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Summary of the event organized in cooperation with the University of Brescia: “Updates in Onco-Dermatology”, featuring renowned speakers Prof. Lallas, Prof. Nagore, Prof. Argenziano & Prof. Thomas.
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Stéphane Fauverghe
NAOS International Medical Relations Director
Dear All,
I am very pleased to present you the 2nd edition of Bioderma Updates Series dedicated to Onco-Dermatology.
For 2 years now, Bioderma is regularly organizing international events dedicated to Dermatology, for dermatologists and all healthcare professionals interested in Dermatology, always presented by renowned experts in their field. In our approach to promote the development of knowledge in Dermatology, we have the pleasure to propose you this new publication that is the summary of the recent event organized in cooperation with the University of Brescia: Updates in Onco-Dermatology, with Prof. Aimilios Lallas from Greece, Prof. Eduardo Nagore from Spain, Prof. Giuseppe Argenziano from Italy & Prof. Luc Thomas from France as speakers.
During this e-symposium, Aimilios Lallas presented clinical and dermoscopic predictors of squamous cell carcinoma of the lips, Eduardo Nagore delivered a lecture on a critical reappraisal of the indications of lymphnode biopsy in melanoma patients, Giuseppe Argenziano presented clinical clues to avoid missing melanoma when morphology is not enough and finally Luc Thomas gave a presentation on the role of skin care in the management of melanoma and squamous cell carcinoma of the nail.
I wish you all a pleasant, enriching and interesting reading.
Aimilios Lallas, M.D., M.Sc., PH.D.
Aristotle University, Thessaloniki, Greece
Squamous cell carcinoma of the lip (lip SCC, Figure 1) composes 25 % to 30 % of all oral cancers. (1) It most frequently begins as a premalignant ulcerative lesion of the lip, known as actinic or solar cheilosis. Approximately 16.9 % of in-situ lip SCC develop into invasive forms. (2- 3).
Its diagnosis may be challenging because, in its early stage, it clinically resembles actinic cheilitis (AC, Figure 2) and inflammatory lesions of the lips. Thus, early diagnosis is very important as the risk of recurrence and metastases ranges from 5 to 20 %, which is about ten times that of SCC developing on the trunk and extremities. (4-5)
Several risk factors have been associated with lip SCC, including male sex, older age, fair skin, and UV light exposure. SCC of the lips is more likely to occur in men, on the lower lip, in individuals above 70 years old and in patients who are immunosuppressed. (1-6) SCC most often develops as an exophytic, ulcerated, and hyperkeratotic nodule, and is easy to clinically diagnose at an advanced stage. (7)
Differential diagnosis between AC and early invasive SCC can be challenging and even be threatening when performed without biopsy. Clinicians should not attempt to differentiate between AC and SCC on the only basis of clinical findings, and any evidence of ulceration or erosion should raise suspicion for SCC. (8)
In most skin cancers, dermoscopy may allow to resolve the diagnosis problem to a substantial extent. On the contrary, on the lips, dermoscopy is not as helpful. Although the dermoscopic variability of cutaneous SCCs, according to their histopathological grade of differentiation, has been well described, very limited data regarding SCC of the lips is available from the literature. (9-10)
Dermoscopic features of lip SCC include ulceration (in 91 % of all cases), small linear vessels, scales, white structureless areas, while halos, and white circles, all of them corresponding to keratinization of the tumor. (11) Concerning actinic cheilitis, the three most frequent dermatoscopic features are white structureless areas, scales, and superficial erosions. (12) Thus, with dermoscopy, there is an overlap between actinic cheilitis and SCC of the lips. However, the most significant difference is ulceration for SCC vs. erosion for actinic cheilitis. Even though, discriminating between both conditions using dermoscopy remains challenging.
Predictors for SCC of the lips include exophytic appearance, hyperkeratosis, ulceration, and white clods. (13) A scaly lesion with exophytic growth, dermatoscopically displaying white clods, ulceration and linear and hairpin vessels is very likely a squamous cell carcinoma of the lips, prompting to lesion excision.
