What Is Cutaneous Squamous Cell Carcinoma (cSCC)?

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer, arising from the flat cells that make up the outer layer of skin. Most cases grow slowly, stay local, and are cured with surgery, but a subset behaves aggressively, spreading to lymph nodes or distant organs with survival rates that drop sharply once that happens. The gap between a routine office procedure and a life-threatening cancer depends on a handful of risk factors that are worth understanding clearly.

How cSCC Starts

The overwhelming driver is ultraviolet radiation from sunlight. UV light damages DNA in skin cells, and one of the genes most frequently hit is p53, a tumor suppressor that normally stops damaged cells from dividing. In a landmark study, researchers found UV-signature mutations in p53 in about 58% of invasive squamous cell carcinomas, with telltale DNA changes that could only have been caused by UV exposure.¹ Those mutations are the starting event for many tumors. Genomic studies have since confirmed that mutations in the NOTCH and p53 pathways are nearly universal in cSCC, with additional hits in pathways that control cell growth, cell-cycle checkpoints, and the structural packaging of DNA.²

One complication for researchers is that sun-exposed skin accumulates enormous numbers of mutations over a lifetime, most of which do nothing. Sorting the mutations that actually drive cancer from the harmless bystanders remains a central challenge in cSCC genomics.³ That high mutation burden, however, turns out to matter for treatment: tumors with lots of mutations tend to produce many abnormal proteins the immune system can recognize, which helps explain why immunotherapy works well in advanced cSCC.

The Precursor Stage That Most People Ignore

Most cSCCs do not appear out of nowhere. An estimated 82% arise from actinic keratoses (AKs), the rough, scaly patches that develop on chronically sun-exposed skin.⁴ AKs are confined to the top layer of skin, and any individual patch has a low chance of progressing to invasive cancer. But people who have a lot of them are playing a numbers game: the more AKs on your skin, the higher the cumulative odds that one will cross the line. Treating AKs with cryotherapy, topical creams, or light-based therapies is essentially intercepting cancer before it forms.

Who Is at Greatest Risk

Fair-skinned people with a history of heavy sun exposure make up the typical cSCC patient, but the single highest-risk group is organ transplant recipients. The immunosuppressive drugs that prevent organ rejection also hobble the immune surveillance that normally catches and eliminates early cancers. In a large U.S. study, the incidence of squamous cell carcinoma in transplant recipients was roughly 1,355 per 100,000 person-years, compared with 38 per 100,000 in the general adult population, a difference of about 35-fold.⁵ These cancers also tend to be more aggressive and carry higher mortality than the same tumors in people with intact immune systems.⁶

Although cSCC is far less common in people with darker skin, when it does occur the consequences can be worse. Nail-unit squamous cell carcinoma in individuals with Fitzpatrick phototypes IV through VI, for example, is frequently misdiagnosed for months or years because skin cancer is not on the clinical radar. A systematic review found that the time between first symptoms and diagnosis ranged from one month to seven years, and about a third of cases ultimately required amputation of the affected finger or toe.⁷ The lesson is that cSCC in darker-skinned patients tends to appear in non-sun-exposed sites like nail beds and chronic wounds, so both patients and clinicians need to think beyond the stereotypical sunburn-on-fair-skin presentation.

Marjolin’s Ulcer and Other Unusual Origins

Not every cSCC traces back to UV damage. Marjolin’s ulcer is a rare but aggressive form that develops in scar tissue, chronic wounds, or areas of long-standing inflammation. Burn scars, pressure sores, and non-healing leg ulcers are classic sites.⁸ The tumors are usually well-differentiated squamous cell carcinomas and most commonly show up on the lower extremities, especially the heel and sole of the foot.⁹ Because they arise in already-damaged tissue that people have often been living with for years, the malignant change can be easy to miss. Marjolin’s ulcers carry a high risk of spreading, which makes early detection and surgical removal critical.

What Makes a Tumor “High Risk”

Most cSCCs are cured with a straightforward excision. The tumors that cause real trouble share a specific set of features that push them into the high-risk category. Tumor thickness matters: tumors 6 mm or deeper carry significantly worse outcomes. Horizontal size above 2 cm, a desmoplastic growth pattern (in which the tumor provokes a dense scar-like tissue reaction), and immunosuppression in the patient are all independent risk factors for recurrence and death.¹⁰

Perineural invasion, where cancer cells grow along or into nerve sheaths, deserves special mention. It is uncommon in ordinary cSCC but dramatically worsens the prognosis when present. In a prospective study of nearly 1,400 tumors, desmoplastic cSCC with perineural invasion had a local recurrence rate of 64% and a tumor-specific death rate of 54%, compared with 3% recurrence and 4% death in standard non-desmoplastic tumors without nerve involvement.¹¹ Patients with perineural invasion often present with numbness, tingling, or pain in the area of the tumor, symptoms that should raise a red flag.¹²

Staging Systems and Why They Differ

You might expect a single, universally agreed-upon staging system for a cancer this common. Instead, several competing systems exist, and they do not always agree on which tumors are dangerous. A cohort study comparing the standard AJCC 8th-edition staging with the Brigham and Women’s Hospital (BWH) classification found that AJCC labeled twice as many tumors as high-stage (18%) compared with BWH (9%), but BWH was better at predicting which patients would actually develop metastases or die of their disease, with higher specificity and positive predictive value.¹³ A separate comparison that also included a Salamanca refinement and a Tübingen system found that all three alternatives produced high negative predictive values but low positive predictive values overall, meaning they were good at identifying who was safe but less precise at flagging who was truly in danger.¹⁴

For patients, the practical takeaway is that staging alone does not perfectly predict behavior. Clinicians often layer staging results with the individual high-risk features described above to make treatment decisions, rather than relying on any single classification.

Surgery as the Standard Treatment

Surgical removal with clear margins is the first-line treatment for most cSCC. The two main approaches are standard wide local excision (WLE) and Mohs micrographic surgery, in which the surgeon removes tissue in thin layers, examining each under a microscope in real time until no cancer cells remain at the edges. For head-and-neck tumors, a retrospective study found that recurrence after standard excision was about 8%, compared with 3% after Mohs, with Mohs-treated tumors at roughly three times lower risk of recurrence after adjusting for tumor size and depth.¹⁵

The advantage of Mohs becomes even more striking in high-stage disease. A study comparing the two approaches specifically in high-stage cSCC found that patients who had wide local excision had roughly double the three-year rate of local recurrence (about 20% vs. 10%) and more than double the rate of disease-specific death (about 18% vs. 7%) compared with those who had Mohs surgery.¹⁶ Mohs is not always available or practical, especially for tumors on the trunk or extremities, but for high-risk tumors in cosmetically sensitive areas like the face and ears, the evidence strongly favors it.

Radiation Therapy

Radiation fills several roles in cSCC management. After surgery, adjuvant radiation is used when margins are close or positive and re-excision is not feasible, or when high-risk features like perineural invasion or bone involvement are present. In one study of lower-lip cSCC, tumors with positive margins that did not receive radiation had a 64% local recurrence rate, versus 6% for those that got postoperative radiation.¹⁷

For patients who cannot have surgery at all, radiation can be the primary treatment. A systematic review pooling over 4,000 tumors found an overall local control rate of about 87% and a local recurrence rate of roughly 9%, though recurrence climbed above 25% for T3 and T4 tumors.¹⁸ Higher radiation doses produce longer disease control in unresectable head-and-neck cases, with two-year overall survival reaching about 65% in a high-dose group compared with 31% in a low-dose group.¹⁹

Immunotherapy for Advanced Disease

The arrival of checkpoint-inhibitor immunotherapy reshaped the landscape for advanced cSCC. Cemiplimab, a PD-1 inhibitor, was the first drug approved specifically for this cancer. In its pivotal trial, about 47% of patients with metastatic disease had a measurable response, and among those who responded, more than 80% were still responding at the time of data cutoff.²⁰ Extended follow-up confirmed a response rate of about 46% overall, with roughly 16% achieving a complete response. The estimated proportion of responding patients who still had an ongoing response at 12 months was about 88%, and median overall survival had not been reached at two years of follow-up, with an estimated two-year survival probability of about 73%.²¹

The high mutation burden of cSCC likely explains why these tumors respond to immunotherapy at rates comparable to melanoma. Research on the tumor microenvironment has found that about half of cSCCs express PD-L1, a protein that helps tumors hide from immune cells, while a separate immune checkpoint called VISTA is expressed in a similar proportion. Intriguingly, VISTA expression correlated more strongly with T-cell activity inside the tumor than PD-L1 did, and the two were not strongly co-expressed, suggesting tumors use distinct strategies to evade the immune system.²² These findings hint at future combination strategies targeting both pathways simultaneously.

