Squamous Cell Carcinoma of the Lip
Cecilia Tran, M.D.
March 13, 2003

Today I will discuss squamous cell carcinoma of the lip. Our case presentation today is a 58-year-old Hispanic male who presented to the Ben Taub Clinic with a two-year history of a lesion on the left side of his lower lip. This lesion was tender, had grown in size, and bled slightly with manipulation. He denies numbness of the lips or chin. He was a retired construction worker with a history of heavy sun exposure. His past medical history was only significant for diabetes and hypertension.

On physical examination, he had a 2cm ulcerative lesion on the left aspect of his lower lip. It extended to the oral commissure and fell just short of midline. The remainder of his oral cavity and oral pharyngeal examination was unremarkable. There was no probable lymphadenopathy. Biopsy in clinic was consistent with well-differentiated squamous cell carcinoma. Neck CAT scan and chest x-ray were negative.

In October 2002, he underwent a wide local excision of his lip lesion with Abbe Estlander local flap reconstruction and left supraomohyoid neck dissection. Frozen and permanent sections revealed well-differentiated squamous cell carcinoma with negative margins. Zero of eight nodes were positive. The patient has done well postoperatively with good wound healing and oral competence. He remains in follow-up at the Otolaryngology Clinic at Ben Taub. He has been advised to stop smoking and to avoid sun exposure.

Today I will be discussing lip cancer, including the anatomy, epidemiology, and clinical presentation. I will review the literature on treatment options, including the roles of radiation and neck dissection, and briefly survey the available reconstructive options.

Cancer of the lip is relatively common among malignancies of the head and neck region, accounting for 25% of all oral cavity cancers and 12% of all noncutaneous head and neck cancers. There are 3500 new cases in the U.S. diagnosed each year and the incidence is approximately 2 per 100,000 population. Ninety percent of these cancers are squamous cell cancers. Basal cell carcinoma, salivary gland cancers, and rarely melanomas may also develop. The lower lip is by far the most common subsite affected due to the predilection for increased solar exposure in this area. Eight percent arise on the upper lip, while only 2% arise from the commissure. Lip cancers can be classified by morphology or grade. The exophytic type grows superficially and metastasizes late. The ulcerative type, as depicted here, has rapid infiltration and invasion, and usually is of a higher histologic grade. Dr. Bergers, in 1920, developed the histologic grading system based on cytoplasmic and nuclear maturation. The top slide would be an example of Grade I: well-differentiated, mature nuclei in cytoplasm. The lower slide would be an example of Grade IV: nuclear atypia, poor differentiation. The early stages of lip cancer are often indolent and protracted. Most tumors remain localized and grow slowly for an extended period of time, while some rapidly infiltrate and invade tissues tracking along the mental nerves. It can involve the mandible by direct extension, perineural invasion, or lymphatic spread into the mental foramen. In advanced stages, lip cancer can spread to the floor of mouth, tongue, or pterygopalatine fossae.

Lip cancer is most common in fair-complexioned white males in their sixth decade of life. Risk factors include environmental factors such as exposure to sunlight, behavioral factors such as smoking, and innate factors such as fair complexion, immunosuppression, genetic predisposition, and gender. There is a 6:1 male to female ratio. The most consistent finding has been the association between the risk of lip cancer and the time spent outdoors. One-third of all the patients have outdoor occupations or outdoor pastimes. The disease is commonly seen with second primary skin malignancies. There is actually a synergy between the outdoor occupation and smoking. It has also been found that there is a higher incidence in sunny places. This graph depicts the incidence of lip cancer in different countries in 1999. The highest rates are in South Australia and Granada, Spain. The lip is susceptible to actinic changes because it lacks the pigmented layer for protection, which may provide some protection.

Patients typically give a history of crusting that bleeds on removal. They are often treated as an outpatient by their primary doctor with several courses of antibiotics. The lesion does not heal; instead it may fully develop into a palpable mass and exam shows a nontender infiltrative ulcer with widespread actinic changes of the lip. It is important for us to distinguish true lip cancer from skin cancer eroding into the vermilion or oral cavity cancer spread outward. Cervical lymphadenopathy detected clinically does not indicate lymph node metastasis. Any lymphadenopathy present is more likely to be inflammatory than metastatic. Only 60% with palpable lymphadenopathy will have metastasis. Incisional biopsy will confirm diagnosis. Panorex or CT is indicated when the tumor is attached to the mandible, when it extends over the gingiva into a tooth root, when the dentition is loose, or when there is hypoesthesia of the mental nerve. An aggressive metastatic workup is not indicated because less than 2% of patients have distant metastasis at time of workup.

