INTRODUCTION — Cancer of unknown primary site is a relatively common clinical entity, accounting for approximately 2 percent of all invasive cancers [1]. Within this category, tumors from many primary sites with varying biology are represented. Squamous cell carcinomas (SCCs) comprise approximately 5 percent of cancers of unknown primary site. (See "Overview of the classification and management of cancers of unknown primary site".)
Effective treatment is available for some patients with SCC of unknown primary site who fit certain clinical syndromes, particularly those with involvement of the cervical or inguinal lymph nodes. For this reason, appropriate evaluation of these patients is essential prior to embarking on treatment.
●The cervical lymph nodes are the most common metastatic sites for SCCs of unknown primary site. Patients with tumor involving the upper or mid-level cervical nodes are likely to have a primary cancer of the head and neck. By contrast, a lung primary should be suspected in those with involvement of the lower cervical or supraclavicular lymph nodes.
●SCCs of unknown primary site involving the inguinal lymph nodes usually arise from a primary anogenital malignancy. Some of these patients may be curable with locoregional therapy directed against their primary tumor.
The diagnosis and management of patients with SCC of unknown primary site, other than those presumed to be of head and neck origin, are reviewed here. The evaluation and treatment of head and neck SCC of unknown primary site are discussed separately [2]. (See "Head and neck squamous cell carcinoma of unknown primary".)
UPPER OR MIDCERVICAL LYMPH NODES — Patients with involvement of the upper or midcervical nodes are usually middle-aged or older adults, and many have a history of substantial tobacco and/or alcohol use. A second group of patients (approximately 25 percent) have human papillomavirus (HPV)-associated cancers [3,4]. Patients with HPV-associated cancers are less likely to have a history of alcohol consumption; primary sites (when identified) are in the oropharynx.
A primary tumor in the head and neck region should be suspected and should be the focus of the initial diagnostic evaluation. The diagnostic evaluation and subsequent treatment of these patients are discussed separately. (See "Head and neck squamous cell carcinoma of unknown primary" and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)
LOWER CERVICAL OR SUPRACLAVICULAR NODES — A primary lung cancer should be suspected when the lower cervical or supraclavicular nodes are involved, although a head and neck primary is possible. Fiberoptic bronchoscopy is indicated if the chest radiograph and head and neck examination are unrevealing.
If the fiberoptic bronchoscopy reveals a primary bronchogenic cancer, patient management is the same as that for advanced non-small cell lung cancer. (See "Overview of the initial treatment and prognosis of lung cancer".)
In the absence of a detectable primary site, treatment results for patients with lower cervical or supraclavicular nodes are poor compared with those with upper and midcervical nodes. Nevertheless, patients with lower cervical nodes and no detectable disease below the clavicle should be treated with the same approach as patients with involved upper cervical nodes, since occasionally such patients will have long-term disease-free survival. Patients with isolated supraclavicular node involvement should be treated following guidelines for locally advanced squamous (non-small) cell lung cancer.
INGUINAL LYMPH NODE DISEASE — The vast majority of patients with SCC involving the inguinal lymph nodes have a detectable primary site in the genital or anorectal area (including the surrounding skin). If the primary site is the cervix or anal canal, these cancers can be human papillomavirus (HPV)-associated.
●In females, careful examination of the vulva, vagina, and cervix is important, with biopsy of any suspicious areas.
●Males should undergo careful inspection of the penis.
●In both males and females, digital rectal examination and anoscopy should be performed to exclude anorectal lesions.
Identification of a primary site in these patients is important since therapy is potentially curative for patients with carcinomas arising in the anogenital region, even after spread to regional lymph nodes. For the occasional patient in whom no primary site is identified, options include lymphadenectomy or regional radiation therapy to the inguinal nodal basin, which sometimes results in long-term survival [5].
Although experience is limited in this uncommon group of patients, the success with concurrent chemotherapy and radiation therapy in other cancers originating in this region (ie, cervix, anus, bladder) suggests a role for this approach.
