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Hypopharyngeal Cancer
Hypopharyngeal cancers correspond for approximately 6 % of all head and neck
cancers. Smoking is the single most important etiologic factor.
The hypopharynx is divided into three distinct regions: the pyriform sinuses; the
posterior surface of the larynx (postcricoid area); and the inferior, posterior, and
lateral pharyngeal walls.
Unilateral sore throat and dysphagia are common symptoms of intraluminal
growth of piriform fossa carcinoma.
The diagnostic evaluation and clinical staging of a patient with a suspected
hypopharyngeal cancer involves a history and physical examination followed by
imaging and panendoscopy with biopsy.
The vast majority of hypopharyngeal malignancies are squamous cells
carcinomas, accounting for more than 95% of cases.
Neck metastasis at presentation is common, and the majority of piriform fossa
lesions are stage III to IV, reflecting a large primary tumor and a high propensity
for nodal metastasis.
The primary objective of treatment of early hypopharyngeal cancer (stage I and
II) is to maximize survival outcomes, maintaining voice production, swallowing,
and airway protected.
Patients with locally advanced (stage III or IV) hypopharyngeal cancer, should
be submitted to a functional organ preservation strategy rather than surgical
resection.
Chapter 6
Abstract
Introduction
Hypopharyngeal cancers correspond for approximately 6 % of all head and neck cancers.
Hypopharynx cancer differs greatly of other carcinomas from head and neck due to its
aggressive biological behavior. Carcinomas of the hypopharynx are usually poorly
differentiated and the majority of patients are usually asymptomatic; early presentations are
unfortunately uncommon. At diagnosis, < 15 % of hypopharyngeal cancers are confined to
the hypopharynx.
Gustavo Arruda Viani
82
Tobacco
smoking
It is the single most important etiologic factor.
Tobacco contains more than 19 known carcinogens and more than 4,000 chemicals
carcinogenic.
Previous
radiation
Postcricoid carcinoma is associated with previous radiation exposure; variously
reported in 4 to 7%of cases.
Alcohol
Alcohol use has a synergistic effect with tobacco and is known to increase the risk of
developing head and neck cancer up to 20 to 120 times than of nonsmoker and
nonalcoholic person
A multidisciplinary team is necessary for an adequate treatment. Preservation of function
can be paramount in the decision-making process. In this chapter we will examine the role of
radiotherapy for organ preservation.
1. Epidemiology
• Hypopharyngeal carcinomas accounting for approximately 6% of all head and neck
cancers.
• The reported incidence rates vary in the worldwide, with Northern France exhibiting
one of the highest incidence rates of 14.8 per 100,000 annually.
• In North America and France hypopharyngeal carcinomas most commonly arise in
the piriform fossa, whereas postcricoid lesions appear more commonly in Northern
Europe.
• The mean age at presentation of hypopharyngeal tumors is approximately 60 years.
Piriform fossa and posterior pharyngeal wall lesions demonstrate the typical male
predominance: for piriform fossa lesions this sex difference is marked in North
America [approximately 5–20 males to 1 female] and extreme in France with ratios
of nearly 50:1.
• Postcricoid lesions, unlike all other sites, show a consistent moderate female
preponderance (approximately 1.5:1 female/male ratio).
References
Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis
for head and neck cancer in the United States: a site-specific analysis of the SEER
database. Int J Cancer. 2005;114(5):806.
Curado MP, Hashibe M. Recent changes in the epidemiology of head and neck cancer. Curr
Opin Oncol. 2009;21(3):194.
2. Risk Factors
Several risk factors have been identified for head and neck cancer from oropharynx
(Table-1).
Table 1. Risk factors for hypopharyngeal cancer
Hypopharyngeal Cancer
83
HPV
Although human papilloma virus has been implicated in oropharyngeal carcinoma, its
role in the carcinogensis of hypopharyngeal cancer is less well defined. Rates of
detection range from 19 to 29%.
Plummer–
Vinson
Syndrome
The syndrome, which tends to occur in females aged 30 to 50 without a history of
tobacco and alcohol use, is characterized by dysphagia, associated weight loss and
iron-deficiency anemia.
Today the syndrome is rare in regions with improved nutrition and fortification of
food with vitamins and iron.
References
Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels AB, Maisonneuve P, Boyle P. Tobacco
smoking and cancer: a meta-analysis. Int J Cancer. 2008;122(1):155.
Wahlberg PC, Andersson KE, Biörklund AT, Möller TR. Carcinoma of the hypopharynx:
analysis of incidence and survival in Sweden over a 30-year period. Head Neck.
1998;20(8):714.
Hashibe M, Brennan P, Benhamou S et al. Alcohol drinking in never users of tobacco,
cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis
in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer
Inst. 2007;99(10):777.
