Malignant Eyelid Lesions

Etiology

Clinicians should recognize that prolonged and cumulative UV radiation exposure is the strongest risk factor for the most common eyelid malignancies, including BCC, SCC, and melanoma.[3] Understanding the mechanisms by which UV radiation induces cellular damage and carcinogenesis can improve recognition of additional risk factors and support earlier implementation of preventive counseling and risk-factor modification strategies.

Although a detailed review of UV-induced molecular injury is beyond the scope of this article, a brief overview of the underlying mechanisms is clinically relevant. UV-A and UV-B radiation contribute to carcinogenesis through complementary pathways. UV-A radiation promotes the formation of reactive oxygen species that damage cellular structures and induce oxidative stress. In contrast, UV-B radiation directly damages DNA through thymidine dimer formation, resulting in mutagenic cellular changes.[4][5] DNA damage may impair normal cellular repair and regulatory mechanisms, leading to mutations that inactivate tumor suppressor genes or promote uncontrolled activation of oncogenes, ultimately contributing to malignant transformation.[6] Additional risk factors for eyelid malignancies may increase susceptibility to UV-induced genetic injury, impair immune surveillance of malignant cells, or promote carcinogenesis through other DNA-damaging mechanisms. These risk factors may be modifiable, such as environmental or behavioral exposures, or non-modifiable, including inherited genetic predisposition.[3] The following sections review lesion-specific pathophysiology and risk factors associated with malignant eyelid lesions. Please see StatPearls' companion resource, "Skin Cancer," for further information. Unique eyelid malignancies that are not primarily associated with UV-induced damage are discussed separately within their respective sections.

Actinic Keratosis

Actinic keratosis, also known as solar keratosis, is considered a premalignant skin lesion for both SCC and BCC, although SCC is more common. Actinic keratosis, as with SCC and BCC, typically arises from prolonged exposure to UV radiation. Other variables also influence their development, including male gender, older age, baldness, and a history of melanoma or SCC .[3] UV-induced mutations in the p53 gene have been observed in actinic keratosis. The p53 tumor suppressor gene is critical to cell apoptosis and the prevention of tumorigenesis; a mutation in this gene leads to the uncontrolled growth of malignant cells.[4][5] 

Given the relation with UV radiation, lesions typically arise on the sun-exposed regions of the body—that is, the dorsum of the hands, shoulders, and face. These lesions can occur alone or as multiple lesions and tend to have overlying yellow/brown scales. Adjacent skin may show signs of sun damage, including telangiectasias and yellow discoloration. Occasionally, heavily pigmented actinic keratosis may resemble lentigo maligna.[3] 

Basal Cell Carcinoma

BCC is the most common skin malignancy worldwide, with approximately 80% of lesions occurring in the head/neck region and 20% on the eyelids.[4] In one study, two-thirds of SCCs and one-third of BCCs were shown to arise from previously clinically diagnosed actinic keratosis in a high-risk population.[5] Risk factors align with those for actinic keratosis and with increased cumulative UV exposure, including age, lack of sun-protective measures, and fair skin type. Additionally, smoking has been implicated as a major risk factor for BCC. Several studies have identified mutations in the PTCH1 gene of the sonic hedgehog pathway and in the p53 tumor suppressor gene in patients with BCC. Interestingly, targeted therapies that inhibit the sonic hedgehog pathway, such as Sonidegib, have shown promising results in BCC treatment.[7] Lastly, several inherited diseases or syndromes predispose individuals to developing BCC; some are listed below.

Systemic conditions that may predispose a patient to BCC include:

• Sturge Weber/Port-wine stain
• Basal cell nevus syndrome
• Gorlin-Goltz syndrome
• Rombo syndrome
• Bazex-Dupré-Christol syndrome
• Xeroderma pigmentosum

For a more in-depth discussion on cutaneous BCC, the authors refer you to the StatPearls article dedicated to this; we will primarily focus on aspects specific to eyelid BCC.

Squamous Cell Carcinoma  and Keratoacanthoma

Eyelid SCC is characterized by abnormal proliferation of cutaneous squamous cells and encompasses a spectrum of disorders ranging from precursors, such as actinic keratosis, to SCC. UV radiation plays a critical role in lesion genesis. Other unique causes include arsenic exposure, human papillomavirus infection, trauma, and HIV infection. SCC can also commonly occur after organ transplantation, with a reported incidence of 30% for lung transplants and 26% for heart transplant patients over 5 years.[8][9] This finding is most likely related to post-transplant immunosuppressants, which reduce the immune system's ability to identify and destroy cancerous cells.

In a recent genetic sequencing analysis of SCC lesions, including ocular SCC, many of the familiar genes were implicated, such as p53, RB1, and CDKN2A. Further stratification of these findings supports treating ocular SCC similarly to SCC elsewhere, given the shared genetic abnormalities.[10] The associated systemic diseases listed below are related to alterations at these genetic loci, such as Fanconi anemia and the p53 gene.

Keratoacanthomas can be considered a well-differentiated variant of SCC, whereas actinic keratoses are precancerous squamous lesions. Keratoacanthoma often presents as a dome-shaped lesion with central hyperkeratosis and ulceration. Clinically, it is characterized by rapid growth followed by spontaneous involution. However, no pathognomonic features differentiate SCC from keratoacanthoma.

