Visudyne photodynamic therapy has also been tried in conjunctival in situ squamous carcinoma, though with higher rates of recurrence than excision. Its use is limited to cases that cannot have surgical excision for relatively localised disease [105]. Recently, a laser-activated anticancer virus–drug particle conjugate has been developed for small uveal melanomas (belzupacap sarotalocan or AU-011; Aura Biosciences, Boston, MA, USA). Such an approach for localised treatment of CSIN/in situ and invasive CSSC is an attractive proposition.
Radiotherapy options include brachytherapy (beta radiation using strontium-90 or ruthenium-106; gamma radiation using iodine-125) directly on the tumour or surgical bed post excision; proton bean radiotherapy (high precision delivery using Bragg peak, 48–60 Gy); gamma knife stereotactic radiosurgery; or external beam radiation. These have been used to preserve the eye, periocular tissues and ocular function; as primary treatment for unresectable invasive CSCC, patients not suitable for surgery, or post-surgery for positive/narrow margins or recurrent disease [106,107,108,109].
Postoperative complications include scarring, symblepharon formation, limbal stem cell failure, ulceration/non-healing defects, glaucoma, cataract and vision loss. Complication rates and risk of recurrence are high (5–56% recurrence; most within the first year but even after 5 years), especially in large tumours and cases with positive surgical margins, warranting close long-term follow up. Lymph node metastases occur in ~2–24% and usually involve preauricular, parotid, submandibular and/or cervical nodes, depending on invasive CSCC location. Distant metastasis may also involve the lungs, bone and spleen and brain (~6.2–18%). Risk factors for metastasis include tumour thickness, histological poor differentiation and spindle cell carcinoma subtype, and orbital invasion/high tumour staging. Poor prognostic indicators include high-staged tumours (T3/T4), positive surgical margins and nodal metastases. Overall 5-year disease-related survival in localised invasive CSCC reported to be as high as 95% but 70% in advanced (T3/T4) cases. The overall risk of tumour-related death ranges from 2 to 5% [8,32,33,34,35,36,110,111,112,113].
The use of genetics for prognostication in invasive CSCC is currently limited. However, advances in characterising invasive CSCC molecular drivers are offering insight into potential targeted therapies already in use of other cancer types. Targeted and immunotherapies have recently become promising options for advanced CSCC as an alternative to orbital exenteration although data are limited, with only those from small case series or single case studies in patients with inoperable disease or as first-line therapy prior surgery in advanced cases [37,38,39,40,41,42,43,44]. A summary of immune checkpoint inhibitors (ICIs), namely PDL-1, is presented in Table 1.
Given the overexpression of EGFR, its role in prognosis, and the success of EGFR inhibitors in treating head and neck SCC, El-Sawy et al. reported significant tumour shrinkage in two patients treated with EGFR inhibitors for advanced orbital SCC who had refused orbital exenteration [19,45]. Small clinical studies have investigated the use of anti-VEGF agents, such as bevacizumab and ranibizumab, given VEGF established role in angiogenesis and tumourigenesis [47,114,115]. Clinical studies on targeted therapies in CSCC patients are summarised in Table 2.
Anti-VEGF and EGFR-targeted approaches show biological activity in a subset of patients but cannot currently be considered standard of care and are best reserved for clinical trials or highly selected refractory cases.
In summary, immune checkpoint inhibitors and targeted therapies have shown very encouraging responses in advanced CSCC; however, the current evidence remains limited and of low level. All data come from small case series or isolated case reports. There are no prospective or randomised controlled CSCC-specific trials. There is clinical heterogeneity exists across cohorts (including CSCC, periocular and orbital SCC) hence limiting CSCC-specific conclusions. Response assessment (Response Evaluation Criteria in Solid Tumours/RECIST criteria) is inconsistent and not standardised, and follow-up duration is generally short, precluding robust evaluation of long-term disease control or survival benefit at present. Toxicity reporting is similarly inconsistent.

7. Future Direction and Conclusions

The progress in cancer genetics and immunology presents exciting new frontiers for better understanding CSCC pathogenesis. Insight into the molecular drivers of disease development and its integration with clinical and histomorphological evaluation will allow earlier diagnosis, improve risk stratification and prognostication, and identify patients for specific therapies (i.e., ‘personalised/precision medicine’). This will further enable the development of clear management guidelines and enrolment into targeted therapies earlier than current practice, facilitating improved treatment outcomes and reduce risk of metastatic disease. Other novel methods through biotechnology and bioengineering, such as biosensors and infrared biomarkers, offer exciting developments in non-invasive methods of earlier diagnosis of preinvasive disease and prognostic prediction. Innovative drug delivery systems are being developed to achieve sustained, localised drug release to minimise complication rates and improve patient compliance and treatment outcomes.
In conclusion, invasive CSCC is an ocular surface cancer with increasing global incidence. Multidisciplinary care in a specialist centre for ocular cancers is required for prompt accurate diagnosis, staging and management. Given its rarity in comparison to other SCCs, international multicentre collaboration is pivotal to obtain sufficient numbers in order to progress translational research and enlist patients into clinical trials

Author Contributions

Conceptualization, Y.K.; writing—original draft preparation, M.M. and Y.K.; writing—review and editing, M.M., Y.K., H.S.M., M.S.S. and S.G.; supervision, Y.K., H.S.M., M.S.S. and S.G. All authors have read and agreed to the published version of the manuscript.

