Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma

INTRODUCTION — In most patients with cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma (BCC), disease remains limited to the skin and is successfully managed with local therapy, such as excision, lesion destruction, or irradiation of the primary lesion. However, in 3 to 7 percent of patients with cSCC and in rare individuals with BCC, locoregional or distant metastases occur, resulting in an increased risk for mortality and the need for alternative approaches to therapy [1-3].

The evaluation for regional and distant metastases in patients with cSCC or BCC will be reviewed here. The clinical features and treatment of cSCC and BCC are discussed elsewhere.

●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

●(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

●(See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

●(See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".)

●(See "Treatment of basal cell carcinomas at high risk for recurrence".)

CUTANEOUS SQUAMOUS CELL CARCINOMA — The identification of patients at increased risk for metastasis and, concordantly, the most appropriate work-up for metastatic disease are important components of the management of patients with cutaneous squamous cell carcinoma (cSCC) [4].

General considerations — Data on the approach to the evaluation for metastatic disease are limited, contributing to the absence of definitive recommendations on the indications for investigative tests and the selection of appropriate studies. In general, clinical assessment by physical examination is considered sufficient for the evaluation of most patients with cSCC, whereas those with tumors who exhibit clinical and/or pathologic high-risk features may need further evaluation with imaging studies [5]. According to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, the definition of high-risk cSCC based on risk factors for local recurrence, metastasis, or death is as follows [6]:

●High-risk cSCC:

•Lesions of any size located on the head, neck, hands, feet, pretibia, and anogenital area

•Lesions >2 to 4 cm located on the trunk or extremities (excluding pretibia, hands, and feet)

•Recurrent tumor

•Histopathologically acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtypes, with perineural invasion

●Very high-risk cSCC:

•Lesions >4 cm on any location

•Histopathologically poorly differentiated tumor, desmoplastic cSCC, >6 mm in thickness or invasion beyond the subcutaneous fat

•Perineural invasion – Tumor cells within the nerve sheath of a nerve lying deeper than the dermis or ≥0.1 mm

•Lymphatic or vascular involvement

Locoregional evaluation

Cutaneous metastases — Infrequently, cSCC can metastasize to the skin. Cutaneous metastases present as multiple small, erythematous papules or nodules that can be ulcerated and crusted. In-transit cutaneous metastases with a linear distribution have been reported in a few patients, most of whom were immunosuppressed [7]. Cutaneous metastases with a dermatomal distribution ("zosteriform cutaneous metastases"), likely due to extensive perineural invasion or retrograde lymphatic spreading of tumor cells, have been very rarely reported in immunosuppressed, as well as immunocompetent, patients [8-10].

Nodal metastases — Lymph nodes are the most common sites for metastasis of cSCC, and regardless of the presence or absence of high-risk features, all patients diagnosed with invasive cSCC should undergo regional lymph node palpation at the time of diagnosis and during post-treatment follow-up. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Follow-up'.)

The impact of sentinel lymph node (SLN) biopsy, which has been used to evaluate lymph node status in select patients with high-risk squamous cell carcinoma (SCC), remains uncertain. (See 'Patients without palpable lymph nodes' below and 'Evaluation for distant metastases' below and 'Sentinel lymph node biopsy' below.)

Regional lymph node palpation — The selection of sites for palpation is based upon knowledge of the pathways for lymphatic drainage (figure 1A-B). Lymphatic drainage on the head is complex, and lesions in close proximity to one another may drain to different lymph node basins. Common initial sites for metastasis from lesions on the face and scalp include [11]:

●Nose and cheek lesions – Submandibular nodes

●Lip and anterior mouth lesions – Submental nodes

●Auricular lesions – Posterior auricular nodes

●Posterior scalp lesions – Occipital nodes

●Anterior scalp, forehead, temple lesions – Parotid nodes

The cervical lymph nodes are additional potential sites of metastasis and also should be palpated in all patients with head or neck lesions.

In addition to palpation for enlarged regional lymph nodes, all patients should receive a complete skin examination that includes palpation of the skin and soft tissue near the tumor. Papules or nodules in the tumor vicinity or between the tumor and a regional lymph node basin may represent in transit metastases (picture 1) [11,12].

