You are in: eMedicine Specialties > Plastic Surgery > HEAD AND NECK Head and Neck Cancer: Squamous Cell CarcinomaArticle Last Updated: May 25, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Jorge I de la Torre, MD, FACS, Professor of Surgery and Physical Medicine and Rehabilitation, Residency Program Director, Division of Plastic Surgery, University of Alabama at Birmingham; Director, Center for Advanced Surgical Aesthetics Jorge I de la Torre is a member of the following medical societies: American Association of Plastic Surgeons, American Burn Association, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Society for Reconstructive Microsurgery, American Society of Maxillofacial Surgeons, American Society of Plastic Surgeons, Association for Academic Surgery, and Medical Association of the State of Alabama Coauthor(s): Emmanuella Joseph, MD, Consulting Staff, Department of Plastic Surgery, Midwest Center for Plastic Surgery Editors: Lawrence Ketch, MD, FAAP, FACS, Head, Program Director, Associate Professor, Department of Surgery, Division of Plastic Surgery, University of Colorado Health Sciences Center; Chief, Pediatric Plastic, The Children's Hospital of Denver; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Jaime R Garza, MD, DDS, FACS, Consulting Staff, Private Practice; Nicolas (Nick) G Slenkovich, MD, Practice Director, Colorado Plastic Surgery Center at Swedish Medical Center; Al Aly, MD, FACS, Consulting Surgeon, Iowa City Plastic Surgery Author and Editor Disclosure Synonyms and related keywords: squamous cell carcinoma, epidermoid carcinoma, oral, pharyngeal carcinoma, SCC INTRODUCTIONSection 2 of 11
  Squamous cell carcinoma represents more than 90% of all head and neck cancers. A malignant tumor of epithelial origin, squamous cell carcinoma has a regional distribution involved in the biological activity of the neoplasm. Behavior of squamous cell cancer depends on its site of origin. Each anatomic site has its own particular spread pattern and prognosis. For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Cancer of the Mouth and Throat. History Evidence of head and neck carcinomas has been found in ancient skulls. The oldest known tumor is contained in a fossil found in east Africa by Leakey that dates back more than 500,000 years. Some historians speculate that there may have been a high incidence of nasopharyngeal cancer in some ancient populations because of the inhalation of wood smoke in poorly ventilated huts. In approximately 400 BC, Hippocrates described a common chronic ulcer at the edge of the tongue that he attributed to the presence of sharp teeth rubbing against the tongue. The ancient Indian physician Sushruta described the removal of tumors and developed great skill in plastic surgery, partly from defects created by frequent amputations of the nose and ears for punishment. Modern Western medicine received its foundation from early roman medical writings. Little medical advancement was made for head and neck cancers until the advent of anesthesia and surgical excision in the 11th century. In 1893, President Grover Cleveland was found to have a squamous cell carcinoma of the hard palate that required surgical excision. The operation was performed secretly on a yacht so that he could manage the "financial panic of 1893." He was known for his heavy cigar smoking and social drinking. Frequency In the United States, squamous cell carcinoma of the head and neck comprises about 4% of all malignancies. This corresponds to an estimated 17 per 100,000 persons with newly diagnosed squamous cell carcinoma of the head and neck per year. Male-to-female incidence rates are greater than 2:1. The discrepancy in the male-to-female ratio is even more pronounced in laryngeal tumors, in which carcinoma is 4-5 times more common in men. This ratio has declined in the last 20 years, possibly reflecting the increased number of women using tobacco products during this period. Laryngeal cancer generally is a disease of the elderly, with a peak incidence in the 50s and 60s. In certain parts of India and Southeast Asia, the practice of mixing cured tobacco with betel nuts has been associated with head and neck cancers. More than 200 million persons are thought to engage in this practice worldwide. A resultant 2.8 times higher relative risk of cancer exists for these individuals, and this increases to more than 10 times when smoking is also practiced. In Brazil and other developing countries, head and neck cancer represents 35% of all malignancies. Etiology Squamous cell carcinoma of the head and neck is most commonly associated with the use of alcohol and tobacco. The risk for oral cancer is additive and is 15 times greater than in those who neither smoke nor drink. In squamous cell carcinoma, mutations in the p53 gene correlate with drinking and smoking habits. Some 15% of patients have a viral etiology. Epstein-Barr virus (EBV) has been implicated in the development of nasopharyngeal carcinoma. Human papillomavirus infection is another factor implicated in the carcinogenesis of upper aerodigestive tract tumors. In particular, human papillomavirus-16 can be isolated in 36% of oral cavity cancers. Environmental exposures to paint fumes, plastic byproducts, wood dust, asbestos, and gasoline fumes have been implicated as risk factors. Gastroesophageal reflux disease is now thought to be a significant risk factor for cancer of the larynx and especially the anterior two thirds of the vocal cords. Irritation from poorly fitting dentures