Squamous cell carcinoma of unknown primary site

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 are curable with locoregional therapy to the area of tumor involvement. Studies suggest that concurrent chemotherapy and radiation therapy is effective, as used in the treatment of cervical cancer and anal cancer.

●Occasionally, SCC of unknown primary site is found in pelvic or retroperitoneal lymph nodes. Evaluation is similar to that described for inguinal node presentations. Concurrent chemoradiation is curative in some of these patients.

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 NODES — 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).

●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.

●Cancer tissue should be tested for human papillomavirus (HPV). If the tissue tests positive for HPV, this strongly suggest a primary site in the cervix or anorectal area. (See "Human papillomavirus infections: Epidemiology and disease associations".)

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. In patients with no primary site identified, some have SCC found only in inguinal lymph nodes, while others have accompanying involvement of ipsilateral iliac and/or retroperitoneal nodes. Both of these groups should be treated with curative intent.

In patients with only inguinal lymph node involvement, long-term survival has been reported with local treatment (lymphadenectomy or regional radiation therapy) alone [5]. However, the proven efficacy of concurrent chemotherapy and radiation therapy in other locally advanced cancers originating in this region (ie, cervix, anus, bladder) suggests a role for combined modality therapy [1]. Patients with isolated inguinal nodes should be evaluated for the option of chemoradiation [1]. Chemoradiation should be used for all patients who have involved iliac and/or retroperitoneal lymph nodes in addition to inguinal nodes. In particular, patients with HPV-associated cancers should be treated following guidelines for cancers of the cervix or anus. (See "Management of locally advanced cervical cancer" and "Treatment of anal cancer".)

PELVIC OR RETROPERITONEAL LYMPH NODES — Occasional patients have metastatic SCC found only in pelvic or retroperitoneal lymph nodes [2]. The evaluation of these patients is the same as to those for patients with inguinal node involvement. (See 'Inguinal lymph nodes' above.)

In case reports of patients with metastatic SCC in the pelvic or retroperitoneal lymph nodes, 10 patients were evaluated for human papillomavirus (HPV), and all tested positive. Treatment varied, but most patients received concurrent chemoradiotherapy to the involved areas. Six of 15 patients remained in complete remission after follow-ups ranging from 6 to 48 months [2].

Although treatment data are limited, patients should be evaluated for combined chemoradiation, when feasible. Patients with HPV-associated cancer should be treated according to guidelines for SCC of the cervix or anus involving regional lymph nodes. (See "Management of locally advanced cervical cancer" and "Treatment of anal cancer".)

OTHER METASTATIC SITES — Metastatic SCC in other areas usually represents metastasis from a primary lung cancer, but primaries of the skin, uterine cervix, anal canal, and esophagus are also possible. Computed tomography (CT) of the chest and fiberoptic bronchoscopy should be offered 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. Human papillomavirus (HPV) testing should also be considered. (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 advanced 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 or pembrolizumab), 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'.)

If HPV testing indicates an HPV-associated cancer, the origin is most likely in the head/neck or anogenital area (cervix, anorectal). A molecular cancer classifier assay may be useful in differentiating these possibilities. Otherwise, treatment should follow guidelines for advanced SCC of the site most consistent with the clinical presentation.

The management of many advanced cancers is impacted by actionable molecular alterations within the tumor. Although experience with molecularly guided treatment remains limited in patients with cancer of unknown primary site, comprehensive molecular profiling is an available option to help guide treatment. In SCC of unknown primary site, molecular alterations that predict response to immune checkpoint inhibitors (tumor mutational burden [TMB], microsatellite instability [MSI], programmed cell death ligand 1 [PD-L1]) are most frequently identified. Other actionable mutations are also occasionally found (eg, human epidermal growth factor receptor 2 [HER2], epidermal growth factor receptor [EGFR], KRAS, among others).

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

●Identifying the primary tumor site – 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.

•Upper or midcervical lymph nodes – 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. (See "Head and neck squamous cell carcinoma of unknown primary".)

•Lower cervical or supraclavicular lymph nodes – 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. (See 'Lower cervical or supraclavicular nodes' above.)

-Lower cervical lymph nodes – For patients with no identifiable primary tumor and lower cervical nodes, we offer treatment for an occult head and neck primary. (See "Head and neck squamous cell carcinoma of unknown primary".)

-Supraclavicular lymph nodes – For those with no identifiable primary tumor and supraclavicular nodes, we offer treatment for advanced squamous (non-small cell) lung cancer. (See "Overview of the initial treatment and prognosis of lung cancer".)

•Inguinal, pelvic, or retroperitoneal lymph nodes – For patients with SCC involving the inguinal, pelvic, or retroperitoneal lymph nodes, an intensive search should be made for an anogenital primary tumor, which can be identified in most cases. When no primary site can be identified, most patients should be evaluated for concurrent chemotherapy and radiation therapy, as is used in the treatment of locally advanced cervical cancer and anal cancer. (See 'Inguinal lymph nodes' above and 'Pelvic or retroperitoneal lymph nodes' above.)

•Other sites – 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, uterine cervix, anal canal, or esophagus. 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.)