Patients with palpable lymph nodes — When an enlarged lymph node is detected on palpation, we typically refer the patient for lymph node biopsy via fine needle aspiration (FNA) [13]. Alternatively, the lymph node may be surgically removed for pathologic examination.

If the FNA or surgical pathology results are positive for metastatic disease, further evaluation with radiologic imaging is indicated. Radiologic imaging provides information on the size, number, and location of involved lymph nodes, which are necessary for disease staging (table 1) [13].

If the cytology of a head or neck nodule that is clinically suggestive of an enlarged lymph node is negative for metastatic disease, re-evaluation of the site via radiologic imaging, repeat FNA, or open surgical biopsy to confirm the benign or malignant nature of the nodule is appropriate [14]. Enlarged lymph nodes on the trunk or extremities that are negative for metastatic disease are typically re-evaluated via open surgical biopsy [14].

Patients without palpable lymph nodes — Definitive guidelines for the investigation for metastatic disease beyond lymph node palpation in patients with cSCC have not been established. In studies of patients with head and neck cancer, palpation has been shown to have a false-negative rate for the detection of lymph node metastases of 15 to 30 percent when compared with radiologic imaging or nodal dissection [15-20]. Hence, it is conceivable that a similar scenario may occur in some patients with cSCC. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Imaging studies'.)

Factors that often lead us to proceed with imaging studies for subclinical nodal disease in patients with cSCC who do not have palpable lymph nodes include [21,22]:

●Tumors larger than 2 cm

●Tumors located near major nerves in the head or neck

●In transit metastases

●Tumors invading deep structures (muscle, bone, cartilage)

●Systemic signs or symptoms suggestive of extracutaneous involvement

●Histopathologic or clinical findings (eg, neurologic signs or symptoms) suggestive of perineural invasion of a large nerve trunk (ie, a nerve with an anatomic name)

●Multiple high-risk features (table 2)

Perineural invasion, which can be detected on histopathologic examination, suspected due to the presence of sensory or motor neurologic symptoms or seen on radiologic studies in advanced cases, portends an increased risk for metastasis [23,24].

In a survey of Mohs surgeons, perineural invasion was the most commonly reported reason for considering radiologic imaging in patients with high-risk SCC [25]. Adenosquamous, spindle cell, or poorly differentiated SCCs are most likely to exhibit perineural invasion [13,26,27]. The facial and trigeminal nerves are most frequently affected [28].

In a single institution study, patients receiving radiologic imaging had a 50 percent lower risk of developing nodal metastases (13 versus 30 percent) and any disease-related outcome (20 versus 42 percent) compared with patients who did not undergo imaging studies [29]. In a subsequent study, almost one-fifth of 99 T2b/T3 primary cSCCs in a high-stage cohort had evidence of metastases at the time of primary tumor treatment, and management was altered in almost one-third of the cohort based on imaging results [30].

Choice of imaging study — Computed tomography (CT) is often used for the evaluation of regional lymph node status in patients with cSCC [25]. Other radiologic studies utilized include magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound (US), and ultrasound-guided fine needle aspiration cytology (USG-FNAC). Comparative studies on the use of these modalities for the evaluation for locoregional metastases in patients with cSCC are lacking. Thus, much of the information used to guide study selection is based upon information from studies in head and neck cancer and other malignancies.

In a 2007 meta-analysis of 17 studies comparing US, USG-FNAC, CT, and MRI in the detection of lymph node metastases among patients with head and neck SCC, the pooled sensitivity and specificity were 87 percent (95% CI 76-93) and 86 percent (95% CI 74-93), respectively, for US; 80 percent (95% CI 57-92) and 98 percent (95% CI 93-100), respectively, for USG-FNAC; 81 percent (95% CI 68-90) and 76 percent (95% CI 62-87), respectively, for CT; and 81 percent (95% CI 65-91) and 63 percent (95% CI 43-80), respectively, for MRI [31]. These results suggest that the diagnostic accuracy in the detection of metastatic lymph nodes in patients with head and neck cancer is similar for all imaging modalities, with US and USG-FNAC having a higher specificity.