Systemic conditions that may predispose patients to keratoacanthoma or SCC include:

• Oculocutaneous albinism
• Epidermolysis bullosa
• Fanconi anemia
• Ferguson-Smith syndrome
• Muir-Torre syndrome
• Mibelli-type porokeratosis
• Rothmund-Thomson syndrome
• Keratitis-ichthyosis-deafness syndrome
• Bloom syndrome
• Epidermodysplasia verruciformis 
• Xeroderma pigmentosum

Sebaceous Carcinoma

Sebaceous carcinoma of the eyelid typically presents as a yellow, painless mass along the eyelid margin originating from sebaceous glands such as meibomian glands or glands of Zeis.[6] The clinical appearance of sebaceous carcinoma may resemble a chalazion or hordeolum, but the clinical history may differ. Additionally, given the origin of sebaceous carcinoma, these lesions may be located on the eyelid margin, caruncle, or the tarsal conjunctiva, demonstrating the importance of double-eversion of the upper lid during the ophthalmic examination.[7][8] Although the exact pathogenesis of sebaceous carcinoma is unknown, multiple associations have been documented in the literature. Muir-Torre syndrome is an autosomal dominant disorder with cutaneous malignancies such as sebaceous carcinoma and internal systemic malignancies such as colorectal and endometrial carcinoma.[11] Muir-Torre syndrome is more commonly associated with sebaceous carcinoma located outside of the periocular region.[12][13][14] Tumor locations, history of immunosuppression, history of radiotherapy, perineural involvement, and pathologic features should all be considered during risk stratification.[15][16][17][18]

Mutations in the TP53 gene have also been implicated in the development of periocular sebaceous carcinoma. A review of 15 patients with sebaceous carcinoma of the eyelid demonstrated that 66.7% contained point mutations in the p53 gene.[19] In Li-Fraumeni syndrome, a germline mutation in TP53 is associated with the development of sebaceous carcinoma.[20] 

The high gene mutation rate of p53 may aid in obtaining an immunohistochemical diagnosis of sebaceous carcinoma. Alterations in the expression of ERBB2, adhesion proteins (ie, E-cadherin), and epithelial-to-mesenchymal transition markers have also been demonstrated.[21]

Melanoma

Eyelid melanoma shares many features with cutaneous melanoma. Risk factors include excessive sun exposure, presence of dysplastic nevi, a personal history of melanoma, older age, and Fitzpatrick skin types I-II.[22][[23]][24] The pathophysiology of melanoma is multifaceted, and knowledge of the various responsible mutations continues to grow. UV signatures are one of the most well-documented features of melanoma. These signatures are defined as C-to-T transitions at dipyrimidine sites.[25] In addition to these UV signatures, other mutations must be present for transformation to melanoma, including activating mutations (eg, BRAF), tertiary mutations, invasive mutations, and immune-system evasion mutations.[26][27]

Approximately 50% of patients with advanced melanoma have BRAF mutations. The RAF isoforms are proteins involved in the activation of downstream pathways; the BRAF mutation leads to an 800-fold increase in kinase activity, leading to increased cellular proliferation.[28] Given the existing body of research on the molecular pathophysiology of melanoma, further discussion is reserved for a dedicated article.

Systemic conditions that may predispose a patient to this include:

• Familial atypical multiple mole melanoma syndrome
• Familial melanoma
• Xeroderma pigmentosum

Merkel Cell Carcinoma

MCC is a poorly understood and multifarious skin lesion. Merkel cells are mechanoreceptors and were historically thought to be the source of MCC. However, MCC is now known to have both epithelial and neuroendocrine origins; for this reason, epidermal stem cells, dermal stem cells, and B cells have also been suggested as alternative cell of origin.[29][30] A notable aspect of the pathophysiology of MCC is that it is among the few cutaneous malignancies associated with a virus, namely, Merkel cell polyomavirus.[31][32] In fact, approximately 80% of MCC samples are associated with Merkel cell polyomavirus. MCC lesions are further classified by viral positivity, as they exhibit distinct characteristics and mutation-related changes. One of the more notable differences is that virus-positive cell lines exhibit a downregulation of MHC-I proteins on the cell surface, inhibiting targeted tumor cell destruction.[33][34][32]

Immunosuppression is a well-documented and significant risk factor for the development of cutaneous MCC; however, its incidence remains unclear. There is a demonstrated link between UV exposure and increased rates of MCC in sun-exposed skin. Additionally, the use of psoralens and associated UV-A light has been associated with an increased incidence of MCC.[35]

Epidemiology

From a global cancer perspective, nonmelanoma skin malignancies are extremely common yet generally associated with low lethality, which often results in their exclusion from large cancer registries. Consequently, robust worldwide estimates of their incidence are limited compared with those of cancers such as lung, breast, and colorectal cancer. Beyond malignant melanoma, large, well-characterized global studies specifically addressing malignant eyelid lesions are even more limited.