3. Anatomy
The hypopharynx is divided into three distinct regions: the pyriform sinuses; the posterior
surface of the larynx (postcricoid area); and the inferior, posterior, and lateral pharyngeal
walls (figure-1). The pyriform sinuses are paired mucosal pouches wrapped around the
larynx, which funnel food around the larynx and into the esophagus. They are bounded
superiorly by the pharyngoepiglottic folds and inferiorly by the cricoid cartilage. The sinuses
come together at the esophageal introitus and cervical esophagus at the level of C6.
4. Clinical features
• Unilateral sore throat and dysphagia are common symptoms of intraluminal growth
of piriform fossa carcinoma.
• These symptoms may be more severe being associated with weight loss. Otalgia is
associated with invasion through the pharyngeal wall and hoarseness from
involvement of laryngeal musculature.
• The rich lymphatic drainage from the piriform fossa results in early nodal metastases,
and up to 75% of patients have pathologically involved nodes on presentation of
which at least 10% are bilateral.
• Other symptoms such as voice change are common because of the proximity of the
larynx. Large retropharyngeal nodes may produce occipital and nape of the neck pain
radiating to the retrorbital area.
Gustavo Arruda Viani
84
• Dysphagia and sore throat are common symptoms of tumors from posterior wall, but
the primary complaint of a neck mass has been reported in until 18% of cases; 10%
are asymptomatic and found incidentally. Like with postcricoid lesions large
retropharyngeal nodes may produce occipital and nape of the neck pain radiating to
the retrorbital area.
Figure 1. Hypopharynx anatomy.
Reference
Hall SF, Groome PA, Irish J, O'Sullivan B. The natural history of patients with squamous cell
carcinoma of the hypopharynx. Laryngoscope. 2008;118(8):1362.
5. Diagnosis and Evaluation
• The diagnostic evaluation and clinical staging of a patient with a suspected
hypopharyngeal cancer involves a history and physical examination followed by
imaging and panendoscopy with biopsy.
• Endoscopic examination under general anesthetic is essential to determine the
mucosal extent of the tumor, involvement of adjacent structures, presence of deep
fixation, and to investigate the possibility of a second primary malignancy, as
showed in figure-2.
• Biopsy of the primary tumor has traditionally been carried out at the time of
panendoscopy. When there is a palpable mass, a fine needle aspiration may be
obtained to confirm suspicion of a metastatic node.
Hypopharyngeal Cancer
85
• Imaging should include computed tomography (CT), and/or magnetic resonance
imaging (MRI), of the neck and superior mediastinum to assess local extension. CT
and MRI are complementary examinations and should ideally be performed.
• CT scanning is particularly valuable in assessing invasion of the thyroid and cricoid
cartilages, as well as assessing adenopathy (figure-2).
• MRI has better soft tissue definition and the potential to detect occult submucosal
disease, invasion of the intrinsic laryngeal musculature or paraglottic space, and
spread along the superior neurovascular pedicle.
• The search for distant metastasis with a chest CT is important for accurate clinical
staging and treatment planning. Functional imaging with fusion positron emission
tomography (PET) combined with CT (PET/CT) is becoming increasingly
recognized as an additional staging tool.
• It has been shown to assist in assessment of the extent of the primary tumor, as well
as assessment of second primaries, distant metastases, and extent of cervical
adenopathy.
Figure 2. Panendoscopy and CT of an early hypopharyngeal tumor.
References
Allison P, Franco E, Black M, Feine J. The role of professional diagnostic delays in the
prognosis of upper aerodigestive tract carcinoma. Oral Oncol. 1998;34(2):147.
Merritt RM, Williams MF, James TH, Porubsky ES. Detection of cervical metastasis. A
meta-analysis comparing computed tomography with physical examination. Arch
Otolaryngol Head Neck Surg. 1997;123(2):149.
Adams S, Baum RP, Stuckensen T, Bitter K, Hör G. Prospective comparison of 18F-FDG
PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head
and neck cancer. Eur J Nucl Med. 1998;25(9):1255.
6. Pathology
The vast majority of hypopharyngeal malignancies are squamous cells carcinomas,
accounting for more than 95% of cases.
Gustavo Arruda Viani
86
Histological type
Description
Espinocelular
carcinoma
85-95% of laryngeal tumors are squamous cell carcinoma
Histologic type linked to tobacco and alcohol abuse
Characterized by epithelial nests surrounded by inflammatory stroma
Keratin Pearls are pathognomonic
Rare types
Verrucous Carcinoma
Fibrosarcoma
Chondrosarcoma
Minor salivary carcinoma
Adenocarcinoma
Oat cell carcinoma
Giant cell and Spindle cell carcinoma
The majority of the remaining malignancies are adenocarcinomas. Occasionally other
tumor types such as sarcomas, lymphomas, and melanomas have been reported. The sites of
hypopharynx more frequently compromised are: pyriform sinus 65%, pharyngeal wall 20%
and postcricoid 15% (table-2).