We have summarized the algorithms for diagnosing lip carcinoma, which is fairly straightforward. Treatment for lip cancer is more complex due to the unique anatomy and functions of the lip. Before I discuss treatment, I would like to discuss the functions and anatomy of the lip because this significantly impacts how we treat lip cancer.

The lips form a junctional structure, a transition zone between the facial skin and the oral cavity mucosa. They maintain oral competence and act as a mobile oral sphincter regulating passage of materials into and out of the oral cavity. They assist in mastication and articulation. They are also important esthetically, contributing to appearance and facial expression, and they are responsible for such social interactive functions as smiling. Lip musculature is derived in the second brachial arch, which migrates to the facial processes. The orbicularis oris is a sphincter lying within the lip and encircling the oral aperture. This muscle extends upward almost to the columella of the nose, attaching to the anterior nasal spine, and downward to the mental crest, interdigitating with the mentalis muscles. Numerous paired muscles of facial expression insert on the lateral deep surface contributing to oral competence and contributing to diversity of facial expression. The major blood supply is from branches of the facial artery, including the superior and inferior labial arteries. These vessels encircle the mouth between the orbicular muscle and the submucosa of the lip. The lips form the anterior boundary of the oral vestibule. According to the American Joint Committee on Cancer, the lip includes only the vermilion surface or that portion coming into contact with the opposing side. Cancer of the lip thus refers to epithelial malignancies only originating on the vermilion portion of the lip. The sensory and motor innervations of the lip are separate. The infraorbital branch of V2 supplies sensation to the skin and mucosa of the upper lip, while the buccal branch supplies the oral commissure and the mental branch supplies sensation to the lower lip. The facial nerve innervates the lip. The buccal branch of the facial nerve supplies the upper lip musculature while the marginal mandibular branch innervates the lower lip musculature.

Treatment of this disease is based on the unique lymphatics of the lip. The upper lip drains differently than the lower lip. Lateral lesions on the upper lip drain mostly to level I nodes and occasionally to infraparotid and preauricular nodes. There is no contralateral drainage because the embryonic fusion plate of the central frontal nasal process separates the lateral maxillary processes and their associated lymphatic connections. In contrast to the upper lip, midline lesions drain bilaterally. Drains from the central third of the lip may go via cross pathways to level I on either side. The lateral thirds of the lower lip rarely drain to the opposite side. This is important in therapy.

Goals of therapy include removing all tissue involved with cancer both at the primary site and regional lymph nodes, as with any other head and neck cancer. Also, one must keep in mind the unique functions of the lip and seek to maintain oral competence in speech, mastication, and retention of saliva. If possible, it is also necessary to maintain satisfactory lip cosmesis and try to permit early rehabilitation.

Radiation and surgery are the primary modalities employed in the treatment of lip cancer. Surgical and radiation therapy are equally effective in controlling early stage lesions. Five-year survival rates for lesions less than 3 cm average 90%. In 1999, Dr. Devonshire performed a retrospective study of 90 patients in radiotherapy and 166 patients who underwent surgery. He followed all these patients for a mandatory follow-up of at least two years. The surgery arm consisted of full-thickness excision and primary closure. All of these tumors were stage I primary squamous cells of the lower lip. He found that the local control rates and the overall survival rates were the same. This is a graph from his article depicting the disease-free survival in months. The lower line depicts the radiation therapy arm while the upper line depicts the surgery arm. The radiation therapy group showed more cervical metastases due to more advanced tumor size. The disease-free survival is lower in the radiation arm due to selection bias. The irradiated patients tended to have more tumor load and more regional metastasis. Even though all these tumors were stage I and less than 2 cm, clinicians tended to give more radiation rather than surgery to the larger tumors. He concluded that radiation and surgery were equivalent in stage I squamous cells of the lip. Therefore, the choice for either form of treatment modality may be determined by other not-tumor-related considerations such as the age and condition of the patient, time and cost, cosmetic and functional results, and the preference of the patient.