However, a recent large retrospective study from the United States using the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS) Registry analyzed nearly 72 million patient records and provided high-quality epidemiologic data on malignant eyelid lesions. The prevalence of any eyelid cancer was 145.1 per 100,000 individuals, with BCC and SCC demonstrating the highest individual prevalence rates at 87.9 and 11.1 per 100,000, respectively. The prevalence of multiple eyelid cancers was 11.2 per 100,000. Demographic factors most strongly associated with malignant eyelid lesions included older age, non-Hispanic White race, male sex, and a history of smoking.[36]

Other large studies evaluating biopsied eyelid lesions, including benign, premalignant, and malignant tumors, reported prevalence rates ranging from 85.7% to 92.5% for benign lesions, 1.1% to 6.0% for premalignant lesions, and 1.5% to 13.1% for malignant lesions. [9][37][38] Among malignant lesions, 48.5% to 60% originated from epidermal cells, whereas 11.8% to 34.6% arose from adnexal cells. Consistent with findings from the IRIS Registry, BCC and SCC were the most frequently identified malignant eyelid tumors. Common benign lesions included melanocytic nevi, squamous cell papilloma, seborrheic keratoses, and epidermal cysts.[9][37][38]

Actinic Keratosis

Understanding premalignant lesions is of great importance to surgeons, as early recognition provides greater opportunity for successful intervention. One of the most prevalent premalignant lesions is actinic keratosis. A 2024 meta-analysis of global actinic keratosis prevalence revealed that nearly 14% of the general population is affected by these lesions, making an estimated 1.1 billion people affected worldwide.[6] However, the prevalence of actinic keratosis may vary widely by location and population risk factors, as observed when comparing the 23% prevalence rate in the South Wales Skin Cancer Study with 60% in patients in Australia.[39][40] As discussed earlier, risk factors for actinic keratosis include male gender, significant cumulative sun exposure, older age, baldness, a personal history of melanoma or SCC, and Fitzpatrick skin types I and II.[39][41] Individuals with actinic keratosis carry a significantly higher risk of developing keratoacanthomas, with studies estimating a greater than 5-fold increased risk.[42]

Basal Cell Carcinoma

In the United States and other Western countries, BCC is the most common malignancy of the eyelid, with a prevalence of 0.088%.[36] Using data from the English Cancer Registries, Saleh et al reported that the incidence of BCC in England was 0.0045%.[43]

As indicated above, regional variations exist, though BCC remains among the top 2 eyelid malignancies in all studied countries. For example, in India, BCC is the second most common eyelid malignancy (24%) after sebaceous carcinoma (53%).[44]

Squamous Cell Carcinoma and Keratoacanthoma

In the United States and other Western countries, SCC is the second most common malignancy of the eyelid after BCC, accounting for <5% of all eyelid malignancies. The American Academy of Ophthalmology's IRIS Registry estimates a prevalence at 0.011%. However, it is still 40 times less common than BCC. SCC typically occurs in patients older than 50, though it can present at any age.

In other countries, SCC remains among the top 3 eyelid malignancies, though prevalence varies by region. For example, in India, SCC is the third most common eyelid malignancy (18%) after sebaceous carcinoma (53%) and BCC (24%).[44]

In addition, SCC occurs commonly after organ transplantation, with a reported incidence of 30% for lung transplants and 26% for heart transplant patients over 5 years. The prevalence of SCC amongst this group is related to post-transplantation systemic immunosuppression, which reduces the immune system's ability to identify and destroy cancerous cells.[8][9]

Sebaceous Carcinoma

Of the described eyelid malignancies, sebaceous carcinoma may be the only one with the unique predilection for females over males. A meta-analysis involving 1333 patients demonstrated that the mean age at diagnosis of sebaceous carcinoma was 65.2 years, with a female predominance of 60.2%.[37] Other studies have shown a female prevalence ranging from 55.23% to 73%.[38][45] However, within the IRIS Registry, no statistically significant predilection exists for females versus males (4.8 versus 5.1 per 100,000), with an overall rate of 0.005%. [36] In terms of anatomical location, the upper eyelid is affected in 59% to 62.6% of cases, more commonly than the lower eyelid, which is involved in 32.8% in 41% of cases.[37]

Melanoma

Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, the incidence of eyelid melanoma from 1975 to 2017 ranged from 0.4 to 0.7 cases per 1 million persons. Of the 30,457 reported cases of melanoma involving the face, scalp, and neck, approximately 2% were documented as eyelid lesions. Lentigo maligna melanoma (24%) was the most common melanoma subtype, whereas nodular melanoma (7.7%) was the least common. [46]

Melanoma shows sex-based variation in anatomic distribution, with males more commonly affected on the back, neck, and scalp, and females more commonly on the limbs. This distribution is theorized to reflect differences in behavioral patterns between sexes.[47] Regarding eyelid involvement, evidence is conflicting with respect to sex predilection. Data from the IRIS Registry suggest a stronger association with male sex, consistent with trends observed across most other cutaneous malignancies. This finding is further supported by a 2025 National Cancer Database evaluation of eyelid melanoma. However, that study noted age-dependent variation, with males more commonly affected between the ages of 60 and 80, whereas females were more commonly affected in patients younger than 50.[48] In contrast, an earlier National Cancer Database review of head and neck melanoma reported a female predominance in eyelid melanoma.[49] For anatomical location, the lower eyelid is the most involved periorbital site, followed by the upper eyelid, eyebrow region, lateral canthus, and medial canthus.[25]

Merkel Cell Carcinoma

Eyelid-specific rates of MCC are not well delineated. However, approximately 1500 cases of MCC are diagnosed each year.[50] Data from the National Cancer Institute from 1973 to 2006 shows that MCC predominantly affects White patients (94.9%) between the ages of 60 and 85. Approximately 71.6% of patients were older than 70 at the time of diagnosis.[51] 

Patients diagnosed at a younger age are typically immunosuppressed in the setting of HIV/AIDS or organ transplantation.[29] Between 45% to 48% of MCC cases arise in the head and neck region, and within this region, up to 20% of these cases originate on the eyelid.[52][53][54] 

Lentigo Maligna

Lentigo maligna exists on the spectrum of melanoma. When invasive, this entity is referred to as lentigo maligna melanoma (LMM).[55] In this manner, lentigo maligna can be categorized as melanoma in situ.[56][57] LMM accounts for 10% to 26% of melanomas in the head and neck region.

