Eyelid Tumors: Classification

and Differential Diagnosis

2
Jacob Pe’er and Shahar Frenkel

Introduction Eyelid Skin

In spite of being a small organ, the eyelids con- The eyelid skin, especially the lower eyelid, is
tain numerous histological elements that can be among the most sunlight-exposed anatomical
the origin of several types of benign or malignant structures. The eye and the eyelids are one of the
tumors. In this chapter, we review the basic anat- most observed parts of the face, and therefore,
omy of the eyelid, outline a clinically relevant eyelid tumors are usually diagnosed at an early
classification of eyelid tumors, and briefly dis- stage. The eyelid skin is the thinnest in the body
cuss their differential diagnosis. and lacks subcutaneous fat, but otherwise con-
tains all other skin structures. In the pretarsal
part, the skin and orbicularis oculi muscle are
Anatomical Features normally firmly attached to the tarsal plate,
whereas in the preseptal part, they are more
The eyelids are composed of four layers: skin and loosely attached. The skin epithelium is keratin-
subcutaneous tissue, striated muscle (orbicularis ized stratified squamous epithelium, the origin of
oculi), tarsus, and conjunctiva [1]. The rest of the all types of benign and malignant epidermal
orbital entrance, which clinically may be consid- tumors. Melanocytes are spread in the basal layer
ered as part of the eyelids, is covered, behind the of the epithelium and may give rise to melano-
skin and the orbicularis muscle, by the orbital cytic cutaneous lesions. The dermis contains also
septum that holds back the orbital fat. fibrous tissue, blood and lymphatic vessels, and
nerves that can give rise to many types of fibrous
tissue tumors, fibrohistiocytic tumors, vascular
tumors, and neural tumors.

Adnexal Glands

J. Pe’er (*) · S. Frenkel The eyelids are rich in glandular tissue that may
Ocular Oncology Service and Ophthalmic Pathology be the origin of various glandular tumors.
Laboratory, Department of Ophthalmology,
Eccrine gland tumors may arise from the sweat
Hadassah - Hebrew University Medical Center,
Jerusalem, Israel glands of the eyelid skin as well as from the
e-mail: [email protected] accessory lacrimal glands of Krause and

© Springer Nature Switzerland AG 2019 7

J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_2
8 J. Pe’er and S. Frenkel

Wolfring. The glands of Moll can give rise to the possible tumors that can originate from this
apocrine tumors. The sebaceous glands of Zeiss tissue are described elsewhere (Chap. 12).
and the meibomian gland are the origin of seba-
ceous gland tumors.
Eyelid Margin

Orbicularis Oculi The eyelid margin is a flat area on the edge of

each eyelid. The anatomical structures that are
The entire orbital entrance is covered by the orbi- seen in the margin from the skin backwards are
cularis oculi—a striated muscle that is divided the eyelashes and their lash follicles, the gray line
into pretarsal and preseptal zones which are part which consists of the tips of the pretarsal orbicu-
of the eyelids and are involved in the eyelid laris muscle (the muscle of Riolan), the meibo-
movements and the orbital zone that is located mian gland orifices, and the mucocutaneous
over the external orbital bones. junction just posterior to them.

Tarsus Vascular System

The tarsi are firm plates composed of dense con- The venous and lymphatic drainage is important
nective tissues that serve as the skeleton of the in understanding the routes of possible eyelid
eyelids. The upper tarsal plates are much larger tumor metastases. The eyelid has extensive vas-
than the lower ones. The meibomian glands, large cularity that comes from two main sources— the
sebaceous glands, are embedded in the connec- internal carotid and external carotid arteries—
tive tissue of the tarsal plates. The superior tarsal with anastomoses between these two systems.
muscle (Muller’s muscle), a smooth muscle, is The venous drainage is into the angular vein
attached to the upper margin of the tarsus. A par- medially, superficial temporal vein laterally, and
allel muscle does not exist in the inferior tarsus, the orbital veins, anterior facial vein, and the
but the aponeurosis of the inferior rectus muscle pterygoid plexus posteriorly. The lymphatic
attaches to the inferior edge of the inferior tarsus. drainage of the medial portions of the eyelids is
The upper and lower orbital septum, a thin sheet into the submandibular lymph nodes and of the
of fibrous tissue, arises from the periosteum in lateral portions into the superficial preauricular
the orbital rim and fuses with the levator aponeu- nodes and then into the deeper cervical nodes.
rosis superiorly and the lower margin of the lower
tarsus inferiorly. All these histological structures
can give rise to rare fibrous, striated, and smooth Nerve Supply
muscular and glandular tumors. The orbital fat
behind the septum and the fat under the orbital The sensory nerve supply to the eyelids is from
part of the orbicularis oculi can be the origin of the fifth cranial nerve, and the motor nerve sup-
rare lipomatous tumors. ply to the striated muscles is from the third and
seventh cranial nerves and to the smooth muscles
from sympathetic nerves.
Palpebral Conjunctiva