Two of the advantages of radiotherapy are that it is noninvasive. It is also the only option for candidates who cannot tolerate surgery. However, the disadvantages are that it prolongs treatment time, often lasting as long as five to six weeks. A whistle deformity may result from tissue loss, with wound contracture with very large tumors. Rarely, osteoradionecrosis of the mandible can occur and it may limit future reconstructive options.

Even though studies by Dr. Devonshire state that surgery and radiation are equivalent in treatment of early stage lesions, surgery is more often selected. It provides us with the opportunity to assess tumor thickness and its histologic grade, two factors that are important in prognosis. One can eradicate disease and control the tumor margins. It is also possible to reconstruct the defect immediately, assisting in rapid rehabilitation. Complications include such usual ones as wound infection and dehiscence. The standard approach to excision of the primary lesion is full-thickness excision with 8-10mm margins and intraoperative frozen section of the surgical margins. Large tumor-size, mandible invasion, mental nerve invasion, or lymph node metastasis may necessitate more aggressive treatment with 2cm margins. Skin incisions should be placed to minimize secondary deformity and facilitate reconstruction, but not at the expense of compromising margins. The tendency to underestimate margins is more common in T2 lesions where local recurrence rates have been higher. Surgery should be combined with radiation in stage III and IV lesions, in recurrent disease after primary surgery, nodal metastasis, and when extracapsular spread and perineural invasion are found on histologic section.

Most mortality is due to uncontrolled disease in the neck. Regional lymph node metastases are found in few patients. The overall determinant five-year survival rate in lip cancer is 89%, but with cervical metastasis, the five-year rate decreases to 40% to 80%. The risk of metastasis is directly related to the size of the primary lip tumor. It is also increased with squamous cell cancer of the upper lip and recurrent primary lesions. If the patient has clinically palpable nodal 1 disease, they should receive selective neck dissection of levels I-IV, while nodal disease involving levels II-V is an indication for modified radical neck dissection with excision of primary tumor. If the intraparotid nodes are involved, a parotidectomy should be performed as well. The chance of long-term survival is significantly reduced if lymph node metastases develop. Any factors that could identify patients with increased risk of occult lymph node metastasis would allow more aggressive treatment and possibly a better outcome. Dr. Zitsch, in Missouri in 1999, sought to identify patients with increased risks of occult lymph node metastasis. He performed a chart review of a thousand cases of squamous cell cancer of the lip and found that the late cervical node metastasis developed in 40 patients. He found that there were no significant differences according to gender, lip subsite, or age. When he looked at which patients did develop metastasis, he noticed significant differences with tumor size, tumor differentiation, and local recurrence. T1 lesions only had a 7% incidence, while T3-T4 lesions had a 16% chance of occult lymph node metastasis. Well-differentiated tumors had only a 5% incidence, while higher grade tumors had a 20% incidence. The role of elective neck dissection has been controversial, but Dr. Zitsch concluded that those with high grade and local recurrence are groups that would benefit from elective treatment of cervical lymph nodes. Not enough studies have been done for high-risk patients with upper lip cancers, but for lower lip cancers the literature would recommend an elective lymphadenopathy for those cancers that are poorly differentiated, locally recurrent, and with a size greater than 2 cm.

What constitutes appropriate elective surgical treatment of the neck? In reviewing the lymphatic drainage, it is found that 90% of patients with metastasis have submandibular nodes; 75% of these patients have only these nodes; and submental nodes are present in 8% of cases, often in conjunction with submandibular metastasis. When the central third of the lower lip is not involved, 95% of metastasis are ipsilateral.

Lip carcinoma is one of the most readily curable malignancies in the head and neck due to the early detection and rare metastasis. But despite treatment, some will experience regional metastasis or delayed relapse. When formulating the treatment plan, one must consider whether the lesion has prognostic factors for a poor outcome because this will affect the aggressiveness of intervention and the reconstructive technique used. These negative prognostic factors include a large tumor size, high tumor grade, lymph node metastasis, a subsite other than the lower lip, and inadequate surgical margins. The most important prognostic indicator is the extent of disease at the primary site at the time of initial presentation. Primary lesions of less than 2 cm have a 90% five-year survival. This is an excellent rate compared to some of the other areas of the head and neck. But once tumors have grown to involve the mandible, the five-year survival rate drops to 40%. As the size of the primary tumor increases, the recurrences occur more often with an incidence of 40% in tumors larger than 3 cm.