The chief concern for this lesion is the transformation from lentigo maligna to LMM, which can occur in 5% to 50% of cases.[58][59] A study from Australia found that the average time to convert from lentigo maligna to LMM was 28.3 years.[60] 

Surgical excision is the primary treatment for these lesions; however, for patients who are poor surgical candidates, topical agents (imiquimod cream, azelaic acid, 5-fluorouracil), cryotherapy, and radiotherapy are alternative treatment modalities.[61][62][63] For a more in-depth discussion, the authors refer you to the StatPearls article on this topic.[64] 

Limited data are available regarding lentigo maligna and LMM in the periocular region. For this reason, patients should be managed with a multidisciplinary approach involving oculoplastic surgeons, dermatologists, and primary care physicians.

Histopathology

Actinic Keratosis

Actinic keratosis demonstrates hyperkeratosis and parakeratosis within the epidermal layer. Dyskeratosis is typically present, as evidenced by premature keratinization of cells in the stratum granulosum and spinosum. The dermal layer exhibits solar elastosis and may have a mild inflammatory infiltrate comprised chiefly of lymphocytes and plasma cells.

Several subtypes exist, such as hypertrophic and atrophic. Cellular atypia is always present, although its severity varies. As such, histopathological evaluation of the entirety of the lesion, including superficial stromal layers, is necessary to exclude the possibility of stromal invasion, which, if present, would indicate SCC.

Special stains are generally not needed for the diagnosis of actinic keratosis. However, pigmented actinic keratosis may mimic early melanoma, in which case special immunohistochemical stains may help an experienced pathologist reach the correct diagnosis.

Melan-A staining may be positive in pigmented lesions. More recent studies suggest a role for HMB-45 in helping differentiate these pigmented lesions.[65][66] Actinic keratosis may also stain positively for cytokeratin.

Basal Cell Carcinoma

Histologically, these lesions originate from the stratum basale of the epidermis. The cells are classically blue and basaloid in appearance and are located below the superficial skin, within the stromal layers. These cells have large, bland, crowded nuclei with a high nuclear-to-cytoplasmic ratio.

Multiple histologic patterns exist; however, all generally form dense islands of tumor cells with classic palisading at their edges. These islands are separated from other dermal components by a clear margin due to refraction artifacts from tissue processing (separation artifacts or clefts). Within the islands, tumor cells show enlarged, crowded nuclei and mitotic figures. Rapidly progressive BCC may demonstrate areas of necrosis.

As BCC is an epithelial tumor, it stains positively with cytokeratin. BerEp4 (an EpCAM stain) is commonly used to assist in diagnosis; it has high sensitivity and specificity for BCC but is negative in normal squamous epithelium.[67] However, it has limitations: it cannot distinguish BCC from MCC, basaloid SCC, or trichoepithelioma, as all are epithelial neoplasms of follicular germinative (trichoblastic) cell differentiation. Thus, other immunohistochemical stains are helpful for further characterization in these instances.

Squamous Cell Carcinoma and Keratoacanthoma

SCC tumor cells originate from the superficial epidermis. SCC tends to form nests and strands that extend into the dermis. The tumor cells are generally large, with prominent eosinophilic cytoplasm and a high nuclear-to-cytoplasmic ratio. Keratin pearls are often present.

SCC is typically classified based on the severity of the characteristics observed in the abnormal squamous epithelium. Key factors used to categorize SCC include the degree of keratinization, the presence of intercellular bridges (desmosomes), pleomorphism, and the presence of mitotic figures. SCC can be classified into different categories: well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Perineural or lymphatic invasion may be present; the former may present with pain.

As SCC is an epithelial tumor, it may stain positive for cytokeratin. Poorly differentiated and undifferentiated forms may be difficult to establish and often require additional immunohistochemical stains, such as desmin, to exclude melanoma or sarcoma.

Keratoacanthoma is often considered a well-differentiated form of SCC. The histologic appearance of heratoacanthoma is similar to that of SCC, characterized by a crater-like depression filled with keratin. However, it can be distinguished by the general well-differentiated nature of the squamous cells.

Depending on the stage of growth or regression, the lesion is often surrounded by a chronic inflammatory response. Because of its many similarities to SCC, which make the 2 difficult to differentiate, and its potential for malignant transformation, many ophthalmologists recommend complete excision of the lesion.

Sebaceous Carcinoma 

Sebaceous carcinoma is of adnexal sebaceous origin, and its histopathologic classification is based on the degree of cell differentiation in the tumor. A well-differentiated tumor contains cells with sebaceous differentiation and foamy vacuolated cytoplasm. A moderately differentiated tumor histopathologically shows that most cells have hyperchromatic nuclei with prominent nucleoli and basophilic cytoplasm, with interspersed areas of well-differentiated sebaceous cells.

A poorly differentiated tumor contains hyperchromatic, atypical cells with high mitotic activity. The comedocarcinoma subtype of sebaceous carcinoma often displays necrosis at the center of the tumor. Staining lipids with Oil Red O or human milk fat globulin-1 can help distinguish sebaceous carcinoma from SCC and BCC.[68]

Sebaceous carcinoma can demonstrate flat (pagetoid) spread to the epidermis of the eyelid and epithelium of the conjunctiva and spread directly to the orbit, intracranial cavity, and paranasal sinuses. Poorly differentiated SCC can have perineural and lymphatic spread, as well as metastatic spread to distant organs.

