13.1 Introduction

The upper and lower lips, which are the central aesthetic feature of the lower third of the face, also serve important functions in facial expression, sucking, kissing, speech articulation, proprioception, hot-cold temperature differentiation, oral secretion management, and the establishment of a labial seal during the oral preparatory phase of swallowing. Alterations in their appearance or function can adversely impact self-esteem, societal acceptance, and quality of life. We are generally unaware of the aesthetic and functional importance of the lips until they are altered, but when they are altered, the impact can be life-changing.

As the point of transition between the skin of the face and the oral cavity, the lips are exposed to environmental agents that cause both skin cancer and oral cancer. Over the past decade, refinements in our understanding of the natural history and biological behavior of lip cancer have helped characterize the differences in diagnosis, management, and outcomes between cancers of the extraoral, or dry vermilion lip, and of the intraoral wet mucosal lip. This review compares and contrasts the treatment for and prognosis of cancers that arise from the mucosal lip and the dry vermilion.

13.2 Anatomy of the Lips

The external surface anatomy of the lips is comprised of the cutaneous lip and the dry vermilion. The boundaries of the upper cutaneous lip extend superiorly to the nostril sill and alar base, and laterally to the melolabial, or nasolabial sulcus. The upper lip is comprised of three aesthetic subunits: two lateral subunits, which extend from each philtral ridge to the melolabial sulcus, and the centrally located philtrum. The vermilion border, or mucocutaneous ridge, of the upper lip has a midline V-shaped indentation that terminates on either side at the philtral ridges known as Cupid’s bow. In contrast, the lower cutaneous lip has one aesthetic unit that extends inferiorly to the labiomental crease. The cutaneous portion of the upper and lower lips terminates at the white roll, where the curvature of the vermilion creates a clearly delineated border.

In cross-section, the lip is a three-layered structure comprising the skin, orbicularis oris muscle, and lining intraoral mucosa. The vermilion region, or the true lip, has a rich vascular plexus that underlies a thin epithelial architecture that gives the vermilion its unique aesthetic appearance. The vermilion zone of the lip is covered by orthokeratinized stratified squamous epithelium that is firmly attached to the underlying orbicularis oris muscle, whereas the intraoral labial mucosa is nonkeratinized. The transition between the intraoral lining mucosa and the wet vermilion is termed the wet line.

The oral cavity, as defined by the American Joint Committee on Cancer (AJCC), “extends from the portion of the lip that contacts the opposed lip (wet mucosa) to the junction of the hard and soft palate above, to the line of circumvallate papillae below, and to the anterior tonsillar pillars bilaterally.” ¹ The mucosal lip is defined as the area that “begins at the junction of the wet and dry mucosa of the lip (the anterior border of the lip that comes into contact with the opposed lip) and extends posteriorly into the oral cavity to the attached gingiva of the alveolar ridge.” ¹ Previous editions of the AJCC Cancer Staging Manual included the dry vermilion, or that portion of the lip located external to the mucosal lip, in the chapter pertaining to the lip and oral cavity. However, cancers arising from the dry vermilion and the vermilion border are now designated as extraoral and are staged as cutaneous cancers. ²

13.3 Incidence and Epidemiology

The estimated worldwide incidence of lip cancer in 2012 was 0.3 cases per 100,000 people annually—0.4/100,000 in males and 0.2/100,000 in females. ^{3 , 4} Papua New Guinea and Australia had the highest incidence rates of 8.9/100,000 and 2.6/100,000, respectively. In contrast, Eastern and Southeast Asia and sub-Saharan Africa had the lowest incidence rates. The incidence of lip cancer in the United states, based on data compiled by the Globocan Project, is between 0.4 and 0.9/100,000. ³ The estimated worldwide incidence of lip cancer is lower than oral cavity cancers (2.7/100,000) and oropharyngeal cancers (1.4/100,000). ³