In clinical practice, a differential diagnosis can be even more difficult to make between actinic cheilitis, SCC, and inflammatory cheilitis which can mimic SCC. Three recent studies intended to differentiate dermoscopic features. In the first one, in which actinic cheilitis was compared with other common nonneoplastic inflammatory cheilitis, no pathognomonic mucoscopic features allowed to differentiate them, and there was a considerable overlap between all types of cheilitis. (14) However, this study confirmed that some features (white-red structureless background, polymorphous vessels in the shape of irregular hairpins, and erosions) were more frequently seen in actinic cheilitis. Results from a second study to determine clinical and dermatoscopic predictors of squamous cell carcinoma of the lip vs. other lip lesions indicated that clinical predictors of lip squamous cell carcinoma were exophytic appearance and clinical hyperkeratosis.(13) White clods and ulceration, in dermoscopy, presented a 6-fold and 4-fold increased risk for squamous cell carcinoma respectively. In the third study, the presence of vessels, scale/crust, and keratinization-associated white structures were the most common dermoscopic clues in lip SCC.(15)
Although making a differential diagnosis can be challenging, presence of ulceration and white clods, on dermoscopy, entails the need for biopsy and excision, because of suspicion of SCC. Think of actinic cheilitis when seeing superficial erosions. If Wickham striae, hallmark of lichen planus white lines are present, the diagnosis is hypergranulosis. Finally, tumors rarely occupy the whole lip surface, while inflammations and infections do it much more frequently.
Eduardo nagore, M.D., PH.D.
Instituto Valenciano de OncologĂa, Valencia, Spain
Accurate staging and patient stratification into clinically relevant stage groups are fundamental for melanoma prognosis assessment and clinical decision making. Since the early 1990s, sentinel lymph node biopsy (SLNB) has been a routine procedure for localized melanoma.(1) It is indicated for >T1b melanomas (or T1a with increased risk: i.e., vascular invasion, ≥ 2 mitoses/mm2) without clinical or radiographic evidence of regional node metastasis, therefore aimed at detecting “clinically occult” metastasis.
There are differences between the American Joint Committee on Cancer (AJCC) 7th and 8th edition staging manuals. In the current edition (8th), all cases are staged with SLNB, and this has changed our view of the prognosis.(2) SLNB allows to move many cases into stage III. Stages I/II are more current and clinically relevant. Regarding melanoma specific survival (MSS), according to stage III groups, stage group stratification is based on both T- and N-category criteria (tumor thickness, ulceration, LN #, SLN (+) or clinically evident regional lymph nodes, microsatellites/ITM satellites). In the 8th edition of AJCC, patients with stage IIIA and IIIB, have a better prognosis than patients with stages IIA or IIB, respectively. With the 8th AJCC, a more advanced stage does not necessarily translate into a worse prognosis.(3)
According to the differential metastasis model, melanoma can either not progress or metastasize to a lymphatic and/or hematogenous environment. (4) Evidences for independent dissemination pathways were observed in a study assessing the risk factors for lymphatic and hematogenous disseminations in patients with stages I to II cutaneous melanoma.(5) Almost 30% of all melanoma lesions exhibited a complete remission, regardless of the lymph node involvement. Prophylactic and sentinel lymph node-guided lymph node dissection had no impact on melanoma specific survival. Moreover, a negative SLNB did not guarantee survival in patients with melanomas that developed exclusively hematogenous metastases. Thus, lymphatic involvement is insufficient to make a melanoma prognosis (distant metastasis and death). Follow-up and adjuvant treatment strategies may need to be adapted to individual clinical, histopathologic, and molecular characteristics.
Complete lymph node dissection is not recommended in patients with melanoma and lymph node micro-metastases of at least a 1 mm diameter or smaller. (6) Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases.(7) No impact of early or delayed lympha-denectomy on melanoma specific survival rate has been reported. According to the NCCC guidelines Version 3.2022, for both sentinel node positive stage IIIA and IIIB/C/D, the primary treatment is nodal basin ultrasound surveillance (generally preferred) or completion lymph node dissection.(8) In 2019, the ECBI guidelines recommended to stop complete lymphadenectomy in patients with sentinel lymph node micro metastases, recommending the use of adjuvant systemic therapy and stage-specific follow-up.(9)
SLNB remains relatively safe but may go along with complications such as lymphoedema, hematoma/seroma, infection, and suture dehiscence in about 10% of patients.(10) False negative results are found mostly for head and neck SLNBs. Thus, SLNB usefulness resides in selecting patients at increased risk who might benefit from adjuvant therapy.