Melanoma

Malignant melanoma is of epidermal melanocytic origin and can arise from lentigo maligna or from an intradermal melanocytic lesion, such as a dysplastic nevus. In the case of the lentigo maligna, atypical melanocytes are present in the basal layers of the epidermis and the adnexal structures, such as the eyelash pilar units. Regardless of its origin, a diagnosis of malignant melanoma is made when these atypical melanocytes are observed beyond the epidermal basement membrane.

Clark's and Breslow's microstaging methods for skin melanoma focus specifically on the tumor's depth. However, these staging techniques are not applicable to eyelid skin due to its unique structure. Instead, the prognosis for eyelid melanoma is based on factors such as eyelid margin involvement, depth of invasion, and the presence of skin ulceration. Notably, skin ulceration is rarely observed in cutaneous eyelid melanoma. Other prognostic factors have been reported, including regional lymph node involvement and distant metastases, but their significance remains uncertain due to the rarity of eyelid melanoma.

Merkel Cell Carcinoma

Merkel cells are neuroendocrine receptor cells present in the mucous membrane and skin. MCC is a rare neurogenic tumor of the upper eyelid and eyebrow, characterized by abundant mitotic figures and round cells with round-to-oval nuclei, prominent nucleoli, and scant cytoplasm. Immunohistochemical staining positive for neuron-specific enolase, neurofilaments, and cytokeratin-20, and negative for S-100 and leukocyte common antigen, can differentiate MCC from other epithelial and neuroendocrine tumors.[52]

History and Physical

Every medical examination begins with history. The medical history should include a personal history of cutaneous or systemic cancer, immunosuppression, fair skin, radiation therapy, a family history of cancer, history of excessive sunlight exposure, and the presence of any non-healing or recurrent cutaneous lesions.

Patients should be asked about any eyelid lesion with symptoms of itching, bleeding, ulceration, blistering, chronicity, changes in color or size, and loss of typical eyelid architecture (eg, loss of eyelashes).

Examiners should ask about the location, onset, character, and time course of eyelid lesions, as well as any prior treatments or previous occurrence of the lesions. Eyelid and adnexal examinations should be performed in ambiently-lit rooms with an additional dermatoscope, slit lamp, or pocket flashlight. The patient’s Fitzpatrick skin type should be noted, and any significant difference in skin tone between sun-exposed and sun-protected areas should be assessed.

Clinicians should assess for lesions with irregular pigmentation, ulceration with crusting or bleeding, telangiectatic vessels, or loss of eyelashes or cutaneous rhytids.

Examination under magnification with a slit lamp or dermatoscope is helpful in better characterizing the lesion. Each suspicious lesion should be measured in millimeters in vertical and horizontal dimensions. The edges of the lesion should be palpated to assess for involvement or fixation to deeper tissues.

Eversion of the lower lid and double-eversion of the upper lid are vital to ascertain the involvement of the conjunctival and fornices. The preauricular, postauricular, submandibular, and submental lymph nodes should be assessed for lymphadenopathy. The lesion should be photographed to document its appearance.

If the patient has any suspicious eyelid lesions, referral to a dermatologist is warranted to ensure a full-body dermatologic examination. The presence of one skin cancer often portends the presence of another pre-cancerous or cancerous lesion elsewhere.

Evaluation

When evaluating eyelid lesions for potential malignancy, the clinician should assess the rate of progression, the timeline of development, and whether the patient experiences any pain associated with the lesions. Additionally, the patient's best-corrected visual acuity, color vision, extraocular motility, pupillary responses, and visual field should also be measured.

These examination findings are often affected by the pathology of the globe, orbit, ocular adnexa, and periorbital tissue. More specifically, the following should be noted during the evaluation of a potentially malignant eyelid lesion:

• Color of the lesion(s)
• Size, measured in millimeters with vertical and horizontal dimensions and depth as applicable
• The appearance of telangiectatic or atypical vasculature
• Distortion of eyelid architecture
• For lesions involving the palpebral conjunctiva, double-eversion of the upper eyelid is recommended to evaluate the conjunctival fornix
• Madarosis
• Ulceration
• Poliosis
• Local lymph node enlargement

Histopathologic examination remains the gold standard for the diagnosis of malignant lesions and is required before definitive treatment. Therefore, close coordination with pathology is imperative for early and accurate diagnosis. Full-thickness or excisional biopsies are preferred for certain malignant lesions (eg, melanoma), as depth of invasion is a critical prognostic factor. In contrast, shave biopsies may be acceptable for lesions suspicious for BCC, although they may be technically challenging in sensitive areas such as the eyelid.[National Comprehensive Cancer Network. Basal Cell Carcinoma (Version 1.2026)][National Comprehensive Cancer Network. Basal Cell Carcinoma (Version 2.2025)][69]

Furthermore, comprehensive care should include a dermatology referral for a full-body skin examination, as patients diagnosed with a single malignant lesion are at increased risk of additional cutaneous malignancies, for which annual surveillance is strongly recommended.[69]

Additionally, when a patient's presentation raises concern for more extensive disease (eg, bony invasion or metastasis), further diagnostic imaging should be pursued for both prognostic assessment and surgical planning. A 2024 systematic review of SCC found that computed tomography (CT) imaging altered management in nearly one-third of high-risk patients and demonstrated excellent sensitivity and specificity (96.4% and 100%, respectively) for detecting nodal metastasis. [70]

Ultimately, care for patients with potentially malignant cutaneous lesions is a multidisciplinary effort that begins with prompt recognition of concerning features and includes appropriate diagnostic, prognostic, and follow-up evaluations.

