Basal cell carcinoma . A 17-year-old female with a lateral canthal basal cell carcinoma
Histopathologic confirmation of a suspicious lesion can be challenging in the pediatric age group. For very young children, biopsy with frozen section evaluation under general anesthesia with immediate full excision with frozen section control of the tumor margins represents the best option for suspicious lesions. Older children will allow conventional biopsy techniques in the clinic setting with later surgical excision using frozen section control of the surgical margins in an operative setting. Tissue-preserving surgical excision is important due to the limitations in pediatric lid elasticity for repairing large defects. Continuous medical follow-up is warranted to maintain surveillance for other cutaneous malignancies associated with syndromes such as basal cell nevus syndrome .
Non-ophthalmic Conditions Associated with Pediatric Basal Cell Carcinoma
Basal cell nevus syndrome
Linear nevus sebaceous syndrome
Squamous Cell Carcinoma
Squamous cell carcinoma of the eyelids is much less common in children and occurs in the setting of predisposing systemic conditions and external influences. No reports exist defining this entity in the pediatric population except for occasional reports of younger patients as part of larger series discussing squamous cell carcinomas occurring in the general population in conjunction with other medical conditions. From those occasional cases, these lesions appear similar to adult squamous cell carcinoma on presentation but are most very likely associated with xeroderma pigmentosa (Fig. 24.2) [10–12]. One report estimates that for patients less than 20 years old with xeroderma pigmentosa, the risk of developing either basal cell or squamous cell carcinoma is 4800 times higher than the general population . Doxanas et al. reported the largest series of squamous cell carcinoma of the eyelids yet had no patient under age 19 in that study .
Xeroderma pigmentosa . (a) Intraoperative photograph showing facial features typical of xeroderma pigmentosa in a 6-year-old patient. Note the epibulbar mass almost filling the interpalpebral space in the left eye and severe ulcerative changes of the right lower lid. (b) Intraoperative photograph of the 5-year-old brother of the patient in (a), showing facial skin changes typical of xeroderma pigmentosa. A translucent medial epibulbar mass is present in the right eye. Inferior corneal opacification is present in the left eye (From Hertle et al. , reprinted with permission from Slack Incorporated)
Sebaceous Cell Carcinoma
Sebaceous cell carcinoma arises from the sebaceous glands of the eyelid (most commonly from the meibomian glands and less occasionally from the glands of Zeis), brow, and caruncle. It occurs more commonly in the upper eyelid due to more numerous glands as opposed to basal and squamous cell. Predominating in an elderly female population, it often masquerades as more benign-appearing entities such as blepharitis, conjunctivitis, or chronic, recurring chalazia. In adults it accounts for approximately 1–5% of all eyelid malignancies but is rare elsewhere in the body . Several cases involving the eyelid have been reported in children.
Three children, two patients aged 12 years, another aged 13 years, and among other reported adults developed sebaceous carcinoma of the eyelid years after high-dose radiotherapy for bilateral retinoblastoma [16–18] (Table 24.1). Knapp reported a 3½-year-old boy with an eyelid sebaceous cell carcinoma, but exact conclusions as to the accuracy of the histopathology are not definitive from his descriptions . Ni et al. included a 16-year-old female in their series of 156 sebaceous carcinomas of the periocular region  but provided no specific information about the potential origins or associations of the lesion. Schlernitzauer and Font reported the development of sebaceous cell carcinoma in the eyelid of a boy treated with radiation therapy for a facial cavernous hemangioma . Mirzamani et al. reported a 15-year-old male with a left cutaneous periorbital/temporal lesion .
Little information can be garnered from these clinical series to help specify incidence, treatment, or clinical course for pediatric sebaceous cell carcinoma. The significance of 15 cases after radiation seems to suggest that radiation and/or chemotherapy increases the likelihood for cutaneous malignancy in children. Whether retinoblastoma survivors treated with radiation therapy represent a group at particular risk remains suspect, with only these three cases reported. Prompt diagnosis followed by surgical excision seems to be the appropriate treatment, just as for adult cases.
Cutaneous melanoma is rapidly increasing in prevalence and incidence over the past 50 years, with nearly 200,000 new cases diagnosed annually . It is unusual to occur as a primary malignancy of the eyelid in children. However it is typically diagnosed in association with large periocular congenital pigmented nevi or following periorbital irradiation for retinoblastoma [24, 25]. Rarely do these lesions arise de novo on the eyelid of children. Multiple series reporting a total of 48 melanomas of the eyelids did not have any children among the cohorts studied [26–29].