Table 2. Histological subtypes of head and neck cancer
Reference
World Heath Organization Classification of Tumors: Pathology and Genetics: Head and Neck
Tumors, Barnes L, Everson JW, Reichart P, Sidransky D (Eds), WHO Press, Switzerland
2005.
7. Routes of Spread
• Neck metastasis at presentation is common, and the majority of piriform fossa
lesions are stage III to IV, reflecting a large primary tumor and a high propensity for
nodal metastasis (Table-3).
• In patients with palpable mass in the neck (cN+) has a significant false positive rate
of 28%. Levels II and III are mainly at risk of micrometastases in cN-negative necks,
but in cN-positive patients the pattern of nodal spread suggests that all levels are at
significant risk of metastasis (table-3 ).
• Involvement of levels I or V is unlikely without simultaneous nodes in levels II, III,
and IV. Patients classified as cN1 are in fact pN2b in 75% of cases (i.e., more than
one node involved).
• Retropharyngeal node involvement has been found in 56% of patients with T 2/3
lesions and bilateral and contralateral nodal disease has been reported in 3 to 30%
associated with advancing T stage but not with tumor differentiation. Involvement of
paratracheal nodes is much lower in hypopharyngeal tumors (8.3%) than with
cervical esophageal carcinoma (71%).
Hypopharyngeal Cancer
87
Levels
Ipsilateral nodes
Contralateral nodes
I
1%
0%
II
58%
7%
III
42%
3%
IV
16%
1% V 11%
1%
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor limited to one subsite of hypopharynx and/or 2 cm or less in greatest dimension
T2
Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures
more than 2 cm but not more than 4 cm in greatest dimension without fixation of
hemilarynx
T3
Tumor more than 4 cm in greatest dimension or with fixation of hemilarynx or extension
to esophagus
T4a
Moderately advanced local disease
Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue*
T4b
Very advanced local disease
Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
Regional lymph nodes (N)•
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2a
Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in
greatest dimension
N2b
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest
dimension
N2c
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest
dimension
N3
Metastasis in a lymph node more than 6 cm in greatest dimension
Distant metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
Table 3. Ipsilateral and contralateral lymph nodes for hypopharyngeal cancer
Reference
Lindberg RD. Distribution of cervical lymph node metastases from squamous cell carcinoma
of the upper respiratory and digestive tracts. Cancer. 1972; 29:1446– 1449
8. Staging
The tumor node metastases (TNM) system of the American Joint Committee on Cancer
(AJCC) and the International Union for Cancer Control (UICC) have been used to stage
hypopharyngeal cancers (table-4)
Table 4. TNM staging for hypopharyngeal cancer
Gustavo Arruda Viani
88
Fator
Description
Location of
disease
Hypopharyngeal cancer has a poor five-year overall survival rate, when compared
to other head and neck cancers.
Pyriform sinus tumors have a higher survival than pharyngeal wall tumors,
followed by postcricoid tumors, which have the worst survival.
Previous
treatment
Patients with a previous history of hypopharyngeal cancer are at increased risk for
second primary tumors from aerodigestive tract, including the oral cavity,
esophagus, and lung.
Alcohol
consumption
Alcohol consumption has a strong relation with developing of another malignancy
after treatment of hypopharyngeal cancer.
Reference
American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton
CC, et al (Eds), Springer, New York 2010.
9. Prognostic Factors
Hypopharyngeal cancer has a relatively poor prognosis compared with other head and
neck tumors, with an estimated 5- year overall survival rates for stage I and stage II of about
50% (table-5).
Table 5. Prognostic factors associated with survival for hypopharyngeal cancer
References
Hall SF, Groome PA, Irish J, O'Sullivan B. The natural history of patients with squamous cell
carcinoma of the hypopharynx. Laryngoscope. 2008;118(8):1362.
Nakamura K, Shioyama Y, Kawashima M et al. Multi-institutional analysis of early
squamous cell carcinoma of the hypopharynx treated with radical radiotherapy. Int J
Radiat Oncol Biol Phys. 2006;65(4):1045.
10. Treatment
• Prior to treatment, all patients with cancer of hypopharynx should be evaluated by a
multidisciplinary team. Selection of a treatment approach depends upon tumor and
patient factors, such as; age, performance status, comorbidity, extent and location,
physician expertise, and the availability of rehabilitation services.
• The hypopharynx can be divided into three subsites: pyriform sinus, postcricoid area,
and posterior pharyngeal wall.
• The primary objective of treatment of early hypopharyngeal cancer (stage I and II) is
to maximize survival outcomes, maintaining voice production, swallowing, and
airway protected.
