Unknown Primary Neck Disease: Considerations and Workup

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Unknown Primary Neck Disease: Considerations and Workup

Head and Neck Surgery
Author Credentials 

Bharat B. Yarlagadda, MD
Assistant Professor
Department of Otolaryngology – Head and Neck Surgery
Boston University School of Medicine, Boston, MA
Senior Surgeon
Division of Otolaryngology – Head and Neck Surgery
Lahey Hospital and Medical Center, Burlington, MA 01805
Email Bharat.yarlagadda@lahey.org

Module Summary

Head and neck cancer of unknown primary is a relatively uncommon entity. A patient will generally present with a persistent painless neck mass. Histopathologic diagnosis of the mass is needed to proceed, and needle aspiration is the preferred modality for this in order to avoid disruption of the cervical tissue planes. Efforts to identify a potential primary tumor are paramount and include a thorough physical examination, nasolaryngoscopy, anatomic and functional imaging. Examination under anesthesia with directed biopsies, including diagnostic palatine and lingual tonsillectomy can increase the yield of localization efforts. If the primary tumor remains unknown, treatment choices are driven by the extent of nodal disease. Early stage disease can be treated with surgery or radiation alone. Surgery followed by radiation or upfront chemoradiation is considered for more advanced nodal disease. Pan-mucosal radiation had traditionally been considered, although long term mucosal emergence rates are found to be relatively low. Tailored radiations fields are oncologically sound in certain circumstances depending on extent and distribution of nodal disease, and associations with HPV or EBV. 

Module Learning Objectives 
  1. Be familiar with the presenting signs and symptoms of head and neck cancer of an unknown primary. 
  2. Demonstrate the ability to work-up and stage a patient with head and neck cancer of an unknown primary site including clinical evaluation and imaging studies. 
  3. Describe and utilize various modalities for attempts at localizing the primary tumor for a patient with head and neck cancer of an unknown primary site. 
  4. Determine the treatment options, surgical and non-surgical, available to a patient with head and neck cancer with an unknown primary site.
  5. Recognize and manage complications that can arise from treatment of head and neck cancer with an unknown primary site.

Embryology

Learning Objectives 

Be familiar with the embryogenesis of relevant structures that can be involved in the presentation of a patient with head and neck cancer of unknown primary.

  1. Understand the pharyngeal arch concept. 
  2. Recognize that the nasopharyngeal mucosa contains both stratified squamous epithelium and pseudostratified columnar epithelium, and can be the source of occult nasopharyngeal cancer.  
References 
  1. Graham A. Development of the pharyngeal arches. Am J Med Genet A. 2003; 119A(3):251-6.

Anatomy

Learning Objectives 

Understand how one can direct the workup and ability to localize an unknown head and neck cancer based on which levels of the neck are involved with pathologic lymphadenopathy. 

  1. Describe pharyngeal and laryngeal subsites. 
  2. Describe the levels of the neck, as divided by the lymphatic basins. 
  3. Understand the basis of which head and neck mucosal subsites are of interest based on which levels of the neck are involved with pathologic lymphadenopathy.
  4. Recognize that supraclavicular or low cervical nodal involvement may indicate an infraclavicular primary tumor site. 
References 
  1. Frank H. Netter, MD. Atlas of Human Anatomy. 6th Edition. Elsevier. 2014. 
  2. Jatin Shah’s Head and Surgery and Oncology. Chapter 11. Cervical lymph nodes. Mosby Elsevier. 2012.

Pathogenesis

Learning Objectives 

Identify risk factors and the relevant patient populations for the development of head and neck cancer of unknown primary site. 

  1. Traditional carcinogenesis including alcohol and tobacco.
  2. Patients with occult human papillomavirus (HPV) related tumors tend to be younger, male, and non smokers. 
  3. Dermatologic neoplasm pathogenetic risk factors such as skin type and sun exposure may indicate the presence of occult skin cancer.
  4. Genetic and ethnic risk factors for the development of occult nasopharyngeal cancer. 
  5. Pathogenetic risk factors for infraclavicular malignancy that may involve the cervical lymph nodes such as lung, prostate, or GI cancers.
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  2. Jatin Shah’s Head and Surgery and Oncology. Chapter 11. Cervical lymph nodes. Mosby Elsevier. 2012.

