Conjunctival Nevus

Abstract

Purpose of Review

To provide an up-to-date review of the epidemiology, presentation, diagnosis, and treatment options for conjunctival nevi (CN).

Recent Findings

Around 17.2%–42% of all conjunctival tumors have been found to be CN, which most frequently present in White individuals between the first to early third decade of life, with equal distribution between males and females. CN commonly occur in the interpalpebral bulbar conjunctiva with pigmentation ranging from amelanotic to dark. Diagnosis is typically made through slit lamp examination, visualized by a well circumscribed, variably elevated, variably pigmented, solitary lesion with clear cysts distributed throughout the pigment. In ambiguous cases, anterior segment optical coherence tomography (AS-OCT) can highlight the presence of sub-clinical cysts, whose presence points to a diagnosis of nevus. However, excisional biopsy with histopathology examination is the gold standard for identifying CN.

Summary

CN are benign, variably pigmented lesions. They are the most common of the conjunctival melanocytic tumors. Due to the extremely low risk of transformation to malignant melanoma (MM), CN are usually managed with routine observation and photo documentation.

Introduction

Conjunctival nevi (CN) are benign pigmented lesions of the conjunctiva [1, 2]. CN are seen more frequently in White individuals and have an equal distribution between males and females [1]. Nevi are further classified into congenital (present during the first 6 months of life) or acquired based on time of first appearance [3]. The majority of CN are acquired, becoming clinically apparent during the first to early third decade of life [1, 4]. CN most commonly appear in the interpalpebral bulbar conjunctiva near the limbus with slight elevation and variable pigmentation, ranging from amelanotic to darkly pigmented [1, 4]. Although risk of transformation into malignant melanoma is less than 1%, routine monitoring for change in size or color is recommended [1, 2, 4].

Epidemiology

In the literature, 17.2% to 42% of conjunctival tumors have been found to be CN [5–14]. The wide prevalence range is likely attributed to variation among different geographic regions and racial/ethnic groups. One retrospective series out of a tertiary referral center in Philadelphia, Pennsylvania examined 5002 conjunctival tumors of 4625 individuals over a 40-year period and found a CN prevalence of 23%. Furthermore, 45% of all melanocytic tumors were found to be CN [11]. Table 1 summarizes studies that examined CN prevalence among all conjunctival tumors in various populations.

Table 1.

Retrospective studies assessing the frequency of conjunctival nevi (CN) within all conjunctival tumors

Study	Location	Mean age at tumor diagnosis	Sample size	% CN within sample
Mirzayev et al., 2022 [7]	Ankara, Turkey	53 years, all conjunctival tumors	410	17.8%
Pellerano et al., 2020 [9]	Dominican Republic	32 years, nevus only	138	34.1%
Garcia Onrubia et al., 2019 [14]	Valladolid, Spain	63 years, all melanocytic lesions	462	29.9%
Dalvin et al., 2018 [6]	Olmsted County, Minnesota, USA	40 years, nevus only	504	41.7%
Shields et al., 2017 [11]	Philadelphia, Pennsylvania, USA	50 years, all conjunctival tumors	5002	23.3%
Novais et al., 2010 [8]	Montreal, Quebec, Canada	40 years, nevus only	271	18.5%
Amoli et al., 2006 [12]	Tehran, Iran	22 years, nevus only	447	38.7%
Shields et al., 2004 [10]	Philadelphia, Pennsylvania, USA	45 years, all melanocytic lesions	1643	27.6%
Grossniklaus et al., 1987 [13]	Baltimore, Maryland, USA	41 years, nevus only	1163	17.2%

In the series of 5002 conjunctival tumors, gender distribution for CN was equal with 50% female and 50% male [11]. For racial breakdown, 83% individuals were White, 6% African American, 7% Asian, 3% Hispanic, and < 1% Middle Eastern [11]. Similar findings were noted in other parts of the world. In a series of 255 patients in Brussels, Belgium, gender distribution was similar between females and males (55% and 45%) and racial breakdown again revealed that White individuals were most likely to present with CN (85% White, 13% African American, 1% Asian, and < 1% Hispanic) [3].