Three adjuvant therapy studies were performed in stage III patients, after complete regional lymphadenectomy. They consist of:(1) CHECKMATE-238: Stage IIIBIIIC, IV (AJCC 7th edition), nivolumab vs. ipilimumab. The adjuvant nivolumab provided clinically meaning ful improvements in RFS, DMFS and OS versus a watch-and-wait strategy in high-risk resected melanoma (11); (2) EORTC 1325/ KEYNOTE-54: Stage IIIA (>1 mm)-IIIC (AJCC 7th edition): pembrolizumab vs. placebo; and(3) COMBI-AD: Stage IIIA (>1 mm)-IIIC (AJCC 7th edition), BRAF+: dabrafenib + trametinib vs. placebo. All of these studies showed a statistically significant impact on disease-free survival and distant metastasisfree survival (DMFS). Adjuvant therapy was also tested for stage IIB/IIC (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) in two studies: (1) KEYNOTE 716: pembrolizumab vs. placebo (rechallenge/ crossover); and(2) Third interim analysis (G Long, ASCO Annual Meeting 2022), in which pembrolizumab significantly improved DMFS (HR 0.64; 95% CI 0.47-0.88; p=0.0029). Neoadjuvant treatments were promising in melanoma, indicating that the presence of melanoma cells increases the efficacy of immunotherapy. The aim of the staging procedure is to modify clinical management, using adjuvant therapy and follow-up. For example: once complete lymph node dissection (CLND) is no longer performed, it is replaced by close follow-up with ultrasounds of the lymph node basin/s. In the same way, SLNB outcome should change clinical management through image re-staging (relevant when the clinical stage is IB-IIA), follow-up, and adjuvant therapy. Thus, in clinical stages (IA)/IB, if SLNB is negative, management shall include follow-up; if SLNB is positive, follow-up/adjuvant therapy is indicated. In clinical stage IIA, follow-up is indicated for SLNB (-) and adjuvant for SLNB (+). SLNB should probably be abandoned in all the cases in which adjuvant therapy is already indicated before knowing the SLNB status. In contrast, SLNB should be offered to patients in clinical stage IIA with a relatively high probability of modifying the management. However, all available data from adjuvant therapy come from pathologically staged patients (with SLNB and CLND). Therefore, there is a lack of direct evidence of the benefit of adjuvant therapy in survival if SLNB is not performed.
There is a current and ongoing debate on the need for SLNB in melanoma. If adjuvant therapy is available and indicated regardless of SLNB status, SLNB can be avoided. In the meantime, decisions at this level, awaiting for consensus/guidelines, should be performed in institution committees and, most probably, case by case. The near future seems to aim at finding prognostic biomarkers (for risk of relapse and death) with many candidates currently under examination.
Guiseppe Argenziano, M.D., PH.D.
Dermatology Unit, University of Campania Luigi Vanvitelli, Naples, Italy
Melanoma is one of the most fatal forms of skin cancer and the most diagnosed in fair-skinned populations.(1-7) In 2008, its incidence worldwide was estimated at 200,000 new cases, with more than 46,000 deaths.(6)
Due to its location, skin melanoma can be easily examined and thus, at least theoretically, can be diagnosed and treated at an early stage. In 90 % of the cases, morphological criteria and dermoscopy are sufficient to diagnose melanoma. (10) However, some melanoma lesions look morphologically inconspicuous, both clinically and when using a dermoscope.(8-9)
When morphology criteria are insufficient, specific rules need to be applied to avoid missing a melanoma diagnosis. The three most important rules are:
Age is by far the most important clinical information influencing the clinician’s decision making. Sometimes it’s extremely difficult to make a diagnosis based on dermoscopy or a morphological examination. However, by combining a non clear-cut morphology (a non-pigmented lesion, pointing toward several different diagnoses when using dermoscopy) with available clinical information (patient’s age and lesion location), an accurate differential diagnosis of Spitz nevus could be made.
