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NEOPLASMS OF THE
LARYNX AND
LARYNGOPHARYNX
Robert A. Weisman, MD
Kris S. Moe, MD
Lisa A. Orloff, MD

There are many types of benign tumors of the larynx and

laryngopharynx, but, as a group, they are uncommon. In gen-
eral, these neoplasms may be managed by observation or
excision, depending on their location and individual behav-
ior. Excision may be performed endoscopically in tumors of
moderate size and accessible location. A decision to remove
the tumor must take into account the morbidity of the pro-
cedure, which for tumors of neural origin will likely mean
some loss of function. Paragangliomas are derived from neu-
roendocrine cells, are associated with the internal branch of
the superior laryngeal nerve and posterior branch of the
recurrent laryngeal nerve, and must be differentiated from
laryngoceles using computed tomography (CT) or magnetic
resonance imaging (MRI). Therapy, if required, is excision
or, less frequently, radiation.
Schwannomas arise from the superior laryngeal nerve and
may present in the aryepiglottic fold. The malignant form is
rare. Neurofibromas are rare in the larynx and consist of a
mixture of axonal or dendritic fibers and Schwann cell ele-
ments. Affected patients are typically young and often have
syndromic neurofibromatosis, with multiple neurofibromas.
The supraglottis is the typical site of origin.
470
 Neoplasms of the Larynx and Laryngopharynx 471

Granular cell tumors also arise from the Schwann cell and
are often multifocal in the head and neck, with the larynx
being the second most common site.
Hemangiomas may occur in the larynx or pharynx and
often present with significant bleeding. Diagnosis is typically
made by appearance, and biopsy may be hazardous. Surgical
excision often requires an external approach, and proximal
and distal control of vessels may be necessary. Preoperative
embolization should be considered.
The subglottic hemangioma presents in infancy, may be
associated with multiple cutaneous or mucosal heman-
giomas, and is often found in association with other con-
genital anomalies.
Lymphangiomas or cystic hygromas present in the supra-
glottis and hypopharynx. They may infiltrate extensively and
often cause airway obstruction. Myogenic tumors presenting
in this region include leiomyoma, myoma, and myoblastoma.
Local excision is usually adequate therapy.

MALIGNANT NEOPLASMS
Laryngeal and laryngopharyngeal cancers are the most com-
mon malignancy of the head and neck. Laryngeal cancer has
historically been a disease with a significant male predomi-
nance, although the gender distribution has been changing as
more women have begun to smoke. There are approximately
10,000 new cases of laryngeal cancer and 2,500 new cases of
hypopharyngeal cancer per year in the United States. The over-
all mortality rate for laryngeal cancer is 32%, with 25% of
patients presenting with regional and 10% with distant metas-
tasis. The majority of patients present between ages 55 and 65.
The most significant risk factors are the consumption of
tobacco and alcohol. Cigarettes carry the greatest risk of laryn-
geal cancer, but cigar and pipe smoking are also risk factors.
The primary carcinogens in tobacco are tars and polycyclic
472 Otorhinolaryngology

hydrocarbons. Only 1% of laryngeal carcinoma occurs in non-

smokers. Inhabitants of urban areas are at greater risk than
rural dwellers, and other possible etiologic factors include gas-
troesophageal reflux, exposure to wood dust, asbestos, volatile
chemicals, nitrogen mustard, ionizing radiation, and immune
system compromise. Ionizing radiation and radioactive iodine
have been implicated. Human papillomavirus (HPV) may
be a cofactor, and HPV 16 deoxyribonucleic acid (DNA) is
commonly demonstrated in laryngeal cancers. Oral herpes
infections may also predispose to laryngeal cancer, as may
deficiencies in dietary intake of the B vitamins, vitamin A,
betacarotene, and retinoids. Anatomic conditions such as sul-
cus vocalis and laryngoceles are associated with laryngeal car-
cinoma, and there is also an association with Plummer-Vinson
syndrome (glossitis, achlorhydria, and atrophic gastritis). The
development of laryngeal and laryngopharyngeal carcinomas
is most likely multifactorial in origin.
Laryngeal cancer has one of the highest rates of second
primary cancers. These second tumors occur synchronously in
1% of cases and metachronously in 5 to 10%. Second primaries
are more common with supraglottic than glottic tumors, and
the most common type is bronchogenic carcinoma. The risk of
a second primary tumor in the lung is proportional to the smok-
ing history and whether the patient continues to smoke.
The role of follow-up screening for primary or metastatic
lung tumors is controversial. Although the tumors might be
detected before they become symptomatic, overall survival is
not likely to change much. Chest CT is highly sensitive but
not specific, but the specificity of positron emission tomog-
raphy may aid in earlier diagnosis of second tumors.