Funding

The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank the clinical imaging team in St. Paul’s Eye Unit, Liverpool, for providing the colour anterior segment photographs.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Yang, J.; Foster, C.S. Squamous Cell Carcinoma of the Conjunctiva. Int. Ophthalmol. Clin. 1997, 37, 73–85. [Google Scholar] [CrossRef] [PubMed]
  2. Gichuhi, S.; Sagoo, M.S.; Weiss, H.A.; Burton, M.J. Epidemiology of ocular surface squamous neoplasia in Africa. Trop. Med. Int. Health 2013, 18, 1424–1443. [Google Scholar] [CrossRef] [PubMed]
  3. Newton, R.; Ferlay, J.; Reeves, G.; Beral, V.; Parkin, D.M. Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. Lancet 1996, 347, 1450–1451. [Google Scholar] [CrossRef]
  4. Sun, E.C.; Fears, T.R.; Goedert, J.J. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol. Biomark. Prev. 1997, 6, 73–77. [Google Scholar]
  5. Darwich, R.; Ghazawi, F.M.; Le, M.; Rahme, E.; Alghazawi, N.; Zubarev, A.; Moreau, L.; Sasseville, D.; Jr, M.N.B.; Litvinov, I.V. Epidemiology of invasive ocular surface squamous neoplasia in Canada during 1992–2010. Br. J. Ophthalmol. 2020, 104, 1368–1372. [Google Scholar] [CrossRef]
  6. Yin, V.T.; Merritt, H.A.; Sniegowski, M.; Esmaeli, B. Eyelid and ocular surface carcinoma: Diagnosis and management. Clin. Dermatol. 2015, 33, 159–169. [Google Scholar] [CrossRef]
  7. Emmanuel, B.; Ruder, E.; Lin, S.W.; Abnet, C.; Hollenbeck, A.; Mbulaiteye, S. Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-AARP Diet and Health Study. Ecancermedicalscience 2012, 6, 254. [Google Scholar]
  8. McKelvie, P.A.; Daniell, M.; McNab, A.; Loughnan, M.; Santamaria, J.D. Squamous cell carcinoma of the conjunctiva: A series of 26 cases. Br. J. Ophthalmol. 2002, 86, 168–173. [Google Scholar] [CrossRef]
  9. Margo, C.E.; White, A.A. Ocular surface squamous neoplasia: Terminology that is conceptually friendly but clinically perilous. Eye 2014, 28, 507–509. [Google Scholar] [CrossRef]
  10. Donaldson, M.J.; Sullivan, T.J.; Whitehead, K.J.; Williamson, R.M. Squamous cell carcinoma of the eyelids. Br. J. Ophthalmol. 2002, 86, 1161–1165. [Google Scholar] [CrossRef]
  11. Gichuhi, S.; Macharia, E.; Kabiru, J.; Zindamoyen, A.M.; Rono, H.; Ollando, E.; Wanyonyi, L.; Wachira, J.; Munene, R.; Onyuma, T.; et al. Clinical Presentation of Ocular Surface Squamous Neoplasia in Kenya. JAMA Ophthalmol. 2015, 133, 1305–1313. [Google Scholar] [CrossRef] [PubMed]
  12. Gichuhi, S.; Sagoo, M.S. Squamous cell carcinoma of the conjunctiva. Commun. Eye Health 2016, 29, 52–53. [Google Scholar]
  13. Gichuhi, S.; Ohnuma, S.; Sagoo, M.S.; Burton, M.J. Pathophysiology of ocular surface squamous neoplasia. Exp. Eye Res. 2014, 129, 172–182. [Google Scholar] [CrossRef]
  14. Kaliki, S.; Vempuluru, V.S.; Ghose, N.; Gunda, S.; Vithalani, N.M.; Sultana, S.; Ganguly, A.; Bejjanki, K.M.; Jakati, S.; Mishra, D.K. Ocular surface squamous neoplasia in India: A study of 438 patients. Int. Ophthalmol. 2022, 42, 1915–1926. [Google Scholar] [CrossRef]
  15. Choi, C.J.; Jakobiec, F.A.; Zakka, F.R.; Foster, C.S.; Chodosh, J.; Freitag, S.K. Conjunctival Squamous Cell Neoplasia Associated With Ocular Cicatricial Pemphigoid. Ophthalmic Plast. Reconstr. Surg. 2017, 33, e157–e160. [Google Scholar] [CrossRef]
  16. Galati, L.; Combes, J.D.; Gupta, P.; Sen, R.; Robitaille, A.; Brancaccio, R.N.; Atsou, K.; Cuenin, C.; McKay-Chopin, S.; Tornesello, M.L.; et al. Detection of a large spectrum of viral infections in conjunctival premalignant and malignant lesions. Int. J. Cancer 2020, 147, 2862–2870. [Google Scholar] [CrossRef]
  17. Hämmerl, L.; Ferlay, J.; Borok, M.; Carrilho, C.; Parkin, D.M. The burden of squamous cell carcinoma of the conjunctiva in Africa. Cancer Epidemiol. 2019, 61, 150–153. [Google Scholar] [PubMed]
  18. Djulbegovic, M.B.; Uversky, V.N.; Karp, C.L.; Harbour, J.W. Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia. Int. J. Biol. Macromol. 2022, 195, 93–101. [Google Scholar] [CrossRef]
  19. Sakai, A.; Tagami, M.; Kakehashi, A.; Katsuyama-Yoshikawa, A.; Misawa, N.; Wanibuchi, H.; Azumi, A.; Honda, S. Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment. PLoS ONE 2020, 15, e0238120. [Google Scholar] [CrossRef]
  20. Scholz, S.L.; Thomasen, H.; Reis, H.; Möller, I.; Darawsha, R.; Müller, B.; Dekowski, D.; Sucker, A.; Schilling, B.; Schadendorf, D.; et al. Frequent TERT Promoter Mutations in Ocular Surface Squamous Neoplasia. Investig. Ophthalmol. Vis. Sci. 2015, 56, 5854–5861. [Google Scholar] [CrossRef] [PubMed]