Treatment / Management

Actinic Keratosis

Clear guidelines for managing actinic keratosis do not exist, given their propensity for spontaneous resolution; however, given the risk for malignant transformation, the clinician should not ignore these lesions. A 2012 review of practice patterns for periocular actinic keratosis found that 60.2% of surveyed surgeons treat actinic keratosis <2mm with local excision and permanent pathology.[71] 

Given the proximity of periorbital actinic keratosis to the globe, treatments such as cryotherapy, topical chemotherapy, photodynamic therapy, and laser therapy may present additional risks. These treatments should be used on a case-by-case basis in conjunction with an ophthalmologist.

Basal Cell Carcinoma

The primary treatment modality for BCC of the eyelid remains surgical excision, typically Mohs micrographic surgery or local excision with 3 to 4 mm surgical margins. The resulting defect is then repaired by the Mohs surgeon or oculoplastic surgeon. If the extensive orbital invasion is identified, orbital exenteration has been performed in the past. More recent studies have shown the use of neoadjuvant vismodegib before surgical excision to avoid disfiguring orbital exenteration.[72][73](B3)

The SINS trial is a landmark study comparing excisional surgery with topical 5% imiquimod for the treatment of BCC. Though the trial was not specific to eyelid tumors, it found that surgery was superior to imiquimod. Although most imiquimod failures were limited to the first year of treatment, sustained benefits were observed in other groups.[74][75][76] These findings suggest a possible role for imiquimod in selected cases of eyelid BCC.(A1)

Squamous Cell Carcinoma and Keratoacanthoma

Due to the difficulty in clinically differentiating SCC and keratoacanthoma, most physicians opt for biopsy. If confirmed as a keratoacanthoma, ophthalmologists may choose to monitor or excise the lesion, depending on its size and location. In contrast, for non-eyelid keratoacanthoma, excision is generally preferred due to a low risk for complications.

If SCC is confirmed on pathology, treatment is primarily surgical excision. This approach most commonly involves Mohs micrographic surgery with histopathologic clearance of surgical margins. The resulting defect is then repaired by the Mohs surgeon or an oculoplastic surgeon. If the SCC shows perineural invasion into the orbit, the patient should be considered for neoadjuvant treatment, globe-sparing or total orbital exenteration (depending on the extent of spread), and sentinel lymph node biopsy. 

Although surgical excision remains the standard of care for SCC, it is not always clinically possible; in such cases, radiation remains a viable option.[77] Additionally, SCC lesions have been shown to have elevated levels of epidermal growth factor receptors. Thus, agents such as cetuximab, erlotinib, and gefitinib, which target and inhibit the epidermal growth factor receptor, have shown promise in SCC treatment, mainly to stabilize disease when surgical management is not possible.[78][79](B2)

Topical imiquimod, a topical immunomodulatory agent of the imidazoquinoline family, functions by activation of the innate and adaptive/acquired immune systems. In 2010, Ross et al were the first to successfully use imiquimod to treat moderately differentiated SCC of the eyelid.[80] More classically, imiquimod is used to treat BCC and precursor tumors, as shown in the landmark SINS trial.(B3)

Following successful surgical excision, patients should be counseled on proper sun protection, including sunscreen, UV-blocking sunglasses, wide-brimmed hats, long-sleeved clothing, and other protective clothing, as well as on limiting sun exposure, particularly during the middle of the day.

Sebaceous Carcinoma

Although no well-defined standard of care exists for the treatment and management of sebaceous carcinoma, the Committee on Invasive Skin Tumor Evidence-Based Recommendations has recently published guidelines for its management.[15] Notably, the recommendations are different between extraocular and periocular sebaceous carcinoma. The Committee on Invasive Skin Tumor Evidence-Based Recommendations guidelines include the following:(A1)

• Biopsy of suspicious eyelid lesions does not require depth for diagnosis. Atypical chalazia or chronic unilateral blepharitis in patients older than 60 should raise concern.
• A complete cutaneous examination and adjacent lymph node examination should be performed. Ocular motility, proptosis, and pupillary abnormalities should be assessed.
• The 8th edition of the American Joint Committee on Cancer staging system for eyelid carcinoma may be used.
• Ultrasonography or CT scans of the nodal basins may be used. Enlarged lymph nodes should be biopsied. Sentinel node biopsy can be considered for periocular sebaceous carcinoma. This approach differs from systemic cutaneous sebaceous carcinoma, where it is not recommended.
• Evaluation of distant metastasis with a CT or positron emission tomography scan should be used for confirmed nodal metastasis.
• Genetic testing for Muir-Torre syndrome is recommended if the Mayo Muir-Torre syndrome risk score is≥ 2.
• Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment should be the primary management for periocular sebaceous carcinoma. Positive surgical margins may be treated with adjuvant double freeze-thaw cryotherapy or topical mitomycin.
• If Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment is not feasible, staged wide local excision can be performed; however, this may increase morbidity.
• Extensive orbital involvement may be treated with orbital exenteration or radiotherapy as a monotherapy. However, the literature shows orbital exenteration appears to have improved mortality rates.
• Adjuvant radiotherapy may be considered in sebaceous carcinoma with perineural invasion.
• Surveillance is recommended every 6 months for the first 3 years after treatment, then annually. Periodic lymph node basin ultrasonography may be considered. 