Pathology
The epithelium of the larynx is chiefly pseudostratified cili-
ated columnar with the exception of the true vocal folds where
it is stratified squamous. The epithelium appears to undergo
 Neoplasms of the Larynx and Laryngopharynx 473

predictable changes as it progresses to invasive carcinoma.

Hyperplasia refers to thickening owing to an increase in the
number of cells. This is typically seen with chronic irritation
or trauma. Hyperkeratosis denotes an increase in the depth of
the overlying keratin layer. Both of these are benign changes.
Dysplasia, however, is a premalignant disorder involving loss
of the normal progressive maturation of cells from the basal
layer to the superficial epithelium. This may range from mild
to severe, the latter being synonymous with carcinoma in situ
(Cis). Once Cis has progressed to penetrate the basement
membrane, it becomes invasive carcinoma. Three percent of
hyperkeratoses without dysplasia, 7% of mild dysplasias,
18% of moderate dysplasias, and 24% of severe dysplasias of
the vocal cords will develop invasive carcinoma. Aneuploidy
on flow cytometry predicts a high risk of progression from
dysplasia to invasive carcinoma.
Cellular differentiation is also important in the prognosis
of laryngeal carcinoma, with lymphatic metastases being more
common in poorly differentiated tumors. Supraglottic tumors
tend to be less differentiated than glottic tumors and behave
aggressively early in their course. Additional pathologic char-
acteristics that influence prognosis include infiltrating versus
pushing borders, presence or absence of a local host inflam-
matory reaction, and vascular or perineural invasion.
Over 95% of laryngeal malignancies are squamous cell
carcinoma. There are variants or subtypes of squamous car-
cinoma. These include verrucous, basaloid squamous, and
spindle cell carcinoma. Verrucous carcinomas are extremely
well differentiated and do not metastasize to lymph nodes.
Basaloid squamous carcinoma is an aggressive tumor occur-
ring more frequently in the hypopharynx. Spindle cell
carcinoma tends to be pleomorphic with areas of standard
squamous carcinoma or Cis. Spindle cell cancers are more
resistant to radiation therapy and may undergo osteocarti-
laginous differentiation after radiation.
474 Otorhinolaryngology

Nonsquamous malignancies of the larynx and laryn-

gopharynx include adenoid cystic carcinoma, typical and
atypical carcinoid, small cell carcinoma, and chondrosar-
coma. Adenoid cystic carcinoma is rare, and most are sub-
glottic or supraglottic owing to their origin in minor salivary
or seromucinous glands. Perineural invasion is common, as
are pulmonary and osseous metastases. Lymphatic invasion is
rare, however, and elective neck dissection is not indicated.
Typical carcinoid of the larynx is extremely rare and occurs
almost exclusively in males. Surgery is typically curative.
Atypical carcinoid is more common, exhibits more atypia
and cellular necrosis, and is more aggressive. Regional and
distant metastases are common, and chemotherapy and radi-
ation therapy should be considered as an addition to surgery.
Chondrosarcoma is a rare, slow-growing tumor and usually
arises from the cricoid cartilage. Surgery is the primary ther-
apy, and lymphatic metastasis is rare.

