Establishing the diagnosis

• Etiology and epidemiology
• Benign eccrine sweat gland tumor
• Most cases are sporadic, but there is a genetic autosomal dominant inheritance pattern (Font, AFIP).
• More common in young women
• Slight predilection in Asians (Font, AFIP)
• Clinical features
• Can be subtle and not noticeable to the patient
• Characteristic appearance: yellow-brown in color, flat or rounded, and cystic (Figure 1)

Figure 1. Syringoma.

• Can be solitary or multiple
• Multiple variants are often bilateral, symmetric, and most prominent on the lower eyelids.
• Range in size from 1–3 mm
• Evaluation to establish the diagnosis
• Definitive diagnosis by histopathology
• Numerous small ducts embedded in sclerotic stroma in the superficial dermis (Font AFIP)
• Walls of ducts are lined by 2 rows of cuboidal-to-flattened epithelial cells (Saitoh 1993).
• Lumen contain periodic acid-Schiff-positive, eosinophilic, amorphous debris.
• Ducts may show a "tadpole" or comma-shaped extension of small basaloid cells.

Risk factors

• Down syndrome
• Chromosomal aberrations in Down syndrome predispose people to dysfunction of sweat glands (Saitoh 1993).
• Up to 18% of people with Down syndrome develop sweat-gland tumors.
• Diabetes mellitus: Pathogenesis unknown
• Marfan syndrome
• Connective tissues and exocrine glands are affected, leading to overproduction of sweat glands (Font, AFIP).
• Ehlers-Danlos syndrome
• Overproduction of sweat leading to sweat-gland tumors (Font, AFIP)

Differential diagnosis

• Acne Vulgaris
• Apocrine hidrocystoma
• Basal cell carcinoma
• Milia
• Pilomatricoma
• Sebaceous adenoma
• Sebaceous hyperplasia
• Trichoepithelioma

Clinical management

• Observation
• Surgical excision, with particular attention to removing the deep core of the lesion
• CO₂ laser ablation (Cho 2011), especially useful when multiple

Complications of treatment

• Rare; recurrence uncommon, unless multiple
• Post-laser transient hyperpigmentation (Hasson 2012)

Establishing the diagnosis

• Etiology and epidemiology
• Originate from the outer sheath of the hair follicle
• Sporadic cases are common (Font, AFIP).
• Most commonly occurs in white females
• Multiple tumors may be a marker of Cowden's disease or multiple hamartoma syndrome, an autosomal dominant condition with an increased risk of breast, thyroid, and gastrointestinal carcinoma.
• Clinical features
• Slow growing, asymptomatic papule and/or plaque on the face
• Can be solitary or multiple (Hidayat 1980)
• Rarely involves the lid margin or the inner canthus
• Flesh-colored, nodular or papillomatous, resembling verruca vulgaris or basal cell carcinoma (Hidayat 1980)
• Vary in size from 1 to 5 mm in diameter on the face or neck (Font, AFIP)
• Testing and evaluation to establish the diagnosis
• Definitive diagnosis by histopathology
• Glycogen-rich cells with clear cytoplasm (Font, AFIP)
• Peripheral palisading of columnar cells
• Often gets misdiagnosed as basal cell carcinoma

Risk factors

• Association with Cowden syndrome: Trichilemmoma is autosomal dominant with abnormal PTEN tumor suppressor gene on chromosome 10q23 (Al-Zaid 2012).
• Postulated that these could be caused by a virus because of morphologic and histologic features that they share with verruca

Differential diagnosis

• Verrucca vulgaris
• Acneiform eruptions
• Cutaneous horn
• Folliculoma
• Trichoepithelioma
• Trichofolliculoma
• Basal cell carcinoma
• Trichilemmal carcinoma

Clinical management

• Observation
• Surgical excision
• Laser ablation (CO₂)
• Cryosurgery (Shields 2008)