In adults, eyelid melanomas first appear as pigmented lesions with a change in color and size except when on the eyelid margin, where little pigmentation may occur and a more papillary appearance can predominate. Guidelines pertaining to the surgical resection of melanomas are set by the National institute of Health and the American Academy of Dermatology Task force on Melanoma. Virtually all lesions are treated with excisional biopsy followed by a variable margin of wide surgical excision (1–2 cm or more of normal surrounding skin) depending on the depth of invasion seen on the excisional biopsy (in situ, <1 mm, 1–2 mm, >2 mm) . All patients subsequently require long-term surveillance for regional and systemic metastasis. Most patients are able to detect a clinical change, suggesting local recurrence of a previously resected melanoma, while systemic testing and physician examination typically helps detect metastasis . Frozen section control and Mohs excision have proven to be inadequate for assessing complete excision in pigmented skin lesions, hence wide surgical excision after pathologic confirmation of the tumor characteristics and depth of invasion is recommended.
The relative risk for developing eyelid cancer in the pediatric population is increased in individuals identified with any of these conditions: congenital giant hairy nevi, xeroderma pigmentosa, and the linear nevus sebaceous syndrome. Pilomatrixoma (also called pilomatricoma) is an upper eyelid or lower eyebrow lesion that has the potential to transform into a carcinoma and is discussed in Chap. 23.
Congenital Giant Hairy Nevi
Congenital giant hairy nevi or congenital nevomelanocytic nevus (CNN) are heavily pigmented melanocytic nevi with raised surfaces , irregular borders, and heavy concentrations of hair that are visible at birth (Fig. 24.3). Approximately 20% involve the head and neck, of which over half have eyelid involvement . Debate remains over the exact risk for malignant transformation to malignant melanoma; reports vary from 4.6 to 41% . The larger numbers reported may be attributable to most of these series being reported from tertiary care centers that see more malignant transformations than benign lesions. A study at the University of Pennsylvania reported a 5.7% cumulative 5 year risk of developing melanoma in a large or giant CNN .
Congenital giant hairy nevus . (a) A 13-year-old male with a right facial congenital giant hairy nevus. Note the extension around the lateral canthus and involvement of the upper eyelid. (b) Close-up of the same patient showing a small conjunctival nevus adjacent to the marginal lower lid nevus
This transformation rate, along with a high mortality rate early after discovery of the malignant degeneration, has led to the recommendation for the prophylactic removal of these nevi to avoid future malignant transformation . Due to their large size, full-thickness skin involvement, and proximity to eyelid margins, complete excision is functionally and cosmetically challenging. Laser therapy offers a better alternative since argon and Q-switched ruby lasers can target melanin. However this technique leaves potential nests of nevus cells for future malignant transformation. Additionally, loss of pigment following laser makes the clinical detection of change in color and potential malignant transformation in the nevi difficult.
The full-thickness excision of these lesions can be challenging. Besides simple excision with primary closure, full-thickness grafting, rotational flaps with or without tissue expansion, and microvascular free tissue transfer of muscle or composite tissue have been utilized in pediatric facial reconstructions. Each nevus requires a unique approach balancing surgical removal and reconstruction against the size and location of the nevus along with the risk of malignant transformation (see Chap. 13, Fig. 13.20).
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disease that affects the enzyme system responsible for DNA repair after damage from ultraviolet radiation. It is characterized by cutaneous, ocular, and neurologic abnormalities (Fig. 24.2) . The earliest manifestations appear between the ages of 1 and 2 years, as sun sensitivity with easy sunburning and freckling. Over time, malignant transformation to cutaneous basal cell carcinoma, squamous cell carcinoma, and malignant melanoma occurs with the latter two malignancies being the most common cause of death in XP patients. Incidence of the disease is low in the USA (1/250000) however it is more commonly seen in patients of Japanese and Middle Eastern descent . A total of 97% of all skin malignancies develop in sun exposed areas, mainly the face, head, or neck regions; the median age for first diagnosis of one of these malignancies is 8 years old . Progressive mental deterioration, deafness, delayed growth, and hyporeflexia are neurologic abnormalities reported in 25% of patients . Any ocular tissue exposed to light can exhibit changes, resulting in eyelid and conjunctival malignancies, with resultant ectropion, exposure keratopathy, corneal neovascularization and loss of vision [10–12].
The most common genetic defect lies in the reduction or elimination of nucleotide excision repair (NER) enzymes. This biochemical defect in fibroblasts results in abnormal DNA repair after UV-induced damage and sets the stage for eventual malignant transformation with continued light exposure . The exact incidence of cutaneous and conjunctival malignancies in this condition is not well established, but Kraemer et al. found 88 patients with neoplasms among the 830 reported cases studied, for an incidence of 10.6% . For lid malignancies alone, his literature review could not pinpoint an exact frequency or histopathologic verification, but it appears that squamous cell carcinoma was the most common, followed by basal cell carcinoma and then malignant melanoma. Again, this syndrome should be considered quite strongly in a child diagnosed with any cutaneous eyelid malignancy.