also has been implicated. Pathophysiology Squamous cell carcinoma is thought to arise from keratinizing or malpighian epithelial cells. The hallmark of squamous cell carcinoma is the presence of keratin or "keratin pearls" on histologic evaluation. These are well-formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments. The term epidermoid can be substituted for squamous. Morphologically, it is variable and may appear as plaques, nodules, or verrucae. These in turn may be scaly or ulcerated, white, red, or brown. Verrucous carcinoma has a more favorable prognosis because of infrequent nodal and distant metastasis. Clinical presentation Squamous cell carcinomas usually begin as surface lesions with erythema and slight elevation. These lesions are termed erythroplasia and deserve biopsy. These early red lesions are asymptomatic and may be either carcinoma in situ or invasive carcinoma. One third of lesions are pure white; they are known as leukoplakia but only 10% of them are carcinoma in situ or invasive carcinoma. The most common sites for squamous cell carcinoma are the floor of the mouth, the tongue, soft palate, anterior tonsillar pillar, and the retromolar trigone. Tender, painful lesions usually are suggestive of perineural invasions. When lesions become palpable masses, symptoms such as a vague persistent sore throat or ear infection occur. In more advanced cases, dissemination to ipsilateral submandibular and jugulodigastric nodes is common, and the patient may present with a mass in the neck. When lymph node or remote bone and organ metastases are associated with an early oral primary lesion, often a second, more advanced primary upper aerodigestive or lung cancer is responsible for the metastases. INDICATIONSSection 3 of 11
Factors influencing choice and type of treatment are the site and stage of the primary tumor. The TNM staging system used for head and neck cancers is a clinical staging system that allows physicians to compare results across patients, assess prognosis, and design appropriate treatment regimens. T refers to tumor size at the primary site, N refers to the status of the cervical chain of lymph nodes, and M refers to the presence or absence of distant metastases. T = Extent of the primary tumor
N = State of regional lymph nodes M = Metastases The same system is employed for laryngeal tumors. The basic premise of these systems is that smaller cancers with no nodal disease have a better prognosis than a larger lesion with positive neck nodes. TNM clinical classification T Primary tumor
Tis Preinvasive cancer (carcinoma in situ) T0 No evidence of primary tumor T1 Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 4 cm T3 Tumor more than 4 cm T4 Tumor with extension to bone, muscle, skin, antrum, neck, etc Tx Minimum requirements to assess primary tumor cannot be met N Regional lymph nodes N0 No evidence of regional lymph node involvement N1 Evidence of involvement of movable homolateral regional lymph nodes N2 Evidence of involvement of movable contralateral or bilateral regional lymph nodes N3 Evidence of involvement of fixed regional lymph nodes Nx Minimum requirements to assess the regional nodes cannot be met M Distant metastases M0 No evidence of distant metastases M1 Evidence of distant metastases Mx Minimum requirements to assess the presence of distant metastases cannot be met Staging Stage 1 T1 N0 M0
Stage 2 T2 N0 M0 Stage 3 T3 N0 N1 M0 Stage 4 T1 T2 T3 T4 N1 M0 Any T N01N1 M0 Any T N2 N3 M0 Any N M1 Depth of infiltration is predictive of prognosis. With increasing depth of invasion of the primary tumor, the risk of nodal metastasis increases and survival decreases. RELEVANT ANATOMYSection 4 of 11
The oral cavity is defined as the area extending from the vermilion border of the lips to a plane between the junction of the hard and soft palate superiorly and the circumvallate papillae of the tongue inferiorly. This region includes the buccal mucosa, upper and lower alveolar ridges, floor of the mouth, retromolar trigone, hard palate, and anterior two thirds of the tongue. The lips are the most common site of malignancy in the oral cavity and account for 12% of all head and neck cancers, excluding nonmelanoma skin cancers. Squamous cell carcinoma is the most common histologic type, with 98% involving the lower lip. This predilection to the lower lip has been attributed to sun exposure. Next most common sites in order of frequency are the tongue, floor of the mouth, mandibular gingiva, buccal mucosa, hard palate, and maxillary gingiva. Tumor site and lymphatic drainage
The pharynx consists of the oropharynx, nasopharynx, and hypopharynx. The most common sites of cancer in the oropharynx are the tonsillar fossa, soft palate, and base of tongue, followed by the pharyngeal wall. The hypopharynx is divided into the pyriform sinus (most common site of tumor involvement), posterior pharyngeal wall, and postcricoid region. Invasion of the cartilage framework of the larynx and mobility of the vocal cords influence the treatment of primary tumors of the hypopharynx and larynx. Ohngren line is an imaginary line drawn from the medial canthus to the angle of the mandible that divides the paranasal sinuses into an infrastructure and suprastructure. Sinus tumors involving the infrastructure have a more favorable prognosis compared to tumors of the suprastructure. WORK-UPSection 5 of 11