Anatomic Subsites and Patterns of

Spread of Laryngeal Tumors
The spread of tumors within the larynx is not haphazard;
rather, it occurs in a relatively predictable fashion under the
influences of local subsites. These influences include
anatomic defenses such as perichondrium and cartilage, as
well as anatomic weaknesses such as blood vessels and lym-
phatic channels. Furthermore, the supraglottis arises from dif-
ferent embryologic anlage than the glottis and subglottis, thus
producing unique routes of lymphatic spread. Understanding
this allows the surgeon to anticipate tumor behavior and
increase the chance of successful local therapy.
The majority of supraglottic tumors begin on the epiglot-
tis and tend to advance by local invasion. Initial barriers to
spread include the perichondrium and cartilage of the epiglot-
tis, with deeper resistance to invasion including the thy-
roepiglottic ligament and finally the thyroid cartilage. The
 Neoplasms of the Larynx and Laryngopharynx 475

quadrangular membrane of the aryepiglottic fold may help

to contain superior and lateral invasion. Supraglottic tumors
tend to spread by lymphatic invasion, with over 30% of clin-
ically N0 cases demonstrating involved lymph nodes on final
pathology. The supraglottic lymphatic drainage is through
the thyrohyoid membrane following the superior laryngeal
veins to levels II and III in the neck.
Glottic tumors arise on the vocal fold or up to 10 mm infe-
rior to it. The vocal folds are known to have very limited lym-
phatic drainage, and glottic tumors remain contained until
lateral invasion allows entry into the paraglottic space, a ver-
tical portal of spread to the rest of the larynx. Vocal fold
tumors allow diagnosis at an early stage owing to ensuing
hoarseness, and lateral invasion is manifested by vocal cord
paresis or paralysis from interference with function of the
thyroarytenoid muscle or cricoarytenoid joint. The anterior
commissure of the vocal folds is an important area of relative
vulnerability to tumor invasion. Here the anterior vocal liga-
ment and vessels perforate the thyroid cartilage, violating the
protective barrier of the perichondrium. Tumors that are rel-
atively small in size can quickly gain T4 staging by penetra-
tion of the cartilage.
Subglottic tumors arise 10 mm or more below the glottis
and are rare, comprising less than 1% of laryngeal tumors.
Direct invasion may occur anteriorly through the cricothy-
roid membrane or inferiorly within or external to the trachea.
Transglottic tumors may involve all three subsites of the
larynx. The spread of these tumors is dictated by the areas
they invade.
Hypopharyngeal tumors may be divided into superior and
inferior. Superior tumors arise on the lingual surface of the
epiglottis, vallecula, or tongue base. Inferior tumors arise
mainly in the piriform sinus. As tumors extend inferiorly in
the pharynx, they have a greater tendency to spread via lym-
phatics and have a high rate of distant metastasis.
476 Otorhinolaryngology

As a group, distant metastasis from laryngeal tumors is a

late event, occurring after local and regional recurrences. Only
8 to 10% of patients present with distant metastases, whereas
25% already have regional nodal involvement. The primary
sites of distant metastases are the lungs, liver, and bone.

Clinical Evaluation
The primary presenting symptom in carcinoma of the glottis
is hoarseness. This occurs early in the disease process but has
often been present for 3 or more months by the time of diag-
nosis. Patients with supraglottic carcinoma tend to remain
asymptomatic until the tumor is locally advanced and often
present owing to nodal metastasis. The rare patient with car-
cinoma of the subglottis typically presents with stridor or
hemoptysis. Other symptoms of concern for laryngeal cancer
are dyspnea, dysphagia, and pain (particularly when referred
to the ear). Pain occurs with advanced tumors, owing to inva-
sion through cartilage and extralaryngeal structures. Pain
radiating to the ear may be caused by involvement of the glos-
sopharyngeal or vagus nerves. Other symptoms are cough,
hemoptysis, halitosis, and weight loss. Coughing is often
attributable to the aspiration seen with glottic tumors, and
weight loss is an ominous sign that often suggests distant
metastases. Tenderness on palpation of the larynx may indi-
cate extension through cartilage.
As the treatment of laryngopharyngeal tumors can be
physically demanding, the overall health and ability of the
patient to undergo treatment are very important. The patient’s
alcohol intake can have a direct bearing on the postoperative
course, and the smoking history may have an impact on
wound healing. Prior therapies such as local radiation are crit-
ical to ascertain.
A complete physical examination is required, with special
attention to the entire upper aerodigestive tract and cervical
region. Complete laryngoscopy is required, either with a mir-
 Neoplasms of the Larynx and Laryngopharynx 477

