High-risk squamous cell carcinoma of the skin: definición, diagnóstico y manejo.
Squamous cell carcinoma is a type of skin cancer that originates from abnormal proliferation of keratinocytes in the epidermis. It is the second most common skin cancer after basal cell carcinoma, accounting for approximately 20% of non-melanoma skin cancer cases. Its incidence has increased in recent decades due to longer life expectancy, greater sun exposure, the use of tanning beds, and improved detection of this type of tumor. In the United States, the incidence is estimated at between 200,000 and 400,000 new cases each year. In Colombia, the incidence of skin cancer rose from 23 cases per 100,000 inhabitants in 2003 to 41 cases per 100,000 in 2007; of these, 25% correspond to squamous cell carcinomas. It is more common in men than in women, with a ratio of 3:1; its incidence increases with age.
The main risk factors that contribute to its development are exposure to ultraviolet radiation, low skin types, exposure to certain chemicals such as arsenic or hydrocarbons, scars or chronic inflammation, human papillomavirus infection, immunosuppression, tobacco use, and pre-existing genodermatosis.
As for its name, when the tumor is located exclusively in the epidermis or in the appendages above the basement membrane, it is called “squamous cell carcinoma in situ,” and when it passes through the dermis and underlying tissues, it is called “invasive squamous cell carcinoma.” In most cases, it is localized and has high cure rates, but in up to 5% of cases, local, regional, or distant metastases appear. Although the literature has identified some clinical and histopathological predictors that lead to a higher risk of recurrence or metastasis, there is no consensus on the definition of high-risk squamous cell carcinoma, nor on the best tests to use.
For diagnostic study, prognosis, and management; therefore, this review aims to present an approach based on the best available evidence.
Definition of high-risk squamous cell carcinoma
There is no consensus on the definition. Multiple scientific societies have described “high-risk” characteristics, but these do not coincide with each other. A retrospective study evaluated 257 patients diagnosed with squamous cell carcinoma using the criteria of the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) and found significant differences: according to the AJCC, 14% were high risk, while 87% were high risk according to the NCCN criteria. The purpose of the AJCC guidelines is to stratify individuals into groups with similar outcomes in order to try to calculate prognosis. One of the biggest problems with the AJCC guidelines is that they only take tumor factors into account, without considering patient factors such as immunosuppression or recurrence. The NCCN guidelines, on the other hand, seek to guide tumor treatment. One of the drawbacks of these guidelines is that they take into account 12 high-risk factors, and having one of them already classifies the tumor as high risk, but they do not stratify different degrees of risk and do not differentiate between a tumor with a single high-risk factor and one with more than one factor, which could lead to higher rates of recurrence or metastasis.
Clinical features
Tumors larger than two centimeters in diameter have been described as a high-risk factor. A review article that included multiple clinical trials from the last 50 years showed that these tumors had recurrence and metastasis rates of 15% and 30%, respectively, compared to those smaller than two centimeters, which had recurrence rates of 7% and metastasis rates of 9%.10 In addition, smaller tumors in special areas such as the head and neck are high risk: Veness and colleagues found that 70% of lesions in this location that metastasized were smaller than two centimeters. The AJCC guidelines determine that a tumor larger than two centimeters is high risk, while the NCCN guidelines are more specific and recommend stricter diameters depending on the location of the tumor.
Certain body locations have also been associated with increased risk. For example, local recurrence in tumors of the lip and ear is 2-20%, and metastasis occurs in 5-19% and 9-12% of cases, respectively. Tumors involving the cheek also have a higher risk of metastasis compared to other locations, such as the legs. Local recurrence increases the risk of metastasis and should be included in the high-risk criteria. The appearance of tumors at sites of chronic wounds, scars, previous burns, or radiotherapy sites suggests aggressive behavior, with metastasis rates averaging between 20% and 50%.
Histological features
High-risk histological criteria have been described, such as depth of invasion, nerve involvement, histological subtype, and degree of tumor differentiation.
The depth of invasion has been shown to increase the risk of complications. The AJCC guidelines recommend Clark greater than or equal to IV and Breslow greater than two millimeters as high-risk criteria. Invasions greater than six millimeters are associated with higher rates of metastasis. Perineural involvement has been associated with an increase in metastasis and local recurrence in an average of 15 to 50% of cases; in addition, some studies have suggested that the risk is higher when large-caliber nerves are involved.
The subtype with desmoplastic growth or invasion has been associated with more aggressive behavior, with up to 10 times more likelihood of recurrence and six times more metastasis than tumors without this type of invasion. 16 Regarding the acantholytic subtype, García and colleagues found no evidence that it was a determinant of high risk of recurrence or metastasis, but it is described in the NCCN guidelines.17 It is unclear whether there are other histological subtypes that increase this risk.
The degree of differentiation is also important when determining prognosis: according to Broders' classification, poorly differentiated tumors (Broders 3-4) metastasize in 30-60% of cases; this value is three times higher than in well- or moderately differentiated tumors.
Other laboratory tests
Overexpression of the epidermal growth factor receptor has been linked to more aggressive behavior, especially in head and neck tumors,although its prognostic value is unclear. Other tests, such as measurement of p16 and the CKS1B gene, are also being studied as high-risk factors.
The technique of nuclear morphometry, which measures the area, perimeter, and shape of the nucleus, has been proposed as a method for differentiating between low- and high-risk tumors, but further studies are needed to support its use.
Staying in place
In 2010, in its seventh edition, the AJCC updated the staging method for squamous cell carcinoma. The method grades according to tumor (T), nodal involvement (N), and metastasis (M). The main changes from previous editions were to separate squamous cell carcinoma from other non-melanoma skin cancers and to include high-risk factors in the tumor component. In 2013, a study suggested an alternative tumor (T) staging system to the AJCC guidelines (Table 4). New studies have continued to propose alternative staging systems for the tumor component.