External Medicine
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Squamous Cell Carcinoma
Squamous Cell Carcinoma: Staging/Prog
WHAT IS THE RISK OF METASTASIS?
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This a challenging question to answer. Broadly speaking, the answer is around 2% based on a New Zealand study. (22592943) This is probably the most generalizable statistic, although potentially not the most relevant for some practice scenarios where there is a tendency to see higher risk patients (i.e. academic medical centers, practices that focus Mohs surgery for where there might be a slight bias towards higher risk cases, etc.). However, a study in a population of patients seen at an academic medical center reported a 3.7% nodal metastasis rate. (23677079) Baseline risk factors were a bit different in each study, but nothing to suggest either was not representative of the populations at large that were trying to be studied.
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Importantly, although these studies suggest general risk of metastasis across all cutaneous SCCs, we do know of factors that help us more reliably predict rates of metastasis that are individual to a specific SCC. This is the basis of staging systems that are reviewed below.
STAGING SYSTEMS
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Identifying and risk stratifying SCCs is crucial as they have drastically different prognoses.
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T1 tumors have a <1% risk of recurrence, a very low likelihood of nodal metastasis, and virtually no risk of death associated with them. These risks increase considerably as the stage increases.
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3 main staging systems: BWH, AJCC, and NCCN; there is also the UICC system.
Brigham and Women's (BWH) FIGURE - link to original article table.
T Stage | Number of Risk Factors | LN Metastasis Rate |
|---|---|---|
T0 | In Situ | 0% |
T1 | 0 | 0.7% |
T2a | 1 | ? |
T2b | 2-3 | ? |
T3 | 4, or any bony invasion | ? |
Risk factors:
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diameter >/= 2cm
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poorly differentiated histology
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depth beyond subcutaneous fat (excluding bony invasion which is automatic T3)
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perineural invasion (of nerve >0.1mm, or named nerve)
Developing a better staging system (than AJCC7):
Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013. PMID: 23325457.
SUMMARY: This is the original paper which set out to create a more predictive staging system than 7th edition AJCC staging for cutaneous SCC, specifically with respect to AJCC T2 tumors. This category (AJCC T2) contains a high rate of events of interest (metastasis and death) and and are still relatively common compared to AJCC T3 and T4 tumors but lacks homogeneity of outcomes (outcomes among T2 tumors vary quite a bit) desired in a staging system. Of note, an AJCC 8th edition has since been released.
Validating the BWH staging system against AJCC 7th edition (and UICC):
Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014. PMID: 24366933.
SUMMARY: Compared to the 7th edition AJCC and UICC, BWH provided better distinction (staging groups correlate with distinct outcomes). This was accounted for by the highest 2 staging categories, T3 and T4, in which AJCC and UICC categories were indistinct. It also showed superior monotonicity (increasing stages correlate with worse outcomes), and homogeneity (outcomes were similar within each staging category).
If you refer to table 3 of the paper, the key difference can be illustrated in the predicted rate of nodal mets, in which not only are all 4 T stages for the BWH criteria distinct, but significantly so, meaning the confidence intervals do not even approach each other, and are somewhat evenly distributed: for stages T1, T2a, T2b, and T3, CIs were 0-0.4, 1-5, 13-27, and 41-100, respectively. For AJCC, stages T1, T2, T3, and T4, CIs were 0-1, 4-9, 37-100, and 34-100. As you can see, AJCC stages T3 and T3 are not distinct, and there is also a large jump from predicted rate of nodal mets from T2 to T3.
T Stage | Criteria | LN Metastasis Rate |
|---|---|---|
1 | </=2cm diameter | ? |
2 | >2cm to </=4cm diameter | ? |
3 | >4cm, or at least 1 of: 1) perineural invasion with tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves, 2) invasion beyond subcutaneous fat, or >6mm (measured from the granular layer of adjacent normal epidermis to the base of the tumor), 3) minor bone erosion | ? |
4a | Tumor with gross cortical bone/marrow invasion | ? |
4b | Tumor with skull base invasion and/or skull base foramen invasion | ? |
National Comprehensive Cancer Network (NCCN)
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The NCCN provides more of a list of criteria delineating low, high, and very high risk rather than true staging criteria. Figure
Criterion | High Risk | Very High Risk |
|---|---|---|
Diameter | any size on the head, neck, hands, feet, pretibia, and anogenital,
OR
>2cm (but </= 4cm) on any other location | >4cm |
Depth | depth alone does not rise to high risk unless meeting very high risk criteria | >6cm, or beyond subcutaneous fat |
Histology | acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) | desmoplastic, poorly differentiated |
PNI/LVI | PNI (as long as it does not demonstrate tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm, which would be a very high risk feature) | PNI with tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm
OR
any LVI |
Other | - recurrent tumors
- tumors arising in sites of radiation or chronic inflammatory processes
- tumors in patients who are immunosuppressed
- tumors causing neurologic symptoms
- rapidly growing tumors
- tumors with poorly defined borders |
40-GENE EXPRESSION PROFILING (CASTLE BIOSCIENCES)
Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2021. Erratum in: J Am Acad Dermatol. 2021. PMID: 32344066. Supplemental at https://doi.org/10.17632/f33w9wmng4.1.
SUMMARY: This is the original paper by Wysong et al looking to validated the 40-GEP for SCC, similar to the test for melanoma. The inclusion criteria were NCCN high risk or greater, or AJCC 8 or BWH T stage of 2 or higher tumors, but 62.6% of the tumors were AJCC8 T1 and 57.9% BWH stage T1, presumably because of the loose NCCN criteria. The overall metastatic rate of 16% in the cohort, up to 8 times the 1.9-2.6% population rate estimated from a cohort of nearly 9000 patients (22592943), is one of the major critiques. Regarding accuracy of the tests (accuracy being how often is the test correct), vs the staging systems, utilizing the formula accuracy = (sensitivity) x (prevalence) + (specificity) x (1-prevalence), only when comparing 40-GEP class 2B vs 1/2A is there an advantage over BWH or AJCC8 staging. Comparing class 2 vs 1 decreases accuracy by approximately 10% compared to BWH and AJCC8.
Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test. Future Oncol. 2022. PMID: 34821148. Supplemental at https://www.futuremedicine.com/doi/suppl/10.2217/fon-2021-1277.
SUMMARY: This is the Ibrahim et al paper. Of note, overall metastatic rate was 15%; BWH T1 tumors had a 9.5% metastatic rate, T2b a 15.2% rate; AJCC8 T1 12.6% and T2 9.3%.
KEY PROGNOSTIC VARIABLES
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Numerous variables have been looked at as potential risk factors for poor outcomes a/w SCC (FIGURE). Some of the most profound include:
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Diameter >2cm: is a/w 2x risk of recurrence, 3x rate of metastasis, and 19x higher risk of death.
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Breslow depth: the most highly a/w metastasis. almost no risk when <2mm, 4% risk when 2.1-6mm, 16% risk when >6mm. 27% if it involves sub-Q fat.
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Ear or lip location: have reported metastatic risks of 9% and 14%, resp., after 5 yrs of follow up.
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SCCs arising in chronic wounds and scars: have a reported 26% metastatic risk.
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