ror or a fiberoptic endoscope, and any abnormality in vocal

fold motion should be noted. Videostroboscopy can be impor-
tant in the evaluation of early glottic cancers as progression
from Cis to invasive carcinoma will be demonstrated by teth-
ering of the mucosa to the underlying stroma with dyskinesia
of the mucosal wave. Documentation of the size, location, and
fixation of any cervical lymph nodes is important.

Imaging Studies
The current modalities most commonly used for imaging of
the upper aerodigestive tract in the United States are CT and
MRI. These have been refined to the point that they can provide
important information on invasion of cartilage, local spaces,
and regional structures, as well as demonstrate lymph nodal
metastases. Both technologies have sensitivities ranging from
60 to 80%, with specificities between 70 and 90%. Additional
information on lymph node size, shape, and appearance may
suggest involvement by metastatic disease. Positron emission
tomography is based on differential uptake of radioactive [18F]
fluorodeoxyglucose. Tissues invaded by tumor typically take
up greater concentrations of the tracer owing to their increased
metabolic demands. Positron emission tomography has been
demonstrated to be more sensitive, specific, and accurate than
CT or MRI in detecting occult nodal disease. It alone does not
provide detailed anatomic information, but it is currently being
coupled with CT, which is expected to enhance the accuracy of
tumor imaging in the future.

Panendoscopy
Panendoscopy is a systematic survey of the upper aerodiges-
tive tract through laryngoscopy, esophagoscopy, and bron-
choscopy. Detailed information on the exact extent of the
primary tumor is obtained while concurrently searching for
additional primary malignancies. During laryngoscopy,
which is performed at the end of the procedure so that bleed-
478 Otorhinolaryngology

ing does not interfere with assessment of the other structures,

the tumor is biopsied. For more precise evaluation, telescopes
can be introduced through the laryngoscope, and suspension
microlaryngoscopy may be performed for “hands-free” view-
ing under magnification.

Tumor Staging
When all clinical investigations have been performed, staging
of the tumor is possible. The system used in the United States
is the tumor, node, metastasis (TNM) classification created by
the American Joint Committee on Cancer, which separates
patients into stages I to IV, with higher stages carrying a
poorer prognosis.

TREATMENT FOR CANCERS OF THE

LARYNX AND LARYNGOPHARYNX
Early Glottic Cancer
“Early” glottic cancer refers to tumors ranging from Cis to T2
lesions that are grouped together in a prognostically favorable
category because the greatest diminution in survival occurs
with progression from T2 to T3 tumors. As a group, early
glottic carcinomas are understaged 40% of the time.
Carcinoma in situ without an invasive component is relatively
rare. T1 lesions of the anterior commissure invade cartilage
early, making them true T4 lesions in many instances.
In most institutions, radiation therapy (XRT) is favored
over surgical treatment of early glottic carcinoma because it
has been thought to result in superior vocal function while
providing cure rates similar to surgery. Primary radiation
therapy is delivered in single fractions over 6 to 7 weeks for
a typical dose of 6,600 cGy and produces a cure rate for T1
cancers of 80 to 90%. Male gender and bilateral vocal fold
involvement have been associated with poorer outcomes. T2
cancers have an overall cure rate of approximately 65% with
 Neoplasms of the Larynx and Laryngopharynx 479

XRT, although there is great variability in the literature. Some

of this variability may be attributable to mixing T2a lesions
(normal vocal cord mobility) with T2b lesions (impaired
mobility). Rates of 85% have been reported for the former,
with a 20% drop for the latter.
The surgical treatment of early glottic carcinoma most
commonly involves vertical hemilaryngectomy. More
recently, endoscopic excision has gained favor and is used
extensively in Europe. Studies of laser excision are demon-
strating survival outcomes equal to or better than XRT, with
a postoperative vocal quality that is comparable. In addition,
40% of these patients can be salvaged with laryngeal conser-
vation surgery should the tumor recur, leaving XRT as an
additional therapeutic option.

Early Supraglottic Cancer

True early supraglottic carcinoma is rare; even those tumors
presenting as T1 or T2 have a high incidence of regional
metastases, making them stage III or IV, with the manage-
ment of regional disease having disproportionate importance
in this group of tumors.
Surgery and XRT appear equally efficacious for the rare
T1 tumors, with local control rates of 90%. T2 lesions also
have similar control rates with both therapies.
Traditional surgical therapy for supraglottic tumors in-
volves supraglottic laryngectomy, with resection of the
epiglottis, aryepiglottic folds, and false vocal folds. Contra-
indications to the procedure include fixation of the vocal fold,
extension of tumor to the anterior commissure, and thyroid
cartilage invasion. Patients must have excellent pulmonary
function to be candidates for this procedure.
As with early glottic carcinoma, laser excision of early
supraglottic carcinoma is also becoming more widely used in
the United States. New bivalved laryngoscopes have
increased the visibility and accessibility of these tumors to
480 Otorhinolaryngology

transoral excision. The local control rates with laser excision

appear to be equal to open procedures for T1 and T2 lesions.
For N0 patients, single-modality therapy for the primary
and regional sites is adequate. Patients with regional metas-
tases typically require combination therapy, and in these
instances, XRT to the primary and combined therapy of the
neck are a rational approach.

Management of Advanced Laryngeal Cancer

Advanced Supraglottic Cancer
T3 carcinoma of the supraglottic larynx implies invasion of
the preepiglottic space, cartilage, medial wall of the piriform
sinus, or fixation of the vocal fold. These tumors all have a
high probability of lymphatic invasion. Treatment options
include single-modality therapy, surgery and XRT, or chemo-
therapy and XRT. The choice of therapy must be individual-
ized to the patient, taking into account the tumor size and
location as well as the age, health, and wishes of the patient.
Laryngeal function should be preserved whenever possible.
Supraglottic laryngectomy can be undertaken for T3 tumors
without the following: fixation of the vocal cords, extensive
involvement of the piriform sinus, thyroid or cricoid cartilage
invasion, or invasion of the tongue base beyond the circum-
vallate papillae. With proper surgical selection, a 3-year
disease-free survival rate of 75% is possible. Laser excision of
supraglottic tumors is also possible, and reports have demon-
strated less dysphagia and aspiration with this procedure than
with open techniques. In addition, the voice results appear to
be improved over extended supraglottic laryngectomies.
Surgical treatment of the neck is also necessary, and when
two or more nodes are positive, or if extracapsular extension
is present, adjuvant radiation therapy is indicated. Because
the supraglottic lymphatic drainage is bilateral, levels II, III,
and IV of both sides of the neck must be addressed. For N+
necks, level V should be treated as well.
 Neoplasms of the Larynx and Laryngopharynx 481

Standard daily radiation therapy for T3 tumors results in

higher local failure rates, lower survival, and lower rates of
laryngeal preservation. Surgical salvage is possible in only
50% of these patients and usually requires laryngectomy.
Hyperfractionated (more than one treatment per day) XRT
appears to produce higher local control and cure rates than
single-fraction schedules.