Melanoma

Primary treatment of local malignancy consists of local, wide skin excision. Different safety margins are typically based on the Breslow thickness of the melanoma. Sentinel lymph node biopsy (SLNB) may aid in the treatment of patients with eyelid melanoma. One study found that 21.4% of patients with eyelid melanoma had positive sentinel lymph node biopsy.[81] 

The most common locations of positive sentinel lymph node biopsy in ocular adnexal melanoma include the preauricular, intraparotid, and submandibular nodal basins.[82] Sentinel lymph node biopsy provides important prognostic information, but guidelines on when to initiate this procedure have yet to be defined.

For patients presenting with metastatic disease, surgical excision is not curative. Dacarbazine, an imidazole carboxamide chemotherapeutic agent, has been the first drug therapy for metastatic melanoma since 2006.[83] 

Biologic immunotherapies (eg, interleukin-2 and interferons), vaccination strategies, and adoptive cell therapy are all immunotherapies that have been employed to combat metastatic malignant melanoma. Most notably, immune checkpoint inhibitors (ie, ipilimumab, nivolumab, and pembrolizumab) are the newest and fastest-growing area of investigation in treating metastatic melanoma. These agents are discussed in greater detail in a separate article.[84][85](B3)

Merkel Cell Carcinoma

Before treating MCC, the tumor should be staged using the AJCC staging system. Given the aggressive nature of MCC and associated high mortality rate, sentinel lymph node biopsy should be considered. Surgical excision, radiation therapy, chemotherapy, and immunotherapy have all been used to treat MCC. For surgical excision, a wide excision with 5 mm margins is recommended. Additionally, given the radiosensitivity of these tumors, adjuvant radiotherapy may be warranted.[86][87] (B2)

Chemotherapy is effective in treating MCC as a first-line treatment for disseminated or metastatic disease rather than as a local or adjuvant treatment.[88][89][90][91] Immune checkpoint inhibitors such as pembrolizumab, nivolumab, and avelumab are currently being added to the treatment portfolio of MCC. Notably, avelumab has demonstrated efficacy in treating eyelid-specific diseases.[92][93](B2)

Differential Diagnosis

The differential diagnosis has been organized based on eyelid tissue types.

Epithelium

Premalignant lesions:

• Actinic or solar keratosis (pre-malignant)
• Seborrheic keratosis
• Keratoacanthoma
• Cutaneous horn

Malignant lesions:

• Carcinoma in situ - Bowen disease (stage 0, noninvasive malignancy)
• BCC
• Nodular
• Noduloulcerative
• Pigmented
• Infiltrating

• SCC
• Merkel cell carcinoma

Melanocytes

Premalignant lesions:

• Dysplastic nevus
• Large congenital nevi (over 20 cm in size) have an estimated risk of malignant transformation of 4% to 20%.
• Blue nevus variants: Blue nevi in their pure histopathological form are benign. However, similar variants have the potential for transformation, as observed in blue nevus-like melanoma. 
• Oculodermal melanocytosis requires semi-annual monitoring for glaucoma and melanoma of the skin, iris, and choroid.

Malignant lesions:

• Melanoma

Adnexal Lesions

Hair follicles:

• Malignant hair follicle tumor (a variant of BCC)   

Sweat glands:

• Malignant syringoma
• Mucinous sweat gland adenocarcinoma  
• Gland of Moll adenosarcoma   

Sebaceous glands:

•  Sebaceous carcinoma

Staging

The eyelid consists of 4 to 7 layers of tissue, depending on the distance from the eyelid margin. Theoretically, each of these layers can give rise to malignant neoplasms. The upper and lower eyelid layers include:

• Skin, subcutaneous tissue, and adnexa (upper and lower lids)
• Orbicularis muscle (upper and lower lids)
• Orbital septum (upper and lower lid)
• Pre-aponeurotic orbital fat (upper lid, superior to tarsus)
• Pre-capsulopalpebral fascial fat (lower lid, inferior to tarsus)
• Levator aponeurosis (upper lid)
• Capsulopalpebral fascia (lower lid)
• Müller muscle (upper lid)
• Tarsus with the meibomian glands (upper and lower lids)
• Palpebral conjunctiva (upper and lower lids)

Adnexal structures in the eyelid skin include eyelashes, sebaceous glands of Zeis, and sweat glands of Moll. The levator and orbicularis muscles are composed of striated muscle, while Müller's muscle is composed of smooth muscle.

The marginal aspect of the orbicularis muscle is called the muscle of Riolan; the superficial part of this muscle is visible as a colored line that separates the meibomian gland orifices from the row of eyelashes. This line, called the gray line, is significant because it demarcates the position of the eyelid septum. Lesions in front of the septum are called preseptal. Most malignant eyelid lesions are preseptal as they originate in the skin. 

Knowledge of the anatomy above aids in staging these lesions according to the American Joint Committee on Cancer (AJCC) TNM Classification System.[94] The AJCC has a standardized staging system that applies explicitly to the eyelid (see Table. TNM Classification for Eyelid Tumors). 

