From Biopsy to Biomarkers: Experts Navigate Skin Cancer Diagnosis and Staging

Accurate skin cancer diagnosis increasingly extends beyond identifying a suspicious lesion. Clinicians must determine when to biopsy, select an appropriate technique, interpret pathology and risk factors, choose between surgical approaches, and, in select patients, consider whether emerging molecular tools can add meaningful information to traditional staging.

During the Diagnosis & Staging session at the Dermatology Times Cutaneous Oncology Workshop in Tampa, Florida, faculty walked attendees through that continuum using clinical pearls, audience polling, and case-based discussions of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), melanoma, and Merkel cell carcinoma (MCC). The session featured Amy Spizuoco, DO; Amit Om, MD; and Angad Chadha, MD.

Recognizing When a Lesion Warrants Biopsy

Spizuoco opened with a review of the clinical features clinicians should recognize across the major forms of skin cancer, beginning with BCC.

Although BCC carries a low overall risk of mortality and metastasis, its potential for local destruction and recurrence makes recognition and appropriate treatment important. Spizuoco reviewed the “ERUPTS” mnemonic—edges that are rolled or raised; rolled, pearly, or translucent appearance; upper lip or another sun-exposed site; pink or red patch; telangiectasia; and a sore that bleeds easily—as one way of remembering characteristic findings.

Risk stratification, however, requires looking beyond whether a lesion simply appears to be a BCC. Micronodular, infiltrative, morpheaform or sclerosing, and basosquamous growth patterns were highlighted as higher-risk subtypes, whereas nodular BCC remains the most common presentation.

Spizuoco similarly reviewed cSCC, emphasizing cumulative UV exposure, chronic inflammation, and immunosuppression as important risk factors. Transplant recipients and other immunosuppressed patients warrant particular attention, as do patients with chronic, nonhealing wounds. The workshop materials outlined progression from actinic keratosis and Bowen disease in situ through microinvasive and invasive SCC.

When the discussion moved to melanoma, Spizuoco returned to the familiar ABCDE criteria—asymmetry, border irregularity, color variegation, diameter greater than 6 mm, and evolution—but emphasized that clinical judgment should remain central when deciding whether to biopsy.

“If you see it clinically with your naked eye, and you're worried about it, don't ever talk yourself out of a biopsy based on your dermoscopic findings,” Spizuoco told attendees.

The point is particularly relevant given the variability of melanoma presentation. Superficial spreading melanoma accounts for the majority of cases, but nodular, lentigo maligna, acral lentiginous, and other subtypes can present differently.

Biopsy technique also matters. Shave or saucerization may be used for superficial lesions, whereas punch biopsy provides a full-thickness sample for deeper or diagnostically ambiguous lesions. When melanoma is suspected, the presentation identified excisional biopsy as the preferred approach because preserving architecture allows accurate evaluation of Breslow depth and microstaging.

Merkel Cell Carcinoma Demands Urgency

Spizuoco concluded her portion of the session with MCC, an uncommon but highly aggressive malignancy that may initially appear deceptively nonspecific.

Approximately one-third of patients have nodal or systemic metastases at diagnosis, and immunohistochemistry is required for accurate diagnosis and differentiation from other tumor types. Risk factors include advanced age, immunosuppression, and Merkel cell polyomavirus, which is associated with approximately 80% of cases.

The AEIOU mnemonic can help clinicians remember characteristic features: asymptomatic or lacking tenderness, expanding rapidly, immune suppression, older than 50 years, and an ultraviolet-exposed site.

Spizuoco stressed that an otherwise unremarkable pink papule should not necessarily be dismissed, particularly in a patient with relevant risk factors. Suspicion of MCC warrants biopsy and prompt referral rather than prolonged observation.

Breslow Thickness Drives Melanoma Surgical Planning

Om then shifted the discussion from diagnosis to surgical management with a case-based review of Mohs micrographic surgery (MMS), wide local excision (WLE), and staging.

For primary cutaneous melanoma, WLE remains the standard surgical approach when recommended clinical margins can be obtained. Those margins are largely determined by Breslow thickness: 0.5 to 1 cm for melanoma in situ, 1 cm for tumors 1 mm or thinner, 1 to 2 cm for tumors between greater than 1 and 2 mm, and 2 cm for melanomas thicker than 2 mm.

The importance of Breslow thickness was reinforced through a case involving a 52-year-old man with an enlarging pigmented lesion on his upper back. Pathology demonstrated superficial spreading invasive melanoma with a Breslow depth of 0.7 mm and ulceration, placing the tumor at T1b.

Om explained that approximately 0.8 mm represents an important threshold for discussing sentinel lymph node biopsy (SLNB), although the decision should not be reduced to a single number.

“Every patient is different,” Om said, noting that younger age and ulceration may make clinicians more inclined to discuss SLNB even with a somewhat thinner melanoma, whereas the balance of risks and benefits may look different in an older patient.

Current NCCN guidance recommends discussing and considering SLNB when the estimated likelihood of a positive sentinel node is between 5% and 10%, which includes clinical stage IB, T1b melanoma.

Importantly, during the live presentation, Om corrected the case slide to clarify that the patient's sentinel lymph node was negative, rather than positive as displayed. The patient underwent WLE with a 1-cm margin and continued surveillance.

Where Does Mohs Fit in Melanoma?

The case led into a broader discussion of an evolving question in cutaneous oncology: whether MMS has a role in selected melanomas.

WLE remains recommended for invasive melanoma when standard clinical margins can be obtained. Data reviewed during the session suggest comparable outcomes between MMS and WLE in some retrospective and pooled analyses, but the evidence has not displaced WLE as the standard surgical approach for invasive disease.

Om discussed how margin-controlled approaches may nevertheless be considered in select circumstances, particularly where tissue preservation is important. The decision becomes markedly different for nonmelanoma skin cancer, for which MMS has a much more established role.

MMS is considered a first-line surgical procedure for many locally invasive, high-risk skin cancers, particularly when maximal preservation of uninvolved tissue is important. BCC and cSCC remain the malignancies most frequently treated with the technique.

A High-Risk cSCC Reveals More Than the Initial Biopsy

A second surgical case demonstrated why risk assessment may change as clinicians obtain additional information.

The patient, a 76-year-old man, presented with a 2.0 × 2.7-cm moderately differentiated cSCC of the left ear associated with pain and bleeding. There was no palpable head or neck lymphadenopathy, and the initial shave biopsy did not demonstrate involvement of the underlying cartilage.

The location itself was significant. The ear represents a high-risk site, and the tumor's size and clinical features further influenced treatment considerations. MMS was ultimately selected after discussion with the patient.

During curettage, however, clinicians identified a 2-mm full-thickness defect in the scapha cartilage. Permanent sections subsequently confirmed that the cSCC had invaded through the auricular cartilage and extended to the posterior ear skin. Clear margins were obtained after 1 Mohs stage. Adjuvant radiation was discussed but declined by the patient and his family, with regular surveillance planned.

The case reinforced the value of complete margin assessment and demonstrated how previously unidentified high-risk features can emerge during treatment.

Evidence presented during the session also showed potentially meaningful outcome differences between MMS and WLE in high-stage cSCC. In a retrospective cohort analysis, 3-year cumulative incidences of local recurrence, nodal metastasis, any recurrence, and disease-specific death were greater following WLE than MMS after inverse probability of treatment weighting.

Can Molecular Testing Refine cSCC Risk?

Chadha brought the session into the rapidly evolving field of molecular testing, beginning with an 80-year-old man with a 1.2-cm, well-differentiated cSCC of the frontal scalp.

The tumor was initially classified as Brigham and Women's Hospital (BWH) T1. During Mohs surgery, however, perineural invasion was identified, resulting in upstaging to BWH T2a. A baseline MRI was negative, and radiation therapy was recommended. Because the patient was hesitant to undergo radiation, 40-gene expression profile (40-GEP) testing was ordered to provide additional information about metastatic risk.

Chadha explained that traditional staging establishes a population-level estimate of risk, whereas GEP testing may further divide patients within the same stage according to the molecular characteristics of their tumors.

“It's a test that can further sort of stratify risk of metastasis in cutaneous squamous cell cancer,” he explained.

The workshop data demonstrated that 40-GEP results can provide additional metastatic risk stratification beyond traditional AJCC and BWH staging.

For the patient in the case, testing returned a Class 1 result. He ultimately chose not to undergo radiation therapy and instead agreed to monitoring and follow-up.

GEP Testing Enters the SLNB Conversation in Melanoma

The role of molecular testing becomes more complicated in melanoma, where Chadha emphasized both its potential and its current limitations.

A 39-year-old woman presented with a changing pigmented lesion on her right forearm. Biopsy demonstrated a 0.9-mm melanoma without ulceration, with a mitotic rate of 2/mm², no lymphovascular invasion, and no evidence of regression, resulting in a T1b classification.

The patient was hesitant to undergo SLNB because she was the primary caregiver for her husband with Parkinson disease. A clinicopathologic gene expression profile (CP-GEP) test was therefore ordered to further assess her risk.

Chadha reviewed results from the prospective MERLIN_001 study, which evaluated CP-GEP in 1761 patients with predominantly T1 to T3 melanoma. Overall, 37% were classified as low risk and 63% as high risk. The low-risk result had a negative predictive value of 92.9%, and a high-risk result was associated with a 3.4-fold greater risk of sentinel node metastasis than a low-risk result.

The distinction is clinically intriguing but not definitive. Chadha noted that the low-risk group did not consistently fall below the less-than-5% threshold NCCN uses to define a sufficiently low likelihood of SLN positivity.

“Our tumor board does not recommend this test regularly,” Chadha said, “but I do think that there is a role for it in the right patient.”

That caveat aligns with updated NCCN guidance presented during the workshop: predictive GEP testing for nodal metastasis risk should not replace surgical oncology discussion of SLNB in eligible patients.

In the presented case, the patient's CP-GEP result returned high risk. She subsequently underwent WLE and SLNB, and the sentinel node was positive.

Emerging Data Add to the GEP Discussion

Chadha also reviewed 2026 findings from the DECIDE study evaluating an integrated 31-GEP test for predicting SLN positivity.

Among patients whose test predicted an SLN positivity risk below 5%, the observed positivity rate was 2.6%. For predicted risks of 5% to 10%, the observed rate was 7.0%, while patients predicted to have greater than 10% risk had an observed SLN positivity rate of 21.4%. Similar separation was observed when the analysis was restricted to T1 through T2a melanoma.

Chadha characterized the findings as promising but emphasized that additional evidence will be important before molecular testing fundamentally changes established staging pathways. The presentation also noted that the i31-GEP test is not currently included in NCCN guidance.

ctDNA Offers a Molecular Window Into Residual Disease

The final portion of the session turned to circulating tumor DNA (ctDNA), which may provide another way to detect molecular evidence of disease that is not apparent clinically or radiographically.

Chadha explained that tumor-informed assays first identify the genetic signature of an individual's tumor and then look for that same signature in serial blood samples.

The underlying concept is straightforward: persistent or newly detectable tumor DNA following treatment may indicate residual or recurrent disease before it otherwise becomes clinically evident. In melanoma, studies reviewed during the presentation associated postoperative or post-treatment ctDNA positivity with poorer recurrence-free and overall outcomes.

But Chadha stressed that a positive association does not automatically establish how clinicians should use the information.

“It is still unclear where this fits in the follow-up algorithm of these patients,” he said.

Questions remain about which melanoma patients should undergo testing, how frequently it should be performed, and what clinicians should do when molecular recurrence precedes detectable disease.

ctDNA Shows a Clearer Role in Merkel Cell Carcinoma

The potential application became more concrete in the final MCC case.

