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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
National Institutes of Health
National Cancer Institute
Bethesda, Maryland 20892
MEMO
TO: Director, Office of Rare Diseases, ODP/OD, NIH
FROM: Head, Surgery Section, CIB, CTEP, DCTDC, NCI
RE: Follow-up to fiscal year 96 ORD-sponsored strategy planning meeting on Head
and Neck Squamous Cell Carcinoma
DATE: February 6, 1997
With the help of funding from the Office of Rare Diseases, the National Cancer Institute sponsored a strategy
planning meeting on clinical staging and operative reporting for multi-institutional trials in head and neck
squamous cancer September 27 and 28, 1996.
Head and neck cancer is relatively infrequent. Approximately 42,000 new cases occur each year. When further
subdivided by site, stage, and operability, it is estimated that only 500 cases per year qualify for multi-modality
treatment trials including surgery. To date, no multi-institutional study that has included surgery as a form of
treatment has demonstrated a significant survival advantage to the experimental arm over the control arm. This
meeting addressed three specific areas of concern: the clinical variables (co-morbid health status)
that cause
heterogeneity in the head and neck cancer population, the inadequacies of the TNM system as it relates to
multi-institutional trials, and the variability in reporting surgical resection and pathologic analysis.
The meeting participants concluded that co-morbid health status should be categorized using the modified
Kaplan-Feinstein Index, Karnofsky Performance Status, tobacco use, and alcohol use, using the CAGE
questionnaire. They proposed a detailed anatomic reporting scheme that would replace TNM staging in
multi-institutional trial settings. In addition, they recommended that surgical reporting in multi-institutional trials
should use a format compatible with computer analysis and identical to the revised staging system.
Surgeons should be personally responsible for coding of the resection. The surgeon and pathologist should
examine and ink the primary specimen at the time of resection. Pathologic reporting should utilize a template
comparable with the staging and operative reporting formats.
The meeting proceedings have been submitted for publication in the journal Head and Neck. Both the American
Society of Head and Neck Surgery and the Society of Head and Neck Surgeons have approved the concept of a
common database. Each has contributed $10,000 for implementation of a national head and neck cancer database. The software for this database will be distributed for beta testing to 22 sites in 1997.
We appreciate the support of the Office of Rare Diseases for this meeting, which will have a major impact on the
design, data reporting, and analysis of multi-institutional trials in squamous cancers of the head and neck.
Edward L. Trimble, M.D., M.P.H.
cc: Roy Wu, Ph.D.
From the June 1998 Federal Practitioner Supplement
Head and Neck Cancer: An Update
William R. Carroll, M.D., F.A.C.S.; Glenn E. Peters, M.D., F.A.C.S.;
and David J. Halvorson, M.D.
This update on cancer in the head and neck region will focus on malignancies originating in the upper aerodigestive tract.
Malignancies arising in the skin and central nervous system will be excluded. This article will be divided into three main sections.
In the first section, general principles including the epidemiology and etiology of head and neck cancer will be discussed as well as
a review of common presenting signs and symptoms. In the second section, specific subsites within the head and neck will be
addressed, with emphasis on detection, evaluation, and treatment of cancers occurring at each site. In the final section, new
developments in the field of head and neck oncology will be presented.
GENERAL PRINCIPLES
Epidemiology and Etiology
In the United States, cancer of the upper aerodigestive tract comprises 5% to 6% of all cancer. To put this in perspective, prostate
cancer comprises approximately 20% of all cancers detected, lung cancer comprises approximately 14%, and breast cancer
comprises approximately 14% of all cancer detected.1 In developing countries, particularly in Asia, the incidence of cancer in the
head and neck region may comprise 40% to 50% of all cancer.1, 2 Most of the malignancies of the upper aerodigestive tract are
squamous cell carcinoma. The salivary glands and thyroid glands are sites of notable exception and will be discussed in more detail
below.
Many epidemiologic studies have established that the risk of cancer of the upper aerodigestive tract is significantly increased among
cigarette smokers. The risk of dying of cancer of the pharynx is increased 27 times for a man 35 years of age and older who smokes.
The risk of dying of cancer of the larynx is 10.5 times greater in smokers compared to nonsmokers.3 Tobacco smoke contains over
3,000 different chemicals. The known carcinogens in tobacco smoke include aromatic hydrocarbons, aromatic amines, aldehydes,
and inorganic compounds. The increased risk of cancer of the upper aerodigestive tract from smoking seems to require 15 to 20
years of smoking cessation before returning to baseline.
Frequent ingestion of alcohol also appears to independently increase the risk of upper aerodigestive tract cancer. A nonsmoker who
consumes 1.5 ounces of alcohol daily has a 2.3 times greater incidence of developing oral cavity cancer than a nondrinker.4 When
used together, alcohol and tobacco have a synergistic effect on producing cancer in the upper aerodigestive tract. It is estimated that
combined exposure to alcohol and tobacco accounts for 75% to 85% of upper aerodigestive tract cancers in the United States.5
Other risk factors for development of carcinoma of the upper aerodigestive tract include viral exposure and nutritional deficiencies.
Human papilloma virus, which has been linked to early cervical cancer in women, has been detected in squamous cell cancer of the
head and neck in young immunocompromised patients. The mutagenic potential of free oxygen radicals has received broad
attention. Antioxidants such as carotenoids and vitamin C act as scavengers for charged oxygen species. Infrequent consumption of
fresh fruits and vegetables probably increases the risk of development of carcinoma of the upper aerodigestive tract.
Presenting Signs and Symptoms
Unfortunately, many patients with carcinoma of the upper aerodigestive tract present with advanced disease. Occasionally, lesions
that are entirely asymptomatic will be detected on a routine physical examination by a physician or an alert dentist. When
interviewing a patient with head and neck complaints, the examiner should ask about difficulties with speech (articulation and sound
production), swallowing, aspiration, airway symptoms, bleeding, pain, and numbness. By the time tumors become large enough to
ulcerate, bleed, or become painful, they are often quite advanced. A notable exception is vocal cord cancer. Because production of a
normal voice requires maintenance of the fine, smooth surface of the vocal cords, even a small irregularity produces hoarseness.