Consultation with a radiologist may assist with the selection of the most appropriate study to evaluate specific targeted features. Patient tolerance for specific radiologic modalities and test availability also influence test selection. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Diagnosis and staging evaluation'.)

Computed tomography and magnetic resonance imaging — We suggest the use of CT or MRI for the evaluation for nodal disease. CT and MRI are the most common initial radiologic tests used in the assessment of patients with cSCC [25]. Both CT and MRI can detect lymph node metastases. In a 2012 meta-analysis of 16 studies evaluating the diagnostic accuracy of MRI in the detection of cervical lymph node metastases in patients with head and neck SCC, the pooled sensitivity and specificity of MRI were 76 percent (95% CI 70-82 percent) and 86 percent (95% CI 73-93 percent) [32].

Radiologic imaging with CT or MRI is also useful for evaluating tumor extent for preoperative planning and staging in patients with large or deeply invasive lesions. CT is superior to MRI for the evaluation of skull base invasion, involvement of cartilage, and bone erosion or destruction, while MRI is more useful for detecting perineural invasion, providing soft tissue contrast, defining tissue planes, and identifying bone marrow infiltration in the absence of significant osseous destruction [33].

CT is less expensive than MRI, and, in many clinical settings, CT is more easily attained. The properties of MRI prohibit use in patients with certain implanted devices. The contraindications for MRI are reviewed separately. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Assessing implants, devices, or foreign bodies for MRI'.)

Positron emission tomography — The use of PET in the setting of malignancy has risen with increasing test availability and decreasing test cost. PET functions through the detection of the accelerated uptake of intravenously administered fluorodeoxyglucose that occurs in tumor cells. A beneficial feature of PET is its ability to detect metastases in sites of fibrosis, necrosis, and dense scarring related to radiotherapy, areas that may be difficult to assess with other studies [34]. However, false-positive results are common with PET due to the incidental detection of metabolically active inflammatory, infectious, or other lesions.

Another, less favorable feature of PET is the poor spatial resolution attained with this study. The integration of PET and CT (PET/CT) has addressed this issue through providing improved anatomic correlation.

Study data on the use of PET for the evaluation of lymph nodes specifically in patients with cSCC are limited to a retrospective study of 12 patients with cSCC in which PET detected lymph node metastases in three out of nine patients with high-risk SCC [35]. In head and neck cancer, the value of PET for the detection of occult metastases is uncertain; PET/CT may be more beneficial. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'PET and integrated PET/CT'.)

Ultrasound and ultrasound-guided fine needle aspiration cytology — The results of studies that suggest that USG-FNAC may be useful for the evaluation of lymph nodes in patients with vulvar SCC and head and neck cancer raise the question of whether the procedure may be of value for lymph node surveillance in patients with cSCC [36,37] (see "Overview of the diagnosis and staging of head and neck cancer", section on 'Fine needle aspiration biopsy'):

●In a series of 44 patients with primary SCC of the vulva, USG-FNAC was more sensitive (80 versus 58 percent) and specific (100 versus 75 percent) than CT for the diagnosis of lymph node metastases [36].

●In a subsequent meta-analysis of three studies examining the performance of USG-FNAC in the detection of nodal metastases in patients with head and neck cancer, the pooled sensitivity and specificity of USG-FNAC were 80 percent (95% CI 57-92) and 98 percent (95% CI 93-100), respectively [31].

US spares the radiation exposure associated with CT, but the utility of this procedure may be compromised by operator-dependent accuracy, difficulty in following specific lesions over time, and reduced ability to detect metastases to deep lymph nodes. The last item may be less of a concern in cSCC, which typically metastasizes to superficial lymph nodes. However, additional studies are necessary to determine the role of USG-FNAC for surveillance in this population.

Sentinel lymph node biopsy — SLN biopsy is a minimally invasive procedure that identifies the lymph node or lymph nodes most likely to harbor micrometastases using lymphoscintigraphy to detect uptake of radiolabeled colloid and blue dye injected at the site of the tumor. The role of SLN biopsy in the management and outcome of patients with high-risk cSCC has not been evaluated in randomized trials. Data from observational studies are insufficient to determine whether early detection of microscopic metastatic disease has a beneficial effect on patient survival [38]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Sentinel lymph node biopsy'.)

Evaluation for distant metastases — The lungs, liver, brain, and bone are the most frequent sites for distant metastases of cSCC. We typically evaluate for distant metastases in patients with lesions that have a very high risk for metastasis, known locoregional metastases, or signs or symptoms suggestive of distant disease.

CT, PET, and PET/CT have been used for whole-body imaging for the evaluation for distant metastases. The comparative efficacy of these studies for the detection of distant metastases has not been evaluated in cSCC. Data on the utility of these studies in head and neck cancer are available separately. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Evaluation for distant metastases'.)

Systemic therapy for metastatic SCC is discussed separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

BASAL CELL CARCINOMA — Compared with cutaneous squamous cell carcinoma (cSCC), there is an even greater lack of data on the evaluation for metastatic disease in patients with basal cell carcinoma (BCC). This is likely related to the rarity of systemic involvement; the risk of metastasis for BCC is estimated to be between 0.05 to 0.1 percent [39,40]. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Locally advanced tumors/metastatic disease'.)

Metastatic BCC most frequently involves the regional lymph nodes, lungs, bone, skin, and liver [41]. Large lesions (particularly those over 10 cm²) and tumors that invade deep structures, such as cartilage, skeletal muscle, or bone, are most likely to metastasize [39]. Perineural invasion, aggressive histologic growth patterns, and longstanding lesions are additional risk factors for metastasis [41].

As in cSCC, CT and MRI may be used for the evaluation for metastases and local tissue invasion. The value of positron emission tomography (PET) and sentinel lymph node (SLN) biopsy in BCC is uncertain. PET detected lymph node metastases in a patient with BCC [42] but was unable to detect primary BCCs in three out of six patients in one series, raising questions about the sensitivity of the test for BCC [43]. In a study of 22 patients with metastatic BCC treated with vismodegib, PET/CT images tended to demonstrate more disease in bone and soft tissue compared with contrast-enhanced CT images; contrast-enhanced CT images tended to demonstrate more disease in the lung [44]. PET/CT was also used to demonstrate response to vismodegib; a decrease in maximum standardized uptake value was associated with improved progression-free survival and overall survival [45]. Detection of lymph node metastasis via SLN biopsy in a patient with pathologic evidence for lymphatic invasion in a primary excision specimen of a BCC has been reported [46].

Systemic therapy for advanced BCC is discussed separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS

●Cutaneous squamous cell carcinoma – Most patients with cutaneous squamous cell carcinoma (cSCC) can be evaluated for locoregional metastatic disease through skin examination and regional lymph node palpation. If features associated with an elevated risk for metastasis are present, further evaluation with radiologic imaging may be indicated. (See 'Locoregional evaluation' above.)

•Patients with palpable lymph nodes – Enlarged regional lymph nodes detected on physical examination should be sampled via fine needle aspiration (FNA) or surgical excision in patients with cSCC. If disease is identified in lymph nodes, radiologic imaging to determine the size, number, and location of involved lymph nodes should be performed. (See 'Patients with palpable lymph nodes' above.)

•Patients without palpable lymph nodes – The indications for further evaluation of lymph node status when lymph nodes appear normal on physical examination are less certain. We typically proceed with radiologic imaging in patients with clinical or histopathologic features that suggest an elevated risk for metastasis. We suggest the use of CT or MRI for the initial evaluation for nodal disease. (See 'Patients without palpable lymph nodes' above and 'Choice of imaging study' above.)

The value of sentinel lymph node (SLN) biopsy in high-risk cSCC is unknown. It has not been evaluated in randomized trials and data from observational studies are insufficient to determine whether early detection of microscopic metastatic disease improves patient survival. (See 'Sentinel lymph node biopsy' above.)

●Basal cell carcinoma – There are few data to guide the use of imaging studies for patients with basal cell carcinoma (BCC) at high risk of recurrence. CT or MRI studies may be used for the evaluation for metastases and deep local tumor invasion. The value of positron emission tomography (PET) and SLN biopsy in BCC is uncertain. (See 'Basal cell carcinoma' above and "Treatment of basal cell carcinomas at high risk for recurrence".)