Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

TNM Definitions

Untreated Metastatic Squamous Neck Cancer With Occult Primary

Current Clinical Trials

Recurrent Metastatic Squamous Neck Cancer With Occult Primary

Current Clinical Trials

Get More Information From NCI
Changes to This Summary (05/22/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of metastatic squamous neck cancer with occult primary. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Diagnosis and pathology.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

The diagnosis of an occult primary tumor is made only if no primary tumor is detected after careful search and does not appear during therapy. Patients with cervical lymph node metastases histologically related to a previously treated primary tumor and patients with lymphomas and adenocarcinoma are excluded. If the biopsy is an undifferentiated carcinoma (in particular, a lymphoepithelioma), the most probable primary site is in Waldeyer ring; for example, the nasopharynx, base of tongue, or tonsil. Most epidermoid carcinomas metastatic to lymph nodes of the upper half of the neck will originate from a head and neck primary site. Squamous carcinomas metastatic to the lower neck may represent a primary site in the head and neck, esophagus, lung, or genitourinary tract. A search for primaries in these areas must be undertaken before assuming that the primary is occult. Primary tumors arising in the nasopharynx may be secondary to Epstein-Barr Virus (EBV) infection, and EBV genomic material may be detectable in cervical nodal tissue after DNA amplification using the polymerase chain reaction. Such a finding should lead to an in-depth search for a primary in the nasopharynx.[1]

The extent of investigation and type of treatment must be individualized depending on the patient's age and wishes, and on the site, histology, and extent of metastatic lymph node involvement of the tumor. When a patient qualifies as having squamous carcinoma of the neck with occult primary, he or she should be checked for other obvious metastatic disease, such as lung, liver, or bone, since this would affect the locoregional approach to therapy.[2]

Three-year disease-free survival rates following surgery and/or radiation therapy for unknown squamous primaries range from 40% to 50% in patients with N1 disease to 38% and 26% for patients with N2 and N3 disease, respectively. Patients who later develop primary lesions have poor survival rates compared to those patients whose primaries remain occult, for example 30% versus 60%.

Patients with neck metastases from an undetectable primary should be given the benefit of definitive treatment. Despite the ominous situation of an undiscovered primary, a significant number of patients do achieve cure by both surgical and radiotherapeutic approaches. In some patients, long-term repeat examinations will eventually disclose the primary tumor, and at a treatable stage.

References

1. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992.  [PUBMED Abstract]
   
   
2. de Braud F, al-Sarraf M: Diagnosis and management of squamous cell carcinoma of unknown primary tumor site of the neck. Semin Oncol 20 (3): 273-8, 1993.  [PUBMED Abstract]
   
   

Cellular Classification

This section helps lead the clinician and pathologist through a differential diagnosis for an unknown primary presenting with cervical node metastases. The therapeutic section, however, relates only to squamous carcinoma and assumes that the primary physician has worked with the pathologist as described below to eliminate other possibilities that would require alternative therapies.

The pathologist plays a central role in evaluating an occult primary tumor. A thorough evaluation of an adequate specimen through histologic or immunohistochemical techniques, and, when appropriate, electron microscopy (EM) provides guidance for the clinical evaluation that ensues. A critical interaction should exist between the pathologist, oncologist, and primary physician.

The complexity of the pathologic evaluation tends to be inversely related to the degree of differentiation of the tumor. For instance, for well or moderately differentiated tumors, the pathologic diagnosis of an epithelial cancer is often readily apparent, in contrast to lymphoma, sarcoma, melanoma, or a germ cell tumor. Commonly used stains such as mucicarmine or diastase-sensitive Periodic Acid Schiff (PAS) can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin.

If the clinician is faced with a male patient younger than 50 years with a poorly differentiated tumor, serum levels of bHCG and AFP should be obtained and specimens should be evaluated with immunohistochemical stains for bHCG and AFP. Certain of these tumors respond to platinum-based combination chemotherapy in a manner similar to extragonadal germ cell malignancies, and this group of patients should be so treated unless other alternative diagnoses are made.[1]

Special studies can help in differentiating more poorly differentiated tumors. Often, a generic distinction is important between a poorly differentiated tumor of epithelial, hematopoietic, neuroendocrine, or neuroectodermal origin (i.e., melanoma).

• Immunohistochemical:

  Immunohistochemical studies can be important in making these broad distinctions, in particular, studies that evaluate staining for keratins, leukocyte common antigen (LCA), and S-100, a neuroectodermal antigen expressed in melanomas.[2]

• Polymerase chain reaction:

  In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma.[3]

  Acinar spaces and microacini are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas. But these features are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, and EM evaluation would be of little value. The use of EM may aid in distinguishing a primary diagnosis not obtained by light microscopy approximately 10% of the time.[4-6]

References

1. Hainsworth JD, Wright EP, Gray GF Jr, et al.: Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy. J Clin Oncol 5 (8): 1275-80, 1987.  [PUBMED Abstract]
   
   
2. Battifora H: Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol 1 (4): 251-71, 1984.  [PUBMED Abstract]
   
   
3. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992.  [PUBMED Abstract]
   
   
4. Hanna W, Kahn HJ: The ultrastructure of metastatic adenocarcinoma in serous fluids. An aid in identification of the primary site of the neoplasm. Acta Cytol 29 (3): 202-10, 1985 May-Jun.  [PUBMED Abstract]
   
   
5. Herrera GA, Reimann BE: Electron microscopy in determining origin of metastatic adenocarcinomas. South Med J 77 (12): 1557-66, 1984.  [PUBMED Abstract]
   
   
6. Mackay B, Ordonez NG: The role of the pathologist in the evaluation of poorly differentiated tumors. Semin Oncol 9 (4): 396-415, 1982.  [PUBMED Abstract]
   
   

Stage Information

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

There is no tumor classification (T) for occult primary cancer metastatic to neck lymph nodes.