In the United States, squamous cell carcinoma (SCC) of the lip comprises approximately 20 to 25% of all cancers of the lip and oral cavity. Greater than 98% of the diagnosed lip cancers occur in the Caucasian population, and more than 60% of these are diagnosed in individuals older than 60 years of age. ⁵ Males comprise more than 80% of the individuals diagnosed. In a review of lip cancers entered into the Surveillance, Epidemiology, and End Results (SEER) database from 1973 through 2012, 90% of lip cancers arose from the lower lip, whereas cancers of the upper lip and labial commissure comprised 9 and 1%, respectively. ⁵ Other investigations, however, have documented that lower lip cancer comprises at least 95% of all diagnosed lip cancers. ^{6 – 8} Analysis of the SEER database also showed that 88.4% (1261/1426) of upper lip SCCs and 88.4% (12311/13928) of lower lip SCCs arose from the dry vermilion, or external portion of the lip. ⁵

Numerous epidemiologic studies have documented the role of chronic sun exposure, or ultraviolet radiation, as the primary etiologic agent in SCC of the dry vermilion. Fishermen, farmers, foresters, and concrete workers who work outside have markedly higher incidence rates of lip cancer. ^{8 – 10} The relationship between cumulative sun exposure and lip cancer is also believed to explain the high incidence of lower lip cancer, since a greater surface area of the dry vermilion of the lower lip is exposed to sunlight relative to the upper lip vermilion.

In contrast, the etiology of mucosal lip SCC is believed to be caused by tobacco and alcohol use, similar to oral mucosal squamous carcinoma. However, epidemiologic evidence in support of this association is limited because the incidence rates of mucosal lip cancer and oral mucosal cancers in tobacco users have not been analyzed separately. Moreover, the association between chronic alcohol use and lip cancer has not been rigorously evaluated, so the causative role of alcohol use has been extrapolated from epidemiologic investigations of oral cancer patients and is largely presumptive.

Solid organ transplant recipients on immunosuppressive agents such as cyclosporine A and azathioprine have a risk of developing lip cancer that is 20 times greater than the general population. ¹¹ Moreover, the risk of lip cancer has been shown to increase as the dose and duration of azathioprine therapy is increased. ¹² Individuals who are immunosuppressed for other reasons, including human immunodeficiency virus infection, are also at increased risk. ¹³ Higher rates of lip cancer have also been associated with the use of antihypertensive agents, including hydrochlorothiazide and nifedipine, presumably because they are photosensitizers. ¹⁴

13.4 Actinic Cheilitis

The precursor to lip cancer involving the dry vermilion, in approximately 95% of patients, is actinic cheilitis. ¹⁵ Ultraviolet radiation is the primary causative agent, and is more common in fair-skinned (Fitzpatrick I-III) individuals. Clinically, actinic cheilitis has a varied appearance, but is frequently characterized by areas of desiccation with a scaly appearance and rough surface texture, atrophic changes, and an increase in the prominence of vertical folds, or fissuring. Color variegation is frequently present with patchy areas of leukoplakia, erythroplakia, or erythroleukoplakia. The typically sharp delineation of the vermilion border may become obscured or retracted (▶ Fig. 13.1). ¹⁶ Ulcerations are frequently associated with more advanced disease.

Biopsy of the most concerning area should be performed whenever clinical examination is consistent with actinic cheilitis. Histopathologic evaluation can demonstrate a spectrum of pathology ranging from hyperkeratosis to dysplasia to invasive SCC. In the cases where carcinoma in situ or invasion is identified, biopsies of other less concerning areas along the surface of the lip may help clarify the indicated treatment (e.g., wedge resection with vermilionectomy). The exclusion of invasive cancer at the time of biopsy is of paramount importance since many of the treatment modalities that are used for actinic cheilitis ablate the epithelial surface in lieu of formal excision. However, choosing the most appropriate area for biopsy may be challenging because areas with a homogeneous appearance have been shown to demonstrate heterogeneous histologic changes. ¹⁷

The rationale for the treatment of actinic cheilitis with dysplasia should be in part based on the risk of malignant transformation. Treatment is clearly indicated whenever the risk of evolution to malignancy is high, but excision or ablation may be optional if the risk of malignant progression is low, and may be based on patient factors, such as cosmetic concerns or patient discomfort.

