Management of the neck in T1 and T2 buccal squamous cell carcinoma.

Buccal squamous cell carcinoma (SCC) appears to behave more aggressively than other oral subsites, in particular with regards to regional disease at presentation and regional recurrence. Adequate management of the neck is of the utmost importance but is still the subject of debate. An international multicentre retrospective review of 101 patients treated for T1-T2 buccal SCC was performed. Twenty-four were staged clinical node positive (cN+) and underwent therapeutic neck dissection, while 77 were node negative (cN0), with 32 undergoing elective neck dissection (END), with an occult nodal metastasis rate of 28.1%. Depth of invasion (DOI) < 4 mm was associated with a significantly lower rate of cervical nodal metastasis (87.5% versus 12.5%; P = 0.033). END demonstrated a non-significantly lower regional recurrence rate compared to observation (6.3% versus 8.9%, P = 0.670). Regional recurrence was more common in pN+ (24%) and undissected cases (8.9%) than in pN0 patients (0%) (P = 0.011) and was associated with DOI > 5 mm (P = 0.002). Regional recurrence resulted in a reduction in survival (24 versus 93 months, P < 0.001). In the pT2cN0 group, END improved survival (123 versus 26 months, P = 0.009). It is suggested that END be performed in cT2N0 buccal SCC, particularly for tumours with DOI > 4 mm.

Clinical findings are not helpful in detecting lentigo maligna melanoma in patients with biopsy-proven lentigo maligna.

BACKGROUND: Lentigo maligna (LM) based on biopsy material might be lentigo maligna melanoma (LMM) after excision. OBJECTIVES: Investigate whether clinical and dermoscopic mapping increases the detection rate of LMM when investigating staged excision specimens of biopsy proven LM. METHODS: Patients with biopsy-proven LM planned for staged excision were included. Using clinical inspection and dermoscopy, spots suspicious for LMM were marked. After the excision, needles were placed at the marked spots. Histological examination using vertical sections was done at the needles followed by the standard amount of vertical sections. RESULTS: In 28 of the 58 biopsy-proven LM, there was clinical suspicion of LMM, only 3 of these 28 cases were upgraded into LMM. These three cases showed LMM in other sections, whereas only 1 case showed LMM around the needle. Within the group without clinical suspicion of LMM, 2 cases were LMM. Biopsy-proven LM were in fact LMM in 8.6% of the cases and were found without the clinical guidance of the dermatologist. CONCLUSIONS: 8.6% of the biopsy-proven LM were LMM after complete histological examination. In this study, the dermatologist was not able to increase the detection rate of LMM by using clinical and dermoscopic mapping.

The complementary value of intraoperative fluorescence imaging and Raman spectroscopy for cancer surgery: combining the incompatibles.

A clear margin is an important prognostic factor for most solid tumours treated by surgery. Intraoperative fluorescence imaging using exogenous tumour-specific fluorescent agents has shown particular benefit in improving complete resection of tumour tissue. However, signal processing for fluorescence imaging is complex, and fluorescence signal intensity does not always perfectly correlate with tumour location. Raman spectroscopy has the capacity to accurately differentiate between malignant and healthy tissue based on their molecular composition. In Raman spectroscopy, specificity is uniquely high, but signal intensity is weak and Raman measurements are mainly performed in a point-wise manner on microscopic tissue volumes, making whole-field assessment temporally unfeasible. In this review, we describe the state-of-the-art of both optical techniques, paying special attention to the combined intraoperative application of fluorescence imaging and Raman spectroscopy in current clinical research. We demonstrate how these techniques are complementary and address the technical challenges that have traditionally led them to be considered mutually exclusive for clinical implementation. Finally, we present a novel strategy that exploits the optimal characteristics of both modalities to facilitate resection with clear surgical margins.

Experimental study on needle insertion force to minimize tissue deformation in tongue tissue.

This study reports on the effects of insertion velocity, needle tip geometry and needle diameter on tissue deformation and maximum insertion force. Moreover, the effect of multiple insertions with the same needle on the maximum insertion force is reported. The tissue deformation and maximum insertion force strongly depend on the insertion velocity and the tip geometry. No correlation was found between the outer diameter and the maximum insertion force for small needles (30G - 32G). The endurance experiments showed no remarkable difference in the maximum insertion force during 100 insertions.

B-cell clusters at the invasive margin associate with longer survival in early-stage oral-tongue cancer patients.

In oral-cancer, the number of tumor-infiltrating lymphocytes (TILs) associates with improved survival, yet the prognostic value of the cellular composition and localization of TILs is not defined. We quantified densities, localizations, and cellular networks of lymphocyte populations in 138 patients with T1-T2 primary oral-tongue squamous cell carcinoma treated with surgical resections without any perioperative (chemo)radiotherapy, and correlated outcomes to overall survival (OS). Multiplexed in-situ immunofluorescence was performed for DAPI, CD4, CD8, CD20, and pan-cytokeratin using formalin-fixed paraffin-embedded sections, and spatial distributions of lymphocyte populations were assessed in the tumor and stroma compartments at the invasive margin (IM) as well as the center of tumors. We observed a high density of CD4, CD8, and CD20 cells in the stroma compartment at the IM, but neither lymphocyte densities nor networks as single parameters associated with OS. In contrast, assessment of two contextual parameters within the stroma IM region of tumors, i.e., the number of CD20 cells within 20 µm radii of CD20 and CD4 cells, termed the CD20 Cluster Score, yielded a highly significant association with OS (HR 0.38; p = .003). Notably, the CD20 Cluster Score significantly correlated with better OS and disease-free survival in multivariate analysis (HR 0.34 and 0.47; p = .001 and 0.019) as well as with lower local recurrence rate (OR: 0.13; p = .028). Taken together, our study showed that the presence of stromal B-cell clusters at IM, in the co-presence of CD4 T-cells, associates with good prognosis in early oral-tongue cancer patients.

Raman spectroscopic analysis of the molecular composition of oral cavity squamous cell carcinoma and healthy tongue tissue.

A Raman tissue spectrum is a quantitative representation of the overall molecular composition of that tissue. Raman spectra are often used as tissue fingerprints without further interpretation of the specific information that they contain about the tissue's molecular composition. In this study, we analyzed the differences in molecular composition between oral cavity squamous cell carcinoma (OCSCC) and healthy tissue structures in tongue, based on their Raman spectra. A total of 1087 histopathologically annotated spectra (142 OCSCC, 202 surface squamous epithelium, 61 muscle, 65 adipose tissue, 581 connective tissue, 26 gland, and 10 nerve) were obtained from Raman maps of 44 tongue samples from 21 patients. A characteristic, average spectrum of each tissue structure was fitted with a set of 55 pure-compound reference spectra, to define the best library of fit-spectra. Reference spectra represented proteins, lipids, nucleic acids, carbohydrates, amino acids and other miscellaneous molecules. A non-negative least-squares algorithm was used for fitting. Individual spectra per histopathological annotation were then fitted with this selected library in order to determine the molecular composition per tissue structure. The spectral contribution per chemical class was calculated. The results show that all characteristic tissue-type spectra could be fitted with a low residual of <4.82%. The content of carbohydrates, proteins and amino acids was the strongest discriminator between OCSCC and healthy tissue. The combination of carbohydrates, proteins and amino acids was used for a classification model of 'tumor' versus 'healthy tissue'. Validation of this model on an independent dataset showed a specificity of 93% at a sensitivity of 100%.

Evaluation of bone resection margins of segmental mandibulectomy for oral squamous cell carcinoma.

Resection margins are frequently studied in patients with oral squamous cell carcinoma and are accepted as a constant prognostic factor. While most evidence is based on soft tissue margins, reported data for bone resection margins are scarce. The aim of this retrospective study was to evaluate and determine the utility of surgical margins in bone resections for oral cavity squamous cell carcinoma (OCSCC). The status of bone resection margins and their impact on survival was investigated in patients who had undergone segmental mandibulectomy for OCSCC. Medical records were retrieved for the years 2000-2012; 127 patients were identified and included in the study. Tumour-positive bone resection margins were found in 21% of the patients. The 5-year overall survival was significantly lower in this group (P<0.005). Therefore, there is a need for intraoperative feedback on the status of bone resection margins to enable immediate additional resection where necessary. Although the lack of intraoperative methods for the evaluation of bone tissue has been addressed by many authors, there is still no reliable method for widespread use. Future research should focus on an objective, accurate, and rapid method of intraoperative assessment for the entire bone resection margin to optimize patient outcomes.

Improved stratification of pT1 melanoma according to the 8th American Joint Committee on Cancer staging edition criteria: A Dutch population-based study.

INTRODUCTION: The 8th American Joint Committee on Cancer (AJCC) staging edition includes revisions regarding pT1 melanomas. We aimed to evaluate the expected impact of this edition on staging and survival in the Dutch pT1 melanoma population. METHODS: In total, 32,935 pT1 melanoma patients, whose data were retrieved from the Netherlands Cancer Registry between 2003 and 2015, were included in the study. Patients were stratified by the 6th AJCC edition (cohort 1: 2003-2009) and 7th edition (cohort 2: 2010-2015) and all reclassified according to the 8th edition. Stage migration, sentinel lymph node biopsy (SLNB) positivity rates and relative survival were analysed. Agreement between staging systems was calculated by Cohen's kappa coefficient. RESULTS: In cohort 2, restaging according to the 8th edition led to an increase of 7% in the total number of patients staged pT1b. The kappa score for agreement between the 6th and 8th edition was 0.15 and 0.25 for agreement between 7th and 8th edition. Restaging according to the 8th edition resulted in a higher SLNB positivity rate for pT1b patients than pT1a patients (8% versus 5%, p = 0.08). Relative survival curves were predominantly similar between the staging editions. CONCLUSIONS: Implementation of the 8th AJCC staging edition will presumably not have major impact on the total number of Dutch pT1b patients. Consequently, the number of patients eligible for SLNB would roughly remain similar. In terms of SLNB positivity, the selection of high-risk pT1 melanoma patients is likely to improve. In addition, the 8th edition criteria for pT1 melanoma seem more workable for pathologists.

Reliability of diagnosis from Mohs slides: interpersonal and intrapersonal agreement on basal cell carcinoma presence and histological subtype.

BACKGROUND: The success of Mohs micrographic surgery (MMS) depends partly on the correct diagnosis of slides. OBJECTIVES: To determine reliability of diagnosis from Mohs slides. METHODS: This was a prospective study evaluating the reliability of diagnosis from Mohs slides of basal cell carcinoma (BCC) presence, BCC location on the slide and BCC subtype among six raters who independently assessed 50 Mohs slides twice with a 2-month interval. Slides were randomly selected whereby difficult-to-diagnose slides were oversampled. For each slide, a reference diagnosis was established by an expert panel. Cohen's kappa (κ) was calculated to determine levels of agreement interpersonally (rater vs. reference diagnosis) and intrapersonally (rater at T1 vs. T2). Multivariable logistic regression was used to determine independent risk factors for slides with interpersonal discordant diagnosis. The variables studied were BCC presence, whether a slide was scored as easy or difficult to diagnose, review duration of the 50 slides, profession and years of experience in diagnosis from Mohs slides. RESULTS: Interpersonal and intrapersonal agreement were substantial on BCC presence (κ = 0·66 and 0·68) and moderate on BCC subtype (κ = 0·45 and 0·55). Slides that were scored as difficult to diagnose were an independent risk factor for interpersonal discordant diagnosis on BCC presence (odds ratio 3·54, 95% confidence interval 1·81-6·84). CONCLUSIONS: Reliability of diagnosis from Mohs slides was substantial on BCC presence and moderate on BCC subtype. For slides that are scored difficult to diagnose, a second opinion is recommended to prevent misinterpretation and thereby recurrence of skin cancer.

A nation-wide epidemiological study on the risk of developing second malignancies in patients with different histological subtypes of nasopharyngeal carcinoma.

OBJECTIVE: Risk assessment of second head/neck and Epstein Barr Virus (EBV)-related malignancies in patients with different nasopharyngeal carcinoma (NPC) subtypes. METHODS: This is a cross-sectional study. Pathology records were retrieved from PALGA (a Dutch pathology registry database) between 1995 and 2013. Second primary malignancy (SPM) data was extracted from PALGA. Odds ratios (OR) for SPM in the head/neck, and the upper/lower airways were calculated using logistic regression. Pearson X(2)-test and Fisher's exact test were used to assess the relationship between NPC (and EBV-status) with SPM. Standardized incidence rates (SIR) were calculated. RESULTS: Histologically diagnosed NPC (keratinizing and undifferentiated and differentiated non-keratinizing subtypes) (n=1175) were identified. NPC patients have an increased risk of second head/neck malignancies (SIR 4.7 95% CI 3.3-6.5). Keratinizing NPCs have an OR of 1.947 (95% CI 1.362-2.782) for SPM, an OR of 4.026 (95% CI 2.308-7.023) for carcinomas of the upper/lower airways, an OR of 4.306 (95% CI 2.299-8.066) for head/neck malignancies, an OR of 5.289 (95% CI 2.740-10.211) for HNSCC with a SIR of 4.7 (95CI 3.3-6.5). Non-keratinizing NPCs also have an increased risk of head/neck malignancies with a SIR of 3.2 (95% CI 1.8-5.1), but less than keratinizing NPCs (p=<0.001). Positive EBV-status is not associated with (EBV-related) SPM. CONCLUSION: NPCs have a higher risk of SPM regardless of EBV status. SPM (especially HNSCC and malignancies of the upper aerodigestive tract) are more prevalent in keratinizing NPC compared to non-keratinizing NPC. Close clinical follow-up of NPC patients, with specific attention on SPM, is justified.

Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision.

BACKGROUND: Lentigo maligna is a slowly growing melanoma in situ. Current guidelines advise wide local excision with a margin of 5 mm as the treatment of first choice, which has recurrence rates ranging from 6% to 20%. OBJECTIVES: To determine retrospectively the recurrence rate of lentigo maligna after staged surgical excision. METHODS: Records of all patients with lentigo maligna treated with our method of staged surgical excision between 2002 and 2011 were retrieved. To identify recurrences we used the computer program Sympathy, which is linked to PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands. RESULTS: We identified 100 patients, who were treated with staged surgical excision with 100% immunohistopathological control of lateral margins. Digital pictures were used to facilitate orientation during the several stages of surgery. After a mean follow-up of 60 months, four patients had a recurrence, after 37, 58, 74 and 77 months of follow-up. CONCLUSIONS: Staged surgical excision is superior in clearance and recurrence rates to wide local excision for lentigo maligna and should be considered as the treatment of first choice in national and international guidelines.

Risk Factors for Positive Deep Pelvic Nodal Involvement in Patients with Palpable Groin Melanoma Metastases: Can the Extent of Surgery be Safely Minimized? : A Retrospective, Multicenter Cohort Study.

BACKGROUND: Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient. AIM: The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future. METHODS: This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] ± positron emission tomography [PET], or PET - low-dose CT). RESULTS: Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p < 0.001), and LNR was significantly lower for negative versus positive deep pelvic nodes [median 0.15 (IQR 0.10-0.25) vs. 0.33 (IQR 0.14-0.54); p < 0.001]. A combination of negative imaging, low LNR, low number of positive inguinal nodes, and no extracapsular extension (ECE) could accurately predict the absence of pelvic nodal involvement in 84 % of patients. CONCLUSIONS: Patients with negative imaging, few positive inguinal nodes, no ECE, and low LNR have a low risk of positive deep pelvic nodes and may safely undergo SGD alone.

Additional review of Mohs slides to optimize Mohs micrographic surgery.