Poor prognosis is also associated with confirmed lymph node metastasis and lesions of the oral commissure. Lesions of the oral commissure are not biologically more aggressive, but it has been found that 82% recurred in the primary site. This is often because the oral commissure involvement results either from the large primary tumor or the clinician performs inadequate resection due to reconstructive consideration. Recurrence can be defined as tumor growth within five years after completion of radiation or surgery. Recurrence causes the five-year survival rate to decrease by 50% because recurrences tend to be larger, with increased incidences of nodal metastasis.

Other poor prognostic factors include differentiation and tumor thickness. Patients with well-differentiated squamous cell lesions had an 86-95% survival, compared with a 38-71% for those with poorly differentiated lesions. Ninety percent of lip cancers immunostained for P53 protein. It has been found that UV radiation may induce P53 mutation and neoplastic transformation. Tumor thickness of greater than 5 mm and perineural invasion have also been found to be associated with poor outcome.

Finally, the lips have many reconstructive options. The lip is typically 6-7cm in length. When a defect is less than half of the lip, various options can be taken. Vermilion mucosal defects can be repaired with mucosal advancement flaps, particularly if the perioral tissue is lax and has not been radiated. When both the vermilion substance and the mucosa have been lost, one can use a muscle mucosa flap from the ventral surface of the tongue. Full thickness defects up to one-half width in thickness can be managed with primary closure. Defects of half- to two-thirds of the lip can be repaired with either a Karapandzic labioplasty or an Abbe Estlander flap. Dr. Karapandzic initially described his labioplasty in 1974. It is an orbicularis oris myocutaneous flap. Advantages include ease of design, and it also allows preservation of the motor and sensory enervation of the lip. However, disadvantages are its relative microstomia and circumoral scars. The Abbe Estlander flap was initially described in 1898 in New York. It is the lip switch flap essentially borrowing full thickness from the upper lip and switching it down to the lower lip defect. It permits close skin texture and color match with surrounding tissue. However, a second stage procedure is often required and the transfer tissue is often denervated. The Bernard repair uses a full thickness advancement flap from surrounding cheek tissue in a one-stage reconstruction. Distal flaps can also be used if the entire lip or adjacent soft tissue of the cheek or the chin are not adequate. Often a radial forearm free flap will be used or a pectoralis major flap.

In conclusion, lip squamous cell carcinoma accounts for 12% of head and neck noncutaneous cancers. It more often involves the lower lip and lymphatic drainage is primarily to group I nodes. The mainstay nowadays is surgical excision for early stage lesions. The literature would recommend treatment of cervical lymph nodes for lesions that are poorly differentiated, locally recurrent, with a size greater than 2 cm. One must take into account the prognosis for the patient when considering the reconstructive options.

Case Presentation

V.Z. is a 58-year-old Hispanic male, who presented to the Ben Taub clinic with a two-year history of a lesion on the left side of his lower lip. This lesion was tender, had grown in size, and bled slightly with manipulation. He denied numbness of lips or chin. He had worked for many years in construction with a long-standing history of sun exposure. He denied trismus, dysphagia, odynophagia, hemoptysis, otalgia, or recent trauma to area.

His past medical history was significant for diabetes mellitus and hypertension. He had smoked one pack of cigarettes per day for the past forty years and drank alcohol socially.

On physical examination, he had a 2cm ulcerative lesion on the left aspect of his lower lip. It extended to oral commissure and fell just short of midline. It was tender to palpation and nonadherent to the mandible. He had poor dentition. The remainder of his oral cavity and oropharyngeal examination was unremarkable. There was no palpable submental, submandibular, or preauricular lymphadenopathy.

This lesion was biopsied in clinic and was consistent with well-differentiated squamous cell carcinoma. Neck CT and CXR were negative. In October 2002, he underwent wide local excision of this lip lesion with Estlander local flap reconstruction and left supraomyohyoid neck dissection. Histology from both frozen and permanent sections revealed well-differentiated squamous cell carcinoma with negative margins, and a pathologically N0 (0/8) neck.

The patient has done well postoperatively with good wound healing and oral competence. He remains in regular follow-up at the Otolaryngology clinic at Ben Taub. He has been advised to stop smoking and to minimize sun exposure.

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