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Carcinoma of unknown primary origin (CUPO) is estimated to represent between 3% and 5% of all head and neck cancer presentations, and can pose a challenge in assessment when diagnosed.1 Metastatic carcinoma from an occult upper aerodigestive tract (UADT) source carries a different prognosis than cancers metastatic to the neck from an infraclavicular source. When patients have a primary site identified, they benefit from the ability to offer site-specific therapy that can reduce the morbidity of treatment. Identification of a primary site also improves the capacity for prognostic counseling while facilitating the long-term assessment for recurrence. With advances in diagnostic imaging, development of new surgical techniques, and the expansion of immunohistochemical (IHC) and gene expression studies for tissue specimens, the assessment of CUPO patients continues to evolve.

The majority of patients initially considered to have a CUPO, in particular when seen with isolated lymphadenopathy of level II/III of the neck, are ultimately diagnosed with a squamous cell carcinoma of UADT.1 Additional sources for CUPO in the head and neck (beyond mucosal-based UADT sources) include skin cancers, lung, breast, ovary, testicular, esophageal/gastric, colon, salivary gland, and thyroid cancer. Metastases to the lower neck (level IV/low level V) are typically from an infraclavicular source and are frequently adenocarcinomas. Greater than 50% of CUPO primary sites, undetected by initial routine clinical examination, are identified after tissue biopsy and radiologic examination.1

Overall, CUPO presentations in the head and neck can be broadly categorized into two groups based on prognosis:

  • “Unfavorable prognosis”—metastatic adenocarcinoma to the bone, brain, and/or viscera

  • “Favorable prognosis”—germ-cell tumors, adenocarcinoma, or squamous cell carcinoma of the head and neck metastatic to a lymph node

For patients diagnosed with CUPO that fall within the first category, median survival ranges between 7 and 11 months. For individuals in latter group, prognosis typically aligns with the biologic behavior of the tumor at the associated primary site. This chapter will focus on them.1


Once a fine needle aspiration (FNA) or open biopsy of a neck mass establishes the diagnosis of a malignancy without an identified primary site, a structured CUPO evaluation should occur. The pathology from the lymph node can provide guidance for the subsequent assessment. Undifferentiated carcinoma, squamous cell carcinoma, and adenocarcinoma can be viewed differently for potential primary sites; however the assessment approach is similar for all of these pathologies. IHC studies on FNA specimens from the neck can also provide guidance for endoscopy and biopsy, but are not a substitute for a systematic assessment.

Individuals with a history of a prior cancer (e.g., lung, breast, colon, stomach, hematologic, cutaneous) should undergo assessments that include an evaluation for possible recurrence and distant spread of these cancers to the head and neck. The patient history should take into account any unique risk factors. Patients with a significant ...

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