  21. Ng, J.; Coroneo, M.T.; Wakefield, D.; Di Girolamo, N. Ultraviolet Radiation and the Role of Matrix Metalloproteinases in the Pathogenesis of Ocular Surface Squamous Neoplasia. Investig. Ophthalmol. Vis. Sci. 2008, 49, 5295–5306. [Google Scholar] [CrossRef]
  22. Ateenyi-Agaba, C.; Dai, M.; Le Calvez, F.; Katongole-Mbidde, E.; Smet, A.; Tommasino, M.; Franceschi, S.; Hainaut, P.; Weiderpass, E. TP53 mutations in squamous-cell carcinomas of the conjunctiva: Evidence for UV-induced mutagenesis. Mutagenesis 2004, 19, 399–401. [Google Scholar] [CrossRef]
  23. Mahale, A.; Alkatan, H.; Alwadani, S.; Othman, M.; Suarez, M.J.; Price, A.; Al-Hussain, H.; Jastaneiah, S.; Yu, W.; Maktabi, A.; et al. Altered gene expression in conjunctival squamous cell carcinoma. Mod. Pathol. 2016, 29, 452–460. [Google Scholar] [CrossRef]
  24. de Alba Graue, P.G.; Esposito, E.; Zoroquiain, P.; Beatriz, A.; Dias, T.; Burnier, M. HER2 as a possible therapeutic target in squamous cell carcinoma of the conjunctiva. Ann. Eye Sci. 2018, 3, AB079. [Google Scholar] [CrossRef]
  25. Asnaghi, L.; Alkatan, H.; Mahale, A.; Othman, M.; Alwadani, S.; Al-Hussain, H.; Jastaneiah, S.; Yu, W.; Maktabi, A.; Edward, D.P.; et al. Identification of multiple DNA copy number alterations including frequent 8p11.22 amplification in conjunctival squamous cell carcinoma. Investig. Ophthalmol. Vis. Sci. 2014, 55, 8604–8613. [Google Scholar] [CrossRef] [PubMed]
  26. Starita, N.; Buonaguro, L.; Buonaguro, F.M.; Tornesello, M.L. Telomerase promoter mutations in human immunodeficiency virus-related conjunctiva neoplasia. J. Transl. Med. 2018, 16, 77. [Google Scholar] [CrossRef] [PubMed]
  27. Lin, S.Y.; Liao, S.L.; Hong, J.B.; Chu, C.Y.; Sheen, Y.S.; Jhuang, J.Y.; Tsai, J.-H.; Liau, J.-Y. TERT promoter mutations in periocular carcinomas: Implications of ultraviolet light in pathogenesis. Br. J. Ophthalmol. 2016, 100, 274–277. [Google Scholar] [CrossRef] [PubMed]
  28. de la Vega, L.L.; Bick, N.; Hu, K.; Rahrig, S.E.; Silva, C.D.; Matayoshi, S.; Picciarelli, P.; Wang, X.; Sugar, A.; Soong, H.K.; et al. Invasive squamous cell carcinomas and precursor lesions on UV-exposed epithelia demonstrate concordant genomic complexity in driver genes. Mod. Pathol. 2020, 33, 2280–2294. [Google Scholar] [CrossRef]
  29. Di Girolamo, N.; Atik, A.; McCluskey, P.J.; Wakefield, D. Matrix metalloproteinases and their inhibitors in squamous cell carcinoma of the conjunctiva. Ocul. Surf. 2013, 11, 193–205. [Google Scholar] [CrossRef]
  30. Kenawy, N.; Garrick, A.; Heimann, H.; Coupland, S.E.; Damato, B.E. Conjunctival squamous cell neoplasia: The Liverpool Ocular Oncology Centre experience. Graefes Arch. Clin. Exp. Ophthalmol. 2015, 253, 143–150. [Google Scholar] [CrossRef]
  31. Yousef, Y.A.; Finger, P.T. Squamous carcinoma and dysplasia of the conjunctiva and cornea: An analysis of 101 cases. Ophthalmology 2012, 119, 233–240. [Google Scholar]
  32. Miller, C.V.; Wolf, A.; Klingenstein, A.; Decker, C.; Garip, A.; Kampik, A.; Hintschich, C. Clinical outcome of advanced squamous cell carcinoma of the conjunctiva. Eye 2014, 28, 962–967. [Google Scholar] [CrossRef]
  33. Faustina, M.; Diba, R.; Ahmadi, M.A.; Esmaeli, B. Patterns of regional and distant metastasis in patients with eyelid and periocular squamous cell carcinoma. Ophthalmology 2004, 111, 1930–1932. [Google Scholar] [CrossRef] [PubMed]
  34. Chauhan, S.; Sen, S.; Sharma, A.; Tandon, R.; Kashyap, S.; Pushker, N.; Vanathi, M.; Sharma, N. American Joint Committee on Cancer Staging and clinicopathological high-risk predictors of ocular surface squamous neoplasia: A study from a tertiary eye center in India. Arch. Pathol. Lab. Med. 2014, 138, 1488–1494. [Google Scholar] [CrossRef]
  35. Yamamoto, H.; Mudhar, H.S.; Cherepanoff, S.; Eberhart, C.G.; Heindl, L.M.; Ferreira, T. Conjunctival squamous cell carcinoma. In WHO Classification of Tumours: Eye and Orbit Tumours, 5th ed.; Board WCoTE, Ed.; WHO Classification of Tumours Series; International Agency for Research on Cancer: Lyon, France, 2025; Volume 13. [Google Scholar]
  36. Heegaard, S.; Alkatan, H.; Eberhart, C.G.; M., H.L. Conjunctival squamous intraepithelial neoplasia. In WHO Classification of Tumours: Eye and Orbit Tumours, 5th ed.; Board WCoTE, Ed.; WHO Classification of Tumours Series; International Agency for Research on Cancer: Lyon, France, 2025; Volume 13. [Google Scholar]
  37. Demirci, H.; Elner, V.M.; Demirci, F.Y.; Robinson, D.R.; Chinnaiyan, A.; Schlachter, D.; Joseph, S.; Worden, F. Immunotherapy for Conjunctival Squamous Cell Carcinoma with Orbital Extension. Ophthalmology 2021, 128, 801–804. [Google Scholar] [CrossRef]