Several treatment modalities have been employed to treat actinic cheilitis, and the preferred modality is frequently based on that clinician’s clinical experience and expertise. Vermilionectomy, or the lip shave, remains the standard by which the efficacy of other techniques must be compared since vermilionectomy is the only excisional procedure. Numerous other techniques have been used with varying success rates, including cryosurgery, 5-fluorouracil, imiquimod, photodynamic therapy, trichloroacetic acid chemical peel, electrodessication, carbon dioxide laser ablation, diclofenac, and dermabrasion. ¹⁸

13.5 Natural History and Clinical Presentation

Clinicians should obtain a thorough history that reviews any symptoms that could be suggestive of invasive cancer, including dysesthesia or analgesia (e.g., the numb chin syndrome), a possible manifestation of perineural involvement. The medical history should be reviewed for conditions or medications that cause immunosuppression, as well as the use of photosensitizing antihypertensive medications. Documentation of the extent of sun exposure and the amount of tobacco and alcohol use is essential to identify possible etiologies.

Lip cancer is usually detected in its early stages due to its conspicuous anatomic location. Cancers arising from the dry vermilion that arise from areas involved by actinic cheilitis tend to be slow growing. Surface changes that are thought to be due to actinic cheilitis may in fact be involved by early invasive cancer that remains undiagnosed until vermilionectomy is performed. Subtle actinic-appearing changes, if untreated, may slowly progress to a raised irregular exophytic lesion, an indurated subcutaneous/submucosal lesion, or an ulcerated lesion. Each of these clinical manifestations is highly suggestive of invasive cancer.

Mucosal SCC arising from the wet mucosa frequently begins as an area of leukoplakia or erythroplakia. The involved mucosa may have a patchy appearance with areas of normal-appearing mucosa. Ulceration or submucosal induration increases the concern for invasive cancer. All of these clinical presentations mandate biopsy of the most concerning area. Biopsy of a necrotic central ulceration may result in a false-negative biopsy result, so biopsy of viable tissue surrounding the central ulceration is preferred.

Clinical evaluation requires careful inspection of the surface anatomy of the lip to characterize any changes of the dry and wet vermilion. Examination for mottling, color and textural changes, fissuring, ulcerations, induration, and obscuration of the vermilion border and normal lip anatomy should be performed. Incisional or punch biopsy is preferred over shave biopsy, which could lead to the incorrect diagnosis of a noninvasive in situ lesion.

Physical examination of the lip and neck is sufficient for smaller lesions, whereas axial imaging should be considered for lesions measuring more than 2 cm in diameter. Computed tomography (CT) with contrast provides valuable information about the extent of soft-tissue involvement, mandibular or maxillary invasion, maxillary sinus involvement, and the presence of cervical and intraparotid lymphadenopathy. Information pertaining to retrograde perineural involvement of the trigeminal nerve and mandibular marrow invasion is ideally assessed with magnetic resonance imaging. Cone beam CT may be used to provide complimentary information about cortical bone destruction that is not appreciated on standard CT scan imaging.

13.6 Staging Lip Cancer

Squamous carcinomas arising from the mucosal lip are staged with the staging system for the lip and oral cavity. ¹ In contrast, squamous carcinomas originating from the vermilion border or the external dry vermilion of the upper and lower lips are now staged according to the staging system for cutaneous SCC of the head and neck. ² These changes in staging reflect the disparate etiology and biological behavior of oral mucosal cancers and cutaneous cancers. Consequently, the definitions of the primary tumor (T) in the most recent edition of the AJCC Cancer Staging Manual differ for the mucosal lip and the dry vermilion. ^{1 , 2} Here is a comparison of the T stage criteria for each site:

• T1 mucosal lip is = 2 cm maximum diameter (MD), = 5 mm depth of invasion (DOI), measured from the level of the basement membrane of the adjacent intact squamous mucosa, whereas T1 external lip is < 2 cm.

• T2 mucosal lip is = 2 cm, DOI > 5 mm, and = 10 mm or > 2 cm but = 4 cm and = 10 mm DOI, whereas T2 external lip is = 2 cm but < 4 cm.

• T3 mucosal lip is > 4 cm or any tumor with DOI > 10 mm, whereas T3 external lip is = 4 cm or minor bone erosion, perineural invasion (PNI), or deep invasion (> 6 mm or beyond the subcutaneous fat).

Adoption of the updated AJCC TNM (tumor size, node involvement, and metastasis status) staging criteria published in the eighth edition may assign a particular cancerous lesion to a different stage group based on its site of origin in the mucosal or the cutaneous vermilion of the lip. For example, a 1.5-cm lesion with 6-mm DOI that is clinically N0M0 would be assigned to prognostic stage group II as a mucosal lip lesion versus stage I as a vermilion border lesion. In contrast, a 2.5-cm lesion with 8-mm DOI that is cN0M0 would be designated as a stage II mucosal lip cancer versus a stage III external lip cancer. While the updated staging criteria reflect our current understanding of lip cancer, they will also result in stage migration that limits our ability to extrapolate treatment outcomes from the existing peer-reviewed literature to the updated stage groups.