Vocal cord cancers are thus frequently detected at an early stage. In contrast, cancers in the sinuses, nasopharynx, tongue base,
supraglottic larynx, and hypopharynx remain asymptomatic for an extended period of time. It is when they become sufficiently bulky
as to interfere with speech, swallowing, or the airway that they are finally detected clinically. At this stage, most have extensive
local invasion and the majority have metastasized to regional nodes.
Physical Findings and the Head and Neck Examination
A complete examination of the upper aerodigestive tract is difficult to accomplish without appropriate mirrors or a flexible fiber-optic
scope. The nasopharynx, inferior one-half of the oral pharynx, hypopharynx, and larynx are simply not visible without these tools.
Recently, flexible fiber-optic scopes for examination of the upper airway have become more widely available for primary care
physicians and will hopefully allow earlier detection of upper aerodigestive tract carcinoma. Even with mirrors or fiber-optic scopes to perform a complete head and neck examination, some areas of the lateral pharyngeal wall, hypopharynx, and larynx are notoriously difficult to visualize in the office. In addition to careful inspection, palpation of the oral
cavity, tongue base, and neck is a very important part of the head and neck examination. In select patients, endoscopic examination
with the patient under anesthesia is required to rule out the presence of a neoplasm.
When should a patient with head and neck complaints be referred to an otolaryngologist or head and neck oncologist? Obviously,
every patient who presents with a sore throat does not require a full ear, nose, and throat examination. As a general rule, most
inflammatory or infectious conditions in the head and neck region will resolve either spontaneously or with appropriate treatment
within 2 weeks of initial evaluation. Patients with persistent pain, adenopathy, sensation of a lump in the throat, hoarseness, chronic
cough, or bleeding should undergo a complete mucosal examination of the head and neck.
Treatment Options
In general, early squamous cell carcinomas of the aerodigestive tract can be treated equally effectively by surgery or radiation
therapy. Standard therapy for more advanced lesions is typically a combination of surgery and radiation therapy. Chemotherapy
(cisplatin and 5-fluorouracil) in combination with radiation therapy has been proven to be effective for advanced squamous cell
carcinoma of the larynx. Chemotherapy has not been proven to be as effective as other treatment methods for any other site of cancer
of the head and neck. Specific recommendations for each subsite are included in more detail as follows.
VARIOUS SITES FOR TUMORS OF THE HEAD AND NECK
Carcinoma of the Oral Cavity/Oral Pharynx
Carcinoma of the oral cavity and oral pharynx represents approximately 3% of all cancers that occur in the United States annually.
Oral and pharyngeal cancers are very common in Asian countries, and the increased incidence in those individuals who immigrate
to the United States should be remembered when examining this specific group. The incidence of carcinoma of the oral cavity and
oral pharynx has been recognized to be two to three times higher in men than in women, although the ratio is decreasing due to the
increasing number of women who smoke tobacco. As with most carcinomas of the head and neck, the incidence increases with age
and the vast majority are diagnosed in the sixth to seventh decade of life.
Approximately 90% of all carcinomas in the oral cavity and oral pharynx are squamous cell carcinomas. Other tumor types include
minor salivary gland tumors, sarcomas, lymphomas, and melanomas. Squamous cell carcinoma may present with several different
morphologic growth patterns including ulcerative, infiltrative, and exophytic. The most common type of lesion to present in the oral
cavity is ulcerative.
Other lesions that are commonly found in the oral cavity that may be precursors to carcinoma include leukoplakia and erythroplakia.
Leukoplakia is a white patch or plaque-like lesion of the mucosa. The term does not connote any particular histologic structure.
Many consider leukoplakia to be a premalignant lesion. The histologic findings may range from epithelial hyperplasia to dysplasia,
carcinoma in situ, or invasive carcinoma. Because of the risk of carcinoma, all leukoplakia lesions should be biopsied and evaluated
histologically. Erythroplakia is a red, velvety, plaque-like lesion that occurs less often than leukoplakia. It primarily occurs in the
floor of the mouth or the gingival buccal sulcus. Erythroplasia carries a much higher risk of malignancy than leukoplakia and should
always be sampled by biopsy for a histologic evaluation.
Examination
Physical examination should involve the careful attention to the teeth, gums, floor of mouth, retromolar trigone area, and the
gingival buccal sulcus of both the mandible and maxilla. The tongue mobility, color, and the presence of any lesions should be noted.
Manual palpation of the submandibular gland both intraorally and externally as well as manual palpation of the floor of mouth,
anterior tongue, and base of tongue should all be performed.
Benign lesions tend to present as mucosally covered enlarging masses without evidence of ulceration. Inflammatory diseases of the
oral mucosa often present as significant ulcerative areas with associated erythema that can often be confused with neoplasms. The
best method to distinguish benign and malignant lesions is with histologic evaluation. In the oral cavity, a biopsy may often be easily
obtained using local anesthesia in the office.
Carcinoma of the Oral Cavity
Specific sites of the oral cavity include carcinoma of the lip, buccal mucosa, floor of mouth, alveolar ridge, palate, retromolar trigone, anterior two-thirds of the tongue, and hard palate.
Carcinoma of the lip accounts for 30% of all cancers of the oral cavity, and the vast majority are squamous cell carcinomas,
primarily involving the lower lip. Carcinoma of the lip has a distinct predominance in men, and 85% of lip cancers occur at the
halfway point between the midline and the commissure of the lower lip. There is an increased incidence of metastases with an
increasing size of the tumor, although neck metastases occur relatively infrequently. Most cases of carcinoma of the lip may be
treated by simple surgical excision. Larger lesions may necessitate the use of local flaps or lip switch flaps to close the resulting
defect.
Carcinoma of the buccal mucosa is an uncommon tumor and comprises only 5% of oral cavity carcinomas. Buccal carcinoma also
occurs more frequently in men and is most often seen in individuals who use smokeless tobacco. The most common site of origin of buccal carcinoma is the region adjacent to the lower third molar and often is heralded by leukoplakia or erythroplakia lesions. Buccal
carcinoma frequently presents as an advanced tumor with trismus because of masseter or pterygoid muscle involvement. Cervical
metastases are found in almost one-half of cases. The presence of cervical metastases indicates a poor prognosis, and surgical
resection often involves complex reconstructive procedures. Early lesions can be treated with surgery or radiation. Surgical therapy is often simpler and more cost effective. Larger lesions require combined surgery and radiation.