Risk Factors

Risk factors for CN are unknown. Viral presence has been examined as a possible contributor to CN development. One study examined various conjunctival tumors (including CN, melanoma, and invasive squamous carcinoma, n = 12) for the presence of human papillomavirus (HPV) types 16 and 18, which are implicated in squamous cell carcinoma of the cervix, anogenital region, and oropharynx [15]. HPV DNA was detected in all of the dysplastic specimens, but not in CN or melanoma specimens. As such, it does not seem that HPV is a risk factor for CN [15].

There are factors, however, linked to the change in appearance of CN; specifically, hormonal alterations such as in pregnancy or puberty [16]. In a study of 149 CN that were observed for an average of 11 years, 20 (13%) lesions developed a change in pigmentation and 12 (8%) lesions developed a change in size [17]. A possible explanation to this observation is the noted presence of hormone receptors within CN. One German study of 27 CN found that 64 ± 25% of CN cells expressed progesterone receptors and 35 ± 34% expressed estrogen receptors [18]. However, the distribution of hormone receptors has varied in the literature. In a Swiss study of 76 conjunctival melanocytic tumors (including CN, primary acquired melanosis (PAM), and melanoma), 96% of the lesions expressed progesterone receptors and 0% expressed estrogen receptors, with no difference in expression between the different lesion types [19]. Sun exposure has also been hypothesized to increase the number of melanocytes, resulting in an increased degree of CN pigmentation and apparent or actual size [20].

Clinical Presentation

CN presents as well circumscribed, variably pigmented lesion ranging from a complete lack of pigmentation (Fig. 1a) (often in children) to a dark brown color (Fig. 2a and Fig. 3) [21, 22]. CN are also variably elevated, ranging from relatively flat to slightly raised and can present as focal or diffuse lesions [20, 22]. Other features of CN include presence of clear cysts uniformly distributed throughout the pigment [16, 21]. Feeder and episcleral vessels may also be present in a minority of CN [1]. The lesions are mostly unilateral and freely mobile across the conjunctiva, except for occasional attachment at the limbus [1, 20]. CN that are located at the limbus do not extend onto the peripheral cornea [21]. Melanocytic lesions that are attached to structures other than the limbus, such as to the episclera or sclera, or extend onto the cornea should raise suspicion for melanoma [20, 21].

Fig. 1.

(a) Slit lamp photo of an amelanotic nevus at the limbus. (b) Optical coherence tomography of a sub-clinical cyst (white arrow), favoring the diagnosis of nevus

Fig. 2.

(a) Slit lamp photo of a pigmented nevus at the limbus with a large adjacent cyst. (b) Optical coherence tomography with a large cyst (white arrow)

Fig. 3.

Slit lamp photo of a pigmented nevus near the limbus with small cysts within areas of pigmentation

In terms of location, a study of 410 individuals with CN living in Philadelphia, Pennsylvania found the interpalpebral bulbar conjunctiva (72%) to be the most common site, followed by the caruncle (15%), plica semilunaris (11%), fornix (1%), tarsus (1%), and cornea (< 1%) [17]. Since the majority of CN are located at the interpalpebral location, one should have a high suspicion for other lesions, such as melanoma, when lesions are located in the forniceal or palpebral regions [4]. In terms of quadrants, CN was more frequent in the temporal (46%) and nasal (44%) quadrants compared to the superior (6%) and inferior (5%) quadrants [17].

Types of Conjunctival Nevi

CN are commonly categorized by histopathology into three main subtypes—junctional, compound, and subepithelial—based on melanocyte localization [1].

Junctional nevi compose about 5% of all CN and are mostly seen in children [22]. They develop from a benign proliferation of nevus cells that can have an epithelioid appearance and mitotic activity [1]. These cells are usually arranged in discrete nests found only within the conjunctival epithelium along the epithelial and subepithelial junction [1, 21]. While it is possible for some nests to protrude into the substantia propria, the basement membrane is usually intact [21]. Clinically, junctional nevi appear flat and may be difficult to detect due to limited production of melanin pigment [1, 21]. On histopathology and clinically, junctional nevi and PAM often have similar features [20]. Therefore, the age of the patient is critical for diagnosis as PAM is usually seen in middle-aged patients, and CN in younger patients [20].