OTHER METASTATIC SITES — Metastatic SCC in areas other than the cervical or inguinal lymph nodes usually represents metastasis from a primary lung cancer, but primaries of the skin and uterine cervix are also possible. Computed tomography (CT) of the chest and fiberoptic bronchoscopy should be considered if other clinical features suggest the possibility of lung cancer. A molecular cancer classifier assay may be useful in identifying the primary site of metastatic SCC in these patients, similar to those with poorly differentiated carcinoma or adenocarcinoma. (See "Poorly differentiated cancer from an unknown primary site", section on 'Molecular cancer classifier assays'.)
If lung cancer is predicted, treatment should follow guidelines for squamous cell lung cancer. Molecular markers predictive of response to immunotherapy (programmed cell death ligand 1 [PD-L1], microsatellite instability [MSI], tumor mutational burden [TMB]) should be assessed. If any elements of adenocarcinoma are present, additional molecular analysis is indicated for specific driver mutations (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS1, BRAF, neurotrophic tyrosine receptor kinase [NTRK] fusions, and others). These multiple molecular alterations are best assessed using a comprehensive profiling platform. Further genotype-directed therapy for advanced non-small cell lung cancer is discussed separately. (See "Overview of the initial treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'NTRK fusions'.)
If metastatic squamous skin cancer is predicted, various systemic treatment options, including immunotherapy (eg, cemiplimab), are available. The approach to therapy in these patients is discussed separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Eligible for immunotherapy'.)
Patients with the diagnosis of poorly differentiated SCC should be evaluated carefully, particularly if other clinical features are unusual for lung cancer (eg, young patient, nonsmoker, unusual metastatic sites). This histologic diagnosis is sometimes based on scant histologic or immunohistochemical criteria and may include patients with poorly differentiated carcinoma, in whom other diagnoses should be considered. For this reason, additional pathologic and molecular evaluation with immunohistochemical stains and molecular cancer classifier assays should be considered in such patients. If the diagnosis is still unclear, a trial of empiric chemotherapy for poorly differentiated carcinoma should be considered. (See "Poorly differentiated cancer from an unknown primary site".)
NUT MIDLINE CARCINOMA — NUT midline carcinomas are aggressive, poorly differentiated tumors that include variable degrees of squamous differentiation in approximately one-half of cases. These tumors are defined by the presence of a chromosomal rearrangement of the NUT gene and have a distinct clinical presentation and clinical course [6,7]. (See "Poorly differentiated cancer from an unknown primary site", section on 'NUT midline carcinoma'.)
SUMMARY AND RECOMMENDATIONS — For patients with an occult squamous cell carcinoma (SCC), the initial diagnostic evaluation should attempt to identify the primary site, which can serve as the basis for optimizing treatment. The initial diagnostic evaluation is based on the site of disease involvement:
●For patients presenting with SCC involving the mid or upper cervical lymph nodes and without an obvious primary, the diagnostic evaluation should focus primarily on identifying an occult head and neck primary. If no primary can be identified, such patients should be treated for locally advanced cancer of the head and neck rather than with empiric chemotherapy. (See "Head and neck squamous cell carcinoma of unknown primary".)
●For patients with SCC involving the lower cervical or supraclavicular lymph nodes, the initial evaluation should include a search for an occult lung primary as well as an occult head and neck lesion.
•For patients with no identifiable primary tumor and lower cervical nodes, we offer treatment for an occult head and neck primary.
•For those with no identifiable primary tumor and supraclavicular nodes, we offer treatment for advanced squamous (non-small cell) lung cancer. (See 'Lower cervical or supraclavicular nodes' above.)
●For patients with SCC involving the inguinal lymph nodes, an intensive search should be made for an anogenital primary tumor, which can be identified in most cases. For the occasional patient in whom no primary site can be identified, options include lymphadenectomy, regional radiation therapy to the inguinal nodal basin, or, in select cases, concurrent chemotherapy and radiation. (See 'Inguinal lymph node disease' above.)
●Metastatic SCC presenting at other sites is rare. Most of these patients have an occult lung primary site, although occasionally patients have primary sites in the skin or uterine cervix. If a specific primary site is predicted by a molecular cancer classifier assay, treatment following standard guidelines for the specific cancer type is appropriate. (See 'Other metastatic sites' above and 'NUT midline carcinoma' above.)