Basic Science

Learning Objectives 

Associate specific immunohistochemical and pathologic findings noted on biopsy of cervical nodal disease with possible primary tumor sites. 

  1. EBV staining as an indicator of an occult nasopharyngeal primary tumor.
  2. HPV PCR or p16 staining as an indicator of an occult oropharyngeal primary tumor, although this can be seen in lung and skin cancer as well. 
References 
  1. Motz K, et al. Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus. JAMA Otolaryngol Head Neck Surg. 2016;142:223-228.
  2. Jannapureddy S, et al. Assessing for primary oropharyngeal or nasopharyngeal squamous cell carcinoma from fine needle aspiration of cervical lymph node metastases. Diagn Cytopathol. 2010;38:795.

Incidence

Learning Objectives 

Know the incidence of head and neck cancer of unknown primary.

  1. Unknown primary incidence represents 1-5% of all head and neck cancer cases.
  2. True incidence is lower than initial presentation due to primary tumors discovered during workup. 
References 
  1. Lefebvre JL, et al. Cervical lymph nodes from an unknown primary tumor in 190 patients. Am J Surg. 1990;160:443–446.
  2. Grau C, et al. Cervical lymph node metastases from unknown primary tumours: Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol. 2000;55:121–129.

Genetics

Learning Objectives 

Know the genetic basis of carcinogenesis as it applies to head and neck cancer of unknown primary.

  1. Carcinogen exposure and p53 mutations.
  2. HPV mediated disease with unknown primary tumor suggesting an occult oropharyngeal primary site, though HPV is noted in nasopharyngeal carcinoma as well.
  3. EBV associated disease with unknown primary tumor suggesting an occult nasopharyngeal primary site.
References 
  1. Somers KD, Merrick MA, Lopez ME, et al. Frequent p53 mutations in head and neck cancer. Cancer Res. 1992;52:5997-6000.
  2. El-Mofty SK, Zhang MQ, Davila RM. Squamous Cell Carcinoma in Cervical Lymph Nodes: A Reliable Predictor of the Site of an Occult Head and Neck Primary Carcinoma. Head Neck Pathol. 2008;2(3):163-168.

Patient Evaluation

Learning Objectives 

Recognize the presenting signs and symptoms of head and neck cancer of unknown primary site and describe the initial workup.

  1. Presenting symptoms include enlarging neck mass, constitutional complaints including weight loss, and cranial nerve deficits from regionally advanced nodal disease.  
  2. Functional status, overall health, frailty, and nutritional status.  
  3. Focused physical examination including cervical nodal palpation and thorough examination of the aerodigestive mucosa. 
  4. Fiberoptic scope examination to identify and characterize a possible mucosal tumor site. 
  5. Confirmation of lymph node pathology.
    1. Fine needle aspiration as first line pathologic confirmation. Repeat if necessary.
    2. Excisional biopsy, with preparation for completion neck dissection if needed, and avoidance of incisional biopsy.
  6. Evaluation for primary tumor.
    1. Physical examination and fiberoptic scope
    2. Anatomic imaging i.e. CT scan – can identify approximately 25% of primary tumors 
    3. Functional imaging i.e. PET scan – can identify an additional 25% of occult primary tumors
    4. Surgical endoscopy and biopsies – see section under surgical therapy
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  2. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Measurement of Functional Status

Learning Objectives 

Apply validated functional status parameters to patients undergoing evaluation for known or suspected head and neck cancer of unknown primary site. 

  1. Validated scales for oncology patients include ECOG-ACRIN performance status, Karnofsky scale, and the WHO/Zubrod score. 
  2. Frailty indices especially for older patients.
  3. Swallowing evaluation with imaging studies such as modified barium swallow when appropriate. 
References 
  1. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Imaging

Learning Objectives 

Determine the appropriateness of various imaging modalities in the evaluation of head and neck cancer of unknown primary site.

  1. CT scan neck with contrast – evaluation of the nodal disease and possible identification of a primary tumor site.
  2. MRI neck with contrast – assessment of prevertebral space invasion, vascular invasion with advanced regional disease.
  3. PET scan imaging – regional and distant metastatic staging, and evaluation for a primary tumor site.
  4. Barium swallow and/or modified barium – functional evaluation of tumor related dysphagia and potential baseline before treatment. 
References 
  1. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Pathology

Learning Objectives 

Describe the common histopathologies of head and neck cancer of unknown primary and known patterns of presentation.