  38. Demirci, H.; Vo, J.N.; Wu, Y.-M.; Elner, V.; Chinnaiyan, A.M.; Robinson, D.; Demirci, F.Y. Next-Generation Sequencing-Based Molecular Profiling of Conjunctival Squamous Cell Carcinoma and Its Potential Application for Therapy. Ophthalmol. Sci. 2025, 5, 100801. [Google Scholar] [CrossRef]
  39. Kanda, M.; Jayawickrema, N.; Davagnanam, I.; Samia-Aly, E.; Gupta, T.; Daniel, C. Cemiplimab in advanced periocular conjunctival and cutaneous squamous cell carcinoma: A United Kingdom case series. Orbit 2025, 45, 63–73. [Google Scholar] [CrossRef]
  40. Esmaeli, B.; Fan, J.; Goldberg, H.; Lu, T.; Gross, N.D.; Akhave, N.; Sousa, L.G.; Ferrarotto, R. Immune checkpoint inhibitors with or without chemotherapy for orbital, conjunctival, and ocular adnexal squamous cell carcinoma. Can. J. Ophthalmol. 2025, 60, e38–e51. [Google Scholar]
  41. Azad, A.D.M.; Zhang, J.J.B.; Emerick, K.S.; Shalhout, S.Z.; Kaufman, H.L.; Miller, D.M.M.; Lee, N.G.; Yoon, M.K.; Freitag, S.K.; Stagner, A.M.; et al. Immunotherapy for Advanced Conjunctival Squamous Cell Carcinoma: Treatment Failures. Ophthalmic Plast. Reconstr. Surg. 2025, 41, 646–650. [Google Scholar] [CrossRef] [PubMed]
  42. Ceylanoglu, K.S.; Eisenberg, A.; Worden, F.P.; Elner, V.M.; Demirci, H. Use of Cemiplimab, an Immune Checkpoint Inhibitor for Conjunctival Intraepithelial Neoplasia. Cornea 2024, 43, 528–530. [Google Scholar] [CrossRef] [PubMed]
  43. Steren, B.B.; Burtness, B.; Bhatia, A.M.; Demirci, H.; Shinder, R.; Yoo, D.; Tse, B.; Pointdujour-Lim, R. Cemiplimab for Orbital Squamous Cell Carcinoma in 11 Cases. Ophthalmic Plast. Reconstr. Surg. 2022, 38, 496–502. [Google Scholar] [CrossRef]
  44. Hoffmann, M.; Schardt, J.; Ionescu, C.; Wolf-Schnurrbusch, U.E.; Wagner, F.; Dettmer, M.S.; Olariu, R.; Özdemir, B.C. Long lasting response to anti-PD-1 therapy of recurrent conjunctival squamous cell carcinoma-A case report and systematic review of the literature. Curr. Probl. Cancer Case Rep. 2021, 4, 100088. [Google Scholar] [CrossRef]
  45. El-Sawy, T.; Sabichi, A.L.; Myers, J.N.; Kies, M.S.; William, W.N.; Glisson, B.S.; Lippman, S.; Esmaeli, B. Epidermal Growth Factor Receptor Inhibitors for Treatment of Orbital Squamous Cell Carcinoma. Arch. Ophthalmol. 2012, 130, 1608–1611. [Google Scholar] [CrossRef]
  46. Youn, G.M.; Case, A.G.; Jarin, T.; Li, B.; Swarup, A.; Naranjo, A.; Bou-Khalil, C.; Yao, J.; Zhou, Q.; Hom, M.E.; et al. The Use of Panitumumab-IRDye800CW in a Novel Murine Model for Conjunctival Squamous Cell Carcinoma. Transl. Vis. Sci. Technol. 2022, 11, 23. [Google Scholar] [CrossRef] [PubMed]
  47. Finger, P.T.; Chin, K.J. Refractory Squamous Cell Carcinoma of the Conjunctiva Treated With Subconjunctival Ranibizumab (Lucentis): A Two-Year Study. Ophthalmic Plast. Reconstr. Surg. 2012, 28, 85–89. [Google Scholar] [CrossRef] [PubMed]
  48. Pe’er, J. Ocular surface squamous neoplasia. Clin. Ophthalmic Oncol. 2005, 18, 27–49. [Google Scholar] [CrossRef] [PubMed]
  49. Turner, H.C.; Budak, M.T.; Akinci, M.A.; Wolosin, J.M. Comparative analysis of human conjunctival and corneal epithelial gene expression with oligonucleotide microarrays. Investig. Ophthalmol. Vis. Sci. 2007, 48, 2050–2061. [Google Scholar] [CrossRef]
  50. Mehta, M.; Fay, A. Squamous cell carcinoma of the eyelid and conjunctiva. Int. Ophthalmol. Clin. 2009, 49, 111–121. [Google Scholar] [CrossRef]
  51. Shields, C.L.; Demirci, H.; Karatza, E.; Shields, J.A. Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology 2004, 111, 1747–1754. [Google Scholar] [CrossRef]
  52. Ateenyi-Agaba, C. Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda. Lancet 1995, 345, 695–696. [Google Scholar] [CrossRef]
  53. Daya-Grosjean, L.; Dumaz, N.; Sarasin, A. The specificity of p53 mutation spectra in sunlight induced human cancers. J. Photochem. Photobiol. B 1995, 28, 115–124. [Google Scholar] [CrossRef] [PubMed]
  54. Dérijard, B.; Hibi, M.; Wu, I.H.; Barrett, T.; Su, B.; Deng, T.; Karin, M.; Davis, R.J. JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994, 76, 1025–1037. [Google Scholar] [CrossRef]
  55. Blackburn, E.H. Telomeres and telomerase: Their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005, 579, 859–862. [Google Scholar] [CrossRef]
  56. Chauhan, S.; Sen, S.; Chauhan, S.S.; Pushker, N.; Tandon, R.; Kashyap, S.; Vanathi, M.; Bajaj, M.S. Stratifin in ocular surface squamous neoplasia and its association with p53. Acta Ophthalmol. 2021, 99, e1483–e1491. [Google Scholar] [CrossRef]