The floor of the mouth accounts for approximately 10% to 15% of the sites for all oral carcinomas and is the most common site of
oral cancer in blacks. Floor-of-mouth carcinoma is frequently associated with multifocal carcinomas, and cervical metastases are
common. Early lesions are equally curable with radiation therapy or surgery. Combined therapy is recommended for larger and more
deeply infiltrative lesions. Surgery for advanced lesions often results in speech and swallowing difficulties. Complex reconstructive
procedures are often necessary.
Carcinoma of the alveolar ridge accounts for approximately 10% of oral carcinomas, and mandibular alveolar ridge carcinoma is
much more common than maxillary alveolar ridge carcinoma. Most tumors arise in an edentulous area and are more common in
patients who chew tobacco. Bone invasion may occur early, secondary to close proximity. Cervical metastases, however, are not
typically seen when alveolar ridge lesions are detected early. Surgical therapy often involves partial mandibulectomy or
maxillectomy.
Carcinoma of the hard and soft palate is rare. Salivary gland malignancies of the hard palate occur as frequently as does squamous
cell carcinoma. The hard palate is the most common site in the oral cavity for minor salivary gland tumors. Cervical metastases are
common in patients with carcinoma of the hard palate, and large tumors may involve significant extension into the nasal cavity and
maxillary sinuses. The lesions often begin as slowly enlarging, submucosal masses. Two benign lesions of the hard palate that are
often confused with carcinoma are necrotizing sialometaplasia and follicular lymphoid hyperplasia. Biopsy with histologic
evaluation often clarifies the diagnosis.
Carcinoma of the retromolar trigone commonly involves adjoining sites, as the retromolar trigone is a small site within the oral
cavity. Adjacent sites include the anterior tonsillar pillar, the lower alveolar ridge, the buccal mucosa, the floor of the mouth, and the
soft palate. Carcinoma of the retromolar trigone, as with other oral cavity carcinomas, is also associated with alcohol and tobacco
use. Unfortunately, most patients with retromolar trigone disease present with advanced disease, and approximately 50% of patients
present with cervical metastases. Bony invasion is common, and trismus may be present because of pterygoid muscle or mandibular
involvement. Otalgia may be the only presenting symptom and results from involvement of the gloss opharyngeal nerve, which
provides sensory innervation to this area.
The anterior two-thirds of the is also considered to be within the oral cavity. The anterior tongue is the second most common site of
oral cavity cancer. Carcinoma of the oral tongue most often presents in the lateral border of the middle third of the tongue, while
larger lesions may involve the floor of the mouth and anterior one-third of the tongue. Approximately one-half of the carcinomas of
the oral tongue present with cervical metastases, and this cancer is considered by many to be a very aggressive disease. Contralateral
adenopathy is often present at the time of surgery, and wide surgical margins with reconstruction
are advocated. In Europe, many
tongue cancers are treated with radiation implants, with reasonable cure rates. Combined surgery and radiation is standard therapy for advanced tongue cancer in this country. Surgical resection of the tongue produces significant speech and swallowing deficits.
Carcinoma of the Oral Pharynx
The subdivisions of the oral pharynx include the base of the tongue, soft palate, tonsillar fossa, tonsillar pillars, and posterior
pharyngeal wall. As with those of the oral cavity, most of the malignancies are squamous cell carcinomas and are most common in
men. Carcinomas of the oral pharynx often present at an advanced stage of disease with cervical metastases. Lymphatics tend to be
very rich in this area, and early dissemination often occurs. The tonsil and tonsillar fossa are the most common locations for
carcinoma of the oral pharynx. Many tonsil cancers, as well as other tumors arising in the lymphoid tissue of Waldeyer's ring, are
more radiosensitive than other squamous call carcinomas. Radiation therapy is often used as initial therapy, with surgery being
reserved for salvage procedures. With advances in reconstructive procedures, however, many surgeons are advocating combined
surgery and radiation initially as the optimum method of disease control.
Base-of-tongue carcinomas most frequently present as advanced lesions secondary to the difficulty in diagnosis. Nodal disease is
present at diagnosis in up to 75% of patients and is often bilateral. Five-year survival rates are well below 50%. Treatment generally
requires a combination of radiation therapy and surgical extirpation. Invasion of the base of the tongue with extension to the larynx
is not uncommon. Achieving a clear surgical margin may require resection of the larynx in addition to the base of the tongue.
Tumors of the Salivary Glands
The salivary glands may be grouped into major and minor salivary glands. The major salivary glands include the parotid gland,
submandibular gland, and sublingual glands. Numerous minor salivary glands are located within the mucous membrane of the lip,
tongue, hard and soft palate, buccal mucosa, pharyngeal walls, larynx, nose, and paranasal sinuses. Saliva is important for initial
digestion of food, lubrication of food, protection of dental structures, and control of oral bacterial counts. The most common benign
and malignant neoplasms of the salivary glands are discussed below.
Pleomorphic Adenoma (Benign Mixed Tumor)
Of all tumors arising in the salivary glands, pleomorphic adenoma is the most
common. In a large series of salivary gland tumors from Memorial-Sloan Kettering Hospital, 46% of all salivary tumors were
pleomorphic adenomas.6 Pleomorphic adenomas often occur in the parotid glands where they comprise approximately 80% of the
benign tumors. Pleomorphic adenomas, also called benign mixed tumors, are so named because they contain both mesenchymal and
epithelial cell lines. Pleomorphic adenomas typically present as a painless enlargement within the parotid gland. Usually the lesion
grows very slowly. Pain or skin ulceration are usually not seen with pleomorpbic adenomas. Facial nerve weakness is extremely rare,
even with very large lesions. Presence of these findings should raise the level of suspicion that a malignancy is present. In the oral
cavity or elsewhere in the upper aerodigestive tract, pleomorphic adenomas present as a painless submucosal swelling.
Evaluation of a pleomorphic adenoma includes a complete head and neck examination. If located in the parotid, the detection of a
painless, solid mass is adequate to recommend surgical excision. Fine needle aspiration cytology can be helpful in distinguishing
benign and malignant salivary gland lesions. Interpretation, however, requires a cytopathologist who is familiar with salivary gland
lesions. These lesions can be very frustrating for the pathologist to characterize.
Preoperative radiographic imaging is not routinely necessary. When the extent of the lesion is not easily determined by physical
examination, when there is suspicion of deep lobe and parapharyngeal space involvement, or if the pleomorphic adenoma is arising
in a minor salivary gland, preoperative computed tomography or magnetic resonance imaging scanning may be extremely helpful.
