Different expression of BRAFV600E, ALK and PD-L1 in melanoma in children and adolescents : a nationwide retrospective study in Finland in 1990-2014

Background Pediatric melanoma may have a different biological background and more favorable prognosis compared with melanoma in adults. The aim of this study was to investigate melanoma in children and adolescents in the Finnish population in terms of incidence, clinical course, treatment, prognosis and BRAFV600E-, ALK- and PD-L1-positivity of the primary tumors. Materials and Methods Primary tumor samples and clinical records of all patients aged 0-19 years diagnosed with cutaneous melanoma in Finland in 1990-2014 were collected using the Finnish Cancer Registry database, Finnish hospitals and private pathology laboratories. BRAFV600E, ALK and PD-L1 were analyzed from 54 primary tumors and BRAFV600E from six metastasis samples. Results A total of 122 patients diagnosed with cutaneous melanoma were retrieved from the Cancer Registry database. The primary tumor samples of 73 patients were obtained for the review, and 56 cases were included in the study. The incidence of pediatric melanoma increased from 0.2 to 1.0/100 000 during the period 1990-2014. Spitzoid melanoma was the most common subtype (66%). The 10-year cancer-specific survival (CSS) was 88.7% in all patients. The 10-year-CSS did not differ in SLNB-positive or -negative groups. BRAFV600E was positive in 48%, ALK in 9% and PD-L1 in 2% of the tumors. BRAFV600E mutation was associated with 83% of melanoma deaths. Conclusions Young melanoma patients had more favorable prognosis and a different staining profile for BRAFV600E, ALK, and PD-L1 in primary tumor than reported in adults. SLNB status was not an indicator for survival. BRAFV600E-positive patients have worse prognosis and could benefit from surveillance and treatment similarly to adults.Peer reviewe

Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma

Objective. In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods. A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results. A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (295%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P <0.001) of dying of EEC compared to the low-risk group. Conclusions. P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities. (C) 2018 Elsevier Inc. All rights reserved.Peer reviewe

Identification of metastatic primary cutaneous squamous cell carcinoma utilizing artificial intelligence analysis of whole slide images

Cutaneous squamous cell carcinoma (cSCC) harbors metastatic potential and causes mortality. However, clinical assessment of metastasis risk is challenging. We approached this challenge by harnessing artificial intelligence (AI) algorithm to identify metastatic primary cSCCs. Residual neural network-architectures were trained with cross-validation to identify metastatic tumors on clinician annotated, hematoxylin and eosin-stained whole slide images representing primary non-metastatic and metastatic cSCCs (n = 104). Metastatic primary tumors were divided into two subgroups, which metastasize rapidly (≤ 180 days) (n = 22) or slowly (> 180 days) (n = 23) after primary tumor detection. Final model was able to predict whether primary tumor was non-metastatic or rapidly metastatic with slide-level area under the receiver operating characteristic curve (AUROC) of 0.747. Furthermore, risk factor (RF) model including prediction by AI, Clark's level and tumor diameter provided higher AUROC (0.917) than other RF models and predicted high 5-year disease specific survival (DSS) for patients with cSCC with 0 or 1 RFs (100% and 95.7%) and poor DSS for patients with cSCCs with 2 or 3 RFs (41.7% and 40.0%). These results indicate, that AI recognizes unknown morphological features associated with metastasis and may provide added value to clinical assessment of metastasis risk and prognosis of primary cSCC.</p

Increased incidence of melanoma in children and adolescents in Finland in 1990-2014 : nationwide re-evaluation of histopathological characteristics

Background Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. Aims The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. Methods Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. Results A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. Conclusions The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed. Key message A nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.Peer reviewe

Severe ulcerative proctitis, pyoderma gangrenosum, hidradenitis suppurativa and fever in a patient with a rare variant of the PSTPIP1 gene

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Different expression of BRAFV600E, ALK and PD-L1 in melanoma in children and adolescents: a nationwide retrospective study in Finland in 1990-2014

Background Pediatric melanoma may have a different biological background and more favorable prognosis compared with melanoma in adults. The aim of this study was to investigate melanoma in children and adolescents in the Finnish population in terms of incidence, clinical course, treatment, prognosis and BRAFV600E-, ALK- and PD-L1-positivity of the primary tumors. Materials and Methods Primary tumor samples and clinical records of all patients aged 0-19 years diagnosed with cutaneous melanoma in Finland in 1990-2014 were collected using the Finnish Cancer Registry database, Finnish hospitals and private pathology laboratories. BRAFV600E, ALK and PD-L1 were analyzed from 54 primary tumors and BRAFV600E from six metastasis samples. Results A total of 122 patients diagnosed with cutaneous melanoma were retrieved from the Cancer Registry database. The primary tumor samples of 73 patients were obtained for the review, and 56 cases were included in the study. The incidence of pediatric melanoma increased from 0.2 to 1.0/100 000 during the period 1990-2014. Spitzoid melanoma was the most common subtype (66%). The 10-year cancer-specific survival (CSS) was 88.7% in all patients. The 10-year-CSS did not differ in SLNB-positive or -negative groups. BRAFV600E was positive in 48%, ALK in 9% and PD-L1 in 2% of the tumors. BRAFV600E mutation was associated with 83% of melanoma deaths. Conclusions Young melanoma patients had more favorable prognosis and a different staining profile for BRAFV600E, ALK, and PD-L1 in primary tumor than reported in adults. SLNB status was not an indicator for survival. BRAFV600E-positive patients have worse prognosis and could benefit from surveillance and treatment similarly to adults.</div

Increased incidence of melanoma in children and adolescents in Finland in 1990-2014: nationwide re-evaluation of histopathological characteristics

BackgroundChanges in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades.AimsThe aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas.MethodsInformation on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time.ResultsA 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas.ConclusionsThe incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed.Key messageA nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.</p

Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma

Objective: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P &lt; 0.001) of dying of EEC compared to the low-risk group. Conclusions: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities