HYPOPHARYNGEAL CANCER

DR. SATINDER

IntroductionHypopharyngeal cancers arise from the mucosa of one of the three anatomical subsites of the hypopharynx.It is characterised by advanced disease at presentation mainly because the hypopharynx is a silent area, allows tumours to grow for a substantial period of time before symptoms occur.Hypopharyngeal cancers are relatively rare neoplasms with unfavourable prognosis among all cancers.Aggressive behaviour represented by strong tendency for submucosal spread.

Early occurrence of nodal metastatic involvement. Direct invasion of adjacent structures in the neck and high incidence of distant metastases. 30% of patients have local disease at the time of diagnosis. 70% have local regional disease.10% present with distant metastases.

EpidemiologyIncidence of less than 1 per 100,000 population.3%–5% of all head and neck cancers.Increased incidence in males of over 2.5:100,000 is seen in India, Brazil, Central and Western Europe.More common in men than in women.Peak incidence in the 6th and 7th decades.Most common site of origin of hypopharyngeal cancer is the pyriform sinus (66%–75%).Posterior pharyngeal wall, and postcricoid area (20%–25%).In India mainly Bombay and Madras heaving high incidence.

AetiologySmoking tobacco.Chewing tobacco.Heavy alcohol use.Eating a diet without enough nutrients.Having Plummer-Vinson syndrome.Тobacco and alcohol represent the major risk factors for the development of hypopharyngeal cancer with more than 90% of patients presenting with a history of tobacco use.There is a significant association with alcohol and smoking, acting synergistically.

• Role of genetic factors- association between tobacco use and p53 mutations is found in a much larger percentage of smokers and drinkers.• The loss of heterozygosity at 9p and abnormalities in chromosome 11 present.• Mutations in the p21 gene have also been identified.• The role of human papilloma virus (HPV) as a contributing factor to carcinogenesis in head and neck squamous cell carcinomas.• Occupational exposures mainly asbestos and welding fumes.

Anatomy

Anatomy of the hypopharynx The hypopharynx is the part of the pharynx • Hypopharynx extend from C3-C6 cervical vertebrae.• Superiorly with the oropharynx and is situated posterior and lateral to the larynx.• Inferiorly where it narrows and becomes continuous with the esophagus. It is divided into three primary anatomic subsites: 1. Pyriform sinuses2. Postcricoid area3. Posterior pharyngeal wall

Pyrifrom sinuses•Lies on either sides of larynx.•Extend from pharyngoepiglottic fold to upper end of oesophagus.•The internal laryngeal nerve run submucosally in the lateral wall of sinus.•Bounded by-•Laterally- thyrohyoid membrane and thyroid cartilage.Medially - aryepiglottic fold, arytenoids, and lateral aspect of the cricoid cartilage.Post-cricod area• It is the part of anterior wall of laryngopharynx.Posterior pharyngeal wall•Extends from the level of the hyoid bone to cricoarytenoid joint.

Lymphatic drainage•Pyriform sinuses- jugulodigastric, midjugular (level II and III), and retropharyngeal nodes.•Posterior pharyngeal wall drain in lateral retropharyngeal nodesinto deep cervical.•Post-cricoid area intoretropharyngeal lymph nodes to the paratracheal,paraesophageal, and lower jugular nodes (level IV and VI).

The wall of the hypopharynx is composed of four layers:1. An inner mucosal lining of stratified squamous epithelium over a loose stroma.2. A fibrous layer of pharyngeal aponeurosis.3. A muscular layer formed by the inferior constrictor muscle and, in the upper part by the distal portion of the middle constrictor. The most distal fibres of the inferior constrictor condense into the cricopharyngeus muscle; just proximal to this muscle on the posterior wall is an area of relative weaknessknown as Killian’s dehiscence.