The posterior eyelid surface is lined by the con- Classification of Eyelid Tumors
junctiva—a translucent mucous membrane that is
composed of epithelium and subepithelial Tumors of the eyelid may be classified, like
stroma—the substantia propria. The anatomical tumors in other organs, according to their tissue
and histological features of the conjunctiva and or cell of origin and as benign or malignant. In
2 Eyelid Tumors: Classification and Differential Diagnosis 9

most groups of tumors, unique histological sub- and other stromal tumors (Tables 2.5 and 2.6) are
types behave differently in spite of being of the less frequent. Lymphoid tumors, hamartomas and
same cell of origin. choristomas, and inflammatory and infectious
The classification of eyelid tumors that lesions that simulate neoplasms are listed in
appears in this section is based primarily on the Table 2.7.
second edition of the World Health Organization
(WHO) International Histological Classification
of Tumors (Table 2.1) [2]. The epithelial tumor Differential Diagnosis
classification has been modified and divided into
groups according to the tumor cell of origin. Various characteristics of the tumor and the
Some tumors that are missing from the WHO list patient’s general health are important in making
have been added from other sources [3–5]. the correct diagnosis. The important features
The vast majority of the eyelid tumors, benign that should be noted in examining the eyelid
and malignant, are of cutaneous origin, mostly tumor are the tumor location (upper or lower
epidermal. These tumors are divided into non-­ eyelid, inner or outer canthus); is it on the eyelid
melanocytic and melanocytic tumors (Table 2.2). margin; the eyelid layer involved (skin, subcuta-
Benign epithelial proliferations, basal cell carci- neous tissue, or palpebral conjunctiva); is the
noma, cystic structures, and melanocytic nevi tumor solid or cystic; tumor size; the color of
represent about 85% of all eyelid tumors [6, 7]. the lesion (pigmented or non-pigmented); skin
The squamous cell carcinoma and the melanoma color (red, pink, yellow, white, or blue); the
are relatively rare [7]. Tumors arising from tumor consistency (hard, soft, or rubbery); its
adnexal structures (Table 2.3), fibrous tissue, surface (smooth, irregular, papillary, ulcerated,
fibrohistiocytic and muscular tumors (Table 2.4), umbilicated, cratered, or keratinized); its shape
(flat or raised, pedunculated, papillary); is the
tumor thin or thick; is the tumor solitary or are
Table 2.1 Major types of eyelid tumors
there several or multiple tumors; is there loss of
Category Subtypes eyelashes; the patient’s race, age, and gender; is
Epidermal Non-melanocytic tumors the tumor movable with the skin or is it fixed to
tumors Melanocytic tumors
the subcutaneous layers; the existence of sys-
Adnexal tumors Sebaceous gland tumors
Sweat gland tumors temic diseases such as genetic diseases (e.g.,
Lacrimal gland tumors neurofibromatosis) or systemic malignancies;
Hair follicle tumors and the existence of diseases or malignancies in
Cystic lesions the surrounding structures (the eyeball, con-
Stromal tumors Fibrous tissue tumors junctiva, orbit, lacrimal drainage system, and
Fibrohistiocytic tumors neighboring skin).
Lipomatous tumors
Certain features of the tumor are suggestive
Smooth muscle tumors
Skeletal muscle tumors
of malignancy [5]. Development of a new lesion
Vascular tumors or changes in size, shape, color, or surface
Perivascular tumors appearance of an existing lesion is suspicious
Neural tumors for malignant conversion. Poorly defined bor-
Lymphoid, plasmacytic, and ders, palpable induration beyond visible bound-
leukemic tumors
aries, loss of fine cutaneous rhytids,
Cartilage and bone tumors
hypervascularity, ulceration, and destruction of
Hamartoma and choristoma
Palpebral conjunctival tumors the normal eyelid architecture are all worri-
Secondary tumors some. Lesions that are not freely mobile due to
Metastatic tumors invasion of underlying structures and those
Inflammatory and infectious lesions that simulate associated with regional lymphadenopathy,
neoplasms hypesthesia, paresthesia or pain, indicating
10 J. Pe’er and S. Frenkel