Treatment of pleomorphic adenomas is surgical. In the parotid gland, where most of these lesions occur, surgical treatment should
include identification and preservation of the facial nerve and resection of the tumor with a generous cuff of normal surrounding
gland. In the past, simple enucleation was often attempted. Because the lesions often had pseudopods extending from their surface,
these cases had a 30% recurrence rate. The risk of injury to the facial nerve is also significantly higher with enucleation procedures.
It is surprising how often a lesion, which on palpation is located at a superficial level within the parotid gland, is found to lie directly
adjacent to the facial nerve on surgical exploration.
Warthin's Tumor (Cystodenoma Lymphomatosum)
Warthin's tumor (named for the pathologist who described the lesion in the early 1900s) occurs almost exclusively within the parotid
gland and is the second most common benign salivary tumor. Elderly men are affected most frequently, and the tumor can be
bilateral in up to 10% of the cases.
Warthin's tumor usually presents as a slowly growing mass in the tail of the parotid gland of elderly men. Needle biopsy may help
confirm the clinical impression. Imaging is rarely necessary. The accepted treatment of Warthin's tumor is complete surgical
excision. Identification and protection of the facial nerve is a priority for this tumor as well. The tumor is unlikely to recur if
completely excised. If the diagnosis is confirmed in an elderly patient who is not an optimal surgical candidate, Warthin's tumor can
be simply followed up by serial physical examinations.
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma is the most common malignant salivary gland tumor. It comprises approximately one-fourth to one-third
of the total number of salivary gland malignancies. About half of these are found in the parotid gland. Mucoepidermoid carcinoma is
by far the most common malignancy within the parotid gland.7 Mucoepidermoid carcinomas contain components that are both
mucous secreting and epidermoid. The malignancies are graded histologically as low grade or high grade. The histologic appearance
seems to correlate with biologic behavior. High-grade mucoepidermoid carcinomas are aggressive and nodal metastases are
common. Low-grade mucoepidermoid carcinomas have a slower growth rate, a lower recurrence rate, and rarely exhibit metastatic
spread. Preoperative evaluation of malignant parotid tumors is similar to that discussed above for benign tumors. Imaging studies are
helpful if there are questions about extent of disease. A fine needle aspirate may help confirm the diagnosis before surgery. Many
surgeons feel that this is helpful in cases of a high-grade malignancy. Others feel that the results of the needle aspirate do not change
their management and elect not to aspirate these lesions.
Treatment of mucoepidermoid carcinomas consists of wide local excision of the parotid gland via a total parotidectomy. The facial
nerve is spared if it is not directly invaded with malignant cells. If the facial nerve is directly invaded, it is frequently sacrificed. If
nodal disease is present at the time of diagnosis, a neck dissection is performed concomitantly. Many surgeons feel that since there is
a high risk of occult metastases to the neck with high-grade mucoepidermoid carcinomas, an elective, selective neck dissection
should be performed in these patients. The authors typically perform a selective neck dissection with high-grade parotid
malignancies even in the absence of palpable disease. Recurrence rates after surgery for low-grade mucoepidermoid carcinomas are
approximately 15%. Recurrence rates after surgery for high-grade mucoepidermoid carcinoma approach 60%. Adjuvant radiation
therapy is commonly included for high-grade lesions.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is the second most common malignant tumor of the salivary glands. In fact, in the submandibular glands
and minor salivary glands, adenoid cystic carcinoma is the most common malignancy. Adenoid cystic carcinoma is a slow and
relentlessly growing neoplasm. It has a particular affinity for invasion of perineural lymphatics. The tumor often invades the
perineural space and microscopically travels long distances from the primary site. There are two important implications of this
perineural spread. First, the tumors often present with chronic, throbbing pain. Second, complete surgical resection of the lesions can
be extremely difficult. In fact, some surgeons say that adenoid cystic carcinoma is never completely cured and if followed up long
enough, will always occur.
Within the parotid gland, these tumors present as a very slowly enlarging mass. Pain and/or facial nerve weakness may be present.
The lesions are slow to metastasize to regional nodes. With continued growth, however, metastatic spread is often seen as a
recurrence, and pulmonary metastases are frequently encountered. Treatment of adenoid cystic carcinoma is primarily surgical. A
total parotidectomy should be performed. Again, if the facial nerve is not directly invaded by the tumor, it can be spared. Because of
the tendency of these lesions to invade nerves, however, some surgeons have recommended radical parotidectomy with removal of
the facial nerve, whether or not direct invasion is seen. It is not clear in the literature that this extremely aggressive approach
improves patient survival.
Lymph node dissections are done only when palpable disease is present. There has been no role for elective lymph node dissection in
adenoid cystic carcinoma. Postoperative irradiation is usually recommended. Recently, neutron beam irradiation has shown promise
in improving local control of adenoid cystic carcinoma even in those cases when complete surgical resection was not possible.8
Adenocarcinoma
Adenocarcinoma is the third most common malignancy in the salivary glands. The majority of adenocarcinomas are found in the
parotid gland. The minor salivary glands are the next most common site. In the parotid gland, they often present as a painless
enlarging mass. In the minor salivary glands, they frequently present as an enlarging submucosal mass. Treatment in either location
consists of wide surgical excision. The facial nerve is typically spared if not directly invaded. Regional nodes are only dissected if
clinically involved. Adenocarcinomas have a higher rate of distant metastases than mucoepidermoid carcinoma or acinic cell
carcinoma. Radiation therapy is often used as an adjuvant, although these tumors are not particularly radiosensitive.
Acinic Cell Carcinoma
This tumor represents one of the more unusual types of salivary gland malignancies. Acinic cell carcinoma has a more benign
clinical course than the carcinomas mentioned above. At one time, acinic cell carcinoma was referred to as acinic cell tumor,
illustrating the difficulty in predicting its clinical behavior. A subset of these tumors with high mitotic rates exhibits aggressive
behavior and early metastatic spread. The tumors are occasionally detected bilaterally. Diagnosis of acinic cell carcinoma in one
parotid gland should always lead to careful search for the same malignancy in the other side.9 Treatment of acinic cell carcinoma is
primarily surgical. A wide local excision should be performed, including a total parotidectomy, if the lesion is found in the parotid
gland. Regional lymph nodes are dissected only if they are clinically involved.