Compound nevi represent about 70–78% of all CN and are thought to develop from junctional nevi as the nevus cells descend from the epithelium into the superficial substantia propria [16, 22]. Therefore, melanocytes in compound nevi are found in the epithelium and within the substantia propria (Fig. 4) [1]. They are characterized by protrusions from the epithelium into the substantia propria forming intralesional epithelial cysts lined by goblet cells [22]. Clinically, compound nevi are often thick and the cystic areas can be used as a distinguishing factor from melanoma, where cysts are rare [1].

Fig. 4.

Nests of nevus cells present within both the epithelium (arrows) and the substantia propria (asterisks), seen with (a) hematoxylin and eosin staining (× 200) and (b) Melan-A with red chromagen staining (× 200)

Subepithelial nevi compose about 9% of all CN and are more common in older individuals [22]. They develop as the epithelial component of the nevus is lost, leaving melanocytes only in the substantia propria, the majority being in a post-mitotic state [21]. Clinically, subepithelial nevi are usually amelanotic and elevated with a cystic component [1, 21].

Other variants of CN that occur less frequently include blue nevi, cellular blue nevi, combined nevi, deep penetrating nevi, inflamed juvenile nevi, and Spitz nevi—all of which are benign lesions [1, 20, 21].

Blue nevi typically present in the sixth decade of life as well circumscribed, dark brown, black, grey, or blue slightly raised lesions (Fig. 5) [1, 23]. They are characterized by spindle-shaped, dendritic, and stellate melanocytes within the substantia propria with no mitotic activity [1, 20, 23]. In contrast, cellular blue nevi have some mitotic activity and contain spindle or polygonal cells arranged in islands [23]. It is possible for blue nevi to occur with compound or subepithelial nevi to form a combined nevi [17, 23].

Fig. 5.

Slit lamp photo showing large, flat, blue-brown lesions on the inferior fornix diagnosed as blue nevi

Deep penetrating nevi (DPN) are darkly pigmented lesions that can also occur in combination with other types of nevi [1]. Histologically, they are composed of spindled to epithelioid melanocytes located primarily in the subepithelium. Suspicion for melanoma within a preexisting nevus may occur when DPN appear with other nevi due to the cells of DPN being larger than that of the other nevi [1].

Inflamed juvenile nevi are classically observed in adolescents with a history of allergic disorders such as allergic or vernal conjunctivitis [1, 24]. They are most commonly located at the limbus and can often raise suspicion for malignancy due to their ability to rapidly enlarge [21, 24]. However, they are histologically benign and characterized by extensive inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils [21]. Other distinguishing features to rule out malignancy include the presence of epithelial inclusion cysts and nests in the substantia propria [21].

Spitz nevi are predominately seen in children as elevated, well-circumscribed, nonpigmented lesions that have the ability to rapidly grow [1]. Histologically, they are characterized by the formation of vertical nests of spindled melanocytes oriented perpendicularly to the epithelium and extending into the subepithelium [1, 21]. Specifically, the melanocytes are observed to have large nuclei with prominent nucleoli and abundant cytoplasm [1]. They may also contain a vascular component and mitotic figures, which when coupled with rapid growth, can raise suspicion for malignancy [1, 21]. However, the presence of eosinophilic globules composed of apoptotic melanocytic elements can exclude the diagnosis of melanoma [21].

Diagnosis

CN are typically diagnosed on slit lamp biomicroscopy based on the features noted above.