BACKGROUND: One significant risk factor for recurrence after Mohs surgery is misinterpretation of slides. OBJECTIVES: To determine how often pathologists detected incompletely excised basal cell carcinoma (BCC) on Mohs slides and to determine risk factors for incompletely excised BCCs. METHODS: This retrospective study included 1653 BCCs treated with Mohs surgery in a university hospital between 2007 and 2011. For routine quality assurance, all slides were additionally reviewed by a pathologist within 1 week of the procedure. For this study, all cases that had divergent interpretations were re-evaluated by a Mohs surgeon and a pathologist. Mixed-effects logistic regression models with Mohs surgeon effects as random effects were used to determine risk factors for incompletely excised BCC. RESULTS: Incompletely excised BCCs were detected in 31 cases (2%), in which defects > 20 mm in diameter were an independent risk factor (odds ratio 3.58, 95% confidence interval 1.55-8.28). Other studied variables (i.e. aggressive subtype, previously treated BCC, location on nose and > 2 Mohs stages) did not affect the risk of incompletely excised BCCs. CONCLUSIONS: The additional review of Mohs slides might increase accurate interpretation, especially in large BCCs.

Discrimination between oral cancer and healthy tissue based on water content determined by Raman spectroscopy.

Tumor-positive resection margins are a major problem in oral cancer surgery. High-wavenumber Raman spectroscopy is a reliable technique to determine the water content of tissues, which may contribute to differentiate between tumor and healthy tissue. The aim of this study was to examine the use of Raman spectroscopy to differentiate tumor from surrounding healthy tissue in oral squamous cell carcinoma. From 14 patients undergoing tongue resection for squamous cell carcinoma, the water content was determined at 170 locations on freshly excised tongue specimens using the Raman bands of the OH-stretching vibrations (3350-3550 cm(-1)) and of the CH-stretching vibrations (2910-2965 cm(-1)). The results were correlated with histopathological assessment of hematoxylin and eosin stained thin tissue sections obtained from the Raman measurement locations. The water content values from squamous cell carcinoma measurements were significantly higher than from surrounding healthy tissue (p-value < 0.0001). Tumor tissue could be detected with a sensitivity of 99% and a specificity of 92% using a cutoff water content value of 69%. Because the Raman measurements are fast and can be carried out on freshly excised tissue without any tissue preparation, this finding signifies an important step toward the development of an intraoperative tool for tumor resection guidance with the aim of enabling oncological radical surgery and improvement of patient outcome.

Next generation diagnostic molecular pathology: critical appraisal of quality assurance in Europe.

Tumor evaluation in pathology is more and more based on a combination of traditional histopathology and molecular analysis. Due to the rapid development of new cancer treatments that specifically target aberrant proteins present in tumor cells, treatment decisions are increasingly based on the molecular features of the tumor. Not only the number of patients eligible for targeted precision medicine, but also the number of molecular targets per patient and tumor type is rising. Diagnostic molecular pathology, the discipline that determines the molecular aberrations present in tumors for diagnostic, prognostic or predictive purposes, is faced with true challenges. The laboratories have to meet the need of comprehensive molecular testing using only limited amount of tumor tissue, mostly fixed in formalin and embedded in paraffin (FFPE), in short turnaround time. Choices must be made for analytical methods that provide accurate, reliable and cost-effective results. Validation of the test procedures and results is essential. In addition, participation and good performance in internal (IQA) and external quality assurance (EQA) schemes is mandatory. In this review, we critically evaluate the validation procedure for comprehensive molecular tests as well as the organization of quality assurance and assessment of competence of diagnostic molecular pathology laboratories within Europe.

Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials.