Advanced Glottic Cancer

Current therapies for advanced glottic carcinoma include
single-modality (laryngectomy or XRT) and multimodality
(XRT with chemotherapy or surgery with XRT) strategies.
Radiation therapy can be administered in daily fractions or
twice-daily fractions (hyperfractionated). Most trials have
indicated an improvement in local tumor control with hyper-
fractionation, but the impact on overall survival is less certain.
Extensive efforts are being directed at organ preservation
protocols. The well-known Veterans Affairs Laryngeal Cancer
Study Group compared laryngectomy with postoperative XRT
to induction chemotherapy followed by XRT in patients
exhibiting at least a partial response to chemotherapy. Survival
rates were similar in the two groups, with 64% laryngeal
preservation in the nonsurgical group. Studies are now demon-
strating superior results with chemotherapy given concomi-
tantly with XRT compared with sequential chemotherapy-
XRT. Induction chemotherapy has also been used before
surgery to downsize tumors requiring laryngectomy to a size
amenable to partial laryngectomy or radiation. More investi-
gation is required before the optimal therapy for advanced
glottic cancer is known, and outcome studies that include
quality of life data are required to assess each intervention.

Recurrent and Metastatic Laryngeal Carcinoma

Local recurrence of lesions managed initially by XRT or par-
tial laryngectomy can at times be managed by salvage surgery,
482 Otorhinolaryngology

depending on the extent of the recurrence. Similarly, when

XRT was not used as an initial modality, it remains a thera-
peutic option. Parastomal tumor recurrence portends a grave
prognosis, and when paratracheal lymph nodes are involved,
the disease is most likely incurable. Recurrences above the
equator of the stoma are at times amenable to resection.
Lesions with the highest risk of distant metastasis are
those in the supraglottis that extend to the hypopharynx and
piriform sinus. This is especially true of patients with N2 and
N3 neck disease. Glottic primaries are the least likely to
metastasize. The most common site of distant metastasis is
the lung (50 to 80% of metastases), followed by the liver and
bone. Metastasis to bone is associated with a survival time of
less than 4 months, whereas patients with pulmonary metas-
tases have a mean survival of 12 months. Patients with incur-
able recurrences suffering from pain, dysphagia, or airway
obstruction can sometimes be palliated by XRT or low-
toxicity chemotherapy. These patients should be offered the
assistance of hospice programs.

Complications of Treatment of Laryngeal Cancer

The complications of XRT for laryngeal cancer include skin
desquamation, mucosal ulceration and dryness, hoarseness,
dysphagia, dysgeusia, and esophageal stricture. Laryngeal
chondroradionecrosis may also occur, is heralded by pain,
and can be difficult to distinguish from recurrent carcinoma.
Surgical complications include hemorrhage, infection,
pharyngocutaneous fistula, aspiration pneumonia, and steno-
sis of the stoma, pharynx, or esophagus. With conservation
surgery, glottic or supraglottic stenosis can also occur. The
risk of surgical complications is somewhat higher after XRT.

Vocal Quality after Surgery for Laryngeal Carcinoma

For early cancers that do not invade the anterior commissure
or vocal process, carbon-dioxide laser excision produces a
 Neoplasms of the Larynx and Laryngopharynx 483

near-normal or normal voice in the majority of patients. When

the entire vocal fold must be removed, however, the resultant
vocal quality is considerably less than that which can be
achieved with XRT. After hemilaryngectomy, the vocal out-
come is variable and probably depends in part on the method
of reconstruction used. Studies comparing the quality of voice
in these patients compared with those who underwent XRT
have not been undertaken, owing in part to the fact that most
patients undergoing hemilaryngectomy are XRT failures.
There are several voice rehabilitation options for patients
who have had a total laryngectomy. An electrolarynx can be
used soon after surgery, although the mechanical voice is of
only fair to poor quality. Another option is esophageal speech,
in which the patient swallows air and expels it through the
pharynx while speaking. This is difficult for most patients to
master and results in short phonatory times. Tracheoesopha-
geal puncture is a third option, in which a prosthesis is placed
in a surgically created tract between the upper tracheostoma
and the pharynx. The patient then covers the stoma with a
finger and exhales forcefully through the prosthesis into the
pharynx. Phonation is generated in the pharyngoesophageal
segment, as in esophageal speech, but the phonatory dura-
tion is much longer, and the intensity of speech can be par-
tially modulated