  1. Histopathology
    1. Squamous cell carcinoma with possible HPV association (primary pathology)
    2. Nasopharyngeal carcinoma
    3. Adenocarcinoma and additional pathologies noted with primary tumors outside of the head and neck
  2. Patterns of nodal involvement
    1. Level II neck mass suggests oropharyngeal primary
    2. Isolated level III neck mass suggests laryngeal or hypopharyngeal primary
    3. Low neck mass suggests primary tumor below the clavicles. 
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.

Treatment

Learning Objectives 

Formulate a treatment plan for patients with head and neck cancer of unknown primary after thorough evaluation for a primary tumor has been performed. 

  1. Treatment recommendations are based on extent of the nodal disease
  2. Patients with TxN1 disease may be offered single modality therapy, either neck dissection or radiation alone
  3. Patients with intermediate stage disease, TxN2a or TxN2b, may be offered dual modality therapy. 
    1. Upfront neck dissection with adjuvant radiation
    2. Upfront chemoradiation with neck dissection for salvage if persistent disease
  4. Patients with advanced disease or known extra-capsular nodal extension may be offered upfront chemoradiation with neck dissection for salvage if persistent disease
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  2. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Medical Therapies

Learning Objectives 

Know the role of radiation therapy for treatment and the roles platinum based chemotherapy and immunotherapy in treatment and palliation. 

  1. Bimodality chemoradiation is offered for advanced stages or those patients with radiographically evident extracapsular nodal extension of disease
  2. Radiation for tumors with unknown primary
    1. Bilateral neck irradiation is common
    2. Pan-mucosal radiation has been traditionally offered
    3. Contemporary regimens may avoid radiating sites of lower suspicion
  3. Platinum based chemotherapy
    1. Radiation potentiation in concurrent regimens
    2. Single agent for palliation of recurrent and untreatable disease, or with distant metastatic disease
  4. Immunotherapy for palliation of recurrent and untreatable disease, or with distant metastatic disease
References 
  1. 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.
  2. Ling DC, Bakkenist CJ, Ferric RL, et al. Role of immunotherapy in head and neck cancer. Semin Radiat Oncol. 2018 Jan;28(1):12-16. 
  3. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  4. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Pharmacology

Learning Objectives 

Understand basic metabolic principles and limitations for the administration of platinum based agents and immunotherapy.

  1. Platinum based chemotherapy
    1. Dosed based on body surface area, requiring adequate renal function
    2. Weekly or Every-3-week dosing for radiation concurrent chemoradiation regimens
  2. Immunotherapy dosing
References 
  1. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937-1944.
  2. 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.
  3. Ling DC, Bakkenist CJ, Ferric RL, et al. Role of immunotherapy in head and neck cancer. Semin Radiat Oncol. 2018 Jan;28(1):12-16. 

Surgical Therapies

Learning Objectives 

Be familiar with the role of, and technical details pertaining to, surgery for evaluation of a potential primary tumor, and performance of neck dissection for management of nodal disease.  

  1. Evaluation under anesthesia
    1. Direct laryngoscopy with pan-mucosal inspection and attention to areas of radiographic suspicion
    2. Directed biopsies of the nasopharynx, base of tongue, tonsillar lesions, pyriform sinuses
    3. Performance of bilateral palatine tonsillectomy
    4. Performance of lingual tonsillectomy with trans oral robotic approach to increase diagnostic yield
    5. Biopsies are generally done after performance of a PET scan to avoid false positive imaging results
  2. Indications for neck dissection
    1. Upfront therapy for early or intermediate stage nodal disease with possible adjuvant radiation
    2. Salvage neck dissection for patients who have undergone upfront radiation or chemoradiation and demonstrate persistent or recurrent nodal disease
  3. Performance of neck dissection generally addresses levels II-IV of the ipsilateral neck
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  2. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx
  3. Jatin Shah’s Head and Surgery and Oncology. Chapter 11. Cervical lymph nodes. Mosby Elsevier. 2012.

Rehabilitation

Learning Objectives 

Formulate a plan and recommendations for rehabilitation for patients who are undergoing or have completed therapy for head and neck cancer of unknown primary cancer.