When Immunotherapy Is Not an Option

Not everyone can receive PD-1 inhibitors. Organ transplant recipients risk triggering organ rejection, and patients with certain autoimmune conditions may experience dangerous flares. For these patients, drugs targeting the epidermal growth factor receptor (EGFR) offer an alternative. A meta-analysis of 12 studies and 324 patients found a pooled response rate of about 26%, with a median progression-free survival of roughly five months and a median overall survival of about 12 months.²³ That is less impressive than immunotherapy, but for patients who have no other options it represents meaningful disease control. Combining an anti-PD-L1 antibody (avelumab) with the EGFR-targeting antibody cetuximab showed a 41% response rate in a phase II trial, with four of fourteen patients who had already failed PD-1 therapy still responding to the combination.²⁴

What Happens When cSCC Spreads to Lymph Nodes

Metastatic cSCC is uncommon overall but carries sobering outcomes. In a study of patients with regional lymph-node metastases from head-and-neck cSCC, five-year overall survival was only about 22%, and disease-free survival was 34%.²⁵ Among the factors that most strongly predicted poor outcomes, extranodal spread, where cancer breaks through the capsule of a lymph node into surrounding tissue, stands out. In one analysis, extranodal spread carried a hazard ratio of nearly 10 for dying of disease, the strongest single prognostic factor identified.²⁶ Immunosuppression, incomplete surgical margins, and the specific treatment approach were the other variables that drove survival differences. Patients with the highest-risk profile had a five-year disease-specific mortality of 56%, while those in the lowest-risk group had just 6%.²⁷

Neoadjuvant Immunotherapy Before Surgery

One of the more promising shifts in management is giving immunotherapy before surgery rather than only after it. The idea is to shrink the tumor and prime the immune system to mop up microscopic disease. A pilot phase II trial of neoadjuvant PD-1 blockade in patients with locally advanced head-and-neck cSCC found that 70% achieved a pathologic complete or major pathologic response, meaning that when surgeons went in, most of the tumor was already gone.²⁸ A subsequent real-world cohort study confirmed these results, with a pathologic response rate of about 47% and a complete pathologic response rate of roughly 37%.²⁹ This approach is still early in its development, but the high response rates suggest it could eventually become standard for tumors that would otherwise require disfiguring surgery.

Nicotinamide for Prevention

For people who have already had one skin cancer, preventing the next one becomes a priority. Nicotinamide (vitamin B3, not to be confused with nicotinic acid or niacin) has shown genuine chemopreventive effects. A randomized trial in high-risk Australians found that 500 mg twice daily reduced the rate of new squamous cell carcinomas by about 30% and cut actinic keratosis counts by 11 to 20% over a year, with essentially no side effects.³⁰ The benefit disappeared when the supplement was stopped, so continuous use is necessary.

A more recent analysis refined the picture: starting nicotinamide after a first skin cancer was associated with a 54% risk reduction, but the benefit was smaller when started after subsequent cancers, suggesting the earlier you begin, the better it works. The benefit was strongest specifically for cSCC.³¹ For organ transplant recipients, the overall effect did not reach statistical significance in pooled data, though early use showed a trend toward reduced cSCC.³² Given its safety profile and low cost, nicotinamide is one of the few evidence-based tools for reducing skin cancer recurrence, though it is a supplement to sun protection, not a replacement.

The Psychosocial Side of cSCC

Because most cSCCs arise on the head and neck, treatment can leave visible scars, tissue loss, or functional changes that affect daily life. The cosmetic and functional outcomes of surgery, especially for larger or deeper tumors, carry real psychosocial weight, affecting confidence, body image, and emotional well-being.³³ Quality-of-life research in cSCC lags behind that in melanoma and other cancers, partly because cSCC has long been considered a minor, easily curable problem. For the minority of patients with advanced or high-risk tumors, that assumption does not hold, and there is a recognized need for better patient-reported outcome tools tailored to this disease.