Complications of treatment

Rare; recurrence uncommon, unless multiple

Establishing the diagnosis

• Etiology and epidemiology
• Develops from hair matrix cells
• Unknown etiology; sporadic and familial
• Familial cases have been observed but mode of inheritance is unclear (Zloto 2014)
• Tendency to affect young individuals
• Involves the periorbital region in 17% of cases (Font, AFIP)
• 40% develop in the first decade of life, 20% in the second (Font, AFIP).
• Pertinent elements of the patient history
• Slow growing, over months to years
• Asymptomatic, but can encounter episodes of inflammation or ulceration
• Rapid growth is rare, but there have been reports.
• Clinical features
• Subcutaneous red to blue mass that is fairly well circumscribed, freely movable, and firm or gritty to palpation (Figure 2)

Figure 2. Pilomatrixoma (Kumar 2008)

• Some reaching 1 cm in 2 weeks (Zloto 2014)
• Characteristic location near the lateral aspect of the eyebrow
• Most commonly involve the head and neck region followed by upper extremities, trunk, and lower extremities.
• Average size of 10 mm or less (Shields 2008)
• Can be cystic to firm with intact overlying skin with telangiectatic vessels
• Testing and evaluation to establish the diagnosis
• Definitive diagnosis by histopathology
• Histopathology shows large masses of shadow cells, combined with basophilic cells, inflammation, foreign body giant cells, calcification, and ossification.
• Ultrasonography shows calcification within an ovoid complex mass at the junction of the dermis and subcutaneous fat (Zloto 2014).
• Fine-needle aspiration leads to misinterpretation of the lesion as carcinoma, basal cell carcinoma, and pleomorphic adenoma (Font, AFIP).
• Calcium deposits are seen in 75% of lesions (Levy 2008).

Risk factors

• Multiple pilomatrixoma cases have been seen to have mutation in CTNNB1 gene (Levy 2008).
• Associated disorders with multiple pilomatrixoma include myotonic dystrophy, Gardner syndrome, hypercalcemia, and sarcoidosis (Levy 2008).
• Some consider pilomatrixoma a cutaneous marker of myotonic dystrophy.

Differential diagnosis

• Epidermoid cyst
• Dermoid cyst
• Sebaceous adenoma
• Juvenile xanthogranuloma
• Chalazion
• Keratoacanthoma
• Kaposi sarcoma
• Pilomatrix carcinoma

Clinical management

• Surgical excision with clean margins using shallow dissection and relaxed skin tension lines where possible

Complications of treatment

Recurrence with incomplete resections

Establishing the diagnosis

• Etiology and epidemiology
• Stems from glandular epithelium and occurs in various organs such as the salivary, thyroid, parathyroid, pituitary, and adrenal glands (Font, AFIP)
• Oncocytic metaplasia of ductal and acinar cells of lacrimal epithelium or conjunctival epithelium
• No clear inheritance pattern
• Often occurs in older individuals (>60 years)
• Male to female ratio is 1:5 (Shields 2008).
• Cutaneous oncocytoma is extremely rare with fewer than 5 case reports (Figure 3)

Figure 3. Oncocytoma (Cameron 2005).

• Most periocular oncocytomas are seen at the caruncle (Wobser 2013) but may also occur at the mucocutaneous border of the eyelid, the lacrimal sac, or the conjunctiva.
• Pertinent elements of the patient history
• Slow growing and asymptomatic
• Rarely presents with unilateral conjunctivitis and epiphora
• Clinical features
• Solitary and unilateral
• Mean size and 4 x 4 x 3 (Shields 2008)
• Can be solid or cystic
• Red/tan color
• Testing and evaluation to establish diagnosis
• Diagnosis established by histopathology
• Benign oncocytes seen on pathology as uniform, oval cells with abundant eosinophilic cytoplasm (Font, AFIP)
• Nuclei are small, round with a single nucleolus
• Occasional goblet cells are scattered within the epithelial lining
• Composed of tubules lined by tall columnar epithelium with finely granular cytoplasm (Font, AFIP)

