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Advanced Squamous Cell Carcinoma

When cutaneous SCC is locally advanced or has spread

Medically reviewed by Dr. Steven Q. Wang, MDLast reviewed

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What Is Advanced Squamous Cell Carcinoma?

Squamous cell carcinoma (SCC) is the second most common skin cancer, and the great majority are cured with a single procedure in a dermatologist's office. A small fraction behave differently — growing quickly and deeply, invading nerves, coming back after surgery or radiation, or spreading to lymph nodes and, less often, to distant organs. Doctors call these tumors "advanced," and they are managed with a different set of tools, usually by a team rather than a single dermatologist.

"Advanced SCC" is an umbrella term for two distinct situations:

Locally advanced SCC

The tumor has grown large or deep, invaded nerves, muscle, cartilage, or bone, or recurred after treatment — and surgery or radiation can no longer clear it without unacceptable damage to function or appearance, or it is considered inoperable. This accounts for the large majority of advanced cases.

Metastatic SCC

The cancer has spread beyond the skin — most often to nearby (regional) lymph nodes, and less commonly to the lungs, liver, or bone. Overall this happens in only a few percent of cutaneous SCCs, but the risk is far higher for tumors with high-risk features or in people who are immunosuppressed.

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Key Topics

Explore these topics to understand what advanced squamous cell carcinoma means, how it is evaluated, and the treatment options available:

What does "advanced" squamous cell carcinoma mean?
Locally advanced vs. metastatic disease, and how uncommon each one is
What makes a squamous cell carcinoma "high-risk"?
Size, depth, differentiation, and the staging systems that flag aggressive tumors
What does perineural invasion mean for my SCC?
When an SCC grows along nerves, and how that changes treatment
When does SCC spread to lymph nodes, and what is a sentinel node biopsy?
Regional (nodal) metastasis, node staging, and when a sentinel node biopsy is offered
How is advanced SCC evaluated before treatment?
Imaging, pathology review, and the multidisciplinary care team
When are surgery and radiation no longer enough?
What "unresectable" and "locally advanced" mean in practice
How does immunotherapy treat advanced SCC?
PD-1 inhibitors (cemiplimab, pembrolizumab) as first-line systemic therapy
How are the side effects of immunotherapy managed?
Immune-related side effects, monitoring, and when treatment is paused
Can immunotherapy shrink an SCC before surgery?
Neoadjuvant therapy to reduce tumor size and preserve tissue
Advanced SCC in transplant recipients and immunosuppressed patients
Why SCC is more aggressive with immunosuppression, and the immunotherapy dilemma
Where do chemotherapy and EGFR-targeted therapy fit?
Cetuximab and platinum chemotherapy when immunotherapy isn't an option
How do I find a clinical trial for advanced SCC?
Where to look, what the phases mean, and questions to ask
What should I ask my care team about advanced SCC?
Questions for your dermatologist, surgeon, radiation oncologist, and medical oncologist
What is the outlook, and what support is available?
Prognosis, follow-up, and supportive care for advanced disease

Signs an SCC May Be Advanced

Most SCCs are small and treated easily. Features that prompt a doctor to consider advanced disease include:

  • •A tumor that has come back one or more times after surgery or radiation
  • •A large growth (roughly 2 cm or more, especially on the head or neck) or one enlarging rapidly over weeks
  • •A lesion fixed to deeper tissue, or that has grown into fat, muscle, cartilage, or bone
  • •Numbness, tingling, burning, weakness, double vision, or facial drooping near the tumor (possible nerve involvement)
  • •A "poorly differentiated" (high-grade) tumor, or one with perineural or lymphovascular invasion on the pathology report
  • •A firm or enlarging lymph node near a known or treated skin cancer (in front of the ear, in the neck, armpit, or groin)

Who Develops Advanced SCC

  • •People whose tumor went untreated for months to years, or was dismissed as a sore that would not heal
  • •Tumors with high-risk pathology — poor differentiation, deep or thick invasion, or perineural invasion
  • •Solid-organ transplant recipients and others on long-term immunosuppression, who develop more SCCs and more aggressive ones
  • •People with chronic lymphocytic leukemia or lymphoma
  • •SCCs arising in old burn scars, chronic wounds, or previously irradiated skin
  • •Rare genetic conditions such as xeroderma pigmentosum or epidermolysis bullosa

Why Timely Treatment Matters

Advanced cutaneous SCC is largely preventable. Most cases follow a tumor that was watched too long, mistaken for a wart or a non-healing sore, or that recurred repeatedly without a change in approach.

An SCC caught and treated early is cured with a single procedure the large majority of the time. The same tumor left to grow can invade nerves, require major reconstruction, or spread to lymph nodes — at which point treatment may involve surgery plus radiation, systemic medication, or a multidisciplinary team. If you have an SCC that has recurred, is growing quickly, or is causing numbness or tingling, ask your dermatologist whether you should be referred to a Mohs surgeon or a head and neck cancer team.

Advanced Treatment Overview

When surgery and radiation cannot cure the disease on their own, advanced SCC is treated with medication that works throughout the body, often alongside local treatment. Every option below is individualized and carries meaningful side effects that are weighed against its benefits.

  • •Immunotherapy (PD-1 inhibitors): Cemiplimab and pembrolizumab help the immune system recognize and attack the cancer. They are now the first-line systemic treatment for locally advanced or metastatic cutaneous SCC that cannot be cured with surgery or radiation.
  • •Surgery and radiation together: For tumors that have reached lymph nodes or carry high-risk features, treatment often combines surgery (sometimes including lymph node dissection) with radiation to the tumor site and/or the draining nodes.
  • •EGFR inhibitors and chemotherapy: Cetuximab and platinum-based chemotherapy are older options, now used mainly when immunotherapy is not appropriate — for example, in some transplant recipients where checkpoint inhibitors carry a high risk of triggering organ rejection.
  • •Clinical trials: New drugs, drug combinations, and approaches such as giving immunotherapy before surgery (neoadjuvant therapy) are under active study and may be an option at any point.

Sources

Clinical Guidelines & Peer-Reviewed Literature

  • Work Group; Kim JYS, Kozlow JH, Mittal B, et al. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018;78(3):560-578. PubMed
  • Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341-351. PubMed
  • Grob JJ, Gonzalez R, Basset-Seguin N, et al. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol. 2020;38(25):2916-2925. PubMed

Patient Resources

Disclaimer: This page is for educational purposes only and is not a substitute for professional medical advice. Always consult a qualified dermatologist or oncologist about your diagnosis and treatment plan.

Printable Discussion Guide

Every question from the topics above, collected into one printable checklist — with a checkbox and space for notes beside each, and header fields for your appointment date and doctor's name.

Download complete advanced SCC discussion guide (PDF)

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