The presence of extranodal extension (ENE) is a criterion that is now used to designate N stage for lip cancers of the mucosal lip and dry vermilion. If there is clinically overt ENE based on physical examination and/or radiographic imaging, the N stage is designated as N3b. The criteria for pathological ENE, however, differ between oral mucosal cancers and cutaneous SCCs of the head and neck. Cancers arising from the mucosal lip receive pathological ENE (+) status only if there is macroscopic ENE, which is defined as “either extranodal extension apparent to the naked eye at the time of dissection or extension > 2 mm beyond the lymph node capsule microscopically.” ¹ In contrast, cutaneous SCCs of the head and neck region, including the dry vermilion, are designated as ENE (+) if there is “extension through the lymph node capsule into the connective tissue.” ²

13.7 Predictors of Regional Metastasis

In general, the likelihood of metastatic cervical lymphadenopathy is related to primary tumor size. Most retrospective case series document metastasis rates of less than 15% in lesions measuring 4 cm or less. Zitsch et al documented cervical metastasis in 7% of patients 2 cm or less in diameter versus 16% in larger cancers. ¹⁹ In a retrospective review of 617 patients, lymph node metastasis occurred in 7.9% of T1-T2 lesions and in 27.9% of patients with T3-T4 lesions. ²⁰ Another series of 299 patients found lymph node involvement in 5.6% of T1-T2 lesions and 17.6% for T3 cancers. ²¹ In a more recent retrospective investigation, however, the rate of cervical metastasis was 9% in 23 lip cancers measuring 2 to 3 cm in diameter versus 43.7% in 16 lip cancers greater than 3 cm but = 4 cm in diameter. ²²

Numerous investigators have documented an increased incidence of nodal metastasis when tumor thickness (TT) exceeds 4 to 5 mm. ^{23 – 25} There are, however, limited data in the peer-reviewed literature pertaining to DOI and the risk of regional metastasis for mucosal lip cancers. Hence, using DOI as a criterion for designating T stage in mucosal lip cancers is largely based on the extrapolation of data obtained from other oral mucosal sites and requires further investigation. Cutaneous lesions with greater than 6 mm DOI or PNI of large caliber nerves (> 0.1 mm) have a greater than 15% risk of regional metastasis. ^{26 , 27} In a study of cutaneous SCC in 615 patients by Brantsch and colleagues, there was a direct correlation between TT and the nodal metastatic rate (NMR): TT = 2.0, NMR = 0%; TT = 2.1 to 6 mm, NMR = 4%; TT > 6 mm, NMR = 16%. ²⁶

The association between the site of the lip cancer and the likelihood of cervical metastasis has also been evaluated. A large retrospective review of 1,036 lip cancers found that 31% of cancers involving the commissure metastasized to the cervical lymph nodes, which was significantly greater than cancers arising from the upper or lower lip. ⁷ A subsequent retrospective series, however, did not confirm any relationship between primary tumor location and regional metastasis. ²⁸

Other independent risk factors for metastasis include poor differentiation, PNI, lymphovascular invasion, and desmoplasia. ^{19 , 26 , 29 , 30} A low histopathological grade at the invasive tumor front is associated with a low rate of metastasis. ³¹ A histologic risk assessment grading system that estimates the risk of regional lymph node metastasis for lip cancer has been evaluated. ³¹ The histologic risk assessment model scores three morphological parameters: worst pattern of invasion (WPOI), ranging from a pushing border (type 1) to “tumor satellites = 1 mm away from main tumor or next closest satellite” (type 5); lymphocytic infiltrate ranging from a “dense complete host response” (type 1) to “little or no host response” (type 3); and PNI, with no invasion, tumor wrapping around nerves less than 1 mm in diameter, or large nerves = 1 mm in diameter. ³² The relationship between the risk assessment score and regional lymph node metastasis is highly significant. ³¹ Nodal metastasis to the parotid gland has also been associated with the presence of lymphovascular invasion in cutaneous SCCs. ³³