BACKGROUND: The presence of human papillomavirus (HPV)-infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modeling. However, most risk models are based on clinical trials which only include a selected patient population. The clinical significance of HPV and other prognostic factors in patients with OPSCC remains to be evaluated in a large, unselected cohort, which also includes patients with stage I/II disease and patients with severe comorbidity. PATIENTS AND METHODS: All patients diagnosed with OPSCC in 2000-2006 in two Dutch university hospitals were included. The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-positive cases. Cox regression analysis was carried out to compare survival rates between HPV-positive and HPV-negative patients and a prognostic model was generated by recursive partitioning. RESULTS: In total, 163 of 841 (19.4%) tumors were HPV-positive. Patients with HPV-positive OPSCC had a more favorable overall survival [73.5% versus 40.9% after 5 years; P < 0.001; hazard ratio = 0.34, 95% confidence interval (CI) 0.25-0.48] compared with patients with HPV-negative OPSCC. Patients with p16-positive but HPV DNA-negative tumors showed a significantly less favorable survival than patients with p16-positive and HPV DNA-positive tumors (P < 0.001). A prognostic model was developed in which patients were classified into three risk groups according to HPV status, nodal stage and comorbidity. [Harrell's concordance index of 0.68 (95% CI 0.65-0.71)]. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with OPSCC. A prognostic risk model was proposed, based on our large, unselected cohort of patients with HPV status, comorbidity and nodal stage being the important prognostic factors. In addition, this study emphasizes the importance of performing an HPV DNA-specific test besides p16-immunostaining.

Frequency of non-histologically diagnosed basal cell carcinomas in daily Dutch practice.

BACKGROUND: Population-based basal cell carcinoma (BCC) incidences are based on cancer registry data; however, these only include histologically diagnosed tumours. OBJECTIVES: First, to investigate the number of subsequent non-histologically diagnosed BCC(s) in patients with a first histologically diagnosed BCC in 2004. Secondly, to observe differences in tumour characteristics between subsequent histologically and subsequent non-histologically diagnosed BCC(s). METHODS: All patients, from four hospitals located in the serving area of the Eindhoven Cancer Registry, with a first histologically diagnosed BCC in 2004 (n = 1290) were selected. A linkage was made with PALGA, the nationwide network and registry of histo- and cytopathology, to obtain pathology reports of subsequent histologically diagnosed BCC(s) up to 1 November 2010. Patient records were extracted from the participating dermatology departments and reviewed up to 1 November 2010 to identify non-histologically diagnosed BCC(s). RESULTS: Overall, 33.2% of the 1089 followed up patients developed subsequent histologically and/or non-histologically diagnosed BCCs. In total, 1974 BCCs were observed of which 1833 were histologically and 141 were non-histologically diagnosed BCCs. The distribution of tumour site and subtype differed significantly between subsequent histologically and subsequent non-histologically diagnosed BCCs. CONCLUSIONS: The total burden of BCC is underestimated by the absence of data on the occurrence of non-histologically diagnosed BCCs in daily dermatological practice. It is pivotal for Dutch healthcare policy makers to acknowledge this to make accurate BCC-related cost estimates.

Cumulative risks and rates of subsequent basal cell carcinomas in the Netherlands.

BACKGROUND: The incidence of multiple basal cell carcinomas (BCCs) is not well documented. OBJECTIVES: To calculate the cumulative risks, rates and risk factors for the development of subsequent histologically confirmed BCCs. METHODS: For this cohort study the Dutch nationwide network and registry of histopathology and cytopathology (PALGA) was used. The first 2483 patients diagnosed with a first histologically confirmed BCC in the year 2004 were followed for 5years. Multifailure survival models were used to study whether gender or age affected the risk of developing subsequent tumours. RESULTS: During our observational period, the 2483 patients developed a total of 3793 histologically confirmed BCCs. The 5-year cumulative risk of developing one or more subsequent BCCs was 29·2%. Incidence rates were 25,318 per 100,000person-years in the first 6months after first BCC diagnosis, decreasing to 6953 per 100,000person-years after 5years of follow-up. Males compared with females had a 30% [adjusted hazard ratio (HR) 1·30, 95% CI (confidence interval) 1·11-1·53] higher risk of developing multiple BCCs and those aged 65-79years had more than 80% (adjusted HR 1·81, 95% CI 1·37-2·41) higher risk of having subsequent tumours compared with patients younger than 50years. CONCLUSIONS: The high incidence rate of subsequent BCCs among patients with a first BCC is highest in the first months after diagnosis of the first BCC but persists long term, indicating that patients with BCC should undergo full-body skin examinations at first presentation and subsequent follow-up visits. Special attention should be paid to males and persons of older age at index lesion.