Hypopharyngeal Cancer
89
Study
Description
Nakamura et
al. (2006)
105 patients with stage I (39) and stage II (76) hypopharyngeal tumors treated by
radiation therapy in 10 institutions between 1990 and 2001.
The 5-year local control rate was 87% for T1 (although 18% required additional
surgery) and 74% for T2. All patients retained their pretreatment voice
The 5-year disease-specific survival rate was 95.8% for T1 disease and 70.1%
for T2
Hall et al.
(2009)
Retrospective population-based study of 595 patients diagnosed between 1990
and 1999.
The authors found no survival advantage for either radiotherapy+/-salvage
surgery or surgery+/-postoperative radiotherapy.
There is no difference in survival for patients with hypopharynx comparing
primary surgery to primary radiotherapy.
Garden et al
(1996)
Retrospective study of patients with hypopharyngeal tumors staged T1 or T2
treated with curative radiation alone.
Eighty-two patients with early-stage (T1, 19 patients; T2, 63 patients)
hypopharyngeal squamous cell carcinomas treated between 1976 and 1992.
The 2-year actuarial local control rates for patients with T1 and T2 disease were
89% and 77%, respectively. Subgroup analysis of T2 patients showed the
following differences in actuarial local control rates at 2 years.
• To maintain the functional outcomes both conservative surgery (figure-3) and
definitive radiation therapy (RT) generally are offered.
Figure 3. Sagital view of tumor cuts for laryngopharyngectomy.
• Both treatments are equivalent in terms of local tumor control and survival, as well
as functional organ preservation. Table-6 summarizes the evidence showing the role
of radiotherapy for early stage laryngeal cancer.
Table 6. Clinical evidence for radiotherapy in early hypopharyngeal cancer
Gustavo Arruda Viani
90
Study
Decription
EORTC 22931 (Bernier
et al. 2004)
334 patients with operable stage III/IV oral cavity, oropharynx, larynx, and
hypopharnx cancer randomized to post-op RT (2/66 Gy) vs. post-op
chemo- RT (2/66 Gy and cisplatin 100 mg/m2 on days 1, 22, 43).
All patients received 54 Gy to the low-risk neck. Eligible stages included
pT3–4N0/+, T1–2N2–3, and T1–2N0–1with extra capsular extension,
+margin,or perineural invasion.
Chemo-RT improved 5-year DFS (59 vs 47%), 5-year OS (65 and 53%),
and 5-year LRC (82%), but increased grade 3–4 toxicity (21 and 41%).
RTOG 95–01 (Cooper et
al. 2004)
459 patients with operable cancer of the oral cavity, oropharynx, larynx, or
hypopharynx who had 2 or more involved lymph nodes, nodal
extracapsular extension, or a + margin were randomized to post-op RT
(2/60–66 Gy) vs. post-op chemo-RT (2/60–66 Gy and cisplatin ×3 c).
Chemo-RT improved 2-year DFS (43 vs 54%), LRC (72 vs 82%), and had
a trend for improved OS (57 and 63%), with increased grade 3–4 toxicity
(34 and 77%).
Pooled RTOG/EORTC
analysis (Bernier 2005)
Chemo-RT improved OS, DFS, and LRC for ECE and/or + margins, but
provided only trend for improvements (p > 0.06) for stage III–IV, PNI,
LVSI, and/or enlarged LN .
References
Nakamura K, Shioyama Y, Kawashima M et al (2006) Multi-institutional analysis of early
squamous cell carcinoma of the hypopharynx treated with radical radiotherapy. Int J
Radiat Oncol Biol Phys 65:1045–1050.
Hall SF, Groome PA, Irish J, O'Sullivan B. Radiotherapy or surgery for head and neck
squamous cell cancer: establishing the baseline for hypopharyngeal carcinoma? Cancer.
2009;115(24):5711.
Garden AS, Morrison WH, Clayman GL, Ang KK, Peters LJ. Early squamous cell carcinoma
of the hypopharynx: outcomes of treatment with radiation alone to the primary disease.
Head Neck. 1996;18(4):317.
• When surgery is indicated to treat early stage hypopharyngeal cancer, a selective
neck dissection of levels II – IV, even in patients with a clinically negative neck, is
recommended. On the other hand, for patients treated by definitive RT, a elective RT
to the bilateral neck, including retropharyngeal and supraclavicular nodes should be
offered.
• Postoperative RT is recommended for patients with positive resection margins,
lymphovascular or perineural invasion, or pathologically positive lymph nodes
identified after surgery. Patients with positive margins or with extracapsular
extension of a positive lymph node may benefit from postoperative concurrent
chemoradiation (table-7).
Table 7. Clinical evidence for adjuvant chemoradiotherapy in hypopharyngeal cancer
References
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck
cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy
trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843-50.