Anterior segment optical coherence tomography (AS-OCT) can assist in the diagnosis by displaying cysts within the lesions that were not apparent clinically (Fig. 6) [16, 25]. In a case series of 57 CN imaged with AS-OCT, the lesion appeared homogenously solid and all margins could be clearly visualized [26]. Intrinsic cysts were visualized in 61.4% of cases on AS-OCT, compared to only 40.3% of cases on slit lamp biomicroscopy [26]. However, the reported utility of AS-OCT in detecting cysts compared to slit lamp biomicroscopy is variable. In another case series of 22 eyes with CN, cysts were visible in 77% of cases on AS-OCT, compared to in 82% of cases on slit lamp biomicroscopy [25]. Specifically, in one case, cysts were visualized with slit lamp biomicroscopy and not on AS-OCT. However, all cysts that were visualized with AS-OCT were also seen on slit lamp biomicroscopy. When compared to histopathology, the sensitivity and specificity of AS-OCT for detecting intrinsic cysts was 80% and 100%, respectively. In contrast, the sensitivity and specificity when comparing histopathology to slit lamp biomicroscopy for intrinsic cyst detection was 100% and 100%, respectively. The main drawback with AS-OCT is that visualization is limited in lesions with dark pigment, with shadowing of the deeper structures [25]. Therefore, the utility of AS-OCT versus slit lamp biomicroscopy for detecting cysts in CN is inconclusive.

Fig. 6.

(a) Slit lamp photo of a temporal pigmented nevus with a cyst (black arrow), also visualized on (b) optical coherence tomography (white arrow). (c) Photo of a nasal nevus with fairly uniform pigment and no cysts visualized on slit lamp. (d) However, on optical coherence tomography, cysts (white arrows) were visualized

The gold standard method for diagnosis of CN is through excisional biopsy and histopathologic examination [27]. In a Belgian study of 255 patients with CN, 75 (29%) underwent excisional biopsy [3]. Of the 75 cases, the decision to biopsy was recommended by the ophthalmologist in 13 cases (17%), and desired by the patient in 62 cases (83%). In the 13 cases, operative excision was recommended due to the ophthalmologist’s concern for malignant transformation either due to suspicious features on slit lamp biomicroscopy (10 cases) or to tumor growth (3 cases). In the 62 cases where operative excision was elected by the patient, concern for cancer by the patient was the main reason (34 cases), followed by ocular surface irritation (19 cases), and lastly, cosmetic concerns (9 cases). Through histopathologic examination, all 75 of the excised lesions were diagnosed as CN (55 compound nevi, 16 subepithelial nevi, and 4 junctional nevi). Factors associated with surgical excision were examined in this cohort. Features found to be predictive of excision (compared to observation) included higher patient age (37 ± 19 years vs. 29 ± 18; p = 0.001), large basal tumor diameter (5.3 ± 2.3 mm vs. 3.9 ± 2.3; p < 0.001), tumor location at the superior bulbar conjunctiva, caruncle, or plica (10.7% vs. 7.2%, 30.7% vs. 18.3%, 14.7% vs. 6.1%; p = 0.023), absence of clear cysts (54.7% vs. 37.8%; p = 0.013), minimal or prominent intrinsic vasculature (72.0% vs. 50.6%; p < 0.001), presence of feeder vessels (46.7% vs. 18.9%; p < 0.001), and corneal involvement (24.0% vs. 11.1%; p = 0.008) [3]. Therefore, decision to undergo excisional biopsy and histopathologic examination can be made based on the presence of features indicating possible malignant transformation or patient preference.

Differential Diagnosis

Other diagnoses to consider when assessing a conjunctival pigmented lesion include primary acquired melanosis (PAM), complexion associated melanosis (CAM), malignant melanoma (MM) and ocular melanocytosis [2, 4].

PAM accounts for 24% of melanocytic lesions and is predominately found in White females in the sixth decade of life (Fig. 7) [1, 11]. The time of first appearance is important to note as pigmented lesions presenting at a young age are more likely to be CN rather than PAM [2]. Clinically, PAM presents as a flat, unilateral, diffuse lesion with dusting of pigmentation from yellow to brown that can change over time [2, 4, 16]. The lack of cystic components and noncircumscribed appearance are helpful features to distinguish PAM from CN [2]. They most commonly present in the temporal region of the bulbar conjunctiva, but may also present in the limbal, palpebral, and caruncular conjunctiva, as well as the cornea and fornix [1, 16]. PAM are divided into two categories – PAM with atypia and PAM without atypia – which can only be distinguished through histopathology [1, 16]. Distinction between the two categories is important as PAM with atypia has up to a 50% risk of transformation into malignant melanoma, whereas risk of transformation in PAM without atypia is nearly 0% [4].

