Carcinoma Larynx- Govt of India Standard Treatment Guidelines

Larynx is not only important for respiratory function but also for deglutition and phonation. Carcinoma of larynx along with carcinoma of oral cavity is the most common malignancies in head and neck malignancy. It often present early when a high cure rate can be achieved. Treatment remains controversial but early cancer may treat with either surgery or radiotherapy, depending on size, site of tumor and patient and doctor preference. Advanced disease treated with radical surgery and post op radiotherapy.

Ministry of Health and Family Welfare has released standard treatment guidelines on Carcinoma Larynx. Following are its major recommendations:-

Surgical Anatomy- The larynx can be embryological, clinically and anatomically divided into Supraglottis, glottis and subglottis.

Supraglottis- the Supraglottis subsites include-

 Epiglottis- including tip, lingual and laryngeal surfaces

 AE fold

 Arytenoids

 Ventricles

 False cords

The inferior boundary of Supraglottis as defined by the AJCC is the horizontal plane passing through the apex of the ventricle. The anatomic division is located at the arcuate line which marks the change from respiratory epithelium to squamous variety.

Glottis- It includes

 True vocal cords

 Anterior commissures

 Posterior commissures

According to AJCC the inferior border of glottis is the horizontal plane 1 cm inferior to level of the upper surface of the vocal cord.

Spread of Tumour- Laryngeal cancer may spread from its original site to other parts of the larynx by direct mucosal and sub mucosal extension, by lymphatic and vascular permeation, by perineural spread or by direct invasion of adjacent structures. These "pathways of spread" have traditionally been the basis of conservation surgical procedures.

Barriers of Tumour Extension-

· Ventricular fold

· Conus elasticus

· Anterior commissure

· Perichondrium

Preferred Pathways for Tumour Extension-

 Epiglottis fenestrations

 Anterior commissure ligament

 Pre/Paraglottic space

 Cricothyroid/ thyrohyoid membrane

Supraglottis-

Supraglottis tumours have a propensity for bilateral spread and also a high propensity for lymph node metastases. Midline tumors may metastasize bilaterally.

Glottic tumours-

The anterior commissure ligament (Broyle's ligament) has been traditionally believed to be resistant to tumour spread. However, once involved, it facilitates subglottic and supraglottic spread along the anterior midline as its fibres extends longitudinally.

Lateral extension to paraglottic space has traditionally been assessed by clinical sign of limitation/fixation of vocal fold movement. Currently imaging should be used to supplement this assessment.

Subglottis-

Early extralaryngeal extension through cricothyroid membrane and circumferential involvement usual.

Epidemiology- 1.5 % of all cancers. Glottic: Supraglottic = 3:1. Incidence in UK 4 per 100000. In India its incidence is 10 per 100000. Peak age of incidence 55-65 years of age with male: female= 3-4:1.

Risk Factors-

 Geographic

 Social class V

 Urban

 Smoking

 Alcohol

 Radiation

Etiology

Until the complex molecular interactions of all associated etiologic agents for any cancer can be understood, these interactions are best thought of as associations. Thinking of intrinsic (eg, genetic) factors and/or extrinsic (eg, smoking) factors as causes is too simple.

To most people, a cause implies a condition that is both necessary and sufficient to produce a pre-specified result. Laryngeal carcinomas have multiple associations.

The foremost risk factor for the development of laryngeal cancer is tobacco use. The risk of developing laryngeal cancer with tobacco increases with use and decreases after cessation. When associated with the intake of alcohol, a strong synergistic effect is created. However, whether or not alcohol alone is an independent risk factor is still unclear.