Table 2.2 Classification of epidermal tumors of the eyelid

Category Subtypes
Non-melanocytic Benign Squamous cell papilloma
Seborrheic keratosis
Inverted follicular keratosis
Reactive hyperplasia (pseudoepitheliomatous hyperplasia)
Premalignant Actinic (solar) keratosis
Intraepithelial neoplasia
Sebaceous nevus (of Jadassohn)
Xeroderma pigmentosum
Malignant Basal cell carcinoma
Squamous cell carcinoma
Mucoepidermoid carcinoma
Keratoacanthoma
Melanocytic Epithelial pigmentation Ephelis or freckles
Lentigo simplex
Solar lentigo
Benign Junctional nevus
Intradermal nevus
Compound nevus
Spitz nevus
Balloon cell nevus
Blue nevus
Cellular blue nevus
Oculodermal nevus of Ota
Premalignant Congenital dysplastic nevus
Lentigo maligna (melanotic freckle of Hutchinson)
Malignant Melanoma arising from nevi
Melanoma arising in lentigo maligna
Melanoma arising de novo

Table 2.3 Classification of adnexal and cystic tumors of the eyelid

Category Subtypes
Sebaceous gland tumors Benign Sebaceous gland hyperplasia
Sebaceous gland adenoma
Malignant Sebaceous gland carcinoma
Sweat gland and lacrimal gland tumors Benign Syringoma
Papillary syringadenoma
Eccrine spiradenoma
Eccrine acrospiroma
Pleomorphic adenoma (benign mixed tumor)
Eccrine cylindroma
Apocrine adenoma
Other benign tumors
Malignant Sweat gland (eccrine) adenocarcinoma
Mucinous sweat gland adenocarcinoma
Apocrine gland adenocarcinoma
Adenoid cystic carcinoma
Porocarcinoma
Hair follicle tumors Benign Trichoepithelioma
Trichofolliculoma/trichoadenoma
Trichilemmoma
Pilomatrixoma (calcifying epithelioma of Malherbe)
Malignant Carcinoma of hair follicles
2 Eyelid Tumors: Classification and Differential Diagnosis 11

Table 2.3 (continued)

Category Subtypes
Other cystic lesions Benign Epidermal inclusion cyst
Sebaceous cyst
Retention cyst
Eccrine hidrocystoma
Apocrine hidrocystoma
Trichilemmal cyst
Other benign cystic lesion

Table 2.4 Classification of fibrous, fibrous histiocytic, Table 2.5 Classification of vascular and perivascular
and muscular tumors of the eyelid tumors of the eyelid
Origin Type Tumor Category Subtypes
Fibrous Benign Fibroma Vascular Benign Nevus flammeus (port wine
Keloid stain)
Nodular fasciitis Papillary endothelial
Proliferative fasciitis hyperplasia
Fibromatosis Capillary hemangioma
Malignant Fibrosarcoma Cavernous hemangioma
Congenital fibrosarcoma Venous hemangioma
Fibrous Benign Xanthelasma Epithelioid hemangioma
histiocytic Xanthoma (angiolymphoid hyperplasia)
Dermatofibroma Arteriovenous malformation
Xanthogranuloma Lymphangioma
Fibrous histiocytoma Malignant Angiosarcoma
Juvenile xanthogranuloma Lymphangiosarcoma
Necrotic xanthogranuloma Kaposi’s sarcoma
Reticulohistiocytoma Perivascular Benign Hemangiopericytoma
Intermediate Atypical fibroxanthoma Glomus tumor
Dermatofibrosarcoma Malignant Malignant
protuberans hemangiopericytoma
Angiomatoid fibrous Malignant glomus tumor
histiocytoma
Malignant Malignant fibrous Table 2.6 Classification of neural, lipomatous, cartilage,
histiocytoma and bone tumors of the eyelid
Malignant giant cell
fibrous histiocytoma Category Subtypes
Malignant fibroxanthoma Neural Benign Traumatic neuroma
Smooth Benign Leiomyoma Neurofibroma
muscle Angiomyoma Plexiform neurofibroma
Malignant Leiomyosarcoma Schwannoma
Skeletal Benign Rhabdomyoma (neurilemoma)
muscle Malignant Rhabdomyosarcoma Others, e.g., neuroglial
choristoma
Malignant Malignant peripheral nerve
sheath tumor
l­ymphatic or perineural spread are also suspi-
Merkel cell tumor
cious for malignancy. Lesions associated with Lipomatous Benign Lipoma
chronic inflammation that respond partially or Others, e.g., hibernoma
temporarily to topical corticosteroids or antibi- Malignant Lilposarcoma
otics also may harbor malignancies. However, Cartilage and Benign Chondroma
one should keep in mind that on the one hand bone Osteoma
malignant tumors can appear without any worri- Malignant Chondrosarcoma
Mesenchymal
some signs, while totally benign tumors can chondrosarcoma
express some of the abovementioned features. Osteosarcoma
12 J. Pe’er and S. Frenkel