A 76-year-old man with chronic lymphocytic leukemia presented with a 1.8-cm enlarging, painless, violaceous nodule on the left cheek. Punch biopsy confirmed MCC, and immunohistochemistry was positive for CK20. The tumor was Merkel cell polyomavirus negative, and whole-body PET/CT initially showed no regional or distant disease.

The patient received neoadjuvant immunotherapy followed by WLE and SLNB. The primary tumor demonstrated a pathologic complete response, but the sentinel node was positive, upstaging the patient to stage IIIA. Postsurgical baseline ctDNA was undetectable.

Serial monitoring then demonstrated the potential value of molecular surveillance.

ctDNA remained undetectable at 3 and 6 months. At 9 months, however, the test became positive despite a reassuring physical examination and no new symptoms. Imaging subsequently revealed a new enlarged lymph node, and core needle biopsy confirmed recurrent MCC. The patient was then treated with anti–PD-L1 therapy while serial ctDNA monitoring continued.

Current NCCN guidance reviewed during the session notes that ctDNA can assess disease burden in both virus-positive and virus-negative MCC and may become positive before or at the time of clinically evident recurrence. For surveillance, testing is often obtained every 3 months.

From the Lesion to the Molecular Level

Across the session, a common theme emerged: no single piece of information determines the management of every patient with skin cancer.

Clinical appearance determines when suspicion begins. Biopsy technique affects the information available to the pathologist. Histology, Breslow thickness, ulceration, anatomic location, perineural invasion, and other features help establish risk. Surgical approaches must balance oncologic control with preservation of healthy tissue. And increasingly, GEP and ctDNA testing may provide another layer of information when conventional staging leaves clinicians and patients facing uncertain decisions.

At the same time, faculty cautioned against allowing newer technologies to outrun the evidence. Molecular testing may refine risk in carefully selected patients, but it does not uniformly replace established staging, surgical evaluation, or multidisciplinary decision-making.

For clinicians, the practical message from the Diagnosis & Staging session was less about choosing one test or staging system than knowing how to integrate each piece of information—and recognizing when a patient's risk warrants escalation, referral, or a broader multidisciplinary discussion.

References

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2. National Comprehensive Cancer Network. (2026). NCCN Clinical Practice Guidelines in Oncology: Melanoma: Cutaneous. Version 3.2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492
3. Wang, D. M., et al. (2025). Mohs micrographic surgery versus wide local excision for primary high-stage cutaneous squamous cell carcinoma. JAMA Dermatology, 161(5), 508-514. https://jamanetwork.com/journals/jamadermatology/fullarticle/2830249
4. Ibrahim, S., et al. (2022). 40-gene expression profile testing for risk stratification in cutaneous squamous cell carcinoma. Future Oncology, 18(7), 833-847. https://pubmed.ncbi.nlm.nih.gov/34821148/
5. Hieken, T. J., et al. (2025). Clinicopathologic gene expression profiling and sentinel lymph node biopsy risk in melanoma: Results from the MERLIN_001 study. JAMA Surgery, 160(12), 1358-1366. https://jamanetwork.com/journals/jamasurgery/fullarticle/2840207
6. Beard, T., et al. (2026). Integrated 31-gene expression profiling for prediction of sentinel lymph node positivity in melanoma: Results from the DECIDE study. Future Oncology, 22(8), 933-938. https://www.tandfonline.com/doi/full/10.1080/14796694.2026.2640227
7. Ansstas, G., et al. (2026). Circulating tumor DNA for postoperative surveillance in melanoma. Clinical Cancer Research, 32(8), 1513-1521. https://pubmed.ncbi.nlm.nih.gov/41632449/
8. Akaike, T., et al. (2024). Circulating tumor DNA as a biomarker for recurrence in Merkel cell carcinoma. Journal of Clinical Oncology. https://pubmed.ncbi.nlm.nih.gov/39052958/