Toluidine blue is recommended for early detection as a guide for optimal biopsy. Toluidine blue clinically stains malignant lesions dark blue but does not stain normal mucosa. Dye is absorbed by the nuclei of malignant cells with increased DNA synthesis. A complete head and neck examination with indirect nasopharyngeal and laryngopharyngeal mirror examination is mandatory. Follow this with fine needle aspiration biopsy for cytology or excisional biopsy. If the diagnosis of carcinoma is made, endoscopic examination should proceed under general anesthesia with random biopsies of Waldeyer ring, the hypopharynx, nasopharynx, and other common sites of metastasis and any suspicious lesions. Subglottis, esophagus, and tracheobronchial tree are routinely evaluated to rule out synchronous primaries, which may have an incidence of 20%. Perform routine hematologic examination to assess the overall medical condition of the patient and the possibility of spread to distant organs. Anemia may be detected with a CBC with platelet count. Liver function test determines hepatic spread. Blood gases, chest radiographs, and pulmonary function tests are useful in this population of heavy smokers. Imaging studies CT is useful in evaluating the extent of the primary tumor and nodal involvement. CT also should include the lung fields and liver for assessment of distant spread. Overall accuracy of nodal staging with CT (90-95%) appears superior to the accuracy obtained by clinical nodal staging (75-80%). Thus, more metastases will be detected when CT is incorporated into the staging protocol of patients with primary head and neck squamous cell carcinoma. Overall accuracy of MRI in staging neck nodes is as yet unsubstantiated by significant clinical/pathologic/radiologic studies. Currently, MRI is inferior to CT in identifying central necrosis or extranodal tumor spread. TREATMENTSection 6 of 11
Several methods for treatment of cancer of the head and neck are acceptable, including surgery, radiotherapy, chemotherapy, and combinations of these. New investigative treatments include immunotherapy and gene therapy. Factors that influence the choice of treatment are the site, grade, and stage of the primary tumor, patient age, and general medical condition. Goals of treatment generally consist of removal of cancer load, maintenance of quality of life, and prevention of subsequent primaries. Medical therapy Early detection and treatment by multiple modalities is important for better prognosis in head and neck cancer. Radiotherapy Nearly all patients with advanced disease require adjuvant radiotherapy, preoperatively or postoperatively. Preoperative radiotherapy has the risk of increased complications of surgery. Radiation dosage in excess of 6000 cGy is recommended with a boost to areas of high risk. Indications for radiotherapy include a bulky tumor with significant risk of recurrence (T3 and T4), histologically positive margins, and perineural or perivascular invasion of tumor. For the neck, indications for radiotherapy include elective treatment of the N0 neck not treated surgically where risk of micrometastasis is high, gross residual tumor in the neck following neck dissection, multiple positive lymph nodes, and extranodal extension of tumor. Chemotherapy Adaptation of traditional chemotherapeutics to local and regional administration techniques in treating head and neck cancers is being actively pursued to provide higher local concentrations of otherwise systemically toxic drugs. Bleomycin with or without electroporation has been used. Cisplatin is another chemotherapeutic drug of choice for head and neck cancers. Although cisplatin is one of the most successful agents in the treatment of cancer, it produces major toxicities to normal cells and organs at the concentrations necessary for effective treatment of malignancies. A combination of cisplatin with interstitial laser therapy has been reported. Hyperthermia produced by the laser is known to augment cytotoxic effects of both radiation therapy and some chemotherapy drugs. Temperatures above 38°C enhance cisplatin therapy. Surgical therapy Surgical resection remains the criterion standard for treatment of head and neck cancer. Management of all but the earliest confirmed neck metastases is best achieved with surgical removal. The literature reports radiation therapy for patients with N0 or N1 necks and concludes that radiation or surgery can treat them equally well. Because patients with cancers of the head and neck often have had previous radiation therapy, flaps must have an adequate blood supply. Neck dissection Lymphatic metastasis is the most important mechanism in the spread of head and neck squamous cell carcinomas. The rate of metastasis probably reflects the aggressiveness of the primary tumor and is an important prognostic indicator. Regardless of the site of the primary tumor, the presence of a single lymph node in either the ipsilateral or contralateral side of the neck reduces the 5-year survival rate by 50%. Modified neck dissection is designed to preserve the spinal accessory nerve, the great auricular, and the sternocleidomastoid muscle. The jugular vein and submandibular gland also have been preserved. In addition, successful results can be achieved through less than complete lymph node removal, selectively removing only those lymph node levels likely to be involved by metastases. Modified radical neck dissection removes all 5 lymph node levels, preserving one or all of the spinal accessory nerves, jugular vein, and sternocleidomastoid muscle. Selective dissection removes either levels 1, 2, and 3 (supraomohyoid neck dissection); levels 2, 