  1. Dysphagia management with SLP referral 
  2. Nutritional counseling and feeding tube placement when appropriate
References 
  1. Rosenthal DI, et al. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol. 2006;24(17):2636-43.

Staging

Learning Objectives 

Know the American Joint Committee on Cancer staging system for cervical nodal metastases. 

References 
  1. Amin MB, Edge SB. AJCC cancer staging manual. Chicago: American Joint Committee on Cancer; 2017.
  2. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Case Studies

  1. A 55 year old male with no history of alcohol and tobacco use presents with a painless right level II neck mass. 
    1. Clinical examination and flexible fiberoptic examination do not indicate a primary tumor site. 
    2. Tissue diagnosis with fine needle aspiration of the neck mass is indicated. This indicates squamous cell carcinoma, p16 testing is positive. 
    3. Recommended imaging includes a CT scan of the neck, and if there is no evidence of a primary tumor of the head and neck, may proceed with PET scan for staging. There is one radiographically abnormal lymph node of the right neck. 
    4. If there is no radiographically evident primary tumor, the patient is offered examination under anesthesia, direct laryngoscopy, and biopsies of the nasopharynx, base of tongue, and hypopharynx. He undergoes bilateral tonsillectomy
    5. All specimens are negative for cancer. He is offered lingual tonsillectomy for further evaluation of a primary site – he declines this and elects to proceed with upfront right neck dissection. The final pathology indicates one involved lymph node, no extracapsular spread. 
    6. Given a stage of TxN1, adjuvant radiation is not recommended. He proceeds with surveillance per NCCN guidelines. 
  2. A 64 year old male with long term smoking and alcohol use presents with a painless left neck mass. 
    1. There is no clinically evident primary tumor. 
    2. Fine needle aspiration of the left neck indicates squamous cell carcinoma, p16 testing is negative.
    3. CT and PET scan do not indicate a primary tumor. There is level II and III confluent matted left cervical lymphadenopathy with radiographic extranodal extension. 
    4. Examination under anesthesia, directed biopsies, palatine and lingual tonsillectomy do not reveal a primary cancer.
    5. Given the radiographic extracapsular extension of the nodal disease, he proceed with upfront chemoradiation. 
    6. There is persistent disease on PET scan performed 3 months after completion of chemoradiation, and he proceeds with salvage left neck dissection. 

Complications

Learning Objectives 

Know and recognize the complications of treatment for hypopharyngeal cancer.

  1. Complications of surgical therapy
    1. Complications of lingual and palatine tonsillectomy – bleeding, pain, dysphagia
    2. Complication of neck dissection – cranial nerve injury, bleeding, infection, wound breakdown, chyle leak
  2. Acute toxicities of non surgical treatment
    1. Radiation related – ex/ dysphagia, mucositis
    2. Chemotherapy related – ex/ mucositis, myelosuppression, alopecia, renal failure
  3. Long term toxicities of non surgical treatment – ex/ dysphagia, dysgeusia, strictures and stenoses, osteonecrosis and soft tissue necrosis
  4. Survivorship concerns
References 
  1. Jatin Shah’s Head and Surgery and Oncology. Chapter 11 Cervical Lymph Nodes. Mosby Elsevier. 2012.
  2. Jatin Shah’s Head and Surgery and Oncology. Chapter 19. Radiation Therapy. Mosby Elsevier. 2012.
  3. Jatin Shah’s Head and Surgery and Oncology. Chapter 20. Chemotherapy. Mosby Elsevier. 2012.

Review

Review Questions 
  1. What are the levels of the neck and the corresponding potential sites of primary tumors draining to these levels?
  2. What is the initial clinical and radiographic diagnostic approach to a patient with pathologic cervical lymphadenopathy and no apparent primary tumor?
  3. What studies can be obtained of cytologic nodal aspirate to aid in localizing a primary tumor?
  4. What are the diagnostic surgical procedures that can be performed to localize a primary tumor?
  5. If no primary tumor is found, what are the treatment options for early stage nodal disease? Advanced stages?
References 
  1. Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328-37.
  2. NCCN Clinical Practice Guidelines in Oncology – Head and Neck Cancer. Version 1.2018. https://www.nccn.org/professionals/physician_gls/default.aspx
  3. Jatin Shah’s Head and Surgery and Oncology. Chapter 11. Cervical lymph nodes. Mosby Elsevier. 2012.
Resources 

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