  57. Dong, Z.; Kase, S.; Ando, R.; Fukuhara, J.; Kinoshita, S.; Dong, Y.; Takashina, S.; Kanda, A.; Noda, M.; Noda, K.; et al. Expression of αB-crystallin and vascular endothelial growth factor in conjunctival squamous cell carcinoma. Anticancer Res. 2013, 33, 3745–3751. [Google Scholar]
  58. Nagarajan, P.; El-Hadad, C.; Gruschkus, S.K.; Ning, J.; Hudgens, C.W.; Sagiv, O.; Gross, N.; Tetzlaff, M.T.; Esmaeli, B. PD-L1/PD1 Expression, Composition of Tumor-Associated Immune Infiltrate, and HPV Status in Conjunctival Squamous Cell Carcinoma. Investig. Ophthalmol. Vis. Sci. 2019, 60, 2388–2398. [Google Scholar] [CrossRef]
  59. Slater, N.A.; Googe, P.B. PD-L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis. J. Cutan. Pathol. 2016, 43, 663–670. [Google Scholar] [CrossRef]
  60. Muchengeti, M.; Bohlius, J.; Dhokotera, T.G. Conjunctival cancer in people living with HIV. Curr. Opin. Infect. Dis. 2021, 34, 1–7. [Google Scholar] [CrossRef] [PubMed]
  61. Ramberg, I.; Møller-Hansen, M.; Toft, P.B.; Funding, M.; Heegaard, S. Human papillomavirus infection plays a role in conjunctival squamous cell carcinoma: A systematic review and meta-analysis of observational studies. Acta Ophthalmol. 2021, 99, 478–488. [Google Scholar] [CrossRef]
  62. Griffin, H.; Mudhar, H.S.; Rundle, P.; Shiraz, A.; Mahmood, R.; Egawa, N.; Quint, W.; Rennie, I.G.; Doorbar, J. Human papillomavirus type 16 causes a defined subset of conjunctival in situ squamous cell carcinomas. Mod. Pathol. 2020, 33, 74–90. [Google Scholar] [CrossRef] [PubMed]
  63. Ramberg, I.; Toft, P.B.; Georgsen, J.B.; Siersma, V.D.; Funding, M.; Jensen, D.H.; von Buchwald, C.; Heegaard, S. Conjunctival intraepithelial neoplasia and carcinoma: Distinct clinical and histological features in relation to human papilloma virus status. Br. J. Ophthalmol. 2021, 105, 878–883. [Google Scholar] [CrossRef] [PubMed]
  64. Cervantes, G.; Rodríguez, A.A., Jr.; Leal, A.G. Squamous cell carcinoma of the conjunctiva: Clinicopathological features in 287 cases. Can. J. Ophthalmol. 2002, 37, 14–19; discussion 9–20. [Google Scholar] [CrossRef]
  65. Krachmer, J.H.; Mannis, M.J.; Holland, E.J. Cornea: Fundamentals, Diagnosis, and Management. Am. Orthopt. J. 2011, 61, 147. [Google Scholar] [CrossRef]
  66. Nelson, K.D.; McSoley, J.J. Clinical findings and management of conjunctival intraepithelial neoplasia. Optometry 2011, 82, 15–21. [Google Scholar] [CrossRef]
  67. Shields, C.L.; Shields, J.A. Tumors of the conjunctiva and cornea. Surv. Ophthalmol. 2004, 49, 3–24. [Google Scholar] [CrossRef]
  68. Kwitko, M.L.; Boniuk, M.; Zimmerman, L.E. Eyelid Tumors With Reference to Lesions Confused With Squamous Cell Carcinoma: I. Incidence and Errors in Diagnosis. Arch. Ophthalmol. 1963, 69, 693–697. [Google Scholar] [CrossRef]
  69. Gichuhi, S.; Macharia, E.; Kabiru, J.; Zindamoyen, A.M.B.; Rono, H.; Ollando, E.; Wanyonyi, L.; Wachira, J.; Munene, R.; Onyuma, T.; et al. Toluidine blue 0.05% vital staining for the diagnosis of ocular surface squamous neoplasia in Kenya. JAMA Ophthalmol. 2015, 133, 1314–1321. [Google Scholar] [CrossRef]
  70. Thomas, B.J.; Galor, A.; Nanji, A.A.; El Sayyad, F.; Wang, J.; Dubovy, S.R.; Joag, M.G.; Karp, C.L. Ultra high-resolution anterior segment optical coherence tomography in the diagnosis and management of ocular surface squamous neoplasia. Ocul. Surf. 2014, 12, 46–58. [Google Scholar] [CrossRef]
  71. Stevens, S.M.; Reyes-Capo, D.P.; Patel, U.; Choudhary, A.; Khzam, R.A.; Tang, V.; Galor, A.M.; Karp, C.L.; Dubovy, S. Clinical and Optical Coherence Tomography Comparison Between Ocular Surface Squamous Neoplasia and Squamous Metaplasia. Cornea 2023, 42, 429–434. [Google Scholar] [CrossRef]
  72. Xu, Y.; Zhou, Z.; Wang, M.; Liu, F.; Qu, H.; Hong, J. The clinical value of in vivo confocal microscopy for diagnosis of ocular surface squamous neoplasia. Eye 2012, 26, 781–787. [Google Scholar] [CrossRef] [PubMed]
  73. Liu, Z.; Karp, C.L.; Galor, A.; Al Bayyat, G.J.; Jiang, H.; Wang, J. Role of optical coherence tomography angiography in the characterization of vascular network patterns of ocular surface squamous neoplasia. Ocul. Surf. 2020, 18, 926–935. [Google Scholar] [CrossRef]
  74. Karp, C.L.; Mercado, C.; Venkateswaran, N.; Ruggeri, M.; Galor, A.; Garcia, A.; Sivaraman, K.R.; Fernandez, M.P.; Bermudez, A.; Dubovy, S.R. Use of High-Resolution Optical Coherence Tomography in the Surgical Management of Ocular Surface Squamous Neoplasia: A Pilot Study. Am. J. Ophthalmol. 2019, 206, 17–31. [Google Scholar] [CrossRef]