Risk factors

• None

Differential diagnosis

• Caruncular nevus
• Papilloma
• Pyogenic granuloma
• Sebaceous adenoma
• Sebaceous hyperplasia

Clinical management

• Observation
• Local excision

Complications of treatment

• Scarring
• Eyelid deformity

Establishing the diagnosis

• Epidemiology
• Results from proliferation of all elements of a peripheral nerve
• Increased incidence with age, most common over 40–50 (Font, AFIP)
• Rare familial forms exist
• Pertinent elements of the patient history
• Gradual onset
• Chronic course
• Clinical features
• Neural tumor that can affect skin in all parts of the body
• Solitary lesions are unassociated with systemic disease
• Multifocal or diffuse lesions are associated with type 1 neurofibromatosis (Shields 2008)
• Eyelid and orbit can be involved by
• Solitary neurofibroma (fibroma molluscum)
• Multiple localized neurofibromas
• Plexiform neurofibroma (Shields 2008)
• Plexiform neurofibromas develop in young children as a thickening of the entire eyelid that causes an S-shaped curve to the margin of the upper eyelid (Figure 4)

Figure 4. Eyelid neurofibroma.

• Plexiform neurofibromas can extend into the eyebrow, conjunctiva, and orbit
• Testing and evaluation to establish diagnosis
• Diagnosis established by histopathology
• Composed of combination of Schwann cells, peripheral nerve axons, neural fibroblasts, and perineural cells (Bechtold 2012)

Risk factors

Type 1 neurofibromatosis (von Recklinghausen's disease)

Differential diagnosis

• Chalazion
• Subcutaneous or orbital capillary hemangioma

Clinical management

• Observation of small, asymptomatic solitary neurofibromas
• Surgical excision or debulking
• Use of CO₂ laser at time of surgical resection for hemostasis (Bechtold 2012)

Establishing the diagnosis

• Etiology
• Hamartomatous neoplasm of endothelial cells (Font, AFIP)
• Exact pathogenesis is unknown
• Speculation of genetic component
• Epidemiology
• Most common benign periorbital tumor of childhood
• 4–5% incidence
• Racial predilection for Caucasians (10–12%) compared to blacks (1.4%) and Taiwanese and Japanese (0.2–1.7%) (Callahan 2012)
• Pertinent elements of the patient history
• Periocular hemangiomas can be noted at birth (Shields 2008)
• Usually become manifest within the first 2-6 weeks of life; nearly all are identified by six months of age
• Clinical features
• Superficial lesions appear as bright red papules or nodules and will blanch with pressure, which distinguishes them from port-wine stains (Figure 5) (Font, AFIP)

Figure 5. Infantile Capillary Hemangioma.

• Deeper lesions cause variable changes in the skin color, sometimes with a blue or purple coloration.
• Usually follows a typical course divided into the following stages (Callahan 2012):
• Nascent (0–3 months)
• Early proliferative (6–10 months)
• Late proliferative (6–10 months)
• Plateau (variable)
• Involution (half by 4 years of age and 3 quarters by 7 years)
• Abortive
• Amblyopia is the most common ophthalmic complication of infantile hemangioma and affects 40–60% of patients.
• Systemic complications are associated with multifocal hemangiomas (more than 5 cutaneous lesions): PHACE syndrome (posterior fossa malformations, hemangioma, arterial abnormalities, cardiac defects/aortic coarctation, and eye abnormalities, Shields 2008)
• Kasabach-Merritt syndrome:  thrombocytopenia with bleeeding diathesis due to platelet entrapment with a large capillary hemangioma
• For superficial lesions, diagnosis is usually clinical.
• Lesions with deeper components can be evaluated with ultrasonography, which shows an increased vessel density and high-flow pattern (Rizvi 2013).
• The extent of deeper lesions can best be evaluated by magnetic resonance imaging, which demonstrates lesions that are isointense to extraocular muscles on T1 imaging and hyperintense on T2.
• Computed tomography is generally not recommended for children in this vulnerable age group.
• For lesions of unclear etiology or unusual appearance, biopsy can be performed.
• Histopathology
• Diagnosis is confirmed with GLUT-1 on immunohistochemistry, which is expressed only in infantile hemangioma endothelium (Font, AFIP).