Table 2.7 Classification of lymphoid tumors, hamarto- can be sessile (Table 2.2). Congenital nevi u­ sually
mas, choristomas, and inflammatory and infectious
appear at birth and acquired nevi between the
lesions that simulate neoplasms
ages of 5 and 10 years. Nevi should be differenti-
Category Subtypes
ated on the one hand from flat epithelial pigmen-
Lymphoid Benign lymphoid
hyperplasia tation such as ephelis or freckles and, on the other
Lymphoma hand, from the flat premalignant lentigo maligna
Plasmacytoma or from malignant melanoma that is relatively
Leukemic infiltration rare in the eyelids.
Hamartomas and Dermoid cyst
choristomas Phakomatous
choristoma
Ectopic lacrimal gland Adnexal and Cystic Tumors
Inflammatory and infectious Chalazion
lesions Pyogenic granuloma The eyelid adnexa include many different glands
Verruca vulgaris that are the origin of various benign and malig-
Molluscum contagiosum nant tumors (Table 2.3). These include cystic
Others lesions such as eccrine and apocrine hidrocys-
Others e.g., myxoma
toma that are totally benign and may be transpar-
ent or have a distinct color like the blue apocrine
hidrocystoma. On the other hand, there are very
Epidermal Non-melanocytic Tumors malignant solid sebaceous gland carcinomas that
may resemble chalazion but unlike chalazion
The most common benign epithelial tumor is the cause loss of eyelashes.
squamous papilloma that is often sessile or
pedunculated with papillary shape and keratin-
ized surface (Table 2.2). Squamous papillomata Stromal Tumors
may be multiple. Other epithelial tumors, includ-
ing the premalignant actinic keratosis or small The stromal eyelid tumors usually have a smooth
squamous cell carcinoma may look similar. Basal surface, being under the skin (Tables 2.4, 2.5, and
cell carcinoma comprises over 90% of all malig- 2.6). The tumor elevation may have normal skin
nant eyelid tumors [7]. Its common location is the color, but many of the tumors will have a distinct
lower eyelid and medial canthus; it is usually firm color. Xanthomatous lesions are usually yellow.
and often has an ulcerated center. Other ulcerated Most hemangiomas, diffuse or localized, are red.
eyelid tumors, such as keratoacanthoma or the Subcutaneous varix is soft and blue, and Kaposi’s
more rare papillary syringadenoma, should be sarcoma is blue or red. Merkel cell tumor is red
differentiated from BCC. Features of keratoacan- or violaceous. Eyelid lymphoma can be mani-
thoma, such as rapid growth and possible sponta- fested as a smooth, firm subcutaneous nodule.
neous regression, can help in its diagnosis. Sometimes also subcutaneous tumors can be ses-
Staging of carcinomas of the eyelid skin and sile or even ulcerated, so such phenomena, which
adnexa can be found in the AJCC Cancer Staging are usually seen in epidermal tumors, should not
Manual [8]. exclude them.

Epidermal Melanocytic Tumors Inflammatory and Infective

Simulating Conditions
The most common pigmented eyelid lesions are
the nevi, which are usually flat or mildly elevated In the differential diagnosis of eyelid tumors, we
and can appear anywhere in the eyelid in any should include lesions that simulate tumors
size, and when appearing on the eyelid margin (Table 2.7). The most common simulating lesions
2 Eyelid Tumors: Classification and Differential Diagnosis 13

are inflammatory lesions such as chalazion or pyo- 2. Campbell RJ, Sobin LH. Tumours of the eyelid.
In: Histological typing of tumours of the eye and
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contagiosum or verruca vulgaris that is clinically Springer; 1998. p. 3–9.
and histologically similar to squamous papilloma. 3. Shields JA, Shields CL. Atlas of eyelid and conjunc-
tival tumors. Philadelphia: Lippincott Williams &
Many dermatological diseases such as amyloido- Wilkins; 1999. p. 3–189.
sis and malakoplakia or connective tissue disease 4. Hassan AS, Nelson CC. Benign eyelid tumors and
and systemic metabolic diseases such as hema- skin diseases. Int Ophthalmol Clin. 2002;42:135–49.
chromatosis may, sometimes, simulate eyelid 5. Soparkar CN, Patrinely JR. Eyelid cancers. Curr Opin
Ophthalmol. 1998;9:49–53.
tumors and should be differentiated from them. 6. Kersten RC, Ewing-Chow D, Kulwin DR, et al.
Accuracy of clinical diagnosis of cutaneous eyelid
lesions. Ophthalmology. 1997;104:479–84.
7. Cook BE, Bartley GB. Epidemiologic characteristics
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