  75. Jaworski, A.; Wolffsohn, J.S.; Napper, G.A. Detection, aetiology and management of conjunctival intraepithelial neoplasia. Ophthalmic Physiol. Opt. 2000, 20, 371–380. [Google Scholar] [CrossRef]
  76. Lee, G.A.; Hirst, L.W. Ocular surface squamous neoplasia. Surv. Ophthalmol. 1995, 39, 429–450. [Google Scholar] [CrossRef]
  77. Erie, J.C.; Campbell, R.J.; Liesegang, T.J. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmology 1986, 93, 176–183. [Google Scholar] [CrossRef]
  78. Grossniklaus, H.E.; Green, W.R.; Luckenbach, M.; Chan, C.C. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987, 6, 78–116. [Google Scholar] [CrossRef]
  79. Mauriello, J.A.; Napolitano, J.; McLean, I. Actinic keratosis and dysplasia of the conjunctiva: A clinicopathological study of 45 cases. Can. J. Ophthalmol. 1995, 30, 312–316. [Google Scholar]
  80. Kao, A.A.; Galor, A.; Karp, C.L.; Abdelaziz, A.; Feuer, W.J.; Dubovy, S.R. Clinicopathologic correlation of ocular surface squamous neoplasms at Bascom Palmer Eye Institute: 2001 to 2010. Ophthalmology 2012, 119, 1773–1776. [Google Scholar] [CrossRef]
  81. Reese, A.; Margo, C.E. Conjunctival squamous intraepithelial neoplasia and its differential diagnosis. J. Clin. Pathol. 2022, 75, 354–358. [Google Scholar] [CrossRef]
  82. Mishra, D.K.; Taneja, S.; Singh, V.; Veena, U.; Kaliki, S. Histopathological spectrum of ocular surface squamous neoplasia: A retrospective study of 776 lesions. Indian J. Pathol. Microbiol. 2022, 65, 3–7. [Google Scholar] [CrossRef]
  83. Hamam, R.; Bhat, P.; Foster, C.S. Conjunctival/corneal intraepithelial neoplasia. Int. Ophthalmol. Clin. 2009, 49, 63–70. [Google Scholar] [CrossRef]
  84. Pizzarello, L.D. Bowen’s disease of the conjunctiva: A misnomer Ocular and adnexal tumors. Am. J. Ophthalmol. 1946, 29, 515–571. [Google Scholar]
  85. Iliff, W.J.; Marback, R.; Green, W.R. Invasive Squamous Cell Carcinoma of the Conjunctiva. Arch. Ophthalmol. 1975, 93, 119–122. [Google Scholar] [CrossRef] [PubMed]
  86. Zhang, Z.; Li, B.; Shi, J.; Xu, X.; Li, L.; Gao, F. Intraocular Extension of Conjunctival Squamous Cell Carcinoma. Ophthalmologica 2007, 221, 200–203. [Google Scholar] [CrossRef] [PubMed]
  87. Cottel, W.I. Perineural invasion by squamous-cell carcinoma. J. Dermatol. Surg. Oncol. 1982, 8, 589–600. [Google Scholar] [CrossRef]
  88. Albert, D.M.; Jakobiec, F.A. Principles and Practice of Ophthalmology; Saunders: Philadelphia, PA, USA, 2000. [Google Scholar]
  89. Vempuluru, V.S.; Kapoor, A.G.; Kaliki, S.; Jajapuram, S.D.; Mohamed, A.; Mishra, D.K. Comparative evaluation of clinical characteristics of biopsy-proven conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma using image processing software programs. Int. Ophthalmol. 2021, 41, 1301–1307. [Google Scholar] [CrossRef] [PubMed]
  90. Nanji, A.A.; Mercado, C.; Galor, A.; Dubovy, S.; Karp, C.L. Updates in Ocular Surface Tumor Diagnostics. Int. Ophthalmol. Clin. 2017, 57, 47–62. [Google Scholar] [CrossRef]
  91. Mittal, R.; Rath, S.; Vemuganti, G.K. Ocular surface squamous neoplasia—Review of etio-pathogenesis and an update on clinico-pathological diagnosis. Saudi J. Ophthalmol. 2013, 27, 177–186. [Google Scholar] [CrossRef]
  92. Singh, S.; Mohamed, A.; Kaliki, S. Ocular surface squamous neoplasia: Analysis based on the 8th American Joint Committee on Cancer classification. Int. Ophthalmol. 2019, 39, 1283–1291. [Google Scholar] [CrossRef]
  93. Brierley, J.D.; Gospodarowicz, M.; Wittekind, C. TNM Classification of Malignant Tumours, 8th ed.; Wiley-Blackwell: Oxford, UK, 2017. [Google Scholar]
  94. Adler, E.; Turner, J.R.; Stone, D.U. Ocular surface squamous neoplasia: A survey of changes in the standard of care from 2003 to 2012. Cornea 2013, 32, 1558–1561. [Google Scholar] [CrossRef]
  95. Shields, J.A.; Shields, C.L.; De Potter, P. Surgical management of conjunctival tumors. The 1994 Lynn, B. McMahan Lecture. Arch. Ophthalmol. 1997, 115, 808–815. [Google Scholar] [CrossRef]
  96. Al Bayyat, G.; Arreaza-Kaufman, D.; Venkateswaran, N.; Galor, A.; Karp, C.L. Update on pharmacotherapy for ocular surface squamous neoplasia. Eye Vis. 2019, 6, 24. [Google Scholar] [CrossRef]
  97. Ali, M.J.; Pujari, A.; Dave, T.V.; Kaliki, S.; Naik, M.N. Clinicopathological profile of orbital exenteration: 14 years of experience from a tertiary eye care center in South India. Int. Ophthalmol. 2016, 36, 253–258. [Google Scholar] [CrossRef]
  98. Karp, C.L.; Galor, A.; Chhabra, S.; Barnes, S.D.; Alfonso, E.C. Subconjunctival/perilesional recombinant interferon α2b for ocular surface squamous neoplasia: A 10-year review. Ophthalmology 2010, 117, 2241–2246. [Google Scholar] [CrossRef]