Carcinoma Ex-Pleomorphic Adenoma and Malignant Mixed Tumors
Carcinoma can occasionally arise from a preexisting pleomorphic adenoma. This lesion is called carcinoma ex-pleomorphic
adenoma. This lesion is an epithelial malignancy. In contrast, true malignant mixed tumors contain malignant cells from both the
epithelial and the mesenchymal components. Malignant mixed tumors are much more rare than carcinoma ex-pleomorphic
adenoma. Together, these two types of malignancies comprise approximately 12% of all salivary gland malignancies.6
Clinically, malignant transformation of a pleomorphic adenoma may manifest as rapid growth and ulceration of a previously
indolent parotid mass. These are very aggressive neoplasms, and wide surgical resection is indicated. Both regional and distant
metastases are commonly seen, and the overall prognosis is poor.
Larynx /Hypopharynx
Cancer of the larynx represents approximately 2% of all carcinomas. The vast majority are squamous cell carcinomas. The incidence
of cancer of the larynx and hypopharynx is much higher in men and is primarily related to heavy smoking and alcohol consumption.
Anatomy
The larynx has three main functions: speech, airway protection, and production of a Valsalva maneuver. The larynx is located at the
divergence of the digestive and respiratory tracts and its most primitive function is as a sphincter, which prevents aspiration.
Externally, the laryngeal framework consists of the hyoid bone, the thyroid cartilage, and the cricoid cartilage. Internally, the larynx
includes the true vocal cords, false vocal cord, aryepiglottic folds, and the epiglottis. The upper portion of the larynx is continuous
with the pharynx and is approximately triangular in shape. The lower portion is contiguous with the trachea and is more circular.
For clinical purposes, the larynx is subdivided into the supraglottic, glottic, and subglottic potions. Neoplasms arising in the different
regions behave differently and have particular patterns of nodal metastasis. The hypopharynx includes the pyriform sinuses, the
postcricoid area, and the posterior pharyngeal wall below the level of the hyoid bone. As with the those in the larynx, almost all
malignancies arising in the hypopharynx are squamous cell carcinomas.
Symptoms
The cardinal symptom of laryngeal cancer is hoarseness due to inappropriate vocal cord approximation. Dyspnea and strider are late
symptoms that are associated with airway obstruction. Ear pain (referred otalgia) or a vague scratchy sensation of the throat are often
present. Dysphagia is often associated with extralaryngeal involvement at the base of tongue, hypopharynx, or supraglottis.
Odynophagia (painful swallowing) is often associated with invasion of extralaryngeal musculature. Chronic cough, hemoptysis,
weight loss, halitosis, and tenderness may all accompany carcinoma of the larynx and hypopharynx.
Examination
The larynx is difficult to examine without appropriate tools. Laryngeal mirrors and appropriate lighting are the simplest method of
obtaining an indirect examination. The technique can be easily mastered with practice and provides an adequate view of the larynx
in most patients. Fiber-optic scopes are widely available today and can be positioned after topically anesthetizing the nose. No special
monitoring is required, and once they are comfortable with the technique, most practitioners can perform the examination safely.
Portions of the larynx and hypopharynx are not fully visible even with a good fiber-optic or mirror examination. For those patients
with persistent symptoms suggestive of abnormal lesions in this region, a direct, operative laryngoscopy may be necessary to fully
complete the examination.
Imaging of the larynx is valuable for staging disease within this region. Extension of a tumor into the deep muscle of the larynx or extralaryngeal extension into the hypopharynx, retropharynx, or prelaryngeal musculature may be detected by computed tomography
or magnetic resonance imaging. This extralaryngeal disease is often very important in treatment planning.
The larynx and hypopharynx have a rich lymphatic network; therefore, metastatic disease often occurs early in the course of
invasion. Cervical node metastases is frequent and occurs in up to 75% of pyriform sinus lesions and 60% of posterior pharyngeal
wall lesions. Cancers originating in the glottic larynx (vocal cords) are a notable exception. The glottis contains relatively few
lymphatics and early nodal metastases are rare. Metastases are much more common in supraglottic laryngeal carcinoma than in
glottic carcinoma, secondary to the rich lymphatic network. It is important to recognize that contralateral nodal metastases often
occur and must be recognized at the time of initial evaluation.
Supraglottic cancers (those arising above the level of the vocal cords) are highly aggressive lesions. They metastasize early and often
bilaterally. Small lesions can be cured with radiation therapy or surgery with fairly similar cure rates. Larger lesions require a
combined surgery and radiation. With the exception of very small lesions involving the most superior tip of the epiglottis, surgical
resection of supraglottic cancers involves at least a supraglottic laryngectomy. This procedure may be safely performed when there is
limited extension into the deeper structures of the larynx or tongue base and when the patient's pulmonary reserve will tolerate the
expected period of aspiration during swallowing rehabilitation.
Glottic cancers (those arising on the vocal cords), in contrast, metastasize more slowly. When detected early, these lesions can be
treated equally well with surgery or radiation therapy. Larger lesions require a total laryngectomy. Surgical treatment for earlier
lesions typically involves a hemilaryngectomy, also known as a vertical partial laryngectomy. Very small tumors arising on the free
edge of the vocal cord, without involvement of the adjacent structures, can be treated with laser surgery. In Europe, surgeons are
known for treating more extensive laryngeal cancers (T2 and T3 lesions) with endolaryngeal laser therapy. Laser therapy for
advanced laryngeal cancers is currently being evaluated in the United States.
The subglottic area is reasonably silent symptomatically, and carcinomas have to be large to develop bleeding or airway obstruction
before they are recognized. These tumors metastasize into the regions of the neck fairly early and cure rates are low. Therapy
typically involves a total laryngectomy and resection of a portion of the cervical trachea. Radiation therapy is often used after
surgery.