Fig. 7.

Slit lamp photo of a flat, pigmented lesion consistent with primary acquired melanosis

CAM, or racial melanosis, comprises 7% of melanocytic lesions and is seen in darkly pigmented individuals (Fig. 8) [11, 16]. Similar to PAM, CAM presents as a flat, diffuse, noncircumscribed lesion with a patchy pigmented appearance that can change over time [4, 16]. However, distinguishing features of CAM from PAM and CN include bilateral presence, darker skin complexion, and location most commonly at the limbus [1]. Similar to CN, transformation of CAM to melanoma is extremely rare [16].

Fig. 8.

Slit lamp photo of perilimbal pigmentation consistent with complexion associated melanosis

MM accounts for 23% of melanocytic lesions and most commonly arises from PAM with atypia, and less commonly de novo or from CN (Fig. 9) [22]. The median age of presentation is 62 years with a slight predominance in males [1]. Clinically, MM appears as a unilateral, elevated, immobile, light to dark brown lesion with vascularity [16]. MM most commonly arises on the bulbar conjunctiva near the limbus in the temporal quadrant and less commonly on the caruncle, forniceal, or palpebral conjunctiva [11]. Although these regions are less common for MM, they are highly atypical for other pigmented lesions and therefore, any lesion in these areas are likely MM and should be biopsied [22]. Additionally, any pigmented lesion with recent increase in size or change in appearance should raise suspicion for MM [16].

Fig. 9.

Slit lamp photo of a dark, irregular, raised lesion and perilimbal pigmentation consistent with malignant melanoma

Ocular melanocytosis is characterized by flat, grey to brown, pigmented regions on the episclera (Fig. 10) [4]. Although these lesions typically do not have conjunctival pigmentation, they may be confused as such since the pigmented episclera appears through the overlying conjunctival tissue. However, unlike CN, the pigment will not be freely moveable with the conjunctiva. In addition to the episclera, the uvea may contain similar pigmentation. There is a 1/400 risk of developing uveal melanoma with ocular melanocytosis, but no risk of developing conjunctival melanoma [4].

Fig. 10.

Slit lamp photo of pigmentation in the episclera consistent with ocular melanocytosis

Treatment

Due to the low risk of transformation to melanoma, CN are usually managed with serial observation [4, 16]. This includes a routine slit lamp examination with photographic documentation every 6 to 12 months to monitor for any changes in size, pigmentation, or evidence of potential malignancy [4, 22]. Any CN that is enlarging or darkening, appears inflamed or acquires new vessels, or located at the forniceal or tarsal conjunctiva, should be excised with subsequent histopathological examination [1].

If excisional surgery is indicated, it should be performed using the no-touch technique to prevent seeding of any potentially malignant cells into adjacent tissues [16]. CN is excised with wide, 4- mm margins in order to avoid direct manipulation or contact with the lesion [16]. For lesions that involve the cornea or the sclera, alcohol epitheliectomy and superficial sclerectomy are performed, respectively, to ensure lesion-free margins [1, 16]. The excised specimen is then oriented and sent for histopathologic examination to assess for malignancy [16]. After excision, double-freeze, slow-thaw cryotherapy is applied to the surgical margins of the bulbar conjunctiva to prevent recurrence in the event that the CN proves to be malignant [1, 16].