Basal Cell Nevus Syndrome
Basal cell nevus syndrome also known as Nevoid basal cell carcinoma , Gorlin syndrome, and Gorlin-Goltz syndrome , is a rare autosomal dominant disorder caused by a mutation in the PTCH gene (Patched) gene found on chromosome 9 with variable penetrance. It is characterized by the development of multiple basal cell carcinomas in the first and second decades of life. Other typical manifestations are jaw cysts (keratocystic odontogenic tumor, found in 75%), bifid ribs, mental retardation, cardiac fibromas, ovarian cysts/fibromas and testicular disorders. Facial features include frontal/temporo-parietal bossing, and mandibular prognathism. About 30% of affected individuals manifest ocular abnormalities [9, 37, 38]. Prominence of the supraorbital ridges, hypertelorism, canthal dystopia, strabismus, congenital cataract, congenital glaucoma, and colobomas of the choroid and optic nerve, and microphthalmia have been seen in patients with this syndrome [37, 38].
Basal cell carcinoma seen in basal cell nevus syndrome occur all over the body namely areas not exposed to the sun such as palms and soles of feet, whereas those in xeroderma pigmentosa occur almost exclusively in sun-exposed areas. Eyelid involvement is frequent in this condition, occurring in about 22% of cases. The upper lid is involved almost 3 times more than the lower lid, as opposed to the general non affected population where the lower eyelid is more frequently involved . Lesions arise at a median age of 13 and bear a resemblance to trichoepitheliomas, except that they are widespread, centrally ulcerated, and large. The trichoepitheliomas seen in Brooke’s tumor concentrate in the nasolabial fold, are small, and do not ulcerate. These basal cell carcinomas are also highly aggressive with 25% of affected individuals requiring exenteration secondary to invasive malignancy in the orbit . Other malignancies in this syndrome are rare, except for cerebellar medulloblastomas, which have been reported in some cases.
Linear Nevus Sebaceous Syndrome
The linear nevus sebaceous syndrome , also known as Schimmelpenning syndrome , is a neurocutaneous condition characterized by one or more sebaceous nevi, usually appearing on the face or scalp. Central nervous system, ocular, skeletal, and cardiovascular anomalies are associated findings [41, 42]. Most cases manifest with a congenital nevus with minimal pigmentation. On histology, epidermal papillomatous hyperplasia is noted with overdevelopment of the sebaceous glands (Fig. 24.4). Clinically, the lesions appear as large, well-defined, yellow to orange in color, with a waxy, pebbly, papillomatous surface that frequently becomes more prominent around puberty . Enlargement after this pubertal change is often associated with development of a secondary tumor, such as basal cell carcinoma or squamous cell carcinoma, and occurs in about 35% of patients .
Linear nevus sebaceous . A 10-year-old male with a linear nevus sebaceous involving the medial right upper lid with extension into the medial forehead
This lesion was first described in in 1895 by Jadassohn as the cutaneous manifestation of a phakomatose syndrome characterized by the triad of linear nevus sebaceous, seizures, and mental retardation [43, 46, 47]. The ocular findings are myriad and occur in approximately 68% of patients [43, 44, 47, 48]. These include upper lid colobomas, ptosis, ectropion, epibulbar choristomas, lipodermoids, corneal leukoma, iris and choroidal colobomas, strabismus, and microphthalmos, as well as numerous other single-case associations. Most malignant degenerations occur within the nevus itself and are typically basal cell carcinomas with rare reports of sebaceous cell carcinoma and squamous cell carcinoma . An estimated malignant transformation rate of 35% warrants complete surgical excision for lesions associated with the linear nevus sebaceous syndrome.
Eyelid Malignancies Associated with Systemic Conditions
Three lid lesions seen in the pediatric age group have a high correlation with being associated with potentially lethal systemic conditions : Kaposi’s sarcoma (in patients affected with AIDS), histiocytic lid lesions (Langerhans cell histiocytosis), and leukemic/lymphomatous lid infiltrations (acute myeloblastic leukemia/lymphoma).
Kaposi sarcoma (KS) is a tumor commonly seen in acquired immunodeficiency syndrome (AIDS) occurring in approximately 50% of affected patients . It presents with cutaneous lesions with or without internal organ involvement and is caused by an infection with Human Herpes Virus 8 (also known as KS-associated Herpes Virus KSHV). The viral cause for this tumor was established in 1994 . Lesions in KS are reddish violaceous lesions that take the forms of macules, nodules, or patches that may be confluent. KS is not a true sarcoma (mesenchymal origin) as the name implies, histologic sections of the tumor reveal elongated spindle cells that form slits containing red blood cells . Uncommon prior to 1982, when only 30 identifiable cases of ocular involvement could be identified, its association with AIDS has led to an epidemic of these cutaneous and visceral lesions . KS infrequently results in significant morbidity or mortality.