Advanced laryngeal cancers have traditionally been treated with surgery and radiation for cure. Surgery typically involves a total
laryngectomy rendering the patient aphonic and with the limitations of a permanent tracheal stoma. Investigators have been seeking
nonsurgical therapy that would provide similar cure rates as traditional surgery and radiation. In 1991, the Veterans' Administration
(VA) Cooperative Study on Laryngeal Carcinoma was published.10 In this study, patients with stage III and stage IV laryngeal cancer
were prospectively randomized to receive either surgery and radiation therapy or induction chemotherapy followed by radiation
therapy. Cisplatin and 5-fluorouracil were the chemotherapy agents used. There were no statistical differences in 5-year survival
between the two treatment groups. Approximately 60% of the patients who began treatment with nonsurgical therapy were able to
maintain their larynx. Induction chemotherapy and radiation according to the VA larynx protocol is considered to be a viable option
for advanced laryngeal squamous cell cancer at this time.
EVALUATION OF THE NECK
Anatomy
The neck contains approximately 150 lymph nodes, all of which may enlarge secondary to inflammatory infectious or neoplastic
processes. There are superficial and deep lymphatic systems. The superficial lymphatic system drains the scalp, external ear, and
skin of the face. The superficial system follows the external jugular vein and more superficial branches of the external carotid artery.
The deep system of lymphatics provides primary lymphatic drainage for most sites in the upper aerodigestive tract. The deep
lymphatics of the neck are divided into five levels. The first level is the submandibular and submental lymph nodes; level 2, the
upper jugular lymph nodes; level 3, the middle jugular lymph nodes; level 4, the lower jugular lymph nodes; and level 5, the
posterior triangle of the neck.
In adult patients, neck nodes do not typically remain enlarged. Though adenopathy may develop after an upper respiratory tract
infection, this should resolve within 2 to 3 weeks. As a rule, if an adult has an enlarged lymph node that has been present for 4 to 6
weeks, the chance of that lymph node containing a malignancy is approximately 80%. Of the malignant lymph nodes indicated in
the neck, 80% contain squamous cell carcinoma and 80% originate from the mucosa of the upper aerodigestive tract. An adult with
lymphadenopathy that does not resolve within the expected time period after an infection should undergo a complete mucosal
examination of the head and neck and subsequently be scheduled for biopsy.
Malignant cervical adenopathy typically presents as a painless enlargement that is nonfluctuating in size and grows slowly over a
period of weeks or even months. Malignant nodes can change rapidly or become painful if hemorrhage occurs within the node or if
the node develops an abscess.
Tissue confirmation of a persistent mass in the neck of an adult is mandatory. Fine needle aspiration cytology may be helpful in
establishing the diagnosis of malignancy. However, a negative needle aspirate is meaningless in a patient with signs and symptoms
suggestive of a malignancy in the neck. Open surgical biopsy with provision made for possible cervical lymphadenectomy is
recommended. A thorough endoscopic examination searching for a primary site of a neck malignancy should be undertaken at the
same time.
Neck dissections have been classified as radical or selective. Radical neck dissections remove all five major groups of deep cervical lymphatics. Selective neck dissections remove one or more groups of deep cervical lymphatics. Generally, when there is extensive
malignant adenopathy present in the neck, a radical neck dissection is performed. When minimal disease is present or if the neck is
being dissected electively to detect microscopic disease, a selective neck dissection may be chosen. Over the past 15 or 20 years,
surgeons have recognized that some of the structures in the neck, such as the spinal accessory nerve, which were originally removed
in classic radical neck dissections, may be preserved safely under certain circumstances. This makes the functional deficit of a neck
dissection less of a problem.
Thyroid Cancer
The most common disorder of the thyroid gland is thyroid nodules, found in 4% to 7%11
of the adult population in America. The
incidence of thyroid nodules increases with age and is also higher in studies where autopsy,12 ultrasound,13 or surgery14 data are used.
Fortunately, the majority of thyroid nodules are benign rather than malignant; in fact, thyroid cancer itself is rare, accounting for
only 1% of all malignancies15 and affecting 4 per 100,000 individuals per year.16 It is estimated that of nodules removed surgically,
8% to 17% are carcinomas.17 However, the most important task facing the clinician when evaluating a thyroid nodule is to rule out a
malignancy.
Papillary and follicular carcinomas are known as the differentiated thyroid carcinomas. The papillary lesion is the most common and
fortunately carries the best prognosis. Other types of thyroid carcinomas include medullary and anaplastic, which have much poorer
prognoses. The thyroid can also be involved with lymphoma. Metastatic cancer is also seen infrequently.
Patients with thyroid cancer usually present with a painless, otherwise asymptomatic mass in the gland. Slow enlargement is the
general rule. Late symptoms may include hoarseness, dysphagia, or respiratory difficulty. Cervical adenopathy may also be a
complaint that leads a patient to seek medical attention. Most patients are clinically euthyroid at the time of presentation.
Physical examination will usually reveal a solitary thyroid nodule; however, cancer may also occur in the presence of a diffusely
enlarged gland or a multinodular goiter. There may be enlarged regional nodes in the central compartment of the neck or along the
jugular chain. Laryngoscopy should always be done in a patient with a thyroid nodule, and the finding of a paralyzed vocal cord is an
ominous finding that heralds extrathyroidal extension and involvement of the recurrent laryngeal nerve.
There is some controversy concerning the diagnostic procedures needed to adequately evaluate a patient with a thyroid nodule and to
rule out a thyroid cancer. Studies including thyroid function studies, thyroid scintigraphy, and thyroid ultrasound have been used
singly or as a battery of tests to evaluate thyroid lesions. Currently, however, most surgeons recommend obtaining only a serum
thyroid stimulating hormone test to rule out an autonomously functioning thyroid nodule and thyrotoxicosis and a fine needle
aspiration biopsy.17 Studies such as computed tomography scans should be reserved for situations where invasion of the upper
aerodigestive tract is suspected.
The role of fine needle aspiration cytology in the evaluation and management of a thyroid nodule
deserves special comment. It is viewed by many as the initial procedure of choice to evaluate a nodule in a euthyroid patient.18 The
procedure is simple, safe, and lends itself readily to the outpatient setting. Although the diagnostic accuracy of the fine needle
aspiration biopsy depends on the skill of the person performing the biopsy and the experience of the pathologist reading the slides,
the reported accuracy rate for the test ranges from 70% to 97%.19 A cystic lesion with its inherently low risk of malignancy becomes
readily apparent with a needle biopsy. Surgery is indicated when the results are reported as frankly malignant, indeterminate, or a
follicular lesion.
