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Metastatic carcinoma to cervical lymph nodes presenting as an unknown primary is quite common. In most cases, the primary site is ultimately identified. Carcinomas that remain of unknown primary after a thorough search are uncommon. This review will focus on those cases that initially present as unknown primaries, since this is the setting in which pathologists first encounter these cases and in which they play an important role in guiding patient management. Most are squamous cell carcinomas, the majority of which are human papillomavirus (HPV)-related and originate in the palatine tonsils and base of tongue. HPV-related oropharyngeal squamous cell carcinomas are increasing in incidence and have unique clinical and pathologic features that make them particularly likely to present as an unknown primary. Understanding these features has led to improved detection of the primary tumors. Further, even when the primary tumor is not found, prognosis is very dependent on characterization of the tumor HPV status. Papillary thyroid carcinomas may also initially present without a known or clinically detectable primary, either as a neck mass or incidentally in a neck dissection performed for another indication. The latter is a very indolent disease. Finally, primary salivary gland carcinomas may mimic an unknown primary and need to be distinguished from cutaneous metastases to the parotid gland, which may present without a recognized skin tumor. Here, we review the clinical and pathologic features of these entities and provide a systematic approach to their diagnosis.

Approach to Metastatic Carcinoma of Unknown Primary in the Head and Neck: Squamous Cell Carcinoma and Beyond