All the potential risk factors for laryngeal cancer that have been studied are as follows:

 Tobacco use

 Excessive ethanol use

 Male sex

 Infection with human papilloma virus

 Increasing age

 Diets low in green leafy vegetables

 Diets rich in salt preserved meats and dietary fats

 Metal/plastic workers

 Exposure to paint

 Exposure to diesel and gasoline fumes

 Exposure to asbestos

 Exposure to radiation

 Laryngopharyngeal reflux

Pathophysiology-

The larynx is an essential organ that is responsible for the following vital functions:

 Maintaining an open air way

 Vocalizing

 Protecting the lungs from more direct exposure to noxious fumes and gases of unsuitable temperatures

 Protecting the lungs from aspiration of solids and liquids

 Allowing leverage, by closing the glottis during a Valsalva maneuver, to increase upperbody strength and to ease solid-waste removal Malignant tumors of the larynx affect laryngeal physiology depending on tumor location and size. Supraglottic tumors usually cause upper airway obstruction. Conversely, glottic tumors affect initially voice quality. In addition, malignant tumors of the larynx affect swallowing physiology. The mechanism of swallowing is altered when tumors invade and alter the physiology of the swallowing muscles. This is expressed as difficulty swallowing and aspiration.

Liquids and solid food gain access into the trachea.

Pathophysiology of malignant tumors of the larynx is at the molecular and histologic level. Histologic progression occurs from normal laryngeal mucosa to dysplastic mucosa to carcinoma in situ to invasive carcinoma. This progression is a multi-step process of accumulated genetic events that lead to the development of larynx tumors.

Presentation-

Given the functions of the larynx mentioned above, one can easily imagine the consequences of a carcinoma destroying and/or obstructing the laryngeal structures and their mechanisms (eg, vocal-cord movement). Symptoms vary with the structures involved by malignancy and its accompanying inflammatory reaction. Although the particular tumor, the site, and the patient's constitution play key roles in any given individual, laryngeal cancers as a whole can cause any of the following findings, alone or in combination:

1. Glottisa)

  a)Hoarseness

  b) Sore throat

  c) localized pain( cartilage invasion)

  d) Dyspnea

  e) Otalgia (involvement of deep structure)

2. Supraglottisa)

  a)Odynophagia

  b) Sore throat

  c) Weight loss

  d) Aspiration

  e) Tone breath

  f) Otalgia

  g) Neck mass (either tumour itself or lymph node)

  h) Lymph node metastases in Supraglottic tumour-

  · T1- 0%

  · T2- 15%

  · T3- 20%

  · T4- 30%

3. Subglottisa)

  a)Dyspnoea

  b) Hemoptysis

Differential Diagnosis

1. Chronic laryngitis- present with hoarseness of voice and mimic early glottic cancer specially in older people or should be differentiated from squamous intraepithelial neoplasia like, Keratosis (keratin formation by superficial layer only), parakeratosis (nucleus retained abnormalities in superficial layer), dysplasia (nuclear variation, mitosis, loss of normal epithelial layering), carcinoma in situ (cells of malignant cytology but confined superficial to basement membrane).

2. Benign tumour papillomas- it constitutes 85% of all benign tumour larynx and can be multiple (Juvenile papilloma) or single (adult papilloma). The causative organism Human papilloma virus type 6 and 11. Malignant changes may occur in a juvenile papilloma but usually only if the patient has been irradiated.

Evaluation-

1. History - As in all clinical evaluations, the history is the first step in gathering the facts.

    Assess or inquire about the following:

  · Weight loss

  · Fatigue

  · Pain

  · Difficulty breathing orswallowing

  · Vocal changes noted by the patient and his or her family

  · Ear pain

  · Coughing up blood or solid material

2. Physical examination-

  · General condition

  · Nutritional status

  · Full head and neck examination which includes inspection and palpation of the oral cavity and oropharynx to rule out second primary tumors or          other lesions, as well as evaluation of dentition.

  · Flexible laryngoscope - to evaluate the function and anatomy of the entire larynx. Evaluation of vocal cord motility and the location and extension        of the tumor are crucial to stage the patient accurately.

  · Palpation of the neck looking for enlarged lymph nodes

  · Evaluation of the cranial nerves should also be included in the physical examination.

Imaging Studies-

It is important to carry out any imaging studies prior to endoscopy and biopsy if possible since FNAC; endoscopic and open biopsy can all create artefactual features on both CT and MRI.