In 2021, the largest analysis of cutaneous melanoma of the eyelid was published. In this study, the 5-year overall survival rate was 88.6% for melanoma in situ and 77.1% for invasive melanoma. Additionally, age 75 or older at diagnosis, T4 staging, lymph node involvement, and the nodular melanoma histologic subtype were associated with poor survival.[95]

Additional risk stratification and staging tools include: 

• Fitzpatrick skin type 
• 8th edition of the AJCC staging system 
• Clark's level of invasion (Please refer to "Melanoma" in the Prognosis section for more information)
• Breslow tumor thickness (Please refer to "Melanoma" in the Prognosis section for more information) 

 Table 1. TNM Classification for Eyelid Tumors

Prognosis

Prognosis is variable and depends on the histopathologic classification and staging of the tumor.

Actinic Keratosis

Although actinic keratosis does not affect survival, the risk of progression to malignancy is the most significant concern, given that it is a benign lesion. Signs of progression from an actinic keratosis to malignancy include ulceration, rapid growth, size >1 cm, and inflammation.[96] Between 21% and 70% of actinic keratosis show spontaneous regression. However, their presence has been shown to incur a 6 times greater risk for skin cancer.[97] 

Basal Cell Carcinoma

Approximately 50% BCC lesions are found on the lower lid, 30% medial canthus, 15% upper lid, and 5% lateral canthus.[101] Prognosis is generally excellent, with a successful cure rate of 95% and a recurrence rate of 1% to 5% per year following surgical excision. The recurrence rate of periocular BCCs has been shown to vary based on surgical techniques. A 2020 meta-analysis of periocular BCCs excised via Mohs micrographic surgery, Frozen Section Examination controlled excision, and Wide Local Excision, with respective rates of 2.9%, 1.9%, and 5.9%. [98] However, patients with BCC associated with basal cell nevus syndrome (ie, Gorlin syndrome) have a lifelong risk of multiple BCCs.

Squamous Cell Carcinoma and Keratoacanthoma

Like in BCC, lesions of the lower lid account for the majority of SCC cases (60.8%), followed by lesions of the medial canthus (17.6%) and lateral canthus (11.8%), and upper lid (9.8%). SCC is typically more aggressive than BCC. The overall mortality prognosis is good as long as clear margins can be obtained, though significant morbidity remains. A 2002 study revealed only one death out of 51 patients with a mean follow-up of 31 months, with the only death occurring in a patient who declined treatment.[99]

Sebaceous Carcinoma

Misdiagnosis plays an integral role in the poor prognosis associated with sebaceous carcinoma. In one study of patients with sebaceous carcinoma, nearly 60% of patients had an average diagnostic delay of 14.7 months. Chalazion and blepharitis represent the most common incorrect diagnoses for sebaceous carcinoma at 15.9 to 20% and 14.4 to 25%, respectively.[37][38] This high likelihood of misdiagnosis leads to its poor prognosis and a mortality rate that was once as high as 50%.[100][101] A trend toward improved prognosis has been shown, with mortality ranging from 4% to 11%.[101][102][103][104]

Melanoma

A retrospective review involving 256 patients found that lesions involving the eyelids or caruncle had more than a 2-fold increase in mortality relative to malignant melanoma of the globe.[105] The Clark level was the first proposed grading system for melanoma and described the anatomic compartments involved by the tumor (ie, epidermis, papillary dermis, reticular dermis, and subcutaneous fat); a limitation of the Clark system was the variation in compartment thickness throughout the body.[83] In the 1970s, the Breslow staging system was created and defined the depth of invasion in millimeters (mm) rather than by anatomical compartment. 

The most commonly used staging system, the TNM (tumor, node, and metastasis) system, was introduced by the American Joint Committee on Cancer (AJCC). In 2021, the largest analysis of cutaneous melanoma of the eyelid was published, showing that the 5-year overall survival rates were 88.6% for melanoma in situ and 77.1% for invasive melanoma. Additionally, the authors found that age ≥75 years at diagnosis, T4 staging, lymph node involvement, and the nodular melanoma histologic subtype are harbingers of poor survival.[95]

Merkel Cell Carcinoma

A diagnosis of MCC imparts a poor prognosis with a mortality ranging from 33% to 46%.[106] This outcome is attributed to the delay of diagnosis, aggressive growth, nodal and distant metastases, and high incidence of local recurrence. Poor predictive prognostic factors include male sex, immunosuppression, tumor size between 2 and 5 cm, nodal metastasis, and older age. Between 10% to 30% of eyelid MCCs metastasize to distant sites, including lymph nodes, bone, brain, liver, and lung.[86][107]

Complications

Misdiagnosis may result in prolonged observation, leading to more extensive local growth of the lesion. Perineural, hematogenous, or lymphatic spread may also lead to the following misdiagnosis. Iatrogenic complications from periocular surgery and radiotherapy carry several risks, including those listed below.[108] 

• Lagophthalmos
• Symblepharon
• Eyelid retraction
• Ptosis
• Ectropion
• Entropion
• Trichiasis
• Dry eye syndrome from exposure, aqueous deficiency, or evaporation
• Damage to the nasolacrimal system
• Diplopia 
• Globe injury and damage to surrounding structures
• Orbital hemorrhage
• Infection
• Poor tissue healing (primarily with radiotherapy)
• Poor cosmetic outcome
• Psychologic distress

Each immunologic and chemotherapeutic agent carries specific complications, and clinicians should work closely with oncologists and pharmacists when considering treatment options.