Surgery has remained the principal form of treatment for thyroid cancer. There exists an ongoing debate centered around the extent
of surgery, however. The minimal acceptable operation is resection of the involved lobe and the isthmus. Total thyroidectomy carries
the increased risk of injury to both recurrent laryngeal nerves and permanent hypocalcemia, but is indicated for large lesions, lesions
extending through the capsule of the gland, and in patients who have obvious lymph node metastases. It should also be considered in
patients over 40 years of age who have unfavorable tumors.20 Functional neck dissection is indicated for patients with differentiated
carcinomas who either present with regional metastases or are found to have involved nodes at the time of surgery. Elective neck
dissection along with total thyroidectomy is indicated in patients with medullary carcinoma.
The most effective adjuvant therapy available for treatment of papillary and follicular carcinoma is radioactive iodine 131, given 6 to
8 weeks after surgery. External beam radiotherapy and chemotherapy are reserved for patients with aggressive recurrent tumors and
anaplastic carcinomas.
Tumors of the Nasal Cavity and Paranasal Sinuses
Malignant neoplasms of the nasal cavities and the paranasal sinuses are the least common cancers occurring in the upper
aerodigestive tract, accounting for only 3% to 5% for head and neck cancers. These arise in an area of complex anatomic
relationships where tumors can readily invade important structures such as the orbit, the brain, the cavernous sinus, the optic nerves,
and the carotid arteries, even before symptoms become readily apparent. Advances in diagnostic and therapeutic modalities have
greatly facilitated management of these patients, improving not only survival but also overall quality of life.
Arising as embryonic out-pouchings of the nasal cavities, the paranasal sinuses are paired structures that are intimately related to the
structures of the midface and base of the skull. These paired sinuses include the maxillary, ethmoid, sphenoid, and frontal sinuses,
all of which, with the exception of the sphenoid sinus, empty into the middle meatus of the nasal cavity on each side. The sphenoid
sinuses empty via separate ostia into the posterior aspect of the superior meatus. Adjacent to the paranasal sinuses are the orbit and
its contents, the anterior cranial fossa, the optic nerves, the carotid arteries, and the cavernous sinuses, all of which have the
potential for involvement by direct tumor extension. Therefore, accurate delineation of the full extent of the tumor is mandatory prior
to initiation of treatment.
There is a great diversity of pathology that occurs in the nasal cavity and paranasal sinuses. Like other sites in the upper
aerodigestive tract, the majority of primary tumors arise from the epithelial surfaces in the area. The major difference in the nasal
cavity and paranasal sinuses is that they are lined with a pseudostratified ciliated columnar epithelium, which contains goblet cells
and minor salivary glands. Therefore, adenocarcinomas play a more important role in addition to the more common squamous cell
carcinomas. There is also an area of specialized sensory epithelium through which the terminal branches of the olfactory nerve enter
the roof of the nasal cavity, which gives rise to a malignant neoplasm known as an esthesioneuroblastoma, or olfactory
neuroblastoma. Less common tumors include lymphomas, various types of sarcomas, and metastatic lesions.
The cause of malignant neoplasms in the nasal cavity and paranasal sinus is still not clear, although several agents have been
implicated: tobacco smoke, industrial chemicals used in the leather and heavy metals industries, and chronic exposure to wood dust.
Viral agents, especially the human papilloma virus, may play an etiologic role. The tumors occur more commonly in men than
women and are seen generally in the later decades of life. They are found with decreasing frequency in the maxillary, ethmoid,
sphenoid, and frontal sinuses.
A patient's presenting symptoms will vary with the location and stage of disease. Symptoms typical of early lesions will often
resemble those of an upper respiratory tract infection and include nasal obstruction, facial pain, and rhinorrhea, which can at times
be blood tinged. The key element that differentiates the symptoms associated with an upper respiratory infection and a malignant
lesion is the duration of the symptoms; an upper respiratory infection will generally clear or at least improve dramatically in several
weeks with appropriate medical management, while symptoms associated with a malignancy will persist. Late symptoms are seen as
a result of persistent tumor growth and invasion of adjacent structures. These include paresthesias of branches of the fifth cranial
nerve (V2 being the most common), progressive pain and swelling in the face, proptosis, chemosis, visual loss, loosening of teeth or
malfitting dentures, trismus, and evidence of intracranial spread of disease.
Physical examination can reveal an obstructing lesion in the nose or a submucosal mass arising in an adjacent sinus. New techniques
in nasal endoscopy have greatly facilitated the examination of the entire nasal cavity including the ostia, through which the sinuses
drain. In many cases, the lumina of the sinuses themselves can now be examined endoscopically. Like the late symptoms, late
physical findings are associated with advanced tumor growth and invasion of adjacent structures such as the orbit, soft tissues of the
face, the pterygomaxillary and infratemporal fossae, and the anterior cranial fossa. Tumors in the nasal cavity and paranasal sinuses
have the potential to metastasize to the cervical lymph nodes and do so in about 15% of the cases. Therefore, patients may present
with cervical adenopathy as well.
Although the new endoscopic techniques have greatly improved our ability to examine the nasal cavities and the paranasal sinuses,
radiographic studies are also necessary to complete the evaluation. The most important studies include the computed tomography
and magnetic resonance imaging scans, usually used in combination. Each scanning technique has its own advantages and
limitations when evaluating a patient with a nasal tumor. The computed tomography scan is the preferred study to evaluate the bony
structures in the area, particularly when there is concern about extension into the orbit or through the cribriform plate into the
anterior cranial fossa. The magnetic resonance imaging scan has the capability to better assess soft-tissue differences, enabling one
not only to differentiate tumor from inflammatory changes in the nose and sinuses but also to determine if there is involvement of
the soft tissues in the orbit, brain invasion, and involvement of the optic nerve and cavernous sinuses intracranially. The magnetic
resonance imaging scan has really turned into the radiographic workhorse for accurate delineation of pretreatment tumor extent and
also for following up patients after treatment.
No evaluation is complete without obtaining material for histopathologic evaluation. Because of the location and diverse nature of
these tumors, special arrangements should be made when considering biopsy. There is always the potential for brisk bleeding from
these tumors; therefore they should be biopsied in a setting where epistaxis can be easily controlled. Endoscopic sinus surgery has
been used more widely for obtaining tissue for biopsy. There is now available the capability to combine endoscopic surgery with
computed tomography graded imaging to direct the surgeon into small recesses of the nose and sinuses and along the base of the
skull, making biopsy not only more accurate but also safer for the patient. Owing to the diverse pathologic lesions encountered in
the nose and sinuses, material obtained from the biopsy should be submitted in saline rather than formalin, in case special immunohistochemical stains, cell marker studies, or electron microscopy is needed to further characterize the tumor.