Conversely, gender is the least important indicator. However, it is still important in one clinical scenario, the presence of inconspicuous melanocytic lesions on middle-aged women’s legs (Figure 1). Lower limbs are the most frequent location of melanoma in women. (12) Thus, a solitary lesion located on the lower limbs of middle aged women should always increase the level of suspicion.
Location is very important, and there are specific rules to follow for specific locations. Face melanomas can be very difficult to diagnose, not only clinically but also when using a dermascope, as melanoma-specific features can be late to appear. Thus, it is important to use the “inverse approach” and to search for 6 specific benign features including scales, pigmented or non-pigmented; white follicles or rosettes; erythema/reticular vessels; reticular lines or fingerprints; sharp demarcation; and classic seborrheic keratosis criteria. If clear-cut benign features are observed, the lesion is benign and can be treated accordingly. If these specific benign criteria are not recognizable, then a melanoma lesion may have to be considered. Regarding nail melanoma, only 3 clinical-dermoscopic scenarios should be considered. In the case of mucosal melanoma, flat and parallel vs. nodular and blue lesions should be compared; and for acral melanoma, the BRAAFF checklist should be used.(13)
Careful lesion comparison is extremely important, especially if multiple lesions are present. The following elements may be considered to avoid missing a melanoma lesion in patients with multiple nevi: (i) examine all the lesions, (ii) use a comparative approach, and (iii) monitor the patient over time. (14-15) If no clear diagnosis can be made, an examination can be made of other lesions that look like the one to be checked in considering the context and in being selective. In a patient with multiple nevi, many lesions may be individually suspicious; thus, only those lesions that look different may be excised. It is important to maximize melanoma recognition while minimizing unnecessary excisions.
For palpable and/or pink lesions/tumors (Figure 2) and if no clear diagnosis can be made, excision should be immediately considered to diagnose a potentially aggressive melanoma.
Patient history is not relevant if morphology may be sufficient to make a diagnosis. Patient history might even become a potentially confounding factor if a confident diagnosis is made based on objective morphological criteria.
Conversely, if the given lesion is inconspicuous from a morphological point of view, the final decision cannot be based on a subjective criterion such as clinical history. Patient clinical history certainly remains a mainstay, but not the patient’s disease history related to a single examined lesion.
Since a clinico-pathologic discussion is possible only if images of the given lesion are available, an extensive clinico-dermoscopic documentation of all lesions undergoing excision and subsequent histopathologic examination should be considered.
Luc Thomas, M.D., PH.D.
Department of Dermatology, Centre Hospitalier Lyon Sud. Lyon Cancer Research Center INSERM U1052. Claude Bernard University, Lyon, France
Nail unit melanoma (NUM, Figure 1) is an uncommon form of melanoma with worse prognosis compared with non-acral cutaneous melanoma. It is often diagnosed at a late stage. Clinical and dermoscopic features may suggest a diagnosis of NUM. However, confirmation requires histologic analysis. Like the clinical diagnosis, histopathologic diagnosis of NUM is also difficult. (1)
Squamous cell carcinoma (SCC) is a common skin tumor that usually develops on sun-exposed areas of the skin. It is the most common tumor of the hand and nail unit, causing 90 % of all hand malignancies (2) Nonetheless, nail SCC (Figure 2) is rare, with an estimated rate ranging from 3 cases in 250.000 hospital admissions to 14 cases in 50.000 dermatological consultations. (3-4) Nail SCC is often misdiagnosed and therefore underreported. (5)
In patients with NUM or nail SCC, a conservative treatment approach consisting in surgery or excision may allow to reduce morbidity and disability. However, this approach requires early diagnosis. Unfortunately, many primary care givers still consider that nail diseases are mainly due to fungal infections. This may explain why many patients are misdiagnosed and lacking adequate treatment. Thus, the main problem remains the diagnosis of these nail conditions. Contrarywise to fungal infections, which may affect several nails, a NUM or nail SCC may affect only one toe. In early diagnosing these conditions, metastatic spread can be avoided, and conservative treatment can be offered.