Risk factors

• Prematurity, low birth weight, multiple gestations, and advanced maternal age
• Chorionic villus sampling has been stipulated as a risk factor, but the literature lacks robust confirmatory data (Callahan 2012).

Differential diagnosis

• Port-wine stain (nevus flammeus)
• Kaposiform hemangioendothelioma
• Tufted angioma (Rizvi 2013)

Clinical management

(Callahan 2012)

• Observation because lesions can involute spontaneously
• Systemic beta blockers: Studies show 100% arrest of progression of hemangiomas and regression of deep orbital hemangiomas.
• Treatment is typically coordinated with pediatrician who will follow for systemic side effects.
• Topical beta-blockers: Superficial hemangiomas are successfully treated with 0.1% or 0.5% timolol maleate twice daily. Studies report a reduction in size ranging from 55–95%.
• Intralesional beta blockers: Injection of propranolol 1 mg/mL demonstrated 40% excellent response, 40–45% fair or good response, and 20% no response.
• Systemic steroids: Large doses of prednisone demonstrated an 84% response rate after 2 months of therapy.
• Intralesional steroids: Mixture of betamethasone and triamcinolone is injected into the lesion with a volume of 1–2 mL depending on the size of the lesion. Response can be drastic and rapid.
• Topical steroids: 1/3 had a good response, 1/3 a partial response, and 1/3 failed to respond.
• Interferon-alpha: Systemic anterferon-alpha induced regression of half or more in 90% of cases.
• Laser (pulse dye laser): destruction of the hemangioma using light of the same wavelength as vessels; effective in treatment of superficial lesions. Laser arrested progression of 97% of hemangiomas, completely resolved 14%, and partially regressed 15%.
• Surgical excision

Complications and side effects of treatment

(Callahan 2012)

• Systemic steroids: behavioral changes, irritability, cushingoid appearance, and growth delay
• Intralesional steroids: ophthalmic artery embolization, cutaneous hypopigmentation, fat atrophy, calcification, and full thickness eyelid necrosis
• Topical steroids: skin hypopigmentation, hypertrichosis, glaucoma, cataract formation
• Interferon-alpha: neutropenia and spastic diplegia with 10–30% risk of neurotoxicity; treatment was abandoned.
• Vincristine: peripheral neuropathy, constipation, jaw pain, and hematologic toxicity
• Pulsed dye laser: hyperpigmentation and atrophic scarring
• Surgery: intraoperative hemorrhage
• Systemic beta blockers: hypotension, bradycardia, bronchospasm, congestive heart failure, hypothermia, sleep disturbance, blunted hypoglycemic response
• Topical beta blockers: sleep disturbance in 1 patient
• Intralesional beta blockers: no side effects