Treatment of nasal cavity and paranasal sinus malignancies has centered around the use of surgery and adjuvant radiotherapy.
Traditional surgical approaches have included the lateral rhinotomy or midfacial degloving approaches for access to the nasal cavity,
medial maxillary area, and the lower ethmoid sinuses. More radical surgery includes radical maxillectomy with or without
exenteration of the orbital contents. When tumors approach the base of the skull often it is necessary to apply a multidisciplinary
approach to their management.
NEW DEVELOPMENTS
Head and Neck Cancer and the Immune System
In patients with cancer of the head and neck, the immune system is often not functioning properly. Malignant cells are not
recognized as foreign, or when recognized, the immune systems ineffectively eradicate cells. Causes of the failure of the immune
system include severe malnutrition, tumor humoral factors that deactivate the immune system, or a genetic predisposition.
Investigators recognize that in the presence of a normally functioning immune system, many of these cancers would be eliminated
before becoming clinically significant. Biologic response modifiers are substances that alter the patient's immune response to tumors.
These substances may enhance the function of an intact immune system or restore the function of an impaired immune system.
Interferons and interleukins are examples of biologic response modifiers that investigators have used to boost the immune system
response. The agents may be administered either locally by direct tumor injection
or systemically (passive immunotherapy) or may be
used in vitro to stimulate lymphocytes that are readministered to the cancer patient in an activated form (adoptive inummotherapy).
Monoclonal antibodies are antibodies raised against tumor-specific antigens. Monoclonal antibodies may be radiolabeled and used to detect malignant cells or used to deliver a dose of radiation selectively to the tumor. Cytotoxic agents may also be coupled to monoclonal antibodies for targeted delivery to cancer cells.21
At the frontier of research in head and neck cancer, molecular biology and gene therapy are providing new insights into the basic
mechanisms of cancer initiation and treatment. Sidransky and coworkers have recognized alterations of the
p53 gene in the tissues
surrounding mucosal malignancies that may prove important in understanding the sequence of events necessary to initiate cancer
growth and are already being evaluated to help determine the adequacy of surgical margin.22 The detection of various oncogenes in
head and neck cancer is progressing rapidly. Gene therapy trials are just beginning in an attempt to introduce genetic material that
would improve immune system recognition of cancer cells.
Reconstructive Surgery
Although surgical treatment of squamous cell carcinoma of the head and neck affords the best chance for cure for many patients, the
results of the surgical efforts have often been extremely disfiguring and functionally debilitating. The changes in facial appearance
and loss of ability to speak, swallow, and breathe normally can be devastating.
Prior to the 1970s, multiple, staged operative procedures were required for resection and reconstruction of head and neck defects.
The patients were often left with open, draining pharyngeal fistulas as they awaited surgical reconstruction. In the early 1970s,
microvascular free tissue transfers (free flaps) were introduced. This technique allowed transfer of tissue along with its vascular
pedicle from a donor site to the head and neck region. Initially, failure rates were fairly high, and few surgeons had the technical expertise to perform the microvascular anastomosis. In the late 1970s, Ariyan introduced the pectoralis major myocutaneous flap for
surgical reconstruction of head and neck defects.23 This flap was a pedicled flap based on the pectoralis major muscle. It was easily
rotated into defects in the head and neck region and required no microvascular expertise to use. The flap was extremely hardy, and
failure rates were low. By the mid 1980s, however, it became apparent that there were limitations of the pectoralis major flap that
could be overcome by using free flaps from various other sites. By then surgeons in most major medical centers were comfortable
with the techniques required for microvascular transfer of tissue and free flaps gradually began to replace pedicled flaps, such as the
pectoralis major flap.
Today, head and neck cancer operations are often approached in a two-team system. If the anticipated surgical defect is too large to
close primarily, often a reconstructive team will harvest tissue from a distant site in the body while the oncology team is removing
the cancer. Once the tumor extirpation is complete, the free flap is inset into the recipient site and the vessels are anastomosed to
branches of the external carotid artery and jugular venous systems. These free flaps may contain skin, muscle, bone, fascia, or bowel,
as indicated by the surgical defect.
Initially, reconstructive teams were more concerned with simply closing the surgical defect and reestablishment of a more natural
form. Recently, attention has been focused much more seriously on reestablishing normal function. Sensory reinnervation of free
flaps has become commonplace and seems to allow improved recovery of function; swallowing, for instance. Dental implants can be
inserted into vascularized bone grafts used to reconstruct the mandible allowing the patient to wear dentures and to chew once again.
Transplantation of functional structures such as the larynx are being actively investigated in the laboratory.
Chemotherapy and Organ Preservation
As discussed above, surgical treatment of head and neck squamous cell carcinoma often results in disfigurement and altered function
for the patient. Head and neck oncologists have sought treatment options that would provide similar rates of cure with improved
maintenance of form and function than traditionally allowed by surgical therapy. For early stage lesions, radiation therapy is often as
successful as surgical therapy in controlling disease. For advanced disease (stage 3 and 4), however, combined surgery and radiation
has been the gold standard.
Organ preservation strategies have focused primarily on the larynx. By using a combination of induction chemotherapy and radiation
therapy for a selected group of patients with advanced squamous cell carcinoma, researchers in the
VA
laryngeal cancer study group were able to demonstrate that survival curves for the surgery versus chemotherapy/radiation
groups have been similar. In the initial report, approximately 65% of the patients initially treated with chemotherapy and radiation
therapy were able to keep their larynx.10 Attempts to extend this strategy to other head and neck sites have generally been
disapproving. Multi-institutional trials continue in the arena of organ preservation.
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William R. Carroll, M.D., F.A.C.S., is Associate Professor of Surgery, Division of Otolarnygology, University of Alabama at
Birmingham.
Glenn E. Peters, M.D., F.A.C.S., is Professor of Surgery, Division of Otolarnygology, University of Alabama at Birmingham.
David J. Halvorson, M.D., is Assistant Professor of Surgery, Division of Otolarnygology, University of Alabama at
Birmingham.
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