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*
• N2: 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, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm 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*

* [Note: A designation of "U" or "L" may be used to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L).]

In clinical evaluation, the actual size of the nodal mass should be measured and allowance should be made for intervening soft tissues. Most masses more than 3 cm in diameter are not single nodes but are confluent nodes or tumor in soft tissues of the neck. There are three stages of clinically positive nodes: N1, N2, and N3. The use of subgroups a, b, and c is not required but recommended. Midline nodes are considered homolateral nodes.

Distant metastasis (M)

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

There is no generally accepted Roman numeral staging system for this disease.

Untreated

Untreated metastatic squamous neck cancer with occult primary means that a patient is newly diagnosed and has had no prior treatment except supportive care.

References

1. Head and neck sites. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 17-88. 
   
   

Untreated Metastatic Squamous Neck Cancer With Occult Primary

Patients with neck nodes from a presumed unknown primary tumor should be evaluated as follows:

1. Surgical biopsy or excision to establish a histologic diagnosis, but only after an aerodigestive tract primary has been carefully ruled out as in the following procedures:
   • Direct nasopharyngoscopy, laryngoscopy, bronchoscopy, and esophagoscopy, with biopsy of any suspicious area.
     • If no suspicious lesions are found, random biopsies of the nasopharynx, base of tongue, tonsil, and pyriform sinus on the side of the lesion should be performed.
     • If the tonsil is not present, biopsy of the tonsillar fossa should be performed.
     • Sinus x-rays are probably indicated; if an abnormality is found, it should be biopsied as well.
2. Selected other studies if indicated. In the detection of head and neck tumors and in the distinction of lymph nodes from blood vessels, magnetic resonance imaging offers an advantage over computed tomography scans and should be considered in the initial evaluation of the patient with metastatic squamous cell cancer in cervical lymph nodes.[1] Positron emission tomography may be helpful in determining the primary site.[2]

   Patients should be managed with either a full course of radiation therapy or adequate neck dissection, when possible. In cases of massive homolateral adenopathy that is fixed or bilateral nodes, radiation therapy should be administered first. The radiation fields should also include the nasopharynx, base of tongue, and pyriform sinuses. If radiation therapy is the primary mode of treatment and the neck mass persists upon completion of radiation therapy, cervical lymph node dissection should be performed. Patients with metastatic carcinoma in the supraclavicular region are best managed with a full course of radiation therapy followed by surgical dissection if palpable tumor persists. Careful continued follow-up of these patients is of utmost importance. Depending on the likely site of origin and histology, chemotherapy appropriate to the most treatable site may be indicated.

   Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who received external-beam radiation therapy to the entire thyroid gland or the pituitary gland. Thyroid function testing of patients should be considered prior to therapy and as part of post-treatment follow-up.[3,4]

Standard treatment options:

1. Radical neck dissection.
2. Radiation therapy.[5,6]
3. Combined surgery and radiation therapy.[7]

Treatment options under clinical evaluation:

1. Chemotherapy followed by radiation therapy.[8]
2. Simultaneous chemotherapy and hyperfractionated radiation therapy.[9]
3. Clinical trials for advanced tumors should be considered.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated metastatic squamous neck cancer with occult primary ⁵. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁶.

References

1. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988.  [PUBMED Abstract]
   
   
2. Rege S, Maass A, Chaiken L, et al.: Use of positron emission tomography with fluorodeoxyglucose in patients with extracranial head and neck cancers. Cancer 73 (12): 3047-58, 1994.  [PUBMED Abstract]
   
   
3. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995.  [PUBMED Abstract]
   
   
4. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995.  [PUBMED Abstract]
   
   
5. Carlson LS, Fletcher GH, Oswald MJ: Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary. Int J Radiat Oncol Biol Phys 12 (12): 2101-10, 1986.  [PUBMED Abstract]
   
   
6. Mack Y, Parsons JT, Mendenhall WM, et al.: Squamous cell carcinoma of the head and neck: management after excisional biopsy of a solitary metastatic neck node. Int J Radiat Oncol Biol Phys 25 (4): 619-22, 1993.  [PUBMED Abstract]
   
   
7. Maulard C, Housset M, Brunel P, et al.: Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 102 (8): 884-90, 1992.  [PUBMED Abstract]
   
   
8. Thyss A, Schneider M, Santini J, et al.: Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck. Br J Cancer 54 (5): 755-60, 1986.  [PUBMED Abstract]
   
   
9. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992.  [PUBMED Abstract]
   
   

Recurrent Metastatic Squamous Neck Cancer With Occult Primary

The prognosis for most treated cancer patients with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, site of recurrence, as well as individual patient considerations. Treatments that are under clinical evaluation are appropriate and should be considered when possible.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent metastatic squamous neck cancer with occult primary ⁷. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁶.

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® ⁸ online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office

Suite 3036A

6116 Executive Boulevard, MSC8322

Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site ⁹ provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator ¹⁰. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Changes to This Summary (05/22/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ¹¹.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ¹²

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ¹³

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ¹⁴

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ¹⁵

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ¹⁶

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ¹⁷

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ¹⁸

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).