Many NUM starts with the appearance of melanonychia striata. Melanonychia striata has multiple causes and many confounding factors. (6) Only one single symptom, a pigmented band on the nail, may lead to several possible diagnoses (nevi, lentiginosis of the nail, drug-induced pigmentation, trauma-induced pigmentation, Bowen’s disease, onychromatricoma, etc.). To avoid a diagnosis using surgery or biopsy, which can be stressful for a patient, dermoscopy, may be adequate to differentiate the conditions. Dermoscopic features including lesions with a brown background and irregular longitudinal lines are typical symptoms of melanoma and are easy to recognize. Another symptom is the micro Hutchinson sign, a very faint pigmentation of the periungual skin.(7) Finally, an uneven level of pigmentation at the free edge of the nail is also in favor of melanoma diagnosis. Unfortunately, in ticker and advanced lesions, dermoscopy is not helpful and conservative treatment may not be adequate.
Dermoscopy of the free edge in early stages may help to correctly diagnose nail SCC. Dermoscopic features reveal lesions from the proximal folds, with uneven and unparallel borders. Dermoscopy of the free edge may also allow to differentiate onychopapilloma, onychromatricoma, and nail SCC.
As NUM, nail SCC should be diagnosed as early as possible. While many cases are thought to be viral warts of the nail, they are in fact nail SCC which can remain undiagnosed for years. Patients frequently receive multiple lines of antifungal treatment with no positive treatment outcome and once the bone is involved, conservative treatment is not indicated anymore, and amputation remains the only treatment option.
Nowadays, conservative treatment remains an efficient treatment option with current melanoma guidelines recommending to reduce excision margins of melanoma to adapt to the anatomy of the patient and to limit disability. (8) As an example, in acral melanoma conservative treatment provided very good results and very often good functional results.
Although there are no official guidelines for surgical treatment of nail SCC, in some cases reducing the safety margin may allow a conservative treatment approach. (9) In example, in the skin, this treatment is frequently chosen to avoid amputation or disabling of the patient.
Total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment option for sub-ungual SCC without bone involvement, with satisfying cosmetic and functional outcomes (10) Surgical procedure consists of an en bloc wide excision of the nail unit including the two lateral nail folds, the proximal nail fold, and the hyponychium of the finger or toe. In some very specific cases, (i.e., only the thumb nail of the right/ left hand of a right/left-handed person) and if during surgery dermoscopy shows that the nail matrix is not too much impacted, a limited excision of the lesion may be proposed allowing for a complete regrowth of the nail. After surgery, administration of analgesics and, if surgery or excision was performed on toenails, use of orthopedic shoes may be indicated. Late postoperative complications may include hypersensitivity to mechanical shocks, mildly increased sensitivity to cold, loss of fine touch sensation, and epidermal inclusion cysts. The recurrence of nail unit melanoma and nail SCC is very low with 2 out of 55 patients, over a 6.6-year mean follow-up.(11)
Of the 7 cases with in situ and minimally invasive subungual melanoma (SUM) treated with conservative treatment in our unit between 2004 to 2009, none had recurrence observed over a mean 45-month follow-up.(12) Some cases, culled from the general literature, were identified during the first surgery, and amputated in one step. No disease recurrence or metastasis occurred if the Breslow thickness was below 0.7 mm, although most of them were melanoma in situ. This confirms that conservative surgical management in patients with in situ or minimally invasive SUM provides a good cosmetic and functional outcome with no changes in the prognosis.(12)
Both NUM and nail SSC require early diagnosis to avoid metastatic spread. Although there is no consensus, conservative treatment is a safe alternative to amputation in in situ or micro-invasive nail acral lentiginous melanoma and a safe alternative to amputation in nail SCC in the absence of bone involvement. However, a histopathologically free lower margin is required. A fully conservative treatment of nail SCC can be proposed in selected cases (dominant thumbnail). While a threshold Breslow’s index of 0.5/0.7 mm is adopted by many experts, a higher Breslow’s index may be considered for specific cases (dominant thumbnail).
International e-Symposium: Advancement in skin oncology (October 2022)
International e-Symposium: Advancement in skin oncology (October 2021)