Specific Uses of Imaging-

  · To assess the extent of primary tumour, its relation to larynx, and any extension into pre and para glottic space

  · To exclude a second primary or distant metastases

  · Involvement of cartilage

  · To assess the neck

Tissue Biopsy- DL scopy and biopsy and panendoscopy

TNM Staging

(Glottic carcinoma)

T1 -   limited to VC, normal mobility (May inv ant/post com.)

T1a - one vocal cord

T1b - both VC

T2   - extends to Supraglottis and/or glottis, impaired VC mobility

T3   - limited to larynx with hemilarynx fixation, paraglottic space/minor thyroid cart erosion (inner cortex)

T4a - invades through thyroid cartilage, /extralarngeal tissues,(trachea, soft tissues, muscles of tongue, strap muscles, thyroid gland &esophagus, l

T4b - Prevertebral fascia, mediastinal structures, ICA.

Treatment protocol- (glottic carcinoma)

1. For carcinoma in situ

  a) Endoscopic removal (stripping/laser)

  b) RT and follow up.

2. For Most T1-2, N0 (total laryngectomy not required)

  a) RT

  b) Partial laryngectomy is the treatment of choice.

3. For most T3; N0-1 Resectable tumors requiring total laryngectomy

  a) CCRT

    - if Primary site: Complete response (N0 at initial staging) then only follow upis required.

    - If Primary site: Complete response (N+ at initial staging) withresidual tumor in neck then Neck dissection can be considered.

    - If Primary site: residual tumor is there then Salvage surgery + neck dissection is indicated.

  b) Second option is Surgery. In case of No disease Laryngectomy with ipsilateral thyroidectomy unilateral or bilateral selective neck dissection                (reconstruction as indicated) and follow up. And in case of N1 disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral comprehensive              neck dissection ± contralateral selective neck dissection (reconstruction as indicated).

    - If pt presented with No adverse features like extracapsular nodal spread, positive margins, pT4 primary, N2 or N3 nodal disease, perineural                invasion, vascular embolism only follow up required.

    - Adverse features chemo/RT can be consider.

4. For most T3, N2-3 disease

  a) CCRT can be tired.

    - If Primary site: complete response but with Residual tumor in neck then Neck dissection can be consider.

    - In case of complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical          exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered.

    - If pt presented with Primary site: residual Tumor then Salvage surgery + neck dissection as indicated.

  b) Second option is Surgery- Laryngectomy with ipsilateral thyroidectomy, ipsilateral or bilateral comprehensive neck dissection (reconstruction              asindicated).

    - If pt presented with No adverse features like extracapsular nodal spread, positive margins, pT4 primary, N2 or N3 nodal disease, perineural                invasion, vascular embolism only follow up required.

    - With Adverse features chemo/RT can be consider.

  c) Third option is Induction chemotherapy x 3 cycles and follows the same principle of management.

5. For most T3, N2-3; Selected T4a

  a) NACT 3 cycle and follow up.

    - If pt presented with Primary site: CR or PR and stable disease in neck then Chemo/RT can be consider.

    - If Primary site: complete response but with Residual tumor in neck thenNeck dissection is done.

    - If pt presented with Primary site: residual tumor then Salvage surgery +neck dissection as indicated.

    - In case of Primary site: < PR or progression in neck then Salvage surgery + neck dissection as indicated.

6. For T4a, Any N disease

  a) Surgery is the only treatment.

    - For N0 disease Laryngectomy with ipsilateral thyroidectomy unilateral or bilateral selective neck dissection (reconstruction as indicated).

    - For N1disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral comprehensive neck dissection ± contralateral selective neck dissection

     (reconstruction as indicated).

    - For N3 disease Laryngectomy with ipsilateral thyroidectomy, ipsilateral or bilateral comprehensive neck dissection (reconstruction as indicated)          followed by Chemo/RT.