3, and 4 (anterior neck dissection); or levels 2, 3, 4 and 5 (anterolateral neck dissection). Modified and selective neck dissections clearly have been demonstrated as oncologically equal to the radical neck dissection in treating N0 neck disease. However, when there is one positive node, the likelihood of another positive node in an unexpected location increases significantly. For this reason, selective neck dissection is usually limited to patients without pathologically involved lymph nodes on the side of the dissection. Classic radical neck dissection was described by Crile in 1901 and includes removal of all 5 levels of cervical lymph nodes en bloc down to the deep muscular fascia. This removal includes the sternocleidomastoid muscle, submandibular gland, jugular vein, and spinal accessory nerve. This operation remains the best procedure for definitive control of neck disease. Radical neck dissection can be combined with resection of the primary cancer and postoperative radiation therapy. Radical neck dissection has significant morbidity because of the resection of the spinal accessory nerve and, in bilateral dissection, the sacrifice of the internal jugular veins. Severing the spinal accessory nerve results in paralysis of the trapezius muscle in approximately 70% of patients. In most patients, the shoulder subsequently loses support, rotates forward, and droops, and the patient has pain and difficulty lifting his or her arm. OUTCOME AND PROGNOSISSection 7 of 11
For all sites and stages in the head and neck region, 5-year survival rates average 50%. Treatment of early lymphatic nodal spread and use of multiple modalities has resulted in improved survival in selected sites. Depth of lesion and percent survival <2 mm—95%
2-9 mm—80% >9 mm—65% Patients with early stage oral cancer have a 75% survival at 5 years but only 35% survival for advanced stages at 5 years. In addition, the incidence of multiple primaries is 40% in long-term survivors; therefore, early detection of head and neck cancers and cessation of alcohol and tobacco use is essential to improve prognosis. FUTURE AND CONTROVERSIESSection 8 of 11
Photosensitizers and interstitial laser therapy Photosensitizing drugs that concentrate in cancer cells form the basis for photodynamic therapy. Activation of the drug with light results in cancer cell death. Laser photothermal ablation may be an alternative to surgery for the palliative treatment of head and neck cancer because of its tissue-sparing access, the possibility of repeated treatment, and experimental evidence suggesting lower recurrence at tumor margins compared with surgery. The combination of interstitial laser therapy with regional chemotherapy agents that are activated by light or heat is under investigation as a combined therapeutic regimen. Immune therapy Recruitment of immune cells and administration of stimulatory immune factors to augment treatment of cancer through the host immune response have been advocated but have had little success to date in treating head and neck cancers. Nonspecific immunoadjuvant systemic treatment with factors, such as levamisole or Bacillus Calmette-Guérin (BCG), or targeted treatment with purified or recombinant factors, such as interferons or interleukin-2 (IL-2), have not improved either response rate or duration. Severe toxicities also are associated with the systemic use of these factors. Gene therapy Gene therapy involves a variety of delivery vehicles that can transfer therapeutic genes to target cells. Therapeutic genes may encode a product that induces a biologic response, such as activation of the immune system with transferred interleukin sequences. Head and neck cancers are known to have high levels of p53 mutations. Normal functions of p53 are cell growth regulation. Insertion of the p53 gene into a variety of tumor cell lines in vitro and into animal models in vivo has resulted in suppressed cell growth through cell cycle arrest and apoptosis. Head and neck cancers are accessible to injection therapy and are good candidates for trials of p53 gene therapy. Another form of therapeutic gene delivery is the adenovirus vector, which uses a genetically engineered virus that is replication incompetent. Prodrug gene therapy, also known as suicide gene therapy, is designed to induce negative selection of cancer cells. By transducing cancer cells with a gene encoding an enzyme that metabolizes a nontoxic prodrug into its toxic form, cancer cells can be selectively killed. Herpes simplex virus is a common human virus that produces a unique thymidine kinase. This viral enzyme preferentially phosphorylates the prodrug ganciclovir, a guanine nucleoside analogue, to produce a metabolite that, after cellular phosphorylation, is incorporated into replicating DNA, inhibiting DNA polymerase and ultimately killing the cell. This therapy is most effective in treating cancer cells growing in tissues where normal cells are not proliferating. Many phase I and II trials are being pursued, and may ultimately provide nontoxic, tumor-specific, locally and regionally active, and biologically active injectable modalities that add therapeutic advantages to the existing treatment of head and neck cancers. ACKNOWLEDGMENTSSection 9 of 11
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Laurence M Baibak, MD, FACS, to the development and writing of this article. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Head and Neck Cancer: Squamous Cell Carcinoma excerpt Article Last Updated: May 25, 2006 | |||||||