When the surgical site defect after excision is too large for primary closure, an amniotic membrane transplant (AMT) or conjunctival autograft (CAG) can be used for reconstruction [1]. Reconstruction of the conjunctival defect helps with wound healing and limits scar and symblepharon formation, decreasing the risk of mobility restriction [16]. Previous studies have compared AMT and CAG to assess the efficacy after surgical excision of pterygium [28–31], but not after CN removal. A study of 44 eyes treated with AMT and 42 eyes treated with CAG post-pterygium removal evaluated the frequency of pterygium recurrence after excisional surgery [29]. The AMT group had a significantly higher proportion of pterygium recurrence compared to the CAG group (40.9 vs. 4.8%; p < 0.001) at up to 12 months postoperatively. Additionally, in the CAG group, all recurrences occurred within 3 months postoperatively, whereas in the AMT group, recurrences were observed at 3 months, 6 months, and 12 months postoperatively [29]. Similar findings were noted in other studies. In a study of 21 eyes who received AMT and 21 eyes who received CAG post-pterygium excision, the AMT group had a higher frequency of inflammation at one month compared to the CAG group (84.2 vs 15.0%; p = 0.02) [31]. Additionally, a higher proportion of individuals in the AMT group required a subconjunctival injection of corticosteroids compared to the CAG group (63.1 vs. 10.0%; p < 0.001). However, the higher frequency of inflammation noted in the AMT group may have been driven by postsurgical sutures being removed 1 week later compared to the CAG group. After control of inflammation, both groups had similar final outcomes measured by pterygium recurrence (10.5 vs. 10.0%; p = 0.92) [31]. Therefore, while the literature is inconclusive regarding whether AMT or CAG is optimal for reconstruction after CN removal, there is a preference for CAG as the material of choice [28–31].

As no studies have compared AMT versus CAG for reconstruction after CN excision, the decision to use AMT or CAG may vary depending on CN size, location, and other patient factors. For example, in surgical excisions that result in a larger conjunctival defect or produce defects in multiple areas, it may not be possible to harvest a CAG large enough to cover the entire region [29, 30]. In addition, in cases where the conjunctiva must be preserved for future procedures such as trabeculectomy for glaucoma, CAG may not be feasible [29, 30]. In these circumstances, AMT is a viable option [30]. AMT has been shown to reduce fibrosis and scar formation by suppressing transforming growth factor-β (TGF-β) and fibroblast differentiation, decreasing the risk of motility restriction [29, 32]. By acting as a basement membrane substrate, AMT may promote epithelial regeneration and proliferation, speeding the healing process [29, 30]. However, in cases where CAG is possible, it should be considered given several studies that found improved outcomes with CAG compared to AMT after pterygium excision [28–31]. For excisions in the limbal area, CAGs containing limbal tissue can be considered to improve healing by providing stem cells to the corneal epithelium [29, 30]. Further studies are needed to evaluate the efficacy of CAG and AMT after surgical excision of CN.

Outcomes After Excision

A few studies have investigated outcomes after surgical excision of CN [17, 33]. In a Danish study of 335 excised CN followed over a period of 21 years, there were 9 (2.7%) recurrent cases [33]. Of these cases, 7 recurred as CN, 1 recurred as MM, and 1 pigmented lesion that was classified as a junctional nevus transformed into PAM. The case that recurred as MM was previously excised as a compound nevus. Six of the CN were excised and recurred during the study period (21 years) and 3 were excised prior to the study period and recurred during the study period. However, no further information was given regarding time to recurrence. Eight of the 9 recurrent cases occurred in females specifically during the teenage years or fourth to fifth decades of life, supporting a potential hormonal mechanism related to recurrence [33]. Another study reported similar outcomes after excision. In a study of 410 CN in Philadelphia, Pennsylvania, of which 160 were surgically excised, 10 (6.3%) cases recurred, with 8 recurring as CN and 2 recurring as MM [17]. For the 2 cases recurring as MM, this occurred over a mean time frame of 7 years. The time frame of recurrence for the 8 cases recurring as CN was not reported [17]. Taken together, these studies provide evidence of the low risk of recurrence after surgical excision of CN, but highlight the possibility of transformation to MM even after removal.

Conclusion

CN are benign, variably elevated and variably pigmented, conjunctival lesions that are managed through periodic observation in the majority of cases. Identifying specific features, such as the presence of clear cysts, well-circumscribed appearance, and mobility across the conjunctiva, can assist in distinguishing CN from other pigmented lesions of the conjunctiva. In more ambiguous cases, diagnostic tools such as AS-OCT may be utilized before deciding to perform excisional biopsy with histopathologic examination. While transformation of CN to MM is extremely rare, these two entities can have overlapping clinical features and an excisional biopsy should be performed for ambiguous lesions. Given the considerable difference in prognosis, accurate diagnosis is crucial for appropriate management and treatment.