Disease-related complications

Amblyopia

Establishing the diagnosis

• Etiology and epidemiology
• Hamartomatous growth of lymph channels (Font, AFIP)
• Eyelid lesions are typically more diffuse, but easier to manage than orbital lesions (Shields 2008).
• Can be associated with concomitant conjunctival and facial lesions
• Majority of eyelid lymphangiomas represent anterior extension of orbital lesions or extension of facial lesions (Pang 1984).
• Caused by blockage of the lymphatic system as fetus develops (Goble 1990)
• More than 50% are evident at birth and 90% become apparent by the 2 year of life (Goble 1990).
• Clinical features
• Deep to epidermis as dark blue, soft, fluctuant mass (Font, AFIP)
• Slow growing
• Might not be clinically apparent until there is bleeding into a pre-existing subclinical lymphangioma
• Spontaneous or post-traumatic bleeding into the lymph channels can produce blood-filled cavitary pseudocysts ("chocolate cysts").
• True regression does not occur with lymphangioma (Shields 2008).
• Can clinically resemble a varix or varices
• Testing and evaluation to establish diagnosis
• Ultrasound biomicroscopy can reveal subcutaneous mass with multicystic internal structure and fluid levels (Horgan 2008).
• Definitive diagnosis by histopathology; 3 types of lymphangiomas:
• Dermal (lymphangioma circumscriptum)
• Cavernous: most common in the ocular adnexa and orbit
• Cystic: frequently involves the neck (cystic hygroma)
• Subepidermal lymphatic vesicles of lymphangioma circumscriptum are endothelium-lined spaces that are completely separate from the normal lymphatic system (Goble 1990).

Risk factors

• Maternal alcohol use (Horgan 2008)
• Viral infections during pregnancy
• Cystic lymphangioma is associated with Noonan syndrome, Down syndrome, and Turner syndrome.

Differential diagnosis

• Hemangioma
• Varix
• Glomus tumor
• Malignant melanoma
• Epidermal cyst
• Venous angiomas
• Herpetic vesicles

Clinical management

• Observation
• Surgical resection for circumscribed tumors
• Surgical debulking for diffuse, symptomatic tumors (Shields 2008)
• Percutaneous drainage and ablation with sclerosing agents. (Hill, 2012)
• There are reports of success with systemic treatment with sildenafil. (Gandhi, 2013)

Complications of treatment

Recurrence with incomplete resections

Establishing the diagnosis

• Occurs on skin of the eyelids, meibomian glands, and sebaceous glands of the caruncle in older individuals (Singh 2005)
• Clinical features
• Tan, pink, or yellow nodules or papules usually 5 mm in greatest dimension (Font, AFIP)
• Can be clinically mistaken for basal cell carcinoma (Singh 2005)
• Can display overlying crusting or ulceration
• Lobular and organoid architecture (Takayama 2013)
• Slow growth
• Sebaceous adenoma associated with Muir-Torre syndrome can undergo cystic change, whereas those of sporadic type do not exhibit this feature (Singh 2005).
• Testing and evaluation to establish the diagnosis
• Definitive diagnosis by histopathology
• Connection or replacement of the overlying squamous epithelium (Font, AFIP)
• Expansion and increased prominence of the peripherally located basaloid cells (Shields 2008)
• Compared to sebaceous hyperplasia, there is an increase in the number of germinative cells (Singh 2005).
• Maintains a prominent population of mature sebocytes often concentrated in the central portion of the neoplasm
• Bubbly or multivacuolated cytoplasm and crenated nuclei are helpful features to differentiate them from other eccrine, melanocytic, keratinocytic, or xanthomatous lesions (Font, AFIP).

Risk factors

• Muir-Torre syndrome (MTS)
• Autosomal dominant disorder characterized by sebaceous gland adenoma or carcinoma, keratoacanthomas, gastrointestinal malignancies, and other systemic tumors (Shalin 2010)
• Number of sebaceous adenomas can range from 1 to >100.
• 43% of patients with MTS were diagnosed with colorectal malignancies followed by genitourinary (21%) and breast (14%) (Rishi 2004)
• Family history of visceral malignancies is prominent in patients with malignancy and MTS (Singh 2005)
• Viral infections during pregnancy (Shalin 2010)
• Cystic lymphangioma is associated with Noonan syndrome, Down syndrome, and Turner syndrome (Singh 2005)

Differential diagnosis

• Sebaceous hyperplasia
• Basal cell carcinoma
• Seborrheic keratosis
• Sebaceous carcinoma

Clinical management

• Complete surgical resection
• Medical workup for Muir-Torre syndrome with referral to gastroenterologist

Complications of treatment

Recurrence with incomplete resections

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