  99. Nanji, A.A.; Moon, C.S.; Galor, A.; Sein, J.; Oellers, P.; Karp, C.L. Surgical versus medical treatment of ocular surface squamous neoplasia: A comparison of recurrences and complications. Ophthalmology 2014, 121, 994–1000. [Google Scholar] [CrossRef] [PubMed]
  100. Joag, M.G.; Sise, A.; Murillo, J.C.; Sayed-Ahmed, I.O.; Wong, J.R.; Mercado, C.; Galor, A.; Karp, C.L. Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia. Ophthalmology 2016, 123, 1442–1448. [Google Scholar] [CrossRef] [PubMed]
  101. Gichuhi, S.; Macharia, E.; Kabiru, J.; Zindamoyen, A.M.; Rono, H.; Ollando, E.; Wachira, J.; Munene, R.; Maina, J.; Onyuma, T.; et al. Topical fluorouracil after surgery for ocular surface squamous neoplasia in Kenya: A randomised, double-blind, placebo-controlled trial. Lancet Glob. Health 2016, 4, e378–e385. [Google Scholar] [CrossRef] [PubMed]
  102. Zein, M.; De Arrigunaga, S.; Amer, M.M.; Galor, A.; Nichols, A.J.; Ioannides, T.; Dubovy, S.R.; Karp, C.L. Therapeutic Response to Treatment of a Papillomatous Ocular Surface Squamous Neoplasia With Intramuscular Human Papillomavirus Vaccine. Cornea 2024, 43, 1049–1052. [Google Scholar] [CrossRef]
  103. Sripawadkul, W.; AlBayyat, G.; Galor, A.; Wylegala, A.; Nichols, A.J.; Ioannides, T.; Karp, C.L. Resolution of a Presumed Conjunctival Papilloma After Therapeutic Treatment With the Human Papillomavirus Vaccine. JAMA Ophthalmol. 2022, 140, 434–435. [Google Scholar] [CrossRef]
  104. Seth, I.; Roberts, P.; Cadieux, D. Gardasil-9 Vaccine as a Possible Treatment Option for Human Papillomavirus Conjunctival Papilloma. Ophthalmology 2023, 130, 532. [Google Scholar] [CrossRef]
  105. Cekiç, O.; Bardak, Y.; Kapucuoğlu, N. Photodynamic therapy for conjunctival ocular surface squamous neoplasia. J. Ocul. Pharmacol. Ther. 2011, 27, 205–207. [Google Scholar] [CrossRef]
  106. Arepalli, S.; Kaliki, S.; Shields, C.L.; Emrich, J.; Komarnicky, L.; Shields, J.A. Plaque Radiotherapy in the Management of Scleral-Invasive Conjunctival Squamous Cell Carcinoma: An Analysis of 15 Eyes. JAMA Ophthalmol. 2014, 132, 691–696. [Google Scholar] [CrossRef]
  107. Panda, B.B.; Dasmajumdar, S.K.; Sadangi, D.; Tripathy, S.R. Radiation therapy in conjunctival squamous cell carcinoma. BMJ Case Rep. 2023, 16, e256262. [Google Scholar] [CrossRef]
  108. Zheng, T.; Wang, D.; Miao, Y.; Dong, M.; Liu, Q.; Zhang, Q.; Bai, H.; Luo, H.; Li, M. Clinical efficacy and safety of proton radiotherapy for ocular conjunctival malignancies: A systematic review and meta-analysis. Front. Public Health 2025, 13, 1486988. [Google Scholar] [CrossRef]
  109. Graue, G.F.; Tena, L.B.; Finger, P.T. Electron beam radiation for conjunctival squamous carcinoma. Ophthalmic Plast. Reconstr. Surg. 2011, 27, 277–281. [Google Scholar] [CrossRef]
  110. Abt, N.B.; Zhao, J.; Huang, Y.; Eghrari, A.O. Prognostic factors and survival for malignant conjunctival melanoma and squamous cell carcinoma over four decades. Am. J. Otolaryngol. 2019, 40, 577–582. [Google Scholar] [CrossRef]
  111. Vempuluru, V.S.; Indusekhar, H.; Mohamed, A.; Kaliki, S. Metastatic conjunctival squamous cell carcinoma: A study of 5 patients. Int. Ophthalmol. 2022, 42, 3097–3108. [Google Scholar] [CrossRef] [PubMed]
  112. Bellerive, C.; Berry, J.L.; Polski, A.; Singh, A.D. Conjunctival Squamous Neoplasia: Staging and Initial Treatment. Cornea 2018, 37, 1287–1291. [Google Scholar] [CrossRef] [PubMed]
  113. Alkatan, H.M.; Al-Motlak, M.A.; Al-Shedoukhy, A.A. Metastatic Squamous Spindle Cell Carcinoma of the conjunctiva. Saudi J. Ophthalmol. 2010, 24, 155–158. [Google Scholar] [CrossRef]
  114. Asena, L.; Dursun Altınörs, D. Topical Bevacizumab for the Treatment of Ocular Surface Squamous Neoplasia. J. Ocul. Pharmacol. Ther. 2015, 31, 487–490. [Google Scholar] [CrossRef] [PubMed]
  115. Faramarzi, A.; Feizi, S. Subconjunctival bevacizumab injection for ocular surface squamous neoplasia. Cornea 2013, 32, 998–1001. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Infographic summarising the aetiology and pathogenesis of CSIN and invasive CSCC (generated in Google Gemini3 Flash).
Figure 1. Infographic summarising the aetiology and pathogenesis of CSIN and invasive CSCC (generated in Google Gemini3 Flash).
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Figure 2. Anterior segment photographs of invasive CSCC with presence of feeder vessels. Middle top row and bottom row images show corneal invasion. Brown surface pigmentation is seen in patients from the tropics (image bottom right). Images on right (top and bottom) shows surface keratinisation.