Clinical presentation•Early hypopharyngeal cancers-mild, nonspecific sore throat or vague discomfort on swallowing.•Predominating symptoms are those related to the locoregional disease spread including • Sore throat -Typically, pain is unilateral and well localized.• Odynophagia• Dysphagia• Weight loss• A mass in the neck• Poor dentition and halitosis

•Hoarseness: This indicates either involvement of the recurrent laryngeal nerve, which runs deep to the anterior wall of the pyriform sinus, or direct invasion of the larynx.•A “hot potato” voice may be due to the involvement of the base of the tongue.•Approximately 50% of patients present with palpable neck lymphadenopathy

•Otalgia: Referred pain to the ear is mediated by branches of the tenth cranial nerve . Invasion of the laryngeal nerve causes spread of neuropathic impulses to the auricular nerve (sensory to posterior external auditory canal and back of pinna).

                           Patient presented with hoarseness and otalgia. On MRI, there was a bulky left pyriform sinus tumor with an area of gadolinium enhancement extending to the carotid sheath. This T4 tumor was unresectable, and the patient was treated with chemoradiation. Despite a good response to chemoradiotherapy, the evaluation for progressive neck pain 4 months later revealed a bulky recurrence in the left neck. Note tumor (white arrows) surrounding the carotid artery (black arrow).

                          Patient presenting with hoarseness and dysphagia.

CT scan demonstrates bulky right pyriform sinus tumor (white arrows) eroding through thyroid cartilage, with displacement of supraglottic airway. A total laryngectomy would have been required, because the patient placed a high value on retaining the ability to talk, chemoradiotherapy was chosen.

                        Patient presenting with hoarseness and dysphagia. CT scan

Demonstrated bulky right pyriform sinus tumor eroding through thyroid cartilage, with displacement of supraglottic airway. Total laryngectomy would have been required, because the patient placed a high value on retaining the ability to talk, chemoradiotherapy was chosen. Following chemoradiotherapy, note persistent fullness in tumor bed. Endoscopy revealed edema and scarring, but the biopsy was negative for tumor. Continued vigilance is needed in this situation.

Routes of primary tumour spread•Hypopharyngeal cancers, particularly those arising in the postcricoid area, have a strong tendency for extensive submucosal spread.•Pyriform sinus cancers- Lateral -thyroid cartilage spreadMedial - aryepiglottic folds and arytenoids, preepiglottic and paraglottic space and intrinsic laryngeal muscles that results in a loss of vocal cord mobility.Superior- extension beyond the lateral pharyngoepiglottic fold into the vallecula can involve the base of the tongue. Inferior -extension beyond the apex can involve the thyroid gland.

A large right piriform fossa carcinoma

Postcricoid tumours

• Tending to grow circumferentially frequently involve the cricoid cartilage, arytenoids and intrinsic laryngeal muscles with resultant vocal cord fixation.•The inferior tumour spread can lead to invasion of cervicalesophagus and trachea. In figure. A large

postcricoid carcinoma extending into thecervical oesophagus with a skip lesion 4 em from the advancingtumour edge (arrow).

Posterior pharyngeal wall tumoursThe tumour usually involves adjacent areas when firstdiagnosed and almost always involves the posterior wall of the oropharynxSuperiorly to the base of the tonsilLaterally to the oropharyngeal wallInferiorly in to the postcricoid region and cervical oesophagus.• As the tumour enlarges and bulges into the pharynx it typically.•Invasion of the prevertebral fascia occurs late. •Retropharyngeal space, and may spread laterally to involve both piriform sinuses.

Regional metastases• Metastases in the neck lymph nodes are already present in appro. 70% of patients at the time of presentation with levels II and III being the most frequently affected sites.• Paratracheal and Paraesophageal nodes (level VI) are most commonly present in patients with cancers in the postcricoid area.• Retropharyngeal lymph node metastases are most frequently present in patients with cancers of the posterior pharyngeal wall and the postcricoid area.•Up to 80 percent of patients with carcinoma of the posterior pharyngeal wall will have neck node metastases at presentation.

A patient presenting with a large right neck mass (an N3 node) due to an ipsilateral piriform fossa cancer.

•In patients with clinically positive neck, the incidence of bilateral occult lymph node metastases is at least 50%•Hypopharyngeal cancers include retropharyngeal and parapharyngeal nodes paratracheal nodes and mediastinalnodes. •Advanced stage at presentation and its involvement or extension to cross the midline, the risk of contralateral metastases is high, with histological identification of tumour in more than 20% of cases treated surgically.Distant metastases• At the time of clinical diagnosis distant metastatic 17%.• Approximately half of the recurrences was distant metastatic disease. • The most common site for distant metastases is the lung, liver, bones and brain.

DifferentialsDifferential diagnoses include the following:

Hodgkin DiseaseLymphoma, Non-HodgkinPharyngitis, BacterialPharyngitis, ViralPlasmacytoma, Extramedullary

Diagnosis1.Complete head and neck examination, including

inspection, palpation, and indirect or fiberoptic examination.

2.Flexible fiberoptic endoscopic examination is important to attempt to localize and stage the primary tumor.

3.Endoscopy easily reveal tumours arising in the upper pyriform sinus and the posterior pharyngeal wall.

4.Typical findings of hypopharyngeal cancer include

• mucosal ulceration• pooling of the saliva in the pyriform fossa • edema of the arytenoids• fixation of the cricoarytenoid joint• true vocal cords, or both.

5. The neck should be examined in a systematic fashion. Any lymph nodes should be assessed with regard to

size, location, and mobility. On neck examination, loss of the grating sensation (laryngeal crepitus) of the laryngeal cartilages over the prevertebral tissues may indicate deep pharyngeal wall involvement.

•Oral examination • The hypopharynx is not visible directly, but other regional pathologies, including the synchronous oral cavity or oropharyngeal tumors, might be seen. • Asymmetry of tonsillar pillars can be a clue to a tumor invading the palatopharyngeus muscle at insertion to the inferior constrictor muscle.

•Larynx and pharynx examinations • The mirror examination is the quickest and simplest screening tool, but it cannot reveal lower pyriform sinus or postcricoid lesions. Fiberoptic laryngoscopy is the examination of choice.• During the flexible laryngoscopy, the assessment of vocal cord mobility or fixation is important for staging purposes. • Findings include mass lesions, hyperkeratotic or erythematous mucosal lesions, ulcerations, and vocal cord paralysis.

Neck examination •Examine and document the size, location, and number of palpable lymph nodes in all cervical and supraclavicular node-bearing areas. •Palpate and wiggle the larynx from side to side. Tenderness suggests invasion, while loss of normal tracheal crepitus suggests invasion of prevertebral tissue or a large postcricoid tumor.

Head examination •Assess cranial nerve function.•Assess jaw mobility. Trismus suggests invasion of pterygoid muscles.•Areas of mass lesions or tenderness are suggestive of regional metastases.

Serial endoscopic images of endoscopic submucosal dissection procedure for the removal of an early hypopharyngeal cancer showing a 10×8 mm sized, slightly elevated lesion with surface irregularity and hyperemia on the left pyriform sinus (A), markings around the lesion with a needle knife (B), circumferential mucosal incision and submucosal dissection with an hook and IT knife (C), and artificial ulcer after complete en-bloc resection (D).

General examination for distant metastases and comorbidities 1. A complete blood count2. Liver function tests3. Renal function tests4. Chest x-ray films may demonstrate

metastases, synchronous lesions, or effusions suggesting metastases to pleura or lymphatic obstruction.

5.CVS examination6.USG Abdomen Hepatomegaly 7.General neurologic examination8.Perform a peripheral lymph node examination

to assess for possible distant lymph node metastases.

Imaging studies1.Chest x-ray films2. Barium study3. CT scan or MRI of oral cavity and neck.4.The contrast-enhanced CT scan is typically used

as the initial imaging modality to assess local tumor extent and evaluate lymph nodes. Perform a CT scan of the head and neck with contrast to assist with delineation of cartilage and bone invasion, lymph node metastasis, and extralaryngeal invasion. As a single modality, this is generally more useful for staging hypopharyngeal cancers.

5. MRI is most often used to study lesions that suggest submucosal spread toward the esophagus on CT scans.

6. PET scan(FDG-PET)-evaluation of locally advanced hypopharyngeal cancer

Advantages and disadvantages of computed

tomography (CT) and magnetic resonance imaging (MRI) in the

evaluation of hypopharyngeal tumoursCT SCAN MRI

Planes of investigation

2 3

Assessment bone/cartilage

Good poor

Differentiate tumour from oedema

Poor Good

Radiation hazard

mild none

6. FDG-PET may• Improve pretreatment staging• Identification of an occult primary site, • Estimation of treatment response, and• Differentiation of early recurrence from scar

tissue.• Integrated PET/CT overcomes poor anatomic

localization of PET together with the morphologic data revealed by CT.

• PET/CT is helpful• In locating and localizing occult primary and

regional disease• Differentiating between malignant disease and

posttreatment changes.7 Abdominal CT scan8 Bone scan

Diagnostic procedures1.Fine-needle aspiration 2.Core biopsy3.Biopsy of primary tumour site4.PanendoscopyHistologic findings

• More than 95% of hypopharyngeal malignancies are squamous cell carcinomas• less than 60% are keratinizing, • 33% are nonkeratinizing, and • Rest all are usually poorly differentiated.• Uncommon histologic types include adenocarcinoma, lymphoma, and sarcoma.

StagingPrimary tumour (T)TX: Primary tumour cannot be assessedT0: No evidence of primary tumourTis: Carcinoma in situT1: Tumour limited to one subsite of hypopharynx and/or 2 cm or less in greatest dimensionT2: Tumour 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 hemilarynxT3: Tumour more than 4 cm in greatest dimension or with fixation of hemilarynx or extension to esophagusT4a: Moderately advanced local disease. Tumour invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue*T4b: Very advanced local disease. Tumour invades prevertebral fascia, encases carotid artery, or involves mediastinal structures

American Joint Committee on Cancer (AJCC) TNM classification of hypopharyngeal cancer

Regional lymph nodes (N)Nx: Regional lymph nodes cannot be assessedN0: No regional lymph node metastasisN1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimensionN2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, not more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, not more than 6 cm in greatest dimensionN2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimensionN2b: Metastasis in multiple ipsilateral lymph nodes, not more than 6 cm in greatest dimensionN2c: Metastasis in bilateral or contralateral lymph nodes,not more than 6 cm in greatest dimensionN3: Metastasis in a lymph node, more than 6 cm in greatest dimension

Distant metastasis (M)M0: No distant metastasisM1: Distant metastasisAnatomic stage/prognostic groups0: Tis N0 M0I: T1 N0 M0II: T2 N0 M0III: T3 N0 M0, T1-T3 N1 M0IVA: T4a N0 M0, T4a N1 M0, T1-T3 N2 M0, T4a N2 M0IVB: Any N M0, Any T N3 M0IVC: Any T Any N M1American Joint Committee on Cancer (AJCC) TNM classification of hypopharyngeal cancer

Risk of nodal disease based on T stage is as follows: T1 - Risk of nodal disease 60%T2 - Risk of nodal disease 60-70%T3 - Risk of nodal disease 84%T4 - Risk of nodal disease 84%

Treatment of hypopharyngeal cancer

1.Early hypopharyngeal carcinoma• Surgical excision neck dissection(s) (endoscopic (CO2) or open surgery)• Conservation surgery bilateral selective neck dissection postoperative radiotherapy chemotherapy• Concurrent chemoradiotherapy to primary site and both necks• Radiotherapy alone – where significant co-morbidity prevents the above options.

2. Locally advanced hypopharyngeal carcinoma

• Concurrent chemobioradiotherapy to primary and neck• Radical surgery; pharyngolaryngectomy reconstruction bilateral selective or modified neck dissection, with postoperative chemoradiotherapy.

Classification of surgery on the hypopharynx.ClassificationInternal excision CO2 laser or ‘cold steel’External excision (with orwithout flap repair) Partial pharyngectomy Partial pharyngectomy/partial laryngectomy Partial pharyngectomy/total laryngectomy Total pharyngolaryngectomy Extended pharyngolaryngectomy

Radiation Therapy and Combined TherapyIndications for radiotherapy include the following:•Definitive treatment•Resectable cancer for organ preservation•Adequate function of the laryngopharynx•Unresectable cancer

1. Cancer that involves the prevertebral fascia2. Cancer that encases the carotid artery

Indications for postoperative radiotherapy include the following:•Primary indications 1. Positive or close margins (< 5 mm)2. T4 tumors3. Invasion of cartilage, bone, or soft tissues by the

primary tumor•Neck indications 1. Two or more lymph nodes with metastasis2. Extracapsular extension

Chemotherapy, Radiation Therapy, and Combined TherapyManagementbased on stage, as follows:1. T1/T2 - Radiotherapy alone (commonly 66-70 Gy) or

surgery (possibly with postoperative irradiation, depending on the pathology findings). Larynx preservation therapy is typically possible and is strongly favored.