TNM Classification-

(Supraglottis)

T1   - one subsite, normal vocal cord mobility

T2   - more than one adjacent subsite of supraglottis/ region outsidesupraglottis (mucosa of BOT, vallecula, PF med wall) without larynx fixation

T3   - limited to larynx with hemilarynx fixation/ invades postcricoid, pre-epiglottic area, paraglottic space/minor thyroid cart erosion (inner cortex)

T4a - invades thyroid cartilage / extra-laryngeal tissues, (trachea, soft tissues, muscles of tongue, strap muscles, thyroid gland &esophagus, l

T4b - pre-vertebral fascia, mediastinal structures, ICA.

Treatment protocol- (Supraglottic Larynx)

1. For Most T1-2, N0 disease not requiring total laryngectomy

  a) Endoscopic resection ± selective neck dissection

  b) Open partial supraglottic laryngectomy ± selective neck dissection

  c) Definitive RT .

  d) if pt presented with One positive node without other adverse features then Consider RT. if pt presented with adverse features: positive margins          then Further surgery or RT or Consider chemo/RT. if pt presented with Adverse features: extracapsular nodal spread then consider Chemo/RT            and follow up.

2. For T3, N0 T4a, N0 requiring total laryngectomy

  a) Low-volume base-of tongue involvement not penetrating through cartilage planned for CCRT.

    - If pt presented with Primary site: Complete response then only follow up required.

    - If pt presented with Primary site: residual tumor then Salvage surgery +neck dissection as indicated.

  b) Second option is Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral selective neck dissection.

    - If pt presented with N0 or one positive node without adverse features thenRT optional.

    - If pt presented with Adverse features then consider Chemo/RT.

  c) Third option is RT if patient not candidate for concurrent chemo/RT and follow up.\

3. For T4, N0 High volume invasion of base of the tongue, penetration through the cartilage

  a) Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral selective neck dissection can be considered followed by Chemo/RT.

4. For Node positive disease T1-2, N+ and selected T3-4a, N0-1disease

  a) CCRT can be tired.

    - If Primary site: complete response but with Residual tumour in the neck then Neck dissection can be considered.

    - In case of the complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered.

  b) The second option is Partial supraglottic laryngectomy and comprehensive neck dissection(s).

    - if there is No adverse features only Observation required. WithAdverse features give Chemo/RT.

5. For Most T3, N2-N3 1disease requiring total laryngectomy

  a) CCRT can be tired.

    - If Primary site: complete response but with Residual tumor in neck then Neck dissection can be considered.

    - In case of the complete response of neck then Post-treatment evaluation (minimum 12 wks) with PET, Contrast-enhanced CT or MRI and Physical exam is required. If inv are negative only observation is required. And inv are Positive then Neck dissection is considered.

    - If Primary site: residual tumour then Salvage surgery + neck dissection as indicated.

  b) The second option is Laryngectomy, ipsilateral thyroidectomy with comprehensive neck dissection. If no adverse features consider RT. With Adverse           Features give Chemo/RT.

  c) Third option Most T3, N2-3 disease NACT 3 cycle and follow up.

    - If pt presented with Primary site: CR or PR and stable disease in neck then Chemo/RT can be considered.

    - If Primary site: complete response but with Residual tumor in neck then neck dissection is done.

    - If pt presented with Primary site: residual tumor then Salvage surgery +neck dissection as indicated.

    - In case of Primary site: < PR or progression in neck then Salvage surgery + neck dissection as indicated.

6. For T4a, N2-N3 Cartilage destruction Skin involvement Massive invasion of base of tongue then Laryngectomy, ipsilateral thyroidectomy with ipsilateral or bilateral neck dissection followed by Chemo/RT can be considered.

Preventive Measures-

 Don't smoke. Don't drink more than 1 or 2 alcoholic drinks, if any, a day.

 Avoid exposure to known toxins.

 Seek the attention of a doctor in case of change of voice and any other throat problem.

The above guideline has been developed by the Ministry of Health & Family Welfare, Govt. of India with Group Head Coordinator of Development Team Dr J M Hans Ex-HOD Dept. of Otorhinolaryngology Dr.RML Hospital New Delhi