1. DIAGNOSTIC EVALUATION
2. EXAMINATION UNDER ANESTHESIA AND BIOPSY
3. TREATMENT
4. FOLLOW UP
5. BIBLIOGRAPHY

I. DIAGNOSTIC EVALUATION:

Clinical Evaluation:

• Complete history
  
  To include history of previous malignancy in the head and neck (skin cancer, melanoma and non-melanoma, thyroid malignancy, etc.); history of malignancy elsewhere; history of radiation in infancy or childhood; history of a previous skin lesion that has disappeared or has been treated surgically or with radiotherapy; history of any upper aero-digestive tract related symptoms (sore throat, otalgia, hoarseness, dysphagia, hearing loss or epistaxis); previous operations (breast, abdomen, chest, etc.)

• Complete examination of the head and neck
  
  To include visualization of the oral cavity, pharynx, larynx and nasopharynx using indirect mirror or fiberoptic examination; palpation of the oral cavity and base of tongue.
  
  Examination of the nasal cavity, orbits, external ear canal and skin of scalp and neck.
  
  Examination of salivary glands and thyroid.
  
  Examination of nodal drainage Levels I-VI documenting the location (Group or Level I - VI), size, mobility, and relationship of the node(s) to adjacent structures and staging of the cervical lymph nodes.
  
  Establish the status of the patient's dentition.

• Complete physical examination for abnormalities elsewhere: breast, axilla, groins, testicles, abdomen or scars in the head and neck or elsewhere indicating previous surgery.

• FNA biopsy of neck node, if above evaluation does not reveal an obvious primary tumor.

Imaging Studies:

• Chest radiographs, PA and lateral

  Panoramic view (Panorex) of the mandible and/or dental X-rays.

  When necessary to adequately assess the status of the patient's dentition.

• Chest radiographs, PA and lateral

  To rule out (1) A synchronous pulmonary tumor, (2) Acute or chronic pulmonary disease (3) Metastatic tumor. Abnormal findings on chest x-ray or suspicious lesions need further imaging including a chest CT.

• CT or MRI of the head and neck and superior mediastinum as appropriate:

  To assess the presence and extent of nodal metastases, their relationship to the carotid and other adjacent structures, and to evaluate the superior mediastinum. These tests may also be useful to identify abnormalities in the base of tongue and nasopharynx that may suggest the location of the primary tumor, and to rule out parapharyngeal or paratracheal adenopathy.

• MRI of head and neck with and without gadolinium
  
  Including the nasopharynx, skull base, and neck, to attempt to locate the primary tumor within the nasopharynx and, if present, assess invasion of adjacent structures, such as the paraspinal muscles, infratemporal fossa, temporal bone, sphenoid sinus, bone marrow of the clivus, carotid artery, cranial nerves, and intracranial structures.
• Panoramic x-ray (Panorex) of the mandible and/or dental X-rays.
  
  When necessary to adequately assess the status of the patient's dentition in anticipation of radiation therapy.
  
• PET scanning

An increasing body of data is being published suggesting the utility of PET scanning in the identification of occult primary tumor location.

• Barium swallow at the physician's discretion.
  
• If FNA demonstrates adenocarcinoma:
  
  Mammography, CT scan of the abdomen and pelvis and GI imaging or endoscopic studies may be in order depending on the location of the neck node, the patient's age, individual risk factors and the results of pelvic/rectal exams.

• Pre-anesthetic tests (according to institutional guidelines)

• Liver enzymes and function tests (since nodal disease in the neck may be manifestation of metastatic disease from a primary site below the clavicle, in which case, metastatic liver disease may also be present).

• If FNA shows poorly differentiated carcinoma, anti EBV antibodies may be useful in treatment decisions and follow-up.

• Radiation Therapy
  
  In anticipation of possible radiation of subsequently detected primary lesion, or possible pre or postoperative radiation.

• Dental:
  
  To assess the status of the teeth and make recommendations considering that radiation therapy may be indicated. The evaluating dentist should be versed in the effects of radiotherapy on dentition. This evaluation should be done with knowledge of the treatment portals planned for the radiotherapy 

• Internal Medicine, Cardiology, Anesthesiology:
  
  As needed to evaluate coexisting conditions that may preclude or increase the risk of general anesthesia

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To attempt to find the primary tumor or tumors, it includes:

• Inspection and palpation of the oral cavity, base of tongue, oropharynx and nasopharynx.

• Direct laryngoscopy and pharyngoscopy.

• Flexible or rigid esophagogastroscopy.

• Flexible or rigid bronchoscopy.

• Biopsy of any abnormal mucosa seen or palpated. If there are no visible or palpable abnormalities, and the FNA suggests squamous cell carcinoma or poorly differentiated malignancy, biopsy of sites of suspected primary depending on the position of the involved nodes. This usually includes biopsies of the nasopharynx, base of the tongue and pyriform sinus. It may include ipsilateral or bilateral tonsillectomy if the neck node is located in Level II - III or V. 

• Repeat needle aspiration biopsy or Tru-cut biopsy: If the original needle aspiration was inadequate or not diagnostic.

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   If a primary tumor is not found:

Poorly differentiated squamous cell carcinoma on FNA or Tru-cut biopsy:

• Treatment consists of radiotherapy to the neck and Waldeyer's ring including the nasopharynx. Neck dissection is reserved for residual disease. Consideration may be given to sparing the nasopharynx, when Anti EBV antibodies (IgA antibodies to viral capsid antigen and early antigen) are not elevated.

Differentiated SCCa on FNA or Tru-cut biopsy:

• Neck dissection removing lymph node Levels I-V depending upon the location of the node(s) involved and preserving structures such as the spinal accessory nerve if not involved by tumor.
  
  Only one/two nodes positive, no extracapsular spread, consideration may be given to treatment with surgery alone.
  
  Multiple nodes positive or extracapsular spread: Postoperative radiation.

Adenocarcinoma on FNA or Tru-cut biopsy:

• Node located at Level IV/supraclavicular region: Excisional biopsy of node. Pathologist should make every effort to identify possible source to guide further diagnostic evaluation.

• Node located at Level II: Excisional biopsy of node. Pathologist should make every effort to identify possible source to guide further diagnostic evaluation. If no source identified clinically or pathologically, neck dissection including the submandibular gland. Intraoperative palpation and preoperative imaging of the parotid will determine whether or not the parotid is should be removed.

Lymphoid cells on FNA or Tru-cut:

• If pathologist deems FNA sufficient to make definitive diagnosis of lymphoma, appropriate lymphoma work-up.

• If FNA equivocal, excisional nodal biopsy with frozen section examination and formal pathologic examination post-operatively. If compatible with lymphoma, appropriate evaluation as per pathologist and medical oncologist. If frozen section is suggestive of a granulomatous/infectious process, appropriate cultures are obtained.

Surgery:

For patients treated with neck dissection, surgical treatment includes:

• Insertion of suction drain(s).

• Orientation and mapping of neck dissection specimen by the surgeon for the pathologist with clinicopathological correlation stressing need to determine presence/absence of extracapsular spread.

Postoperative care includes:

• Hospitalization for 1 to 5 days

• Hospitalization for 1 to 5 days

• Low pressure suction to drains.

• Removal of drains when output less than 30-50 ml per 24 hours.

• Suture removal from neck wound in 5-10 days.

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IV.FOLLOW UP:

Follow-up appointments are scheduled on an individual basis determined by the risk of recurrence, to survey for the appearance of the primary tumor, development of second primary tumors, to deal with morbidity from treatment (i.e. speech and swallowing problems as well as wound care), to provide social and psychological support, and to deal with comorbidity not directly related to the cancer itself.

• Periodic examinations by the head and neck surgeon may be necessary during radiation therapy in patients experiencing difficulty with nutritional intake, airway or pain control.

• Periodic examinations by the radiation oncologist and a dentist in patients that received radiation therapy

• After all treatment is completed a general formula which is modified according to the individual patient's characteristics is:
  
  

  1st year post treatment:	1-2 months
  2nd year post treatment:	2-4 months
  3rd year post treatment:	3- 6 months
  4th and 5th years:	4- 6 months
  After 5 years:	Every 12 months

• Chest radiographs, yearly.

• Thyroid function tests should be monitored annually if the patient received radiation to the lower neck. These studies should be repeated according to clinical findings on follow-up examinations.

• In the nasopharynx was irradiated, the physician should remain aware of the possibility of pituitary dysfunction. In the presence of any suggestive symptoms an appropriate evaluation should be initiated.

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Lee NK, Byers RM, Abbruzzese JL, Wolf P. Metastatic Adenocarcinoma to the Neck From an Unknown Primary Source. Am J S, 162: 306-309, 1991.

Jesse RH, Perez CA, Fletcher, CH, Cervical Lymph Node Metastasis: Unknown Primary Cancer, Cancer, 31: 854-859, 1973.

Lee DJ, Rostock RA, Harris A, Kashima H, Johns M. Clinical Evaluation of Patients with Metastatic Squamous Carcinoma of the Neck with Occult Primary Tumours. South Med Jour 79, No. 8: 980-983, 1986.

Leipzig B, Winter ML, Hokanson JA. Cervical Nodal Metastases of Unknown Origin. Laryngoscope 91: 593-598, 1981.

Mohit-Tabatabai MA, Dasmahapatra KS, Rush BF, Ohanian M. Management of Squamous Cell Carcinoma of Unknown Origin in Cervical Lymph Nodes. Am Surg 52: 152-154, 1986.

Wang RC, Goepfert H, Barbar AE, Wolf P. Unknown Primary Squamous Cell Carcinoma Metastatic to the Neck. Arch Otol Hd Neck Surg 116: 1388-1393, 1990.

Young JEM, The Unknown Primary: Operative Evaluation. Hd Neck Cancer 1:286-288, 1985.