2. T3/T4 (resectable) - Partial or total laryngopharyngectomy, neck dissection, postoperative radiotherapy, or radiotherapy alone with altered fractionation or concurrent chemoradiotherapy or participation in prospective clinical trials.

3. Unresectable or medically unstable - (1) Radiotherapy alone with altered fractionation or concurrent chemoradiotherapy or (2) participation in prospective clinical trials including the study of induction chemotherapy

NCCN Guidelines Hypophyarnx

Surgical therapy1. Partial laryngopharyngectomy (PLP) for

tumors of the medial pyriform sinus 2. Near-total laryngopharyngectomy3. Total laryngopharyngectomy 4. Total laryngopharyngectomy with

esophagectomy5. Extended total laryngectomy for tumors of

the pyriform sinus

Total laryngopharyngectomy

Lateral view of tumor cuts for laryngopharyngectomy.

The tendency for submucosal spread of advanced hypopharyngeal tumors mandates wide margins, and primary closure is often not possible. These procedures often require free tissue transfer for closure.

Extended total laryngectomy for tumors of the pyriform sinus

Chemotherapeutic agent1. Cisplatin (Platinol)2. Fluorouracil Paclitaxel (Taxol)3. Methotrexate (Folex,

Rheumatrex)4. Docetaxel (Taxotere5. Cetuximab (Erbitux)6. Leucovorin (Folinic Acid,

Wellcovorin)

Stage I Hypopharyngeal Cancer Treatment of stage 1 hypopharyngeal cancer may include the following:

1. Laryngopharyngectomy and nec disections with or without high-dose radiation therapy to the lymph nodes of the neck.

2. Partial laryngopharyngectomy with or without high-dose radiation therapy to the lymph nodes on both sides of the neck.

Stage II Hypopharyngeal Cancer

Treatment of stage II hypopharyngeal cancer may include the following:

1. Laryngopharyngectomy and neck dissection. High-dose radiation therapy to the lymph nodes of the neck may be given before or after surgery.

2. Partial laryngopharyngectomy. High-dose radiation therapy to the lymph nodes of the neck may be given before or after surgery.

3. Chemotherapy given during or after radiation therapy or after surgery.4. A clinical trial of chemotherapy followed by radiation therapy or surgery.

Stage III Hypopharyngeal CancerTreatment of stage III hypopharyngeal cancer may include the following:

1. Radiation therapy before or after surgery.2. Chemotherapy given during or after radiation therapy or after surgery.3. A clinical trial of chemotherapy followed by surgery and/or radiation

therapy.4. A clinical trial of chemotherapy given at the same time as radiation therapy.5. A clinical trial of surgery followed by chemotherapy given at the same time

as radiation therapy.

Stage IV Hypopharyngeal CancerTreatment of stage IV hypopharyngeal cancer that can be treated with surgery may include the following:

1. Radiation therapy before or after surgery.2. A clinical trial of chemotherapy followed by surgery and/or radiation

therapy.3. A clinical trial of surgery followed by chemotherapy given at the same

time as radiation therapy.

Surgical treatment and follow-up of stage IV hypopharyngeal cancer is complex and is ideally overseen by a team of specialists with experience and expertise in treating this type of cancer. If all or part of the hypopharynx is removed, the patient may need plastic surgery and other special help with breathing, eating, and talking.

Treatment of stage IV hypopharyngeal cancer that cannot be treated with surgery may include the following:

1. Radiation therapy.2. Chemotherapy given at the same time as radiation therapy.3. A clinical trial of radiation therapy with chemotherapy.

1. Radiation therapy alone.2. Concurrent chemoradiation. 3. Induction chemotherapy

followed by radiation 4. therapy alone.5. Induction chemotherapy

followed by concurrent chemoradiation.

6. Postoperative concurrent chemoradiation.

Radiation Therapy

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