Figure 2. Anterior segment photographs of invasive CSCC with presence of feeder vessels. Middle top row and bottom row images show corneal invasion. Brown surface pigmentation is seen in patients from the tropics (image bottom right). Images on right (top and bottom) shows surface keratinisation.
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Figure 3. Haematoxylin and eosin staining photomicrographs showing in situ conjunctival squamous carcinoma (image on the (left, ×200)) and invasive CSCC (image on the (right, ×100)).
Figure 3. Haematoxylin and eosin staining photomicrographs showing in situ conjunctival squamous carcinoma (image on the (left, ×200)) and invasive CSCC (image on the (right, ×100)).
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Table 1. Anti-PDL1 therapies in invasive CSCC.
Table 1. Anti-PDL1 therapies in invasive CSCC.
StudyPatient (s)StagePrimary TreatmentAgent UsedDosageOutcomeAdverse Reactions
Esmaeli et al., 2025 [40]17 (5 CSCC)Primary advanced periocular SCC (orbital, conjunctival, lacrimal)Single systemic ICI or combined with systemic chemotherapyCemiplimab or PembrolizumabVarious cycles. Dosage not specified.Five complete responses, eight partial responses, four stable disease. At least one CSCC with nodal metastasis achieved complete response and avoided surgeryOne patient diabetic ketoacidosis but others not specified
Azad et al., 2025 [41]5Primary advanced CSCCSystemic ICI therapyCemiplimab or Pembrolizumab350 mg IV every 3 weeks; 400 mg IV every 6 weeks, respectivelyAll showed progression, three required exenterationNot specified
Kanda et al., 2025 [39]9Primary advanced invasive CSCCSystemic ICI therapyCemiplimab350 mg IV every 3 weeks22% complete response, 33% partial response, 44% progressedHypothyroidism, hepatitis
Ceylanoglu et al., 2024 [42]2Primary CSIN; one patient also with metastatic cutaneous SCC Excisional biopsy with cryotherapyCemiplimab350 mg IV every 3 weeksResponse shown in metastatic lesions. CSIN continued to grow in both.Not specified
Steren et al., 2022 [43]11One patient with primary CSCC with orbital involvement; 10 patients with orbital SCCExcisional biopsyCemiplimab350 mg IV every 3 weeksComplete response in 9/11 patientsPneumonitis, diarrhoea, fatigue, rash
Hoffmann et al., 2021 [44]59 years old, FemaleRecurrent CSCCRadiotherapyCemiplimab3 mg/kg IV every 2 weeksResolution after 19 months of treatmentNone
Demirci et al., 2020 [37]5Two patients recurrent CSCC and three patients primary CSCC all with orbital involvementFour excisional biopsy; one radiotherapyPembrolizumab or CemiplimabPembrolizumab—350 mg every 3 weeks
Cemiplimab—200 mg every 3 weeks		4/5 patients complete response; one showed progressionColitis, rash
(Not specified = no specific details included in the study for dosage or adverse drug reactions, respectively).
Table 2. Targeted therapies in invasive CSSC.
Table 2. Targeted therapies in invasive CSSC.
StudyPatient (s)StagePrimary TreatmentAgent UsedDosageOutcomeAdverse Reactions
Asena et al., 2015 (anti-VEGF) [114]6Primary CSINTopical targeted therapyBevacizumab5 mg/mL eye drops, 4 times daily for 8 weeks2/6 complete tumour resolutions, four patients required excisional surgeryNone reported
Faramarzi et al., 2013 (anti-VEGF) [115]10Combination of primary CSIN and CSCCPerilesional/subconjunctival injection with excision/cryotherapy if neededBevacizumab2.5 mg injection given twice 2 weeks apartMean tumour area reduced by 25% after first and 42% after second injection, complete resolution in two patientsNone reported
Finger et al., 2012 (anti-VEGF) [47]5Recurrent CSCCExcision, cryotherapy and topical interferon α or MMCRanibizumab 0.5 mg monthly or bimonthly3/5 complete responses, two failed treatmentsNone reported
El Sawy et al., 2012 (EGFR Inhibitor) [45]90 years old, femaleMedial canthal and orbital SCCSystemic EGFR inhibitionErlotinib150 mg orally once daily, increased to 200 mg orally once dailySignificant tumour reductionNone reported
El Sawy et al., 2012 (EGFR Inhibitor) [45]81F, maleAdvanced orbital SCCSystemic EGFR inhibitionCetuximab400 mg/m2 intravenous loading dose, followed by 250 mg/m2 intravenous weeklyMarked tumour shrinkageSkin reaction
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Mir, M.; Mudhar, H.S.; Sagoo, M.S.; Gichuhi, S.; Krishna, Y. Conjunctival Squamous Cell Carcinoma: A Clinical Review of Diagnostic Features, Genetics, Current Management and an Update on Targeted and Immunotherapies. Cancers 2026, 18, 940. https://doi.org/10.3390/cancers18060940

AMA Style

Mir M, Mudhar HS, Sagoo MS, Gichuhi S, Krishna Y. Conjunctival Squamous Cell Carcinoma: A Clinical Review of Diagnostic Features, Genetics, Current Management and an Update on Targeted and Immunotherapies. Cancers. 2026; 18(6):940. https://doi.org/10.3390/cancers18060940

Chicago/Turabian Style

Mir, Murad, Hardeep Singh Mudhar, Mandeep S. Sagoo, Stephen Gichuhi, and Yamini Krishna. 2026. "Conjunctival Squamous Cell Carcinoma: A Clinical Review of Diagnostic Features, Genetics, Current Management and an Update on Targeted and Immunotherapies" Cancers 18, no. 6: 940. https://doi.org/10.3390/cancers18060940

APA Style

Mir, M., Mudhar, H. S., Sagoo, M. S., Gichuhi, S., & Krishna, Y. (2026). Conjunctival Squamous Cell Carcinoma: A Clinical Review of Diagnostic Features, Genetics, Current Management and an Update on Targeted and Immunotherapies. Cancers, 18(6), 